WO2020160328A1 - Administration de cannabinoïdes par infiltration tumescente - Google Patents

Administration de cannabinoïdes par infiltration tumescente Download PDF

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Publication number
WO2020160328A1
WO2020160328A1 PCT/US2020/015963 US2020015963W WO2020160328A1 WO 2020160328 A1 WO2020160328 A1 WO 2020160328A1 US 2020015963 W US2020015963 W US 2020015963W WO 2020160328 A1 WO2020160328 A1 WO 2020160328A1
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Prior art keywords
tumescent
cannula
subcutaneous
infiltration
delivery
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PCT/US2020/015963
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English (en)
Inventor
Jeffrey Alan Klein
Paytra Alan Klein
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Hk Pharma
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Priority claimed from US16/264,440 external-priority patent/US11241412B2/en
Application filed by Hk Pharma filed Critical Hk Pharma
Priority to EP20747957.7A priority Critical patent/EP3917507A4/fr
Publication of WO2020160328A1 publication Critical patent/WO2020160328A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • the present embodiments relate to compositions, kits and methods of use of a solution comprising an anesthetic component, a vasoconstrictor component, and an active agent such as an antiviral component, an anti-inflammatory agent and/or a chemotherapy agent for use in medical procedures involving tumescent delivery of high doses of actives for local subcutaneous treatment.
  • liposuction may be performed entirely by tumescent local anesthesia, which was invented by Jeffrey A. Klein. Dr. Klein first published the description of tumescent local anesthesia to perform liposuction in 1987 (Klein JA. The tumescent technique for liposuction surgery. J Am Acad Cosmetic Surg 4: 263- 267, 1987). The tumescent technique was developed in order to eliminate the dangers of liposuction surgery under general anesthesia and the associated excessive bleeding. With proper technique, tumescent infiltration permits liposuction totally by local anesthesia with virtually no surgical blood loss.
  • Infiltrators are known as sprinkler-tip or KleinTM needle infiltrators.
  • These cannula are constructed out of a rigid stainless steel and have one or more apertures, which are typically round or oval, and are distributed about the distal end of the cannula. The apertures are distributed over about 15% to 25% or less than 5.0 cm of the distal end of the cannula needle.
  • These traditional infiltration cannula are intended to be inserted through a small incision in the patient’s skm and then moved in and out through the subcutaneous tissue while a dilute solution of local anesthetic (or other pharmaceutical solution) is ejected through the distal apertures.
  • the cannula needle Since the cannula needle is moved in and out, only the distal end (e.g., about 15% to 25%) of the cannula needle may have apertures. Otherwise, fluid may squirt out of the apertures and onto medical professionals when the cannula needle is moved out too much.
  • Such infiltrators typically have a blunt tip and require the placement of a small hole (made by a one mm skin-biopsy punch or a small surgical blade) through which the blunt tipped cannula can be passed. Unfortunately, the piston-like in and out motion of the cannula causes the patient discomfort.
  • infiltration cannula is the sharp tipped tumescent infiltration cannula which is available as 1) a single long sharp needle similar to a spinal needle and 2) a group of short sharp hypodermic needles each connected by separate plastic tube to a manifold that distributes Tumescent Local Anesthesia (TLA) solution.
  • TLA Tumescent Local Anesthesia
  • the first type of needle is inserted into subcutaneous fat and infiltration proceeds while the needle is continuously moved in and out along paths that radiate from the skin puncture site. A targeted area is eventually anesthetized after multiple skin punctures.
  • the second type the group of short sharp needles, consists of a group of individual hypodermic needles each attached to an individual IV extension tube, which are in turn connected to a multi-port manifold which connected to a reservoir (IV bag) of tumescent fluid.
  • IV bag a reservoir of tumescent fluid.
  • PICC line a peripherally inserted central catheter
  • IV intravenous
  • a PICC line may be used when a patient needs to receive intravenous (IV) fluids, such as medication or nutrients over a prolonged period of time, such as a w3 ⁇ 4ek or more.
  • the On-Q® Pain Management System marketed by I-Flow® Corporation employs a flexible plastic or silicone catheter system for continuously providing local anesthetic. This system provides prolonged local anesthesia by means of an elastomeric (elastic container) device that continuously infiltrates a solution of local anesthesia over many hours.
  • the On-Q® device comprises a long soft flexible tube with many small holes arranged along a significant portion of the tube.
  • the On-Q® device is designed to be initially positioned within a surgical wmund at the time of surgery. After the surgical wound is closed, the On-Q® device permits slow steady infiltration of a local anesthetic solution into the wound, thereby attenuating post-operative pam.
  • the On-Q® device cannot be inserted through a tiny hole in the skin when there is a need. Therefore the On-Q device cannot achieve infiltration of local anesthesia and prevent post-operative pam in a preemptive fashion.
  • a long flexible multi-holed catheter is inserted subcutaneously using an introducer wire and an introducer catheter. This device requires a large sterile field (an area upon which to lay all of the sterile devices used during the insertion process), a complicated insertion protocol, and either general anesthesia or careful pre-insertion infiltration of local anesthesia.
  • the Massengale device is not intend for or capable of being repeatedly inserted in and out of different areas of subcutaneous tissue; it cannot be inserted quickly by untrained personnel in- the-field and far from a sophisticated medical facility. It has been shown that preemptive local anesthesia in the form of peripheral nerve blocks, can prevent nociception by the central nervous system (CNS) during general anesthesia, and thereby prevent chronic post-operative pain syndromes similar to "phantom-limb syndrome.”
  • CNS central nervous system
  • a simple device that can permit the direct percutaneous insertion of a multi-holed infiltration cannula into subcutaneous tissue for the localized delivery of medications such as local anesthetics, chemotherapeutic agents, or crystalloids for parenteral hydration.
  • medications such as local anesthetics, chemotherapeutic agents, or crystalloids for parenteral hydration.
  • a device that can easily provide localized fluid resuscitation to bum victims whereby fluid is infiltrated into the subcutaneous tissue directly sub
  • a system for infiltration of a local anesthetic into intact subcutaneous tissue which decreases patient discomfort preemptively, and allows prolonged local anesthesia either by rapid (less than 10 to 15 minutes) bolus injections, extended infiltration (e.g. over intervals ranging from 15 minutes to several hours) or continuous slow infiltration over many hours to days.
  • a device that can provide pre-emptive local anesthesia before a surgical wound is created.
  • a percutaneously-insertable infiltration cannula with applications that are unrelated to the delivery of local anesthesia, which can be easily inserted by rescuers with minimal clinical skill or training.
  • a cannula that permits emergency fluid resuscitation in situations where an IV cannot be established such as nighttime military' combat conditions where using a flash light to establish an IV access would be extremely dangerous.
  • Another example is the need to provide emergency fluid resuscitation to large numbers of patients in acute epidemic diarrhea (dehydration) associated with biological warfare, or mass- trauma situations such as a natural disaster (earth quake) or terrorist attack.
  • a device that can easily provide localized fluid resuscitation to burn victims whereby fluid is infiltrated into the subcutaneous tissue directly subjacent to burned skin.
  • U.S. Pat. Pub. No. 2003/0009132 (Schwartz et al.) is directed to a micro- intravascular (never extra-vascular) catheter for infusing milliliter quantities of drugs for the lysis of intravascular blood clots (i.e., a micro target).
  • Another embodiment of the Schwartz device is intended to improve the precision and safety of intra-myocardial delivery of micro- liter volumes of fluid for biologic gene therapy based angiogenesis.
  • the Schwartz device requires a sterile high tech hospital environment and demands fluoroscopy and ultrasound guidance.
  • the Schwartz device requires a highly trained, experienced and skilled medical professional to operate.
  • the Schwartz infiltration catheter is defined by its obligatory guidewire and intravascular target.
  • the intravascular insertion of the catheter via the guidewire is a complex procedure that requires significant clinical training, experience and skill.
  • the method involves 1) preparation with a sterile surgical field, 2) making a skm incision and inserting an introducing catheter having coaxial stylet into the targeted vessel, 3) removing the stylet, 4) inserting the guidewire through the introducing catheter and into the vessel, 5) withdrawing the introducing catheter from the vessel without disturbing the intravascular location of the guidewire, 6) slipping the distal tip of the infiltration catheter over the proximal end of the guidewire, and advancing the infiltration catheter over the considerable length of the guidewire through the skin and into the intraluminal space of the targeted vessel, 7) withdrawing the guidewire and attaching the proximal end of the infiltration catheter to a source of the therapeutic fluid to be delivered into the targeted vessel.
  • This insertion procedure is so specialized that a majority of physicians do not have the requisite expertise to qualify for hospital privileges for inserting an intravascular catheter using a guidewire. Locating a clotted blood vessel and inserting the Schwartz catheter into the vessel requires ultrasound guidance.
  • an important feature of the Sclxwartz device is the shape, size, direction and pattern of the holes on the infiltration cannula.
  • the Schwartz device is intended to improve directional control over the direction of injection of minute volumes of mjectate.
  • the Schwartz device appears to be specifically designed to avoid vascular compression.
  • vascular compression resulting from injecting excessive volume of drug into myocardium may precipitate infarction or arrhythmia.
  • vascular compression appears to be contraindicated.
  • the goal of infusing fluid into a vessel containing a blood clot is to open the vessel, and not compress it.
  • the Schwartz device also appears to be incapable of large volume (e.g , multi liter) subcutaneous infiltration.
  • the long plastic Schwartz catheter appears to be specifically intended for intravascular use.
  • Schwartz cannula cannot have holes distributed along 100% of its entire length based on a contention that such situation will lead to a contradictory situation.
  • the Schwartz device does have holes along its entire length then either the entire length of the cannula would have to be positioned inside a vessel (unlikely without ataching the cannula proximal ly to another catheter in winch case the bulky attachment mechanism would have to be passed through the wall of the vessel) or else some of the holes would have an extravascular loeation(unlikely because the therapeutic fluid would either leak onto the patient’s skin or extravasate into the perivascular and subcutaneous tissues). In either case, the potential for serious adverse effects would be significant.
  • the Schwartz device does not appear to be capable of being reciprocated in and out of the subcutaneous tissue of the patient to locally anesthetize an entire compartment.
  • the Schwartz infiltrator is intended for 1) intravascular insertion which demands a complex guidewire procedure involving several steps,
  • Meglin device Another type of device for delivering fluid to a patient is described in U.S. Pat. No. 6,524,300, issued to Meglin. Similar to the Schwartz device, the Meglin device appears to be an intravascular device intended to inject a“medical agent into the target lumen of the body.” (see, Col. 2, ins. 41-48). Meglin is specifically intended to be inserted intraluminally into“a lumen of a blood vessel or another cavity within a patient’s body.” (see Col. 1 , Ins. 14-19). This is precisely opposite the goal of a tumescent infiltration cannula. A tumescent infiltration cannula is intended to deliver drugs to the subcutaneous space which excludes the vascular space and cavitary space.
  • the Meglin device appears to be specifically designed to avoid vascular compression and to not induce vasoconstriction.
  • An important aspect of the Meglin device appears to be the size and density of the apertures to control the rate of flow of fluidic medication.
  • the medical professional utilizing the Meglin device requires a great deal of training, expertise and education based on a contention that the infusion segment of the device is located intravascularly by locating a radiopaque marker band with a fluoroscopy.
  • Surgical site infections are a significant source of post-operative morbidity and mortality. They account for 17% of all hospital acquired infections, require prolonged hospital stays and contribute substantially to health care costs. The incidence of surgical site infection is a function of the type of surgical procedure, the surgeon, and the hospital. The risk of surgical site infection is significantly associated with a number of factors including anesthetic risk scores, wound class and duration of surgery.
  • Antimicrobial prophylaxis with intravenous (IV) antibiotics is currently the most important clinical modality for preventing surgical site infection.
  • the consensus recommendation for antimicrobial prophylaxis is for antimicrobial agents to be given as an IV infusion of antibiotics administered within the first 60 minutes before surgical incision and that prophylactic antimicrobial agents be discontinued within 24 hours of the end of surgery.
  • An IV infusion of fluid is a common medical procedure to treat patients.
  • an IV infusion is associated with an inherent expense, difficulty and risk.
  • an IV line cannot be established in the patient.
  • the patient may be burned such that a vein of the patient cannot be located to establish an IV access.
  • the patient may have been traumatized in such a way that will not allow a doctor to perform an IV cut down procedure.
  • the patient may be very obese such that the vein of the patient is difficult to locate. In other situations, occurring in remote locations where a trained medical professional is not available to establish the IV, such as the international space station or on an airplane.
  • Other methods of delivering a drug to a patient other than IV administration may be oral delivery of the drug.
  • oral delivery of the drug results in inconsistent absorption of the drug into the gastrointestinal tract.
  • the drug may alternatively be delivered via periodic intramuscular injections.
  • the fluidic drug serum may have varying levels of concentration at each of the periodic injections.
  • Some embodiments relate to a method of subcutaneous deliver ' of a drug or a therapeutic agent to a subject including administering to said subject a tumescent composition that includes:
  • infiltration of the tumescent composition achieves both prolonged local drug concentration within a tumescent subcutaneous tissue as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissue into a systemic circulation.
  • a pharmacokinetic profile of the systemic absorption resembles a slow, constant, intravenous (IV) infusion.
  • the subcutaneous concentration of the drug or therapeutic agent achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional IV, IM or oral delivery' of the drug or therapeutic agent.
  • the tumescent composition further includes an anesthetic component.
  • the anesthetic component is a local anesthetic.
  • local and systemic blood viscosity are reduced in the subject and local and systemic oxygenation of tissues in the subject is increased.
  • the local anesthetic is hdocaine.
  • the concentration of lidocaine is approximately' 100 mg to 1,500 mg per L of solution.
  • the tumescent composition further includes an anti- inflammatory' agent.
  • the tumescent composition further includes an antibiotic component
  • the antibiotic component includes cefazolin.
  • the drug or therapeutic agent is an antiviral agent.
  • the antiviral component is acyclovir.
  • the vasoconstrictor component includes epinephrine.
  • the concentration of epinephrine is approximately 0.2 to 1.5 mg/L
  • the subject has a localized viral infection.
  • the subject is infected by the varicella-zoster virus.
  • the tumescent composition includes an agent that reduces neuropathic pain or the risk of developing neuropathic pain
  • the neuropathic pain is selected from the group consisting of postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, diabetic neuropathy, carpal tunnel syndrome, sciatica, degenerative disk disease, spinal cord injury, post-surgical pain and cancer.
  • the tumescent composition includes a chemotherapy agent, wherein the method treats a localized cancer.
  • the localized cancer is selected from the group consisting of skin cancer, breast cancer, lymphoma, Pancreatic Adenocarcinoma, Insulinoma, lung cancer, colon cancer, prostate cancer, ovarian cancer and a metastatic cancer.
  • the skin cancer is selected from the group consisting of Basal Cell Carcinoma, Squamous Cell Carcinoma, melanoma, Merkel Cell Carcinoma and Kaposi’s Sarcoma.
  • Some embodiments relate to a method of treating or preventing sepsis or Systemic Inflammatory Response Syndrome (SIRS) in a subject including:
  • tumescent composition acts as a reservoir for the drug or therapeutic agent, simultaneously providing a sustained high local interstitial drag concentration and a sustained systemic concentration of the drug or therapeutic agent resembling a slow constant IV infusion in the subject, thereby effectively treating or preventing sepsis or SIRS in the subject.
  • a tumescent solution for treating a localized varicella-zoster viral infection (shingles) including:
  • an antiviral agent selected from acyclovir, valacyclovir, famciclovir, brivudine, docosanol, idoxuridine, penciclovir or trifluridine, or combinations thereof;
  • the antiviral agent is present at a concentration of 0.1 g/L-10 g/L
  • the epinephrine is present at a concentration of 0.5 to 1 mg per L
  • the local anesthetic is present at a concentration of 500 mg to 1,000 mg per L.
  • the local anesthetic is an amide-type or an ester- type local anesthetic.
  • the local anesthetic is selected from the group consisting of lidocaine, benzocaine and bupivacaine.
  • the local anesthetic is a neurotoxin-type local anesthetic.
  • the neurotoxin-type local anesthetic is neosaxitoxin.
  • the local anesthetic includes an amide-type local anesthetic and/or an ester-type local anesthetic in combination with a neurotoxin-type local anesthetic
  • kits for treating a localized varicella-zoster viral infection including:
  • an IV-like bag including a pharmaceutically acceptable carrier selected from the group consisting of a saline solution, a lactated Ringer’s solution, and Hartmann’s solution;
  • a sterile solution including a bicarbonate buffer in concentrated form
  • an infusion cannula optionally an infusion cannula.
  • Some embodiments relate to a tumescent composition
  • a tumescent composition comprising a cannabinoid dissolved in a tumescent solution, wherein the tumescent solution consists of:
  • the cannabinoid is a variant of cannabidiol (CBD) or tetrah y dr ocannabi nol (THC) .
  • the cannabinoid is a variant of THC, wherein the alkyl side chain of thereof is derivatized.
  • the cannabinoid is a variant of THC, wherein the phenolic hydroxyl group thereof is derivatized.
  • the cannabinoid is an emulsion comprising CBD and/or THC.
  • emulsion is a micro- or nano-emulsion.
  • the local anesthetic is iidocame.
  • the concentration of Iidocame is approximately 100 mg to 1,500 mg per L of solution.
  • the vasoconstrictor component comprises epinephrine.
  • the concentration of epinephrine is approximately 0.2 to 1.5 mg/L.
  • Some embodiments relate to a tumescent composition including a cannabinoid dissolved in at least 500 ml of a tumescent solution, wherein the tumescent solution includes:
  • a tumescent concentration of the cannabinoid is 1-2000 pg/kg and is simultaneously: 1) below a threshold for local, subcutaneous tissue toxicity,
  • Some embodiments relate to a method of subcutaneous delivery of a cannabmoid to a subject including administering to said subject the tumescent composition as disclosed herein.
  • infiltration of the tumescent composition achieves both prolonged local drug concentration within a tumescent subcutaneous tissue as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissue into a systemic circulation.
  • a pharmacokinetic profile of the systemic absorption resembles a slow, constant, intravenous (IV) infusion.
  • the subcutaneous concentration of the cannabinoid achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional IV, IM or oral delivery of the cannabinoid.
  • the local anesthetic is hdocaine.
  • the concentration of lidocame is approximately 100 mg to 1,500 mg per L of solution.
  • the vasoconstrictor component includes epinephrine.
  • the concentration of epinephrine is approximately 0.2 to 1.5 mg/L
  • the subject is treated for a condition selected from the group consisting of surgically-induced neuropathic pain, shingles, inflammation, appetite loss, pain, multiple sclerosis, nausea, vomiting, and epilepsy.
  • the surgically-induced neuropathic pain results from breast cancer surgery, limb amputation, thoracotomy or hernia repair.
  • the breast cancer surgery is mastectomy or lumpectomy.
  • the tumescent composition further comprises an antiviral drug.
  • the antiviral drug is acyclovir.
  • Figure 1 is a side elevation view of a stainless steel infiltration cannula with a closed tip shown inserted in subcutaneous tissue shown in partial cross section;
  • Figure 2 is a section view of the infiltration cannula shown in Figure 1 ;
  • Figure 3 is a side elevation view of a plastic infiltration cannula with a closed tip shown inserted m subcutaneous tissue shown in partial cross section;
  • Figure 4 is an exploded view' of the infiltration cannula shown in Figure 3 with a closed end;
  • Figure 5 is a flow diagram illustrating an exemplary procedure for using an infiltration cannula such as the one shown in Figure 1 or the one shown in Figure 3;
  • Figure 6 is an exploded side elevation view of a plastic infiltration cannula through which a stylet can be inserted with an open end;
  • Figure 7 is a side elevation view of a hollow sharp-tipped stylet with holes located along nearly the entire length of the stylet.
  • Figure 8 shows the results of a comparison study of tumescent antibiotic delivery (TAD) versus IV delivery of Cefazolin.
  • FIG. 9 Cefazolin log-linear concentration vs time profiles following one IV antimicrobial delivery (IV AD) and two tumescent antimicrobial deliveries (TAD).
  • IV AD IV antimicrobial delivery
  • TAD tumescent antimicrobial delivery
  • the IV AD dose was lOOOmg.
  • the TAD doses were both lOOOmg, but the cefazolin concentrations in the TAD solutions were different at 9Q0mg/L and 450mg/L.
  • Doubling the cefazolin mg, A concentration in the tumescent solution, at a constant mg dose doubles the Cmax in TISF and increases the subsequent cefazolin concentrations in serum at every time point.
  • FIG. 10 Cefazolin log-linear concentration vs time profiles following one IV antimicrobial delivery (IV AD) and two tumescent antimicrobial deliveries (TAD).
  • IV AD IV antimicrobial delivery
  • TAD tumescent antimicrobial delivery
  • the IV AD dose was l OOOmg. Both TAD doses were 500mg, but cefazolin concentrations in the TAD solutions were different at 450mg/L and 225mg/L.
  • the TAD solution contained equal 500mg doses and equal 413mg/L concentrations of metronidazole and cefazolin.
  • C Log-linear concentration-time profiles of cefazolin and metronidazole. When equal 500mg doses of cefazolin (open circles) and metronidazole (open diamonds) were given by IV antimicrobial delivery, the concentration-time profiles in serum were significantly different. In contrast when equal doses and concentrations of cefazolin (closed squares) and metronidazole (closed triangles) were given by tumescent antimicrobial deliver ⁇ ', the concentration-time profiles in tumescent interstitial fluid were identical.
  • FIG. 13 (A) Antibiotic log-linear concentration-time profiles of cefazolin comparing tumescent antimicrobial delivery (TAD) alone with IV antimicrobial delivery (IVAD) alone and with concomitant TAD+IVAD. When 1200mg of cefazolm was simultaneously delivered by TAD (800mg) and by IV AD (400mg), the Cmax for cefazolin in subcutaneous TISF was 9.2 times higher than in serum following 1200mg of cefazolin delivered by IV AD alone.
  • concentration of antibiotic in the TAD solution is approximately equal to the antibiotic concentration within the subcutaneous tissue following tumescent infiltration.
  • TI comprises a novel mode of drug delivery having a unique multi-compartment pharmacokinetic performance and presenting unique therapeutic opportunities. From a pharmacokinetic perspective, TI is functionally distinct from IV (intravenous), IM (intramuscular), PO (per os, oral), topical (percutaneous) and simple subcutaneous injection.
  • ISF subcutaneous interstitial fluid
  • TISF tumescent interstitial fluid
  • TI drug delivery is the direct subcutaneous infiltration of drug(s) dissolved in a large volume of a physiologic crystalloid solution such as 0.9% physiologic saline or lactated Ringer’s solution.
  • a TI solution may contain a dilute vasoconstrictor (e.g., epinephrine) for delayed systemic absorption or a dilute capillary vasodilator (e.g., lidocaine or niacin) for rapid systemic absorption (see, U.S. Patent No. 7,572,613).
  • TI drug delivery provides unique subcutaneous and systemic concentration- time profile (bioavailability) of a wide range of drugs (antibiotic, antiviral, antifungal, anticancer, analgesic, local anesthetic, biologic, etc.) following subcutaneous tumescent infiltration ( ⁇ ) drug delivery. Specifically TI simultaneously produces:
  • TI comprises a combination of a unique delivery vehicle with unique properties and a drug delivery method.
  • TI drug delivery consists of a drug (D) dissolved in a dilute tumescent solution that typically consist of iidoeaine ( ⁇ Igm/L), epinephrine ( ⁇ lmg/L), sodium bicarbonate lOmEq/L in 0.9% physiologic saline.
  • D drug
  • ⁇ Igm/L iidoeaine
  • ⁇ lmg/L epinephrine
  • sodium bicarbonate lOmEq/L 0.9% physiologic saline.
  • Alternative embodiments of TLA can involve higher or much lower concentrations of these components and/or alternative local anesthetics.
  • TI drug delivery' permits safe and effective local (subcutaneous or deep tissue) infiltration of a large dose of a drug m a large volume of a dilute solution, which otherwise could not be injected because of dose-related systemic toxicity (typically manifested as pain, inflammation or necrosis.
  • TI drug delivery consists of a large volume of dilute tumescent drugs injected subcutaneously.
  • a small volume of dilute tumescent anti-tumor drugs is injected directly over a certain time interval, often prolonged, into a deep parenchymal tissue to target a malignant neoplasm.
  • Examples of specific embodiments of ⁇ drug delivery include:
  • tumescent antifungal deliver ⁇ ' for local treatment of cutaneous superficial or deep fungal infections with a relatively high local drug concentrations while significantly reducing the peak serum concentration associated with nephrotoxic, hepatotoxic and ototoxic drags
  • tumescent anti-neoplastic delivery for treating cutaneous and subcutaneous malignancies or metastases, for example“in-vivo gene transfer” or biologic drug delivery targeting pancreatic adenocarcinoma,
  • tumescent delivery of a biologic drug consisting of a large molecule snake antivenin for targeting the toxic venom proteins as they are absorbed via lymphatic vessels.
  • Tumescent Infiltration Drug Delivery has a unique ability to achieve both a relatively high prolonged local drug concentration within the tumescent subcutaneous tissues as well as a prolonged slow constant systemic absorption of drugs from the tumescent tissues into the systemic circulation, where the pharmacokinetic profile of the systemic absorption resembles a slow constant IV infusion.
  • This unique feature of tumescent infiltration ( ⁇ ) cannot be matched by any other mode of drug delivery.
  • TI is a novel mode of concomitant prolonged local and prolonged systemic drug delivery with unanticipated therapeutic benefits.
  • TTAR The definition of TTAR: The tumescent therapeutic ambit range
  • TTAE tumescent concentration of D
  • the subcutaneous concentration of the drug, or therapeutic agent, achieved is from about 1-100 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug or therapeutic agent.
  • the subcutaneous concentration of the drug or therapeutic agent achieved is from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 times the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug or therapeutic agent.
  • Some drugs may not have a tumescent therapeutic ambit range.
  • a sufficiently safe dilution may be too dilute to have a positive therapeutic effect; or the subcutaneous bioavailability of the drug by TI is equal to that of either IV, IM or PO delivery.
  • Some drugs are inherently painful upon injection. Dilute Tumescent infiltration of a drug is less painful because dilute drug is less painful than more concentrated drug solutions and because dilute hdocaine in the solution eliminates the pain caused by subcutaneous delivery.
  • tumescent lidocame In certain clinical situations tumescent lidocame (high prolonged wide spread local subcutaneous concentrations) provides important unanticipated therapeutic benefits that are not available with IV, IM or oral delivery. For example, tumescent lidocame (at concentrations that are significantly higher than can be safely achieved by IV, IM or PO delivery) has antibacterial, antithrombotic and anti-inflammatory properties. These are a unanticipated unique features of TI drug deliver ⁇ ' that IV, IM, and PO delivery do not provide.
  • a lidocame component of ⁇ drug delivery can provide pain relief for pain associated with a disease being treated by TI.
  • TLA can relieve the acute pain associated with Herpes zoster. This is a unique feature of TI drug delivery that IV, IM, and PO delivery do not provide.
  • the subcutaneous bioavailability of D is often significantly greater by TI compared to IV, IM or oral delivery.
  • TI drug deliver ⁇ An important pharmacokinetic advantages of TI drug deliver ⁇ is a prolonged local drug effect (e.g., prolonged T>MIC) in relatively avascular subcutaneous fat and concomitant prolonged systemic concentrations with relatively small Cmax in serum.
  • the small serum Cmax is particularly advantageous with tumescent infiltration antibiotic deliver to prevent or treat a localized skin infection while simultaneously minimizing the peak antibiotic concentration within the gut and thus reducing the risk of antibiotic-associated C. difficile diarrhea.
  • TI drug delivery can be performed by any primary care provider
  • TI pharmacokinetic profiles include TI (antibiotic & lidocaine) delivery ? and TI (acyclovir & lidocaine) delivery:
  • TI antibiotic & lidocaine drug deliver ⁇ prevents and treats systemic inflammatory response syndrome (SIRS) and bacterial sepsis.
  • SIRS systemic inflammatory response syndrome
  • bacterial sepsis a systemic inflammatory response syndrome
  • local TI antibiotic & lidocaine delivery prevents SIRS by engulfing and isolating damaged (traumatized or infected) subcutaneous tissue within a persistent mass of vasoconstricted tumescent fluid.
  • Systemic TI antibiotic & lidocaine delivery treats SIRS by significantly down regulating systemic inflammatory mediators.
  • ⁇ lidocaine deliver ⁇ ' prevents platelet activation both locally and systemically and thereby and attenuates platelet-mediated inflammatory response. It is known that TI lidocame prevents thromboembolism (U.S. Patent No. 8,957,060 B2, Tumescent antibiotic solution).
  • TI delivery achieves subcutaneous acyclovir concentrations that far exceed concentrations achievable by IV delivery; the result is decreased varicella zoster virus (VZV) replication, decreased extent, severity of VZV dermatitis, shortened duration of VZV dermatitis, decreased inflammatory' damage to nerves and decreased risk of chronic post-herpetic neuralgia.
  • VZV varicella zoster virus
  • systemic absorption of acyclovir following subcutaneous TI acyclovir delivery produces sustained therapeutic serum acyclovir concentrations and thereby reduces VZV viremia.
  • TI allows direct subcutaneous infiltration of drugs which otherwise cannot be injected subcutaneously because of pain or tissue toxicity. Indeed, there are a number of drugs that are never injected subcutaneously because the Food and Drug Administration (FDA) approved package insert labeling states explicitly that the drug should NOT be injected subcutaneously.
  • FDA Food and Drug Administration
  • Acyclovir is a specific example of a drug for which the FDA countermands subcutaneous injection.
  • the FDA-approved package insert labeling for IV acyclovir states, “Acyclovir Injection is intended for intravenous infusion only, and should not be administered topically, intramuscular ly, orally, subcutaneously, or in the eye.” Nevertheless, we have found that, in clinical practice, TI delivery of acyclovir is safe and effective.
  • phenytoin calcium gluconate, potassium chloride, calcium chloride, dopamine, dextrose solutions, epinephrine, sodium bicarbonate, nafcillm, propofol, norepinephrine, arginine, promethazine, vancomycin, tetracycline, dobutamine, vasopressin, acyclovir, amphotericin, ampieiilin, cloxacillm, gentamicin, metronidazole, oxacillin, penicillin, amiodarone, albumin, furosemide, lorazepam, immunoglobulin, morphine, and sodium valproate. Careful formulation of dilute TI solutions of these drugs may allow safe and effective subcutaneous tumescent infiltration.
  • Pharmacologic properties that contribute to cutaneous and subcutaneous tissue toxicity include pH, osmolality, diluent, vasoactive properties, and inactive ingredients. With appropriate formulation of the subcutaneous TI solution these drugs can be injected (delivered) subcutaneously in a manner that is safe, comfortable and uniquely effective.
  • TI local and simultaneous systemic delivery
  • TI provides therapeutic subcutaneous concentrations that are not achievable by any other mode of delivery and TI simultaneously provides therapeutic serum concentrations with a pharmacokinetic concentration-time profile resembling a slow continuous IV infusion. No previously described mode of drug delivery can achieve these results.
  • the standard tumescent solution consisting of lgm of lidocaine, Img of epinephrine and lOmEq of sodium bicarbonate m a liter of 0.9% physiologic saline is the functional equivalent to a drug delivery vehicle.
  • the epinephrine component of the tumescent solution determines the degree of local subcutaneous vasoconstriction. Reducing the epinephrine concentration in the tumescent solution attenuates pharmacologic capillary vasoconstriction. Infiltration of a tumescent solution with no epinephrine and a trace of lidocaine produce capillary vasodilation.
  • the tumescent (augmented) interstitial pressure also accelerates trans-capillary fluid absorption into the systemic circulation and similarly accelerates systemic drug delivery.
  • the lidocaine component of a tumescent solution has local anesthetic, local antibacterial and systemic anti-inflammatory effects. Locally, dilute lidocaine eliminates the pain associated with the subcutaneous injection of other drugs and provides rapid onset of prolonged widespread surgical local anesthesia.
  • the continuous sy stemic absorption of 28mg/kg of tumescent lidocaine conveniently provides safe predictable therapeutic serum lidocaine concentrations (I pg/ml to 2pg/ml) for 12 hours or more.
  • Epidural lidocaine may reduce bacterial growth at a surgical site (Igarashi T, Suzuki T, Mori K, Inoue K, Seki TI, Yamada T, Kosugi S, Minamishima S, Katori N, Sano F, Abe T, Morisaki H.
  • Subcutaneous tumescent lidocaine at concentrations far exceeding the therapeutic serum concentrations of lidocaine following IV delivery, is anti-bacterial and provides pre-emptive, inter-operative and post-operative analgesia.
  • Lidocaine local anesthesia reduces post-operati ve narcotic use with earlier return of normal bowl function and earlier postoperative ambulation (Sakuragi T, Ishino H, Dan K. Bactericidal activity of clinically used local anesthetics on Staphylococcus aureus. Reg Anesth. 21 : 239-42, 1996; Pan- AM, Zoutman DE, Davidson JS. Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection. Ann Plast Surg.
  • lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol-remifentanil- based anaesthesia. Eur J Anaesthesiol. 2010; 27: 41-46).
  • Lidocaine down regulates many inflammatory mediators and has significant pharmacologic anti-inflammatory properties (Hatakeyama N, Matsuda N. Alert cell strategy: mechanisms of inflammatory response and organ protection. Curr Pharm Des 2014; 20:5766-78; Berger C, Rossaint J, Van Aken H, Westphal M, Hahnenkamp K, Zarbock A. Lidocaine reduces neutrophil recruitment by abolishing chemokine-induced arrest and iransendothelial migration in septic patients. J Immunol.
  • lidocaine Influence of lidocaine on endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo. Anesthesiology.1997; 87: 617-24).
  • a tumescent solution of lidocaine and antibiotics engulfs large volumes of damaged tissue and prevents the spread of locally generated inflammatory cytokines, chemokines, histones and pathogens and blunts systemic inflammatory responses.
  • Tumescent lidoeaine inhibits platelet function, limits platelet leukocyte aggregation, limits activated-platelet induced inflammation and may reduce the risk of thromboembolism.
  • Tumescent lidoeaine decreases blood viscosity, resulting m increased oxygenation of local and systemic tissues.
  • TI antimicrobial delivery is the direct subcutaneous infiltration of antimicrobial drug(s) dissolved in a large volume of a tumescent lidocaine anesthesia (TLA) solution.
  • TLA tumescent lidocaine anesthesia
  • the standard TLA solution consists lidocaine (lgm) and epinephrine (Img) and sodium bicarbonate (10 mEq) in a 1000ml bag of physiologic saline.
  • a TLA solution consists of at least a 10-fold dilution of commercial 1% lidocaine with epinephrine 1 : 100,000 plus sodium bicarbonate (ImEq/ml) in a liter of normal saline.
  • Wide spread subcutaneous vasoconstriction resulting from a large volume of dilute tumescent epinephrine produces prolonged local anesthesia and reduced surgical blood loss (Klein JA.
  • Cefazolin and metronidazole were selected because they are water soluble, safe, well tolerated in subcutaneous tissue, effective and economical for prevention of SSIs (Meyer NL, Hosier KV, Scott K, Lipscomb GH. Cefazolin versus cefazolin plus metronidazole for antibiotic prophylaxis at cesarean section. South Med J. 2003; 96: 992-5; Morris WT, limes DB, Richardson RA, Lee AJ, Ellis-Pegler RB. The prevention of post- appendicectomy sepsis by metronidazole and cefazolin: a controlled double blind trial.
  • Subcutaneous antibiotic delivery for systemic effect is commonly used for palliative therapy (Azevedo EF, Barbosa LA, DeBortoli Cassiani SH. Administration of antibiotics subcutaneously: an integrative literature review. Acta Paul Enfertn. 2012; 25: 817-22; Robelet A, Caruba T, Corvol A, Begue D, Gisselbrecht M, Saint- Jean (), Prognon P, Sabatier B. Antibiotics par intuitive sous-cutanee incurla vulgar agee Presse Med. 2009; 38: 366-76; Frasca D, Marchand S, Petitpas F, Dahyot-Fizelier C, Couet W, Mimoz O.
  • Tumescent Infiltration ( ⁇ ) drug delivery is the slow rate of systemic absorption of antibiotic following TI produces a serum antibiotic concentrations-time profile resembling a slow constant IV infusion.
  • the serum concentrations (at each time point after TI infiltration) increased with increasing total mg dose of antibiotic in the tumescent solution.
  • the serum concentrations (at each time point after TI infiltration) increased with increasing mg/L concentration of antibiotic in the tumescent solution.
  • Tumescent infiltration can safely provide prolonged relatively high drug concentration in subcutaneous TISF.
  • achieving similar subcutaneous drug concentrations solely by IV infusion may be impossible or pose a significant risk of systemic toxicity and harm to the patient.
  • the aminoglycoside antibiotics gentamicin and amikacin are associated with dose and concentration related potential ototoxicity' and nephrotoxicity.
  • Achieving prolonged high subcutaneous concentrations by means of IV delivery' requires high-prolonged IV dosages with the inherent risk to hearing (inner ear) and kidney damage.
  • TI of antibiotics for prevention of surgical site infection is optimally delivered with the use of either HK Monty stainless steel re-usable cannulas or HK SubQKath disposable catheters (U.S. Patent Nos. 7,572,613; 7,914,504; 8,105,310; 8,167,866; 8,246,587; 8,512,292; 8,529,541) and tumescent peristaltic infiltration pump and tubing.
  • the present embodiments take advantage of the tumescent technique in order to provide intermittent or continuous, brief or prolonged multi-liter infiltration of local anesthetic, physiologic fluid, antibiotics or other therapeutic solution with a significant decrease in patient discomfort due to the elimination of the piston-like in and out motion of the cannula.
  • Once the cannula is positioned in place there is no need to repeatedly move the cannula in and out through the tissue in order to deliver the fluid to a wide area.
  • the time needed in order to complete the infiltration of a targeted anatomic area is reduced to nearly half of the time required when using traditional cannula.
  • the device and method of the present embodiments can use multiple (e.g., two or more) infiltration cannula simultaneously. While one cannula is actively dispersing tumescent fluid into the subcutaneous tissue, the surgeon can reposition a second infiltration cannula. This allows the infiltration process to proceed without interruption, whereas prior art techniques of infiltration must be ceased each time the cannula is withdrawn from the skin and re-inserted into another direction.
  • the flexible plastic cannula version of the present embodiments provides a means for relatively rapid fluid resuscitation in emergency situations such as when establishing an intravenous (IV) access is not feasible.
  • a large volume of a tumescent crystalloid solution to treat intravascular fluid deficit may be delivered subcutaneously when an intravascular (IV) line cannot be started for fluid replacement (e.g., remote area, obese patient, burn/trauma victim, unavailable trained medical professional, etc.).
  • rapid systemic absorption of physiologic saline can be achieved by adding a vasodilator drug to saline and using the tumescent technique to deliver the solution into subcutaneous tissue.
  • the flexible cannula may also have important applications in treating a wounded soldier in night-time combat conditions when establishing an IV access in total darkness is nearly impossible or using a flashlight might attract enemy fire.
  • the flexible cannula may similarly have important applications in other areas of use such as treating mass- casualty victims suffering hypovolemia as a result of epidemic infections, biologic warfare, or trauma such as explosions, burns or radiation exposure.
  • the flexible cannula similarly has applications in surgical patients wherein the surgeon can provide localized pre-operative preemptive analgesia and simultaneously provide tumescent delivery of a prophylactic dose of an antibiotic aimed precisely at tissues targeted for surgical intervention.
  • the tumescent technique was discovered by Jeffrey Alan Klein, M.D. (the present applicant) in 1985. Dr. Klein first published a description of the tumescent technique in 1987 when he described the use of dilute lidocaine and epinephrine to permit liposuction totally by local anesthesia. The technique for tumescent local anesthesia is well known in dermatologic and plastic surgery literature. A detailed description of the tumescent technique has not been published in anesthesiology literature, and therefore, the unique benefits of the tumescent technique are not recognized by anesthesiologists.
  • the tumescent technique comprises a drug deliver system that takes advantage of a recently discovered reservoir effect of injecting a relatively large volume of relatively dilute solution of a drug into the subcutaneous tissue.
  • the drug is isolated from the systemic circulation because only the drug on the outer boundary of the mass of drug is the available for absorption, whereas the portion of the drug located within the central portion of the mass of fluid is virtually isolated from the systemic circulation by virtue of profound capillary vasoconstriction.
  • the tumescent fluid does not contain epinephrine there is no clinically significant vasoconstriction after tumescent infiltration, and the tumescent fluid is absorbed relatively rapidly. This has important clinical applications in situations where patients are hypovolemic or dehydrated and unable to be given fluids by mouth or intravenously.
  • the tumescent technique permits rapid systemic hydration by direct subcutaneous or intramuscular injection of a large volume of fluid through a multi- fenestrated infiltration cannula described in this invention.
  • hypodermoclysis involves the slow and continuous infiltration of fluid subcutaneously using a type of steel hypodermic needle, known as a butterfly needle, having a single distal aperture in order to provide fluid to patients who cannot be given fluids by mouth and for whom an IV access cannot be established, such as in the treatment of infants, or cancer patients.
  • the technique of hypodermoclysis is typically used to deliver relatively small volumes of fluid, for example an adult might receive 70 ml per hour. At this small hourly volume hypodermoclysis is not an efficient method for the rapid systemic delivery of fluid in emergency situations that might require two to four liters per hour.
  • the reason is that when using a cannula with only a single distal aperture, the local interstitial fluid pressure increases rapidly immediately adjacent to the single aperture as fluid infiltrates locally, which in turn dramatically slows the rate of subsequent fluid flow into the area.
  • the multiple apertures formed along the length of the cannula as described in the present invention distribute the fluid throughout a much larger volume tissue before there can be a sufficient increase in the interstitial fluid to decrease the rate of additional infiltration. Also, the amount of pain is reduced because the rate of fluid flow through each of the apertures is less than the rate of fluid flow through the single aperture at the distal end.
  • a preferred suitable peristaltic infiltration pump is described in pending United States Patent Application Number 10/811,733, filed March 29, 2004, entitled INFILTRATION PUMP HAVING INSULATED ROLLERS AND PROGRAMMABLE FOOT PEDAL, the disclosure of which is expressly incorporated herein by reference.
  • the peristaltic pump provides a sufficient degree of pressure to easily overcome the localized increased interstitial pressure associated with the local effects of a tumescent infiltration.
  • the present invention still permits relatively rapid tumescent infiltration by virtue of the multiple holes distributed along the length of the flexible cannula.
  • external hydrostatic pressure can be applied to the fluid flowing into the flexible cannula from the fluid reservoir by means of gravitational force derived from elevating the reservoir one to two or more meters above the patient.
  • the infiltration process can be continuous or intermittent in exemplary embodiments, the intermitent injections are administered at intervals ranging from every few minutes to eight to twelve hours or more.
  • Figures 1 and 2 illustrate a stainless steel (reusable) infiltration cannula 10 and Figures 3-4 and 6 illustrate a (single use) plastic infiltration cannula 30.
  • the cannula 10, 30 can be inserted under the skin 52 and into the subcutaneous tissue 50 and tumescent local anesthesia can be infiltrated either continuously until the clinical goal is achieved or intermittently (by way of example and not limitation, once every eight to twelve hours).
  • Stainless steel infiltration cannula 10 such as the one shown in Figures 1 and 2, are formed having precision high quality and are preferably reusable. These cannula can be used to provide tumescent local anesthesia for surgical procedures, such as liposuction, which require tumescent local anesthesia over a relatively large area
  • the cannula 10 includes a tubular needle portion 12 which has a proximal end 14 and a distal end 16.
  • the proximal end 14 of the tubular needle 12 is attached to a hub 20 that is used by the anesthesiologist or surgeon to grasp and hold the cannula 10 during the infiltration procedure.
  • the hub 20 is connected to the tubular needle 12 at a first end 22 and has a connector 24, such as a luer lock, at an opposing second end.
  • the connector 24 is connected to a fluid source, such as tubing connected to an IV bag. Fluid enters the cannula 10 via the connector 24.
  • the tip at the distal end 16 is closed.
  • the local anesthetic is infiltrated into the patient via apertures 18 located proximate the distal end 16 of the tubular needle 12 of the cannula 10.
  • the apertures 18, 38 and 54 discussed herein may have a helical, spiral, linear or any random or ordered pattern.
  • the apertures 18 are disposed along the distal end 16 of the cannula 10 in a spiral or helical pattern and are distributed over the distal 33% to 100% of the tubular needle 12 of the cannula 10.
  • the pattern of apertures of the cannula 10 are preferably distributed over 33% of the tubular needle 12 of the cannula 10.
  • the size of the aperture and density of apertures on the tubular needle is limited by the structural integrity of the cannula. If the apertures 18 are too large or too close together then the cannula may bend or break during use (e.g., routine clinical applications).
  • Prior art cannula wherein the apertures are limited to the distal 25% of the cannula eject the fluid into the subcutaneous tissue at a high rate so as to cause discomfort to the patient.
  • the apertures 1 8 which are located along a greater length of the cannula compared to prior art cannula allows fluid fo flow out of each of the apertures at a slower rate but to achieve a greater amount of fluid flow as an aggregate so as to reduce the amount of discomfort to the patient due to the rate at which fluid flows out of each of the apertures.
  • tumescent fluid When tumescent fluid is injected into subcutaneous tissue, tumescent fluid spreads by means of simple bulk-flow through the interstitial gel substance. This process is extremely rapid and unimpeded by fibrous tissue.
  • the proximal portion 14 of the cannula 10 may be devoid of apertures in order to prevent fluid from leaking out of the cannula insertion site in the skin.
  • the hub may be used to prevent fluid from leaking out of the cannula insertion site in the skin in the follower manner.
  • the hub of the infiltration cannula serves as a connector. The distal end of the hub ataches to the cannula, while the proximal end of the huh detachably connects to the plastic tube set which carries tumescent solution to the cannula.
  • the hub can also assist in reducing or virtually eliminating leakage of tumescent fluid out through the skin incision or adit site.
  • An adit is a small round hole in the skin typically produced by a biopsy punch.
  • the hub 20 may have a conical configuration.
  • the hub 20 may become narrower from the proximal end of the hub to the distal end of the hub.
  • the rate at which the hub 20 becomes narrow may be less than about fifteen degrees with respect to a centerline of the hub.
  • the outer surface of the hub 20 may have a plurality of rounded circular ridges equally spaced apart.
  • the adit may be formed so as to have a diameter which is less than a diameter of the cannula or the outer surface of the hub.
  • the cannula may initially be inserted into the adit.
  • the adit is slightly stretched to accommodate the cannula.
  • the cannula may be fully inserted into the subcutaneous tissue of the patient such that the distal end of the hub contacts the adit.
  • the hub may then be pushed into the adit such that the inner diameter of the adit expands and slides over the rounded circular ridges formed on the distal end of the hub.
  • the hub is gently wedged into the adit until there is a snug fit between the infiltration cannula and the adit.
  • Leakage of fluid out of the adit may also be minimized by placing the proximal most aperture on the cannula sufficiently deep within the subcutaneous tissue such that fluid injected from the most proximal hole produces localized interstitial tumescence and a snug fit of the tissue against the cannula. It is also contemplated that the hub has other shapes such as curved, linear, parabolic, or combinations thereof.
  • Flexible plastic infiltration cannula 30, such as the one shown in Figures 3, 4 and 6 are single use cannula and can be used in one of several unique ways. First, an anesthesiologist, surgeon, untrained first responder, or even a victim can insert infiltration cannula 30 with stylet 46 into the subcutaneous tissue 50, remove the stylet 46, then attach IV tubing to the infiltrator and inject tumescent local anesthesia or other tumescent fluid into the targeted area without subsequent repositioning of the infiltration cannula 30.
  • the plastic flexible nature of the tubular needle 32 of the disposable plastic cannula 30 allows the patient to move or change position of the body without risk of injury that might result if a patient moves while a rigid steel cannula is inserted.
  • the stylet 46 is formed of a rigid material such as metal, stainless steel, or plastic material.
  • the stylet 46 should be sufficiently rigid so as to guide the tubular needle 32 of the cannula 30 into the subcutaneous tissue 50.
  • the stylet 46 may be solid (see Figure 4) or hollow (see Figure 7) through its center.
  • the stylet may either be straight or curved.
  • the plastic cannula 30 can be blunt-tipped with the metal stylet tip 48 covered by the rounded tip 39 of the plastic cannula 30, as shown in Figure 4.
  • the plastic cannula 30 can be open-ended with the stylet 46 extending a short distance past the end 39 of the plastic cannula 30 as shown in Figure 6.
  • the stylet 46 can be either blunt-tipped (see Figure 6; requiring a skin incision to permit insertion into the subcutaneous space), or sharp-tipped (see Figure 7; permitting the cannula to be inserted directly through the skin and into the subcutaneous space or muscle without requiring a preparatory' skin incision).
  • the sharp-tipped stylet 46 can be formed in either a solid (see Figure 4) or hollow (see Figure 7) cross-sectional configuration.
  • a sharp tipped hollow stylet is that it can be inserted directly through the skin and then advanced painlessly through the subcutaneous tissue by slowly injecting local anesthetic solution through the stylet as it is slowly advanced, thereby anesthetizing the tissue in advance of the stylet ’ s tip.
  • apertures 54 may be formed along an entire length or along a portion (e.g., about 33% to 100%) of the length of the tubular needle 56 of the stylet 46, as shown in Figure 7.
  • the hollow' stylet 46 may be utilized in a similar fashion as the cannula 10 shown in Figures 1 and 2 and described herein.
  • the tubular needle 56 shown in Figure 7 may be inserted into the cannula 30.
  • the combined tubular needle 56 and cannula 30 may be inserted through the subcutaneous tissue 50 of the patient.
  • the tubular needle 56 may be removed from the patient and the cannula 30.
  • the tubular needle 56 of the stylet 46 may now be reinserted into the patient at a different site and used as a rigid cannula similar to the cannula 10 discussed in relation to Figures 1 and 2.
  • the stylet 46 shown in Figure 7 has apertures 54 about the periphery of tubular needle 56 of the stylet 46.
  • the apertures 54 may have a pattern which is dissimilar to the pattern of apertures 38 formed m the tubular needle 32 of the cannula 30.
  • the apertures 54 may have a pattern which is identical to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
  • some of the apertures 54 may have a pattern which is identical to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
  • some of the apertures 54 may have a pattern which is dissimilar to the pattern of apertures 38 formed in the tubular needle 32 of the cannula 30.
  • the medical professional may insert the stylet 46 (see Figure 7) with apertures 54 into the cannula 30.
  • the apertures 54 of the stylet 46 may be aligned or misaligned to the apertures 38 of the tubular needle by turning the stylet 46 within the cannula 30.
  • the stylet 46 may have a hub with a similar configuration as hub 40.
  • the hub of the stylet 46 may also be wedged into the adit of the patient to minimize or eliminate leakage of fluid, as discussed herein.
  • the plastic cannula shown in Figures 3 and 4 is similar to an IV catheter except the sharp hollow stylet used for the insertion of an IV catheter can be replaced by a solid obturator/stylet 46 that can be either sharp or blunt tipped. Except for the removable stylet 46, the plastic cannula 30 is similar to the stainless steel cannula 10 shown in Figures 1 and 2 and described above.
  • the plastic cannula 30 includes a flexible tubular needle 32 having a proximal end 34 and a distal end 36. The distal end has apertures 38 and the proximal end 34 may be devoid of apertures.
  • the pattern of apertures 38 m the cannula 30 are distributed over the distal 33% to 100% (see Figure 4) of the tubular needle 32 of the cannula 30.
  • the tubular needle 32 of cannula 30 shown in Figures 3 and 4 has a length D of 15 cm and the pattern of apertures are distributed over a length dl of 13.5 cm, then the apertures 38 are distributed over 90% of the cannula.
  • the tubular needle 32 of cannula 30 shown in Figures 3 and 4 has a length D of 15 cm and the pattern of apertures are distributed over a length dl of 15 cm, then the apertures 38 are distributed over 100% of the cannula.
  • the hub may be wedged into the adit site, as discussed above.
  • a typical infiltration cannula 10, 30 may have a diameter equivalent to 20, 18, 16 or 14 gauge with small apertures 18, 38 placed every 5 mm along the cannula in a spiral or helical pattern.
  • the infiltration cannula 10, 30 may be 20-14 cm in length.
  • a typical infiltration cannula 10, 30 is 15 cm or 20 cm in length. It will be appreciated that the dimensions used herein are exemplary' and that the cannula dimensions, range of gauge, length range of cannula, relative size shape and pattern of apertures can vary greatly depending upon clinical preference.
  • the proximal end 34 of the tubular needle 32 shown in Figures 3 and 4 is attached to a hub 40 that is used by the anesthesiologist or surgeon to hold the cannula 30 during the infiltration procedure.
  • the hub 40 is connected to the tubular needle 32 at a first end 42 and has a connector 44 at an opposing second end.
  • the connector 44 is connected to a fluid source.
  • the stylet 46 can be inserted and removed from the cannula 30.
  • infiltration using a plastic infiltration cannula 30, such as the one shown in Figures 3 and 4 can be accomplished using an infiltration pump.
  • the force of gravity could be used to push the tumescent fluid into the tissues by hanging a reservoir plastic bag of tumescent local anesthesia (or other dilute drug, such as a chemotherapeutic agent or antibiotics) on an IV pole and connecting bag to the infiltration cannula by an IV line.
  • Tumescent local anesthesia may be provided to a localized area through which a surgeon plans to make a surgical incision. Tumescent local anesthesia involves the administration of dilute anesthetic solutions into the subcutaneous fat compartment.
  • a tumescent solution used m a liposuction procedure comprises a combination of 500-1 OOOmg of the anesthetic lidocaine per liter of solvent (typically normal saline or lactated Ringer’s solution) along with a vasoconstrictor such as epinephrine to control the rate of lidocaine absorption and reduce bleeding.
  • Bicarbonate may be included to reduce patient discomfort from an otherwise acidic solution.
  • Anti-inflammatory agents may also be included.
  • tumescent local anesthesia converted liposuction from a hospital- based procedure requiring general anesthesia and often blood transfusions to an office-based procedure.
  • the tumescent technique has subsequently been adapted for use in a variety of other surgical procedures including hair transplantation, phlebectomy, mastectomy, sentinel node biopsy, and others.
  • a tumescent epinephrine induces profound local vasoconstriction resulting m significantly delayed systemic absorption of a tumescent antimicrobial drug from subcutaneous tissue.
  • the systemic absorption of an aqueous solution of lidocaine requires approximately 2 to 4 hours.
  • the systemic absorption of tumescent lidocaine requires 24 hours or more.
  • a tumescent antibiotic can be expected to remain within the peri-incisional tissue at least 12 times longer than a routine aqueous antibiotic solution and the action would be far more effective.
  • a tiny hematoma within an incision may be an isolated avascular space and a potential nidus for an infection.
  • hypothermia is a major risk factor for postoperative surgical site infection. Mild perioperative hypothermia is common among patients having surgery under general anesthesia. The incidence of SSI w3 ⁇ 4s 5.8% in the normothemnc (core body temperature 37 degrees C) group and 18.8% in the hypothermic group (34.4 degrees C) in a randomized, double blind trial. (Kurtz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infections and shorten hospitalization. Study of wound infection and temperature group. N Eng J Med 334: 1209-15, 1996). Hypothermia also causes delays in moving the patient out of the recovery room. With surgery totally by tumescent local anesthesia there is no evidence of post-operative hypothermia.
  • Some embodiments relate to infiltration of a tumescent solution comprising an anesthetic component, a vasoconstrictive component, and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising a vasoconstrictive component and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising an anesthetic component and an antibiotic component. Other embodiments relate to infiltration of a tumescent solution comprising an anesthetic component and a vasoconstrictive component. Some embodiments relate to infiltration of a tumescent solution comprising an anesthetic component. Some embodiments relate to infiltration of a tumescent solution comprising a vasoconstrictive component. Some embodiments relate to infiltration of a tumescent solution comprising an antibiotic component. Some embodiments relate to infiltration of a tumescent solution comprising crystalloid fluids/electrolytes.
  • infiltration of a tumescent solution comprising iidocaine, epinephrine, and an antibiotic improves surgical site infection prophylaxis.
  • Tumescent infiltration of antibiotics into peri-incisional skin and subcutaneous tissue offers the following advantages: prolonged local tissue concentrations of antibiotics and prolonged systemic delivery of antibiotic to tissues distant from the incision site.
  • the systemic absorption of tumescent Iidocaine mimics IV delivery of iidocaine which is known to reduce postoperative pain and hasten postoperative discharge from the hospital.
  • Embodiments of the infiltration cannula discussed herein may be used for tumescent delivery of antimicrobial drugs.
  • tumescent technique to provide an easily accessible route for systemic administration of crystalloid fluids/electrolytes for systemic hydration or for other types of drug therapy.
  • Potential clinical applications include emergency resuscitation with systemic fluids in situations where insertion of an IV catheter into a vein cannot he readily achieved. Examples of situations where emergency access for intravenous delivery' of fluids might not be possible include acute trauma or burn 'ound in civilian or military situations and very obese patients in which finding an accessible vein for IV access can be difficult even for a physician skilled in performing“IV cut-down” procedures.
  • Embodiments of the infiltration cannula discussed herein may be a valuable adjunct to fluid resuscitation in an ambulance or an emergency room.
  • Another application may be the emergency treatment of dehydration associated with pandemic influenza, prolonged vomiting or diarrhea as a result of chemical warfare or biological warfare (e.g., epidemic cholera among pediatric patients in rural third world settings) or other types of medical emergencies which overwhelm a medical center’s capacity to care for incoming victims.
  • a subcutaneous infiltration catheter can easily be introduced by a layman, whereas inserting an IV catheter into a vein of a patient that is severely dehydrated can be difficult even for a skilled physician. Delivery of systemic fluids by subcutaneous infiltration is safer than an IV infusion in a zero gravity' ⁇ situation (for example, the Space Station).
  • capillar vasodilator e.g., methylnicotinamide
  • methylnicotinamide e.g., methylnicotinamide
  • the continuous systemic drug delivery by tumescence has a similar therapeutic effect to continuous IV infusion but without the inherent expense, difficulties, and risk of an IV infusion.
  • continuous systemic delivery is preferred in order to achieve prolonged and relatively uniform blood concentrations of the drug. This is especially true in critically ill patients.
  • Tumescent delivery of a drug, placed in a tumescent solution containing epinephrine as a vasoconstrictor produces prolonged continuous system absorption of the drug over an interval of more than 24 hours.
  • the simplicity and inexpensive equipment required to achieve continuous tumescent systemic drug delivery is clearly an advantage among medically impoverished populations, and in the demanding conditions of battlefield or at the scene of a mass casualty 7 .
  • Yet another application is related to astronauts and systemic delivery of medication.
  • the therapeutic options for treating an injured astronaut are limited.
  • the fate of injured airplane pilots, passengers and astronauts are similar in that we presently have virtually no in-flight capability for treating an acute traumatic injury. If a pilot or astronaut survives the immediate effects of an explosion, burn, or decompression injury, or if there is an acute non-traumatic medical illness, it is assumed that the victim must return to terra firma for any significant therapeutic intervention such as providing systemic fluid replacement.
  • the tumescent infiltrator is capable of providing systemic fluid and thus it is successfully solving a problem that has either never before been recognized, or has never before been solved by a simple device and technique.
  • the present embodiments allow improved emergency medical care for an injured astronaut on-board the International Space Station Repeated and prolonged extra vehicular activities (EVA) expose astronauts to greater risk of physical trauma injury.
  • Potential injuries to astronauts include decompression injury-induced neurological injury and coma, acute pneumothorax, bums, and radiation injury .
  • Assembly and maintenance of the International Space Station requires an unprecedented number of spacewalks, which expose astronauts to the risk of decompression sickness (DeS).
  • DeS decompression sickness
  • the cannula 10, 30 is intended to be inserted far enough through the skin 52 so that all of the apertures 18, 38 are within the fat 50 or muscle of the patient. If the apertures 18, 38 are distributed over about 100% of the cannula, the hub may be wedged into the adit to prevent or minimize leakage of the tumescent fluid out of the adit.
  • the cannula 10, 30 Once the cannula 10, 30 is properly positioned, it can remain stationary while the local anesthetic (or other pharmaceutical) solution is injected. Since the cannula remains stationary, the associated pam or discomfort typically caused by the reciprocating in and out movement of prior art cannula is reduced or eliminated. Accordingly, the cannula of the present invention permits infiltration of multi liter volumes of tumescent fluid into the patient m a safe and painless manner.
  • the infiltration is briefly terminated (either by turning off the pump or by clamping the IV tubing) while the cannula 10, 30 is repositioned into another area of the subcutaneous tissue.
  • the cannula is repositioned at the rate of about once per minute.
  • the infiltration is then restarted with the cannula stationary' in its new position. Since the apertures are distributed over the distal 33% to 100% of the cannula, the apertures distribute tumescent fluid into the patient along the entire length of cannula insertion.
  • the cannula does not have to be reciprocated in and out to infiltrate the subcutaneous tissue like prior art cannula.
  • the infiltrator 10, 30 can also be used in the traditional mode whereby the cannula 10, 30 is moved through the targeted tissue while the fluid is simultaneously pumped through the cannula 10, 30 and into the subcutaneous tissue 50.
  • Another unique aspect of the tumescent technique’s reservoir effect is that one can conveniently achieve a long, slow, steady absorption of a drug delivered to the subcutaneous space 50 using periodic injections of a tumescent solution.
  • the alternative technique can achieve a slow systemic absorption of a drug but may be difficult require greater clinical expertise, be more expensive, and therefore, less practical than the technique described herein.
  • FIG. 5 is a flow diagram illustrating steps performed in an exemplary infiltration procedure using a cannula 10, 30 such as the one shown in Figures 1 and 2 or the one shown in Figures 3 and 4, respectively.
  • the procedure begins by inserting the tubular needle 12, 32 of the infiltration cannula 10, 30 into a desired subcutaneous tissue site 50, e.g., via an incision in the patient’s skin 52 (block 100). Fluid is then transported from the fluid source (e.g., an IV bag) into the cannula 10, 30 via the connector 24, 44 that is connected to the fluid source. The fluid is transported from the connector 24, 44 through the hub 20, 40 and to the tubular needle 12, 32 (block 102). The fluid is then ejected from the cannula 10, 30 into the subcutaneous tissue 50 of the patient via the apertures 18, 38 at the distal end 16, 36 of the tubular needle 12, 34 of the cannula 10, 30 (block 104).
  • the fluid source e.g., an IV bag
  • the fluid is transported from the connector 24, 44
  • the fluid is transported (block 102) and ejected (block 104) until infiltration at the current site is completed (yes in decision block 106). Complete infiltration at the current site may take approximately one or two minutes.
  • the fluid can be injected into multiple sites in order to distribute the solution over a greater area.
  • Infiltration at a particular site may be deemed complete upon emptying of the fluid source or based on the anesthesiologist or surgeon’s decision to stop the infiltration at the current site.
  • the infiltration can be briefly terminated (either by turning off the pump or by clamping the IV tubing) while the cannula 10, 30 is repositioned into another area of the subcutaneous tissue. The infiltration may then be restarted with the cannula stationary m its new position. If the infiltration at a site is complete (yes in decision block 106), the cannula is removed from the current site (block 108). If the infiltration at the current site is not complete (no in decision block 106), fluid is transported from the fluid source (block 102) and ejected into the subcutaneous tissue (block 104) until infiltration at the site is complete (yes in decision block 106).
  • the tubular needle 12, 32 of the infiltration cannula 10, 30 is inserted into a new area of subcutaneous tissue 50.
  • the tubular needle 12, 32 may be inserted into a new area adjacent the current site.
  • the adjacent site may be partially anesthetized by infiltration of the anesthetic solution at the current site. As such, pain to the patient caused by insertion of the tubular needle 12, 32 is minimized, eliminated or greatly reduced.
  • Tins process can be continuous or repeated intermittently. It is contemplated that infiltration of up to about 50% of the patient’s body may be achieved in the manner described herein.
  • a second or additional cannula can be inserted (block 100) at the same time as a first cannula is being removed (block 108).
  • the second cannula may be inserted parallel to the first cannula and into an area immediately adjacent to the area in which the first cannula is inserted.
  • the pam usually associated with the insertion of the cannula into the patient’s fat tissue is reduced or eliminated because the first cannula has already at least partially anesthetized the area in which the second cannula is inserted.
  • the second cannula is positioned adjacent the first cannula approximately every one or two minutes.
  • the first cannula may then be removed from the patient’s body after the second cannula is inserted.
  • the infiltration process need not be interrupted in order to reposition a single cannula. Progressing repeatedly in this fashion, eventually all the fat within a targeted area becomes tumescent and profoundly anesthetized. As such, such method can obviate the need for general anesthesia or heav IV sedation.
  • the plastic infiltration cannula shown in Figures 3 and 4 may be used by either a lay person or a clinical professional for the delivery- of tumescent fluid for either tumescent local anesthesia, tumescent antimicrobial therapy, or emergency deliver of systemic fluids by tumescent infiltration.
  • tumescent local anesthesia e.g., tumescent local anesthesia
  • tumescent antimicrobial therapy e.g., tumescent antimicrobial therapy
  • emergency deliver of systemic fluids by tumescent infiltration e.g., tumescent infiltration
  • cannula 10, 30 may be utilized for continuous systemic tumescent delivery of a drug which produces continuous system absorption of the drug over nearly 24 hours in a fashion similar to a continuous IV infusion
  • the infiltration cannula 10, 30 discussed herein is a subcutaneous device and not an intravascular device for infiltration of multi-liter volumes of fluid into areas of up to 50% of the total body surface area.
  • the infiltration cannula 10, 30 infiltrates approximately 1,000 times the volume of fluid delivered by the Schwartz device discussed in the background.
  • the tumescent technique may be used to deliver an antimicrobial solution by subcutaneous infiltration.
  • the antimicrobial solution may comprise an antibiotic.
  • the antimicrobial solution may also comprise a local anesthetic and/or a vasoconstrictor.
  • the tumescent technique can be advantageously employed to deliver antibiotics and other agents to a surgical site or the sites of other medical procedures.
  • Some embodiments relate to tumescent antibiotic delivery (TAD) to areas of infection. TAD may be employed prophylactically to prevent an infection or TAD may be employed to treat an existing infection.
  • a large volume (> 1 L for example) of dilute antibiotic solution is provided to a site where antibiotic is needed, foregoing the disadvantages of systemic delivery ' .
  • the antibiotics for tumescent delivery ' may be provided in a solution of tumescent local anesthetic or without combination with local anesthetic.
  • TLAnti Tumescent Local Antibiotics
  • the anesthetic component may be comprised of a mixture of 2 or more anesthetics.
  • the vasoconstrictive component may be comprised of a mixture of 2 or more vasoconstrictors.
  • the antibiotic component may be comprised of a mixture of 2 or more antibiotics.
  • the anesthetic component may possess both anesthetic and antibiotic properties.
  • TLAnti may additionally comprise an antiviral and/or an antifungal component.
  • the TLAnti may comprise additional pharmacological agents, such as, but not limited to, anticonvulsants, stimulants, sedatives, antihistamines, retinoids, corticosteroids, calcium antagonists, chemotherapy agents, prostacyclins, and vasodilators.
  • additional pharmacological agents such as, but not limited to, anticonvulsants, stimulants, sedatives, antihistamines, retinoids, corticosteroids, calcium antagonists, chemotherapy agents, prostacyclins, and vasodilators.
  • TLAnti comprises a water-soluble antibiotic component.
  • the water-soluble antibiotic may be Cefazolm.
  • Cefazolin is a first generation cephalosporin that has been sold under the brand names Ancef and Kefzol. This medication is particularly effective against many varieties of gram-positive bacteria that are typically present on the epidermal surface such as Staphylococcus aureus. Antibiotic coverage for such ubiquitous organisms is particularly important in surgical procedures because they can enter the surgical site during the procedure and are therefore a likely cause of post-operative infection.
  • cefazolin is used at a dosage of approximately 250 to 750mg per liter of solvent.
  • cefazolin is used in 1 liter of TLAnti.
  • cefazolm may be used at a dosage of approximately lOOmg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, BOOnig, 850mg, or 9Q0mg per liter of solvent.
  • TLAnti may comprise a combination of two or more water-soluble antibiotics.
  • penicillins, cephalosporins, carbapenems, aminoglycosides, sulfonamides, qumolones, rnacroiides, tetracyclines, lipopetides and oxazolidinones may be used.
  • metronidazole is used m TLAnti.
  • Suitable antibiotics can be substituted m cases wherein a patient has a known or suspected hypersensitivity to a class of antibiotics, such as cephalosporins, or if the procedure is being performed in an area where resistance to a particular antibiotic is prevalent.
  • TLAnti may be used to treat an existing infection.
  • the infective agent may be determined and tested for antibiotic resistance.
  • the antibiotic or combination of antibiotics may be specifically selected based on the resistance profile of the bacterial flora.
  • antibiotics include, but are not limited to: amoxicillin, ampicillin, bacampicillin, carbenicillm, cloxacillin, dicloxacillm, flucloxacii!in, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, Piperacillin, Pivampicillin, Pivrnecillinam, Ticarei!lin, cefacetrile, cefadroxil, cephalexin, cefaloglycin, eefalonium, cefaioridine, cefalotin, cefamandole, cefapirin, cefatoxin, cefatrizme, cefazaflur, cephalexin, cefazedone, cefazolm, cefepime, cefradme, cefroxadine, ceftezole, cefaclor, cefomcid, cefprozil, cefuroxime, cefa
  • TLAnti may also comprise an anesthetic component.
  • the anesthetic component may comprise lidocaine.
  • !idocaine may be provided at a concentration of between 30mg and 1500mg per liter of solvent.
  • lidoeaine may be provided at a concentration of between 400mg and 1250mg per liter of solvent.
  • lidoeaine may be provided at concentrations of 30mg to 40mg, 40mg to 50mg, 50mg to 60mg, 60mg to 70mg, 70mg to 80mg, 80mg to 90mg, 90mg to lOOmg, lOOmg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 800mg, 800mg to 900mg, 900mg to l ,000mg, l,000mg to 1, lOOmg, 1, lOOmg to l,200mg, ! ,200mg to l ,300mg, l,300mg to l,400mg, l ,400mg to l ,500mg, and 500mg to l,000mg per liter of solvent.
  • anesthetics other than lidoeaine can be used.
  • Traditional local anesthetics include amide-type or ester-type local anesthetics.
  • Non- traditional anesthetics include neurotoxin-based local anesthetics.
  • anesthetics that are used in tumescent compositions include, but are not limited to saxitoxm, tetrodotoxm, benzocame, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, larocaine, propoxy caine, novocaine, proparacaine, tetracaine, amethocaine, articane, bupivacaine, carticaine, cmchocame, dibucaine, etidocaine, levobupivacaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecame. In some embodiments, combinations of two or more anesthetics may be used.
  • Suitable concentrations of anesthetic are approximately 30mg to 40mg, 40mg to 50mg, 50mg to 60mg, 60mg to 70mg, 70mg to 80mg, 80mg to 90mg, 90mg to lOOmg, lOOmg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to BOOmg, 800mg to 900mg, 900mg to l,000mg, l,000mg to 1, lOOmg, 1 , lOOmg to l ,200mg, l ,200mg to l,300mg, l,300mg to l,400mg, l,400mg to l ,500mg, and 500mg to l,000mg per liter of solvent.
  • the concentration of the anesthetic component can he varied depending on the sensitivity of the treatment area and the sensitivity of the patient to pain. If the TLAnti is to be used in sensitive areas such as the face or breasts, a higher concentration of anesthetic can be used. Lower concentrations of anesthetic can be used m the TLAnti solution for procedures in less-sensitive areas such as the hips.
  • Neurotoxins are a varied group of compounds, both chemically and pharmacologically. They vary in both chemical structure and mechanism of action, and produce ver distinct biological effects. Neurotoxins act on various ion channels, e.g., sodium, potassium, calcium and chloride channels. Neurotoxins acting on voltage-gated sodium channels can bind to six different sites in the channels, distinguished both by binding site(s) on the ion channels and by effect(s) of a toxin’s action.
  • ion channels e.g., sodium, potassium, calcium and chloride channels.
  • Neurotoxins acting on voltage-gated sodium channels can bind to six different sites in the channels, distinguished both by binding site(s) on the ion channels and by effect(s) of a toxin’s action.
  • Neosaxitoxin is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans (Lobo, K. et al. 2015 Anesthesiology 123(4): 873-885). Neosaxitoxin can be used in small doses.
  • Other neurotoxin-based local anesthetics include tetrodotoxin, saxitoxin and conotoxins, such as w -conotoxin (Prasanna, C. et al. (2014 Int J Anesthesiology Res 2: 11-15).
  • an anesthetic is efficacious for at least 6 hours, 12 hours, 1 8 hours, 24 hours, 30 hours, 36 hours or 48 hours.
  • a local anesthetic solution that can last for 2 days is ideal for treating certain types of conditions, e.g., Herpes zoster (shingles).
  • TLAnti may further comprise a vasoconstrictor component.
  • a vasoconstrictor serves two functions. The first is to control the otherwise substantial bleeding resulting from the removal of adipose or other tissue. The second is to control the systemic distribution of the anesthetic and antibiotic components of TLAnti from the subcutaneous fat compartment into the systemic circulation. This helps to concentrate these medications in the area where they are needed for a prolonged period of time, thereby enabling them to exert sufficient anesthetic and antibiotic effects in the surgical site post-operatively or at the site of infection.
  • the use of a vasoconstrictor limits the systemic absorption of other medications, which reduces the risk of sy stemic toxicity from elevated serum levels of these medications and thereby minimizes the risk of side effects.
  • the vasoconstrictor component is epinephrine.
  • Epinephrine may be provided at a concentration of ⁇ 1 mg/L.
  • epinephrine is present in a concentration of 0 4 to 1.2mg per liter of solvent.
  • epinephrine may be present in a concentration of 0.2 to 0.3mg, 0.3 to 0.4mg, 0.4 to 0.5mg, 0.5 to 0.6mg, 0.6 to Offing, 0.7 to 0.8mg, 0.8 to 0.9mg, 0.9 to Img, 1 to 1.1 mg, 1.1 to !
  • TLAnti solutions containing epinephrine would be manufactured with a moderately acidic pH in the range of 3.8 to 5.0 in order to optimize the shelf life of the TLAnti solution.
  • the TLAnti solution can be neutralized prior to subcutaneous infiltration by the addition of approximately 10-25 mEq of sodium bicarbonate.
  • vasoconstrictors other than epinephrine can be used in some embodiments of TLAnti.
  • suitable vasoconstrictors include, but are not limited to, methoxamine, metraminoi, ephedrine, noradrenaline, vasopressin, levonordefrin, prostaglandins, thromboxane A2, leukotriene D4, angiotensin II, neuropeptide Y, and endotheiin
  • TLAnti other constituents may optionally be present in the TLAnti.
  • bicarbonate can be present in the TLAnti. This helps to neutralize the otherwise acidic solution and reduce the burning sensation reported by many patients.
  • the TLAnti can further comprise perf!uorocarbons. An example can be found in United States Patent No. 6,315,756, the disclosures of which are incorporated in their entirety by reference thereto.
  • TLAnti can further comprise an anti-inflammatory component. Examples of anti-inflammatories include but are not limited to glucocorticoids and NSAIDS. Persons skilled in the art will note that there are a number of potential compounds that can be added to the TLAnti.
  • TLAnti comprises lidocaine as the anesthetic component.
  • Lidocaine has a synergistic effect with antibiotics m the prevention and/or treatment of infection at the surgical site. While primarily used as for anesthesia, lidocaine has also been found to have antibiotic properties. Lidocaine is well known to be bactericidal based on in-vitro studies although the precise mechanism has not been explained. Lidocaine is a trans-membrane anion (Na+, K+, Ca+) transport pump inhibitor in prokaryotic cells. Not to be bound by a particular theory, it is believed that lidocaine also acts as an antibiotic efflux pump inhibitor (inhibitor of multidrug resistant efflux systems in bacteria).
  • Lidocaine can thus act synergistically at the local tissue level when both lidocaine and an antibiotic are delivered directly into the targeted tissue using the tumescent drug delivery technique.
  • lidocaine By inactivating efflux pumps, lidocaine eliminates a mechanism of potential resistance to the cefazolin or other antibiotics used in TLAnti.
  • tumescent antibiotic delivery of antibiotics together with tumescent lidocame provides a unique therapeutic benefit in preventing and treating biofilm infections.
  • the IV delivery' of antibiotics is relatively ineffective against biofilm infections.
  • Tumescent delivery of pharmaceutical agents can provide a highly localized and sustained dosage of the pharmaceutical agent to the delivery site.
  • use of the tumescent technique to deliver TLAnti can provide a high, sustained dosage of antibiotics directly to a surgical site.
  • IV intravenous
  • the concentration of the antibiotic drug and the local anesthetic drug within the TLAnti (which equals the maximum concentrations of these drugs within the tissues infiltrated with the TLAnti) far exceed the concentrations of these drugs which can be safely achieved by intravenous delivery.
  • the concentration of antibiotic in the subcutaneous tissue at the surgical site may be three times or more than the measured maximum serum concentration of the same drag when administered intravenously prior to the procedure.
  • Another advantage is that the therapeutic dosage of antibiotics at the surgical site lasts significantly longer with tumescent administration of TLAnti as compared to IV antibiotics. The result is that any bacteria present at the surgical site are exposed to a higher dosage of antibiotics for a longer period of time when TLAnti is used in place of IV antibiotics.
  • the bioavailability and effectiveness of an antibiotic can be assessed using the area under the curve (AUC) measurement of the tissue-concentration of the antibiotic as a function of time.
  • AUC area under the curve
  • the serum-antibiotic AUC may be more than 100 times greater than the serum-antibiotic AUC following tumescent antibiotic delivery.
  • the subcutaneous tissue-antibiotic AUC following the IV delivery of an antibiotic is less than 1/100th the tissue-antibiotic AUC following tumescent antibiotic delivery.
  • the peak serum concentrations of an antibiotic is higher after IV infusion compared to tumescent antibiotic, while the peak tissue concentration of antibiotic is lower after IV infusion compared to tumescent antibiotic. Tumescent antibiotic delivery produces significantly lower systemic concentrations of antibiotic while at the same time the local tissue concentration of antibiotic at the site of tumescent antibiotic infiltration is dramatically higher than that which can be achieved by IV antibiotic delivery.
  • Some embodiments relate to a method of using TLAnti during various surgical procedures. For example, in a liposuction procedure, a therapeutic quantity of TLAnti is injected into the subcutaneous compartment. Once sufficient anesthesia is achieved, another cannula is inserted and adipose tissue removed. The cannula is subsequently removed and the surgical site dressed and/or closed as appropriate. The high levels of antibiotics that remain for some period of time in the surgical site can reduce the risk of postoperative infection. Similarly, a large number of general surgical procedures including, but not limited to, open gastrointestinal surgery, obstetric surgery, orthopedic surgery, and vascular surgery are appropriate for the use of subcutaneous TAD.
  • Some embodiments relate to methods for using tumescent solutions in the subcutaneous space to treat a variety of medical conditions where systemic administration of medications is undesirable or impossible.
  • Various embodiments include, but are not limited to, methods for using tumescent solutions as an anesthetic for medical procedures by clinicians, methods for using tumescent solutions in the administration of fluids to patients by medical professionals and first responders, methods for using tumescent antibiotic solutions to prevent and/or treat infections, methods for providing a chemotherapy agent to tissue after tumor removal and methods for using tumescent solutions in the controlled release of antibiotics and other pharmaceutical agents.
  • Tumescent administration of anesthetics, antibiotics, vasoconstrictors, and/or other pharmaceutical agents can improve the outcome of surgical procedures to remove tumors.
  • Tumors may be benign or malignant, cancerous. Benign tumors are well circumscribed and are generally treated by surgery alone. Malignant/cancerous tumors on the other hand are more difficult to treat. When malignant tumors are localized, surgical removal is a common treatment option. Approximately 40% of all cancers are treated with surgery alone. In most other cases where surgery is an option, it is combined with other treatments—usually radiation therapy or chemotherapy.
  • One danger of the surgical removal of malignant tumors is the possibility of spreading or seeding the cancerous cells during the process of removing the tumor.
  • Tumescent delivery of a vasoconstrictor to the surgical site can reduce the risk of malignant cells entering the bloodstream.
  • the tumescent technique may also be used to locally deliver chemotherapy agents. Local administration of chemotherapy agents allows for higher localized dosages of the chemotherapy agents than would be tolerated systemically and a reduction of adverse side effects.
  • chemotherapy agents include, but are not limited to: actinomycin D, adriamycin, alkeran, ara-C, arsenic trioxide (trisenox), avastin, BiCNU, busulfan, carboplatinum, CCNU, cisplatinum, cytoxan, daunorubicin, DTIC, 5 ⁇ FU, eriotinib, fludarabme, gemcitabine, herceptin, hydrea, idarubicin, ifosfamide, irinoteean, lapatinib, leustatm, 6-MP, methotrexate, mithramycin, mitomycin, mitoxantrone, navelbine, nitrogen mustard, rituxan, 6-TG, taxol, taxotere, topotecan, velban, vincristine, VP-16, and xeloda.
  • angiogenesis inhibitors may also be tumescently delivered.
  • angiogenesis inhibitors include, but are not limited to, angiostatin, endostatin, and tumstatin.
  • the tumescent solutions can be premixed and packaged prior to being sent to the provider.
  • one or more components of the tumescent solution can be added shortly before or during the medical procedure wherein they are to be used.
  • the bulk of the tumescent solution comprises a physiologically compatible solvent.
  • solvents can include, for example, saline solution comprising sterile water and 0.9% sodium chloride. More dilute saline solutions can also be used.
  • a laetated Ringer’s solution may be used. This comprises a mixture of sterile water, sodium, chloride, lactate, potassium and calcium that is isotonic with blood. Hartmann’s solution can also be used as a solvent in some embodiments. Individuals skilled in the art will recognize that there are a wide variety of possible biologically compatible solvents for use in the solution.
  • tumescent solution may be provided as a kit.
  • the tumescent solution is TLAnti.
  • TLAnti can be pre mixed at a manufacturing site and distributed to practitioners in a ready to use form.
  • the TLAnti can be packaged in a form that allows easy interface with a tumescent reservoir or pumping system.
  • packaging can come in a variety of sizes: however typical kits would include one liter or more of tumescent solution.
  • the tumescent solution may require rehydration or dilution to an administrable concentration.
  • a kit can comprise a one liter solution of .9% normal saline, 500mg of cefazolin, 500mg lidocaine 2%, I mg epinephrine, lOmEq bicarbonate.
  • concentration of lidocaine can be used depending on the intended clinical use.
  • embodiments comprising higher dosages of lidocaine, optionally buffered with additional bicarbonate can be used when a procedure is to be performed in a sensitive area.
  • Variations on the type and concentration of antibiotic component are also possible.
  • Some embodiments can also include various concentrations of epinephrine or different types of vasoconstrictors. Persons skilled in the art will recognize that many standardized variations are possible and the above example should not be deemed to be limiting.
  • the tumescent solution or components for preparing the tumescent solution can be packaged along with a set of cannula, tubing and possibly other surgical instruments for performing liposuction.
  • kits can include an appropriate mix of tumescent solution components for the body part where the procedure is to be performed along with appropriately sized, sterile instruments.
  • the sterile instruments are capable of interacting with standardized liposuction equipment (i.e., peristaltic pumps, adipose tissue receptacles, etc.).
  • Kits for TLAnti use in mastectomy procedures can be prepared comprising the tumescent solution along with any appropriate instruments.
  • the tumescent solution can be provided in prefilled tumescent reservoir bags.
  • Such bags could be manufactured by a pharmaceutical company and be sold as“ready to use.”
  • Manufactured tumescent delivery bags are a more efficient and economical use of hospital staff than having to custom mix the tumescent solution for each surgical patient.
  • commercially produced prefilled tumescent reservoir bags would eliminate pharmacist error in mixing and preparing tumescent solution.
  • a TLAnti solution is provided in a prefilled tumescent reservoir bag comprising a dilute solution of local antibiotic such as lidocame ( ⁇ 1 g/L) or other water soluble antibiotic and a vasoconstrictor, such as epinephrine ( ⁇ 1 mg/L) in a physiologic electrolyte solution sodium chloride.
  • TLAnti solutions containing epinephrine can be manufactured at a moderately acidic pH to optimize epinephrine stability.
  • the TLAnti solution can be neutralized prior to administration by the addition of approximately 10-25 mEq of sodium bicarbonate. An appropriate amount of sodium bicarbonate can be included for addition to the prefilled tumescent reservoir bag.
  • TLAnti solution is safe when infiltrated into subcutaneous tissue; rapid, systemic infusion of TLAnti may be lethal. There is thus a need to prevent inadvertent IV administration of tumescent solutions.
  • Various safety features may be incorporated into the prefilled tumescent reservoir hags. Tumescent reservoir bags can be designed to be readily distinguishable from standard IV bags. Distinguishing features include, but are not limited to, unique shape, color-coding, and/or printed warnings.
  • tumescent reservoir bags may be provided as kits in conjunction with a non-standard (non-luer) connector system to prevent inadvertent connection to an IV line.
  • Tumescent solution can be injected into the subcutaneous space during surgical procedures using a variety of infiltration cannula that are well known to persons skilled in performing surgical procedures.
  • the TLAnti can be injected into the treatment area using an infiltration cannula comprising a flexible cannula, a hub, and a rigid stylet.
  • the flexible cannula has a proximal end and a distal end.
  • the flexible cannula can also have a plurality of apertures disposed in a pattern about the distal end. The apertures are configured to infiltrate fluid into the subcutaneous tissue of a patient.
  • the hub is configured to be held by a person performing the infiltration procedure.
  • the hub has a first end and an opposing second end.
  • the first end is attached to the proximal end of the flexible cannula and the second end includes a connector configured to connect to an input source for receiving the fluid to be infiltrated into the subcutaneous tissue of the patient.
  • the fluid flows from the connector, through the hub and into the flexible cannula.
  • the tumescent solution can also be delivered via a disposable catheter that can be used in emergency situations or under conditions when establishing intravenous access is difficult or impossible.
  • the tumescent solution can be injected into the subcutaneous space via a flexile cannula with a rigid stylet that can be fabricated from stainless metal or rigid plastic.
  • the distal end of the cannula can be closed to cover the tip of the rigid stylet or open with a hole allowing the tip of the rigid stylet to protrude.
  • the tip of the rigid stylet can be sharp to facilitate the direct insertion through the skin of the patient.
  • the stylet can be formed to have either a solid or hollow cross-sectional configuration.
  • the hollow rigid stylet may have small holes distributed along its length in a pattern dissimilar or identical to the patern of holes placed along the flexible cannula into which the stylet is inserted.
  • the stylet itself can be used as an infiltration cannula.
  • Tumescent Infiltration Lidocaine Anesthesia has the ability to:
  • systemic lidocame attenuates activity of inflammatory mediator associated with innate immunity and thus reduce the risk of sepsis and systemic inflammatory response syndrome.
  • the tumescent technique may be used to treat localized viral infections. Surprisingly, while some antibiotics and antiviral agents are not recommended for subcutaneous use, the tumescent technique allows such agents to be safely used at relatively high, localized therapeutic dosages. For instance, the antibiotic gentamycin and the antiviral compound Acyclovir, which is commonly used to treat infections caused by herpes viruses, such as genital herpes, cold sores, shingles, and chicken pox, are not recommended for subcutaneous administration.
  • the tumescent technique is amenable to treatment of localized viral infection, such as for treatment of viral diseases related to herpes virus (including Herpes Simplex I, Herpes Simplex II, herpes zoster (shingles), herpetic conjunctivitis, keratitis, and genital herpes).
  • Herpes Simplex I Herpes Simplex II
  • herpes zoster herpetic conjunctivitis
  • keratitis heratitis
  • genital herpes Other types of localized viral infection include Molluscum Contagiosum, a common skin infection caused by a pox virus that affects both children and adults and Kaposi's sarcoma (KS), a connective tissue cancer caused by human herpes virus 8.
  • a non-exhaustive list of antiviral agents used to treat localized viral infection includes: Abacavir, Acyclovir, Adefovir, Amantadine, Amprenavir, Ampligen, Arbidol, Atazanavir, Atripla, Balavir, Brivudine, Cidofovir, Combivir, Dolutegravir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Eeoliever, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Ganciclovir, Ibaeitabme, Imunovir, Idoxuridine, Imiquimod, Interferon type I, Interferon, Lamivudine, Lopinavir, Loviride, Maraviroc, Mor
  • the subcutaneous concentration of the antiviral agent achieved is simultaneously; (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (li) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the antiviral agent.
  • the subcutaneous concentration of the antiviral agent achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the antiviral agent.
  • Acyclovir is used at a diluted concentration of 0.1 g/L-10 g/L, preferably 0.5g/L ⁇ 5g/L, more preferably l-2g/L, or at Ig/L.
  • Gentamycm is used at a diluted concentration of 0.1 mg/L-lg/L, preferably 50-800 mg/L, more preferably 50-200 mg/L or at 80 mg/L.
  • a tumescent composition used to treat localized viral infection typically contains an antiviral component and a vasoconstrictor.
  • the tumescent composition may optionally comprise other components, such as antibiotic, anesthetic and anti inflammatory components.
  • VZV Varicella-zoster virus
  • varicella chickenpox
  • herpes zoster shingles
  • Varicella is highly contagious. It initially enters the host by penetrating the respirator ⁇ ' epithelium causing viremia and the classic vesicular chickenpox rash. From the skin, VZV migrates within cutaneous sensory neurons to arrive at sensoiy dorsal root ganglia (DRG). As the host develops a cellular immunity involving CD4 & CDS cells and a serologic immune response, the rash subsides and the VZV virus within the ganglion becomes latent.
  • DDG sensoiy dorsal root ganglia
  • the latent VZV can reactivate, proliferate and migrate along a sensory nerve from the dorsal root ganglion toward the skin of the corresponding dermatome.
  • H zoster The initial manifestation of H zoster is abrupt onset of localized pain that extends over the next few days within a localized unilateral area of skin spanning 1 to 3 adjacent dermatomes. Patients often attribute the acute onset of the pain to be the result of muscle strain, back-muscle spasm, or a bacterial infection. Within 2-4 days there is the onset of. The host’s immune response produces an intense inflammatory reaction with a potential for permanent sensor ⁇ nerve injury. [0230] The area and intensity of painful skin tends to enlarge over the next 2 to 3 days.
  • Zoster pain is intense, and has 3 clinically distinct components: a deep burning unremitting pain, sporadic acute sharp lancinating pain, and a paresthetic pain that is elicited by light touch or temperature change (mechanical aliodynia).
  • Post herpetic neuralgia is the most common and perhaps the most dreaded complication of Herpes zoster. PHN is defined as pain that persists for more than 3 months after acute herpes zoster. PHN often does not respond well to narcotics or other analgesics. The incidence of post herpetic neuralgia (PHN) is approximately 10%, but among patients with hematologic malignancy it is at least 48%.
  • Herpes zoster patients with greater pain and rash severity have greater risk of PHN. This suggests that greater neural damage (caused by more severe acute infection) contributes to risk of PHN. Indeed, acute pain seventy is a major risk factor for PHN (Dworkin RH, Boon RJ, Griffin DRG. Postherpetic neuralgia: Impact of Famciclovir, age, rash severity and acute pain in Herpes zoster patients. JID 1998; 178 (Suppl) S76-S80). Current approaches to acute zoster pain rely on aggressive analgesic intervention that merely attenuates zoster pain.
  • TI acyclovir tumor lidocame and acyclovir
  • TTAR tumescent therapeutic ambit range
  • PHN is a neuropathic pain that is resistant to treatment, preventing PHN is of prime importance.
  • TI of acyclovir delivers unprecedented high and prolonged subcutaneous concentrations of lidocame, eliminates 100% of pam for up to 12 hours or more without repeat dosing and thus reduces the risk of neuropathic pam and PHN.
  • Tumescent lidocaine+ acyclovir is more effective than IV acyclovir at reducing the risk of
  • the zoster blister contains large amounts of infectious VZV viral particles.
  • the risk of severe H. zoster and the risk of PHN are closely correlated with the intensity of the host’s secondary inflammatory immune response to VZV, the degree of pathologic damage to sensory nerves, the total area of blistering, the intensity and duration of epidermal necrosis, and the intensity and duration of acute pain.
  • Antiviral drugs do not provide anesthesia and do not eliminate acute zoster pain.
  • the intensity and duration of any acute pain increases the risk of a permanent neuropathic pain syndrome.
  • PHN is an example of neuropathic pain.
  • Acyclovir, vaiacyclovir and famciclovir treat certain, but not all, aspects of H. zoster. They reduce the intensity and duration of zoster pain and decrease the risk of developing PHN.
  • Tumescent iidocaine + acyclovir can both eliminate 100% of pain (for hours) and can decrease viral replication rate and the extent and intensity.
  • the risk factors that have been shown to increase the incidence of PHN include: a) increasing age, b) intensity of pain upon initial presentation, c) duration of pain upon initial presentation, d) extent of the H. zoster rash upon presentation, e) intensity of pain one week after initiating antiviral therapy, f) progression of pain one week after initiating antiviral therapy and g) progression of dermatitis one week after initiating antiviral therapy.
  • An important embodiment of the present invention is the safe and effective subcutaneous infiltration of an antiviral agent for the treatment of Herpes zoster.
  • Herpes Zoster or Shingles is an unusually painful disease caused by 7 the varicella zoster virus that affects one million people in the United States annually. Among persons 85 years of age or older, 50% will eventually have herpes zoster. H. zoster can progress into chronic, potentially devastating, post-herpetic neuralgia (PHN).
  • Methods disclosed herein involve the subcutaneous infiltration of a tumescent solution of dilute lidocaine and epinephrine and one or more zoster-specific antiviral drugs (e.g. acyclovir) and/or a broad-spectrum antiviral (e.g., cidofovir), with or without anti-inflammatory drugs (e.g., steroidal anti-inflammatory drugs such as triamcinolone, non-steroidal anti-inflammatories)), and with or without sodium bicarbonate.
  • zoster-specific antiviral drugs e.g. acyclovir
  • a broad-spectrum antiviral e.g., cidofovir
  • anti-inflammatory drugs e.g., steroidal anti-inflammatory drugs such as triamcinolone, non-steroidal anti-inflammatories
  • the antiviral drugs acyclovir (Zovirax®), valacycfovir (Valtrex ⁇ ) and famcyclovir (Farnvir®) effectively treat H. zoster. Only Acyclovir is available for IV deliver ⁇ ' . At present, oral deliver ⁇ ? is considered sufficient for most cases of H. zoster. IV delivery is usually reserved for patients requiring hospitalization, for example disseminated H.
  • zoster in immunocompromised hematopoetic transplant patients or HIV (AIDS) patients, severe forms of zoster such as herpes zoster ophthalmicus that can cause blindness, herpes oticus (Ramsay-Hunt syndrome) which can cause unilateral facial paralysis and/or permanent hearing loss, CNS zoster and Zoster pneumonia.
  • herpes zoster ophthalmicus that can cause blindness
  • herpes oticus RVamsay-Hunt syndrome
  • CNS zoster and Zoster pneumonia the sooner treatment begins, the less severe the intensity of the rash and pain and the shorter its duration.
  • Subcutaneous tumescent drug delivery of acyclovir and lidocaine typically eliminates 100% of acute zoster pain for 12 hours or more. This is unique among ail forms of Herpes zoster treatments. Using an elastomeric pump to provide continuous subcutaneous infiltration, TI-acyclovir can eliminate zoster pain for days.
  • Tumescent infiltration can also be used to treat local and systemic fungal infections.
  • a partial list of antifungal drugs includes:
  • Polyenes amphotericin B, candicidin, Filipin, Hamycin, Natamycin, Nystatin and Rimocidin;
  • Imidazoles Bifonazole, Butoconazole, Clotrimazole, Econazole, Fentieonazoie, Isoconazole, Ketoconazole, Luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, Sulconazole and Tioconazole;
  • Triazoles Albaconazole, Efmaeonazole, Epoxiconazo!e, Fluconazole, Isavuconazole, Itraconazole, Posaconazole, Propiconazole, Ravuconazole, Terconazole and Voriconazole;
  • Tumescent infiltration can also be used to treat local and systemic protozoa infections.
  • a partial list of antiprotozoal drugs includes: Antinematodes: Mebendazole, Pyrantel pamoate, Thiabendazole, Diethylearbamazine, and Ivermectin;
  • Anticestodes Niclosamide, Praziquantel, and Albendazole;
  • Antitrematodes Praziquantel
  • Antiamoebics Rifampin and Amphotericin B;
  • Antiprotozoals Melarsoprol, Efl ornithine, Metronidazole, Timdazole and Miltefosine.
  • Neuropathic pain is a complex, chronic pam state that is generally accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves might be damaged, dysfunctional, or injured. These damaged nerve fibers send incorrect signals to other pain centers.
  • the clinical causes of neuropathic pain are diverse and include both trauma and disease. For example, traumatic nerve compression or crush and traumatic injury to the brain or spinal cord are common causes of neuropathic pain. Furthermore, most traumatic nerve injuries also cause the formation of neuromas, in which pam occurs as a result of aberrant nerve regeneration.
  • cancer-related neuropathic pain is caused when tumor growth painfully compresses adjacent nerves, brain or spinal cord.
  • Neuropathic pam can be caused by various diseases, such as viral infections and diabetes and alcoholism. For example, post herpetic neuralgia is caused by herpes viral infection and can cause moderate to severe chronic pain in the infected skin area to the subject.
  • neuropathic pain often do not provide adequate pain relief.
  • current therapies have serious side-effects including, for example, cognitive changes, sedation, nausea and, in the case of narcotic drugs, addiction.
  • Many patients suffering from neuropathic pain are elderly or have other medical conditions that particularly limit their tolerance of the side-effects associated with available drug therapy.
  • a number of anti-inflammatory, anxiolytic, narcotic and even anti-convulsants are currently used by the practitioners to treat neuropathic pain, but with limited success.
  • SSRIs serotonin reuptake inhibitors
  • other antidepressants ven!afaxine, bupropion
  • Another common treatment of neuropathic pain includes anti-seizure medications (carbamazepine, phenytoin, gabapentin, lamotrigine, and others).
  • Pregabalin and duloxetine can also be effective for nerve pain. Like amitriptyline, they may be given alongside other pain medications in the most troublesome nerve pain conditions.
  • Duloxetme is licensed for pain from nerve damage resulting from diabetes, which most often starts in the feet.
  • Neuropathic pain may be brought on by trauma, disease or irritation. There are countless types of neuropathic pain. Some of the common types include:
  • Postherpetic neuralgia is neuropathic pain that is brought on by an outbreak of shingles, and persists after the condition has cleared.
  • Trigeminal neuralgia is characterized by shooting neck and facial pam. The pam is often worse with light touch, and may make activities like shaving very painful.
  • Phantom limb pain can occur in some people after a limb is amputated. This pain feels as if it is coming from part of the limb that is no longer there.
  • Diabetic neuropathy causes burning or stabbing pain in the hands and feet of some people who suffer from diabetes.
  • Carpal tunnel syndrome is caused by nerve compression in the wrists, and causes pain in the wrist, thumb and fingers.
  • Sciatica is caused by compression or irritation of the sciatic nerve, and often results in shooting pain that radiates down the back of leg.
  • Chronic neuropathic pain can also be caused by other chrome pain disorders. For instance, someone with degenerative disk disease, a form of arthritis, may experience neuropathic back pain if the condition causes damage to the nerves entering or exiting the spine. Some other conditions that may cause chronic neuropathic pain include spinal cord injury, post-surgical pam and cancer.
  • the subcutaneous concentration of drug achieved is simultaneously: (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drug.
  • the subcutaneous concentration of the drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the drag.
  • the tumescent technique allows anti inflammatory agents to be safety administered at relatively high concentrations.
  • anti-inflammatories include but are not limited to glucocorticoids and non-steroidal anti inflammatory drugs (NSAIDS).
  • NSAIDS non-steroidal anti inflammatory drugs
  • Example glucocorticoids include triamcinolone, dexamethsasone, prednisolone, methylprednisolone, budesonide betamethasone, hydrocortisone and cortisone.
  • Example NSAIDS include Aspirin (Anacin®, Ascnptin®, Bayer®, Bufferm®, Ecotrin®, Excedrin®); choline and magnesium salicylates (choline magnesium trisalicylate (CMT), Tricosal®, Trilisate®); Choline salicylate (Arthropan®); Celecoxib (Celebrex®); Diclofenac potassium (Cataflam®); Diclofenac sodium (Voltaren®, Voltaren XR®); Diclofenac sodium with misoprostol (Arthrotec®); Diflumsal (Dolobid®); Etodolac (Lodine®, Lodine XL®); Fenoprofen calcium (Nalfon®); Flurbiprofen (Ansaid®); Ibuprofen (Advil®, Motrin®, Motrin IB®, Nuprin®); Indomethacin (Indocin®, Indocin , Indoc
  • glucocorticoids remain at the forefront of anti inflammatory and immunosuppressive therapies. They are widely used to treat both acute and chronic inflammations, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis and eczema, as well as being used in treatment of certain leukaemias and in immunosuppressive regimes following organ transplant.
  • the anti inflammatory effects are mediated either by direct binding of the glucocorticoid/glucocorticoid receptor complex to glucocorticoid responsive elements in the promoter region of genes, or by an interaction of this complex with other transcription factors, in particular activating protein- 1 or nuclear factor-kappaB.
  • Glucocorticoids inhibit many inflammation-associated molecules such as cytokines, ehemokines, arachidomc acid metabolites, and adhesion molecules.
  • NSAIDs comprise a large class of drugs with many different options.
  • Ibuprofen e.g. brand names Advil®, Motrin®, Nuprin®
  • Naproxen e.g. brand names Aleve®, Naprosyn®
  • COX-2 inhibitors e.g., Celebrex®
  • Tumescent drug delivery provides both local tissue effects and systemic effects.
  • the concentration of the drug within the tumescent solution for example, a cannabinoid
  • the primary intended effect of TDD of a drug may be a systemic effect.
  • the TDD of a cannabinoid provides a subcutaneous depot of the cannabinoid, wherein the cannabinoid is slowly absorbed into the systemic circulation over a prolonged interval of time for up to 48 hours or more.
  • the specified concentration of the cannabinoid within the tumescent solution can intentionally exceed the range of cannabinoid concentrations that are effective within local subcutaneous tissue.
  • the maximal concentration of a cannabinoid within any tumescent solution should never exceed the clinically defined threshold for local tissue toxicity.
  • the maximal total milligram dose of a cannabinoid should never exceed the clinically defined threshold for systemic toxicity.
  • cannabinoids readily mixed into water, either as a suspension or a true solution, after soaking in cold water, or being soaked in hot water as a“cannabinoid tea”.
  • a“aqueous tea solution” is pharmacologically active when delivered orally for systemic effect.
  • a sterile aseptic cannabinoid tea can be added to a tumescent solution for local or systemic effect.
  • Cannabinoid receptors include CBl, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system.
  • CBl and CB2 receptors have been found on immune ceils suggests that cannabinoids play an important role in the regulation of the immune system.
  • Administration of THC into mice triggers marked apoptosis in T ceils and dendritic cells, resulting in immunosuppression.
  • cannabinoids down regulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses.
  • the endocannabmoid system is also involved in immunoregulation.
  • endocannabinoids For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endoeannabinoids, leads to immunosuppression and recovery from immune-mediated injury to organs such as the liver.
  • Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo is a potent treatment modality against inflammatory disorders.
  • Cannabinoids are hydrophobic oily substances and, as such, not water-soluble. They can, however, be formulated to be water-compatible and appear w3 ⁇ 4ter ⁇ soluble.
  • CBD eannabidiol
  • THC tetrahydrocannabinol
  • w3 ⁇ 4ter-soluble CBD has lately been extensively used throughout the medical cannabis industry.
  • Water-soluble means able to homogeneously incorporate into water by separating into molecules or ions (dissolve like sugar, alcohol or salt). Oily substances, however, are repelled by water, which forces them to stay separate from it.
  • Hydrophobic cannabinoids can be made water compatible if they are formulated as micro- or nanoemulsions, which are stable and visually homogeneous oil/water mixtures. Both micro- and nanoemulsions can be prepared in concentrated forms that are fully miscible with water and, therefore, appear water-soluble. Both require the use of surfactants, which dilute the products, but are not otherwise a major concern, since several natural options are available with minimal negative effects. It is, of course, beneficial to use as little surfactants as possible. This is where nanoemulsions have a clear advantage: the amounts of surfactants used for their preparation are up to 10 times lower that those needed to make microemulsions.
  • cannabis extract nanoemulsions provide exceptionally high bioavaiiability and therapeutic effect, and are absorbed by the body, e.g., subcutaneously, very rapidly and completely. This means higher potency and faster onset of action for lower doses. See e.g., the internet ati. blog.sonomechanics.com/blog/water-soluble ⁇ cbd.
  • hydrophobic cannabinoids such as CBD THC
  • CBD THC can be rendered water-soluble by derivatization.
  • the alkyl side chain and/or the phenolic hydroxyl group of tetrahydrocannabinol can be derivatized.
  • Water-soluble cannabinoids are useful for various treatments including treatment of inflammation, cancer, post-traumatic stress and related conditions, appetite loss, pain, multiple sclerosis, nausea and vomiting, and epilepsy.
  • Preferred water-soluble eannabinoid compounds for tumescent delivery have high CB1 and CB2 receptor affinity' and high bioavailability.
  • Structural alterations in tetrahydrocannabinol increase its water solubility and/or miscibility.
  • structural alterations By making structural alterations m the alkyl side chains and at the phenolic hydroxyl group of tetrahydrocannabinol, a series of analogs can be made that are soluble and/or miscible in water, and which show high bioavailabihty, as summarized in U.S. Application Publication No. 2008/0064679, for example.
  • the analogs exhibit high affinity for the CB1 and CB2 receptors, and are thus water-soluble eannabinoid agonists.
  • the compounds are useful for treating diseases and disorders related to CB1 and CB2 receptor function, including inflammation, appetite loss, nausea and vomiting, pain, multiple sclerosis and epilepsy.
  • Water-soluble cannabinoids may be provided as a salt (e.g. HCi, iodine, ammonia, sulfates, tartrates, succinates, quaternary salts, etc.).
  • a salt e.g. HCi, iodine, ammonia, sulfates, tartrates, succinates, quaternary salts, etc.
  • any salts of the compounds may be used, so long as the salt retains water solubility.
  • Water-soluble cannabinoids may be synthesized based on two approaches to modification of tetrahydrocannabinol: structural alterations in: 1) the alkyl side chains; and 2) at the phenolic hydroxyl group.
  • the resulting analogs are soluble and/or miscible in water, show high bioavailability, and exhibit high affinity for the CB1 and CB2 receptors (i.e., they are eannabinoid agonists.)
  • water-soluble applies to compounds in which at least 0.2 mg, 0.3 mg, 0.4mg, 0.5 mg, 0.6 rng, 0.7 mg, 0.8 rng, 0 9 mg or 1 mg of material, when dissolved in 1 ml of water, gives a clear solution and is water miscible.
  • the total dosage of a drug such as a eannabinoid may be in the range of 1 pg/kg to 2,000 pg/kg.
  • the dosage of cannabinoid administered tumescently is in the range of 10- 1500 pg/kg, 10-1000 pg/kg, 10-700 pg/kg, 10-300 pg/kg or 100-300 pg/kg.
  • “High affinity” compounds exhibit a Ki in the range of about 0 03 nM to about 80 nM, and preferably from about 0.03 nM to about 50 nM, for either the CBl or CB2 receptors, or both.
  • the subcutaneous concentration of the anti-inflammatory drug achieved is simultaneously: (i) below r the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the anti-inflammatory drug.
  • the subcutaneous concentration of the anti inflammatory drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 1 10%, 1 15%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the anti-inflammatory drug.
  • Treating a localized cancer or reducing the growth of a tumor by localized delivery of a cancer medication can be achieved by using the tumescent technique.
  • Using chemotherapy to treat cancer typically has unpleasant side effects.
  • the toxic effects of the medication affect healthy cells, as well as those of the tumor itself. This leads to symptoms like nausea, hair loss or reduced effectiveness of the immune system.
  • the tumescent technique allows higher doses of medication to be used, while the rest of the patient's body remains unaffected.
  • Chemotherapy agents are selected based on the type of cancer, the stage of the cancer (how far it has spread), the patient’s age, the patient’s overall health, other serious health problems (such as heart, liver, or kidney diseases) and the types of cancer treatments given in the past.
  • Chemotherapy regimens or treatment plans may use a single drug or a combination of drugs, which may be more effective than a single drug, because the cancer cells can be attacked in several different ways.
  • Alkylating agents directly damage DNA (the genetic material in each cell) to keep the cell from reproducing.
  • DNA the genetic material in each cell
  • These drugs work in all phases of the cell cycle and are used to treat many different cancers, including leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary. Because these drugs damage DNA, they can cause long-term damage to the bone marrow. In rare cases, this can lead to acute leukemia.
  • the risk of leukemia from alkylating agents is“dose-dependent,” meaning that the risk is small with lower doses, but goes up as the total amount of the drug used gets higher.
  • the risk of leukemia after getting alkylating agents is highest about 5 to 10 years after treatment.
  • Alkylating agents are divided into different classes, including: Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan; Nitrosoureas: such as streptozocin, carmustme (BCNU), and lomustine; Alkyl sulfonates: busulfan; Triazmes: dacarbazine (DTIC) and temozolomide (Temodar®); and Ethylenimines: thiotepa and altretamine (hexamethylmelamme).
  • Nitrogen mustards such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan
  • Nitrosoureas such as streptozocin, carmustme (BCNU), and lomustine
  • the platinum drugs (such as cisplatin, carboplatin, and oxalaplatin) are sometimes grouped with alkylating agents because they kill cells in a similar way. These drugs are less likely than the alkydating agents to cause leukemia later.
  • Antimetabolites interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. These agents damage cells during the S phase, when the cell’s chromosomes are being copied. They are commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer.
  • antimetabolites include: 5-fluorouracil (5-FU), 6- mercaptopunne (6-MP), Capecitabine (Xeloda®), Cytarabine (Ara-C®), Fioxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxyurea, Methotrexate and Pemetrexed (Alimta®).
  • Anthracyc!ines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. Examples of anthracyclines include: Daunorubicin, Doxorubicin (Adriamycin®), Epirubicin and Idarubiein. A major concern when giving these drugs systemieal!y is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs. However, with the tumescent technique, this problem is avoided.
  • Anti-tumor antibiotics that are not anthracyclines include: Actinomycin- D, Bleomycin, Mitomycin-C, and Mitoxantrone (also acts as a topoisomerase II inhibitor).
  • Topoisomerase inhibitors are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Topoisomerase inhibitors are grouped according to which type of enzyme they affect.
  • Topoisomerase I inhibitors include Topotecan and Irinotecan (CPT-1 1).
  • Topoisomerase II inhibitors include Etoposide (VP- 16), Teniposide and Mitoxantrone (which also acts as an anti-tumor antibiotic).
  • Topoisomerase II inhibitors can increase the risk of a second cancer - acute myelogenous leukemia (AML) - as early as 2 to 3 years after the drug is given.
  • AML acute myelogenous leukemia
  • Mitotic inhibitors are often plant alkaloids and other compounds derived from natural products. They work by stopping mitosis in the M phase of the cell cycle but can damage cells in all phases by keeping enzymes from making proteins needed for cell reproduction.
  • mitotic inhibitors include: Taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®); Epothilones: ixabepilone (Ixempra®); Vinca alkaloids: vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®); and Estramustine (Emeyt®). They are used to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs may cause nerve damage, which can limit the amount that can be given. Corticosteroids
  • Corticosteroids often simply called steroids, are natural hormones and hormone-like drugs that are useful in the treatment of many types of cancer, as well as other illnesses. When these drugs are used as part of cancer treatment, they are considered chemotherapy drugs. Examples of corticosteroids include: Prednisone,
  • Methylprednisoione Solumedroi ⁇
  • Dexamethasone Dexamethasone
  • Some chemotherapy drugs act in slightly different ways and do not fit well into any of the other categories. Examples include drugs like L-asparaginase, which is an enzyme, and the proteosome inhibitor bortezomib (Velcade®).
  • a localized cancer is usually found in the tissue or organ where it began, and has not spread to nearby lymph nodes or to other parts of the body, or the spread is limited in scope.
  • Non-limiting examples of localized cancers include single-lesion skin cancers, solitary pulmonary nodules (single lung tumor), Adrenal Cancer, Anal Cancer, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain/CNS Tumors In Adults, Brain/CNS Tumors In Children, Breast Cancer, Breast Cancer In Men, Cancer in Adolescents, Cancer in Children, Cancer m Young Adults, Cancer of Unknown Primary, Cast] e an Disease, Cervical Cancer, Colon/Rectum Cancer, Endometrial Cancer, Esophagus Cancer, Ewing Family Of Tumors, Eye Cancer, Gallbladder Cancer, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumor (GIST), Gestational Trophoblastic Disease, Hodgkin Disease, Kaposi Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngea!
  • localized cancers suitable for treatment by tumescent delivery of a chemotherapy drug include: Pancreatic cancer. Ovarian cancer, Lung cancer. Breast cancer. Liver cancer. Melanoma, Kidney cancer, Colon cancer, as well as discrete metastatic lesions.
  • the subcutaneous concentration of the chemotherapy drug achieved is simultaneously: (i) below the threshold for local tissue toxicity while sufficiently concentrated to result in a significant positive local therapeutic effect, and (ii) greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery' or oral delivery of the chemotherapy drug.
  • the subcutaneous concentration of the chemotherapy drug achieved is equal to or about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, 200%, 250%, 300%, 350%, 400%, 450% or 500% greater than the maximum subcutaneous interstitial fluid concentration that can be achieved by conventional intravenous delivery or oral delivery of the chemotherapy drug.
  • Biologic drugs generally consist of large organic molecules derived from biological sources. Traditional anticancer chemotherapy drugs are akin to weapons of mass destruction that can damage any living cell. An anticancer chemotherapy drug is only therapeutic if it is more toxic to cancer cells than to healthy cells. In contrast biologic drugs are focused weapons that targets specific pathologic cells or pathologic cellular products. Examples of Biologic drugs include: cytokines, chemokines, growth factors, viral antigens,
  • HH enzymes hormones, neurotrophms, antibodies, proteins that target specific genes, antibody to a specific antigen.
  • CD Cluster of Differentiation or Classification Determinant
  • Lymph node targeted drug delivery of anticancer medications using tumescent infiltration provides a unique mode of drug delivery. Lymphatic vessels specifically absorb large molecules from interstitial tissue spaces and return these large molecules to the systemic circulation via lymph nodes. Tumescent infiltration drug delivery can target metastatic cancer cells within lymph nodes. For example, a large volume of dilute solution of proteinaceous anti-melanoma drugs, if infiltrated into the subcutaneous tissue around the site of a primary melanoma tumor, will be absorbed into the lymph vessels that drain the primary tumor site and deliver the drugs directly to the lymph nodes which might have trapped metastatic melanoma cells, thus preventing further, more wide spread metastases.
  • Snake antivenin delivery is another unique application of tumescent infiltration.
  • Snake venom contains multiple large proteins, which have both local and systemic effects.
  • Antivenin contains antibodies to the venomous proteins.
  • Snakebite is painful. Tumescent infiltration of a snake antivenin can, 1) immediately relieve the pain (lidocame effect), dilute the venom decreasing tissue toxicity, neutralize much of the venom at the site of the bite before it is systemical!y absorbed.
  • Venom is absorbed via lymphatic vessels. Large molecular antivenin antibodies are also specifically absorbed via lymphatic vessels. Following tumescent infiltration around the site of a snakebite, the antivenin is absorbed into the same lymphatic vessels as the venom. In this fashion, tumescent antivenin can neutralize the venom within lymphatic vessels before the venom reaches the systemic circulation.
  • Sepsis is a body's overwhelming and life-threatening response to an infection, which can lead to tissue damage, organ failure, and even death. Patients are given a diagnosis of sepsis when they develop clinical signs of infections or systemic inflammation. Sepsis is not diagnosed based on the location of the infection or by the name of the causative microbe. Physicians draw from a list of signs and symptoms m order to make a diagnosis of sepsis, including abnormalities of body temperature, heart rate, respiratory rate, and white blood cell count. For example, sepsis may be diagnosed in a 72-year-old man with pneumonia, fever, and a high white blood cell count, and in a 3 -month-old with appendicitis, low body temperature, and a low white blood cell count.
  • Sepsis is defined as severe when these findings occur in association with signs of organ dysfunction, such as hypoxemia, oliguria, lactic acidosis, elevated liver enzymes, and altered cerebral function. Nearly all victims of severe sepsis require treatment in an intensive care unit for several days or weeks. While most cases of sepsis are associated with disease or injury, many events follow routine, even elective surgery.
  • Tumescent drug delivery can achieve a localized reservoir of a drug, which is present at a relatively high concentration in local interstitial tissues. While the high concentration of drug delivered by the tumescent technique is confined to localized tissues targeted, a lower systemic level of the drug can also be atained, originating from the localized reservoir established by tumescent delivery.
  • antibiotic or anti-inflammatory agents delivered tumescent can provide ongoing systemic levels of the antibiotic or anti inflammatory agent, which can effectively prevent or treat sepsis in a subject.
  • TLAnti can be used to provide anesthesia, hemostasis, and antibiotic prophylaxis during liposuction or other medical procedures.
  • Liposuction is a well-known procedure that is disclosed in U.S. Patent Nos. 5,052,999 and 5,472,416, the disclosures of which are incorporated herein in their entirety by reference thereto.
  • TLAnti is infiltrated into the subcutaneous fat compartment (“infiltration procedure”) using a small gauge injection cannula, typically beginning at the location that the practitioner expects to be the deepest portion of adipose tissue removal.
  • This area is filled with a sufficient quantity of TLAnti so that it becomes saturated and swollen or“tumescent.”
  • the operator can recognize whether sufficient TLAnti has been injected during the infiltration procedure if the area appears swollen, pale and relatively cool because of vasoconstriction.
  • the removal of adipose tissue can begin through a cannula capable of suctioning fat out of the body and into a reservoir.
  • An example of such a procedure albeit one involving standard tumescent anesthesia without the use of TLAnti is described in Jeffrey A. Klein, Tumescent Technique Blogs, DERMATOLOGIC SURGERY, vo!. 21, pp. 449-457, 1995.
  • the cannula typically used in such procedures include a tubular needle portion with proximal and distal ends.
  • the proximal end of the tubular needle is attached to a hub that is used by the anesthesiologist or surgeon to grasp and hold the cannula during the infiltration procedure.
  • the hub is connected to the tubular needle at a first end and has a connector, such as a luer lock, at an opposing second end.
  • the connector is, in turn, connected to a fluid source, such as tubing connected to a fluid reservoir containing the TLAnti such as an IV bag.
  • the TLAnti enters via the connector.
  • the distal end of the cannula is sealed and the TLAnti exits the cannula through a plurality of apertures located proximate of the distal end in a linear, helical, or spiral pattern distributed over the distal 33% to 100% of the tubular needle.
  • TLAnti exits the cannula through a plurality of apertures located proximate of the distal end in a linear, helical, or spiral pattern distributed over the distal 33% to 100% of the tubular needle.
  • the TLAnti can be withdrawn from the reservoir and injected into the patient manually using a syringe, hand pump or electrical pumping system.
  • the TLAnti is injected from the reservoir using a peristaltic pump.
  • a peristaltic pump can be found in United States Patent No. 5,236,414, the disclosure of which is incorporated herein m its entirety by reference thereto.
  • Another embodiment of a peristaltic pump that can be used with the current disclosure is described m pending U.S. Patent Application Ser. No. 1 1/641,228. Persons skilled in the art will recognize that there are a number of possible mechanisms that can be used to transfer the TLAnti from the reservoir to the subcutaneous fat compartment.
  • the same cannula that is used for the removal of adipose tissue can be used for the delivery' of TLAnti.
  • the cannula can have two lumens, one for incoming adipose tissue and blood and a second lumen for outgoing TLAnti.
  • such cannula can have a single lumen that can be used aiternatingly for the removal of adipose tissue and the injection of TLAnti.
  • the practitioner can switch the cannula from a mode wherein incoming adipose tissue and blood is being drawn into the cannula lumen, to an alternative mode wherein TLAnti passes out of the cannula lumen into the subcutaneous fat compartment.
  • a switching system can be found in United States Patent No. 4,696,669, the disclosure of which is incorporated herein in its entirety by reference thereto.
  • Such embodiments can comprise separate pumping systems, for example, one for incoming tissue and fluid and another for the TLAnti.
  • Other embodiments can utilize a single, reversible pumping system.
  • An example of this technique, albeit one using standard tumescent anesthesia can be found in United States Patent No. 5,472,416 the disclosures of which are incorporated herein in their entirety by reference thereto.
  • TLAnti can be used during mastectomy procedures.
  • the surgical excision of breast cancer is associated with a beter prognosis than other therapeutic options such as chemotherapy, immunotherapy, endocrine therapy, or radiation therapy.
  • surgery under general anesthesia is associated with significant systemic metabolic, neuroendocrine, and cytokine side-effects which may induce a transient perioperative inhibition of immune function including immune mediated anticancer surveillance thus enabling malignant cells to successfully spread to other parts of the body during the surgical procedure.
  • Local anesthesia using the tumescent technique can reduce or prevent the immunosuppressive effects of general anesthesia.
  • Lumpectomy and mastectomy are safer when performed by tumescent local anesthesia instead of general anesthesia.
  • the tumescent technique also reduces or eliminates the need for postoperative narcotics which can inhibit immune function.
  • TLAnti can also help to reduce the risk of metastases by preventing malignant cells from entering the bloodstream through a number of mechanisms.
  • the tumescent technique induces profound vasoconstriction, thus providing a physical barrier to malignant cells entering the blood stream and thereby reducing the risk of metastasis to distant organs.
  • the use of TLAnti can reduce platelet activation which prevents endothelial wall retraction and reduces the likelihood of cancer cells entering the body.
  • the surface of an activated platelet contains newly synthesized bioactive molecules including thromboxane Ai and thrombin. Activated platelets may produce and release products which augment tumor cell survival and decrease the effectiveness of immune surveillance.
  • High localized tissue concentrations of tumescent lidocaine inhibit platelet activation and thereby reduce the risk of surgery-precipitated metastasis.
  • TLAnti is administered utilizing the Klein infiltration cannula (Klein cannula) described in pending United States Patent Application Ser. No. 11/800,355.
  • Klein cannula are sealed on the distal end so that the TLAnti can exit the cannula from a senes of apertures on the side of the cannula.
  • This enables the operator to insert the cannula into the target area without the need for the operator to repeatedly push the cannula in and out of the surgical area during the infiltration procedure.
  • the procedure can be performed using cannula other than the Klein cannula.
  • TLAnti can help to reduce the risk of surgical site infection.
  • Some embodiments relate to the tumescent delivery of chemotherapeutic agents.
  • Some embodiments relate to the prevention of chronic pain after mastectomy or other surgical procedures by administration of TLAnti to achieve preemptive analgesia and reduce post-surgical pain.
  • Use of TLAnti along with a Klein cannula can reduce the risk of chronic pain after mastectomy.
  • PMPS Post-mastectomy pain syndrome
  • the prevalence rate of PMPS is estimated to be 43%.
  • the most important factor associated with chronic pain and phantom pain after mastectomy is the intensity of acute post operative pain. This fact suggests that aggressive management of acute postoperative pain may reduce chronic post-mastectomy pain.
  • Preemptive surgical analgesia such as can be achieved by tumescent delivery of local anesthetic
  • Preincisional paravertebral block (a form of local anesthesia) reduces the prevalence of chronic pain after mastectomy.
  • paravertebral blocks are relatively difficult achieve, require considerable clinical expertise, and are associated with a relatively high risk of systemic local anesthetic toxicity as a result of inadvertent IV injection.
  • the tumescent technique is relatively easy to perform with virtually no risk of toxicity associated with tumescent infiltration using a Klein cannula.
  • TLAnti can be used in a variety of surgical procedures. When so employed, TLAnti can also reduce the risk of deep vein thrombosis and post-operative thromboembolism. Thromboembolism, a leading cause of perioperative morbidity and mortality, is the direct result of platelet activation by surgical trauma. There is both clinical and experimental evidence that lidocaine can reduce surgical trauma-associated platelet activation and aggregation. For example, in vivo bleeding volume and bleeding time tests show prolonged bleeding after local subcutaneous infiltration of tumescent local anesthesia containing dilute lidocaine, indicating a decrease in platelet activity.
  • Blood platelet activation is associated with a degranulation and release of vasoactive and thrombogenic chemical mediators including serotonin and thromboxane- A2, which play a role in acute coronary thrombosis and arrhythmias.
  • the lidocaine present in the TLAnti solution can affect platelet function by means of several diverse mechanisms: For example, the release of the phospholipid messenger lysophosphatidate from activated platelets is inhibited by the extracellular application of lidocaine in concentrations injected into surgical wounds.
  • iidoeaine may inhibit platelet aggregation by acting on adenosine diphosphate (ADP).
  • ADP adenosine diphosphate
  • the tumescent drug delivery system in conjunction with tumescent local anesthesia and tumescent antibiotic delivery-, is uniquely able to deliver long-lasting elevated lidocaine concentration to the site of surgical trauma and thereby prevent thromboembolism.
  • the tumescent technique is capable of producing sufficient concentrations for lidocaine to achieve its antithrombic effects.
  • safe systemic concentrations e.g. ⁇ 6 micrograms/ml
  • lidocaine seems to have no effect on platelet aggregation.
  • tissue concentrations achieved after infiltration of TLAnti there is a significant inhibition of in-vitro platelet aggregation.
  • lidocaine concentrations equal to or greater than 0.5mg/ml.
  • concentration of lidocaine in TLAnti typically ranges from 0.4 mg/ml to ! .2mg/ml.
  • in-vitro testing of the effect of lidocaine on platelet aggregation has shown that the longer the incubation time with lidocaine, the more efficient the anti-aggregating effect.
  • the local tissue vasoconstriction associated with TLAnti impairs systemic absorption of tumescent lidocaine and dramatically prolongs the local tissue concentrations of lidocaine. Tumescent local anesthesia infiltrated into the site of surgical incision produces very high and prolonged local tissue concentrations of lidocaine and can thereby significantly reduce platelet activation and the risk of perioperative thromboembolism.
  • thromboembolism is a greater risk with surgery under general anesthesia compared to the same surgery under local anesthesia. For example, comparisons of orthopedic surgical procedures of the knee done under general anesthesia versus procedures done under epidural/spmal regional local anesthesia show that the incidence of pulmonary embolism and deep vein thrombosis associated with the procedure is reduced. Lidocame, a component of the regional local anesthesia used may have contributed to the reduction in thromboembolism observed. Circumstantial evidence also supports the potential role of TLAnti in preventing the occurrence of thromboembolism. When liposuction is performed under general anesthesia, pulmonary embolism is the leading cause of death. However, there have been no reported cases of pulmonary embolism associated with liposuction under tumescent local anesthesia.
  • TLAnti may be delivered to the surgical site while the patient is under general anesthesia.
  • the higher tissue concentration of lidocame achieved with TLAnti may inhibit platelet function far more effectively than either IV delivery or peripheral nerve block delivery'.
  • the preoperative infiltration with of the surgical site with TLAnti enables the lidocaine concentration within surgically traumatized tissues to reach sufficiently high levels for the lidocame to achieve an antithrombic effect.
  • TLAnti can reduce the risk of perioperative thromboembolic disease such as deep vein thrombosis (DVT) and pulmonary embolism (PE), while the systemic concentrations of lidocaine remain uniformly well below the toxic threshold.
  • lidocaine provided in TLAnti may act synergistical!y with other antibiotics to decrease the risk of surgical site infection.
  • Lidocaine is known to affect nerve conduction by inhibiting cell membrane sodium pumps. Not wishing to be bound to a particular theory, it is likely that lidocaine exerts its antibiotic affect through inhibition of trans-membrane ion transport or antibiotic efflux channels.
  • lidocaine and other antibiotics such as cefazolin or metronidazole
  • MIC minimum inhibitory concentration
  • MMC minimum bactericidal concentration
  • Time-Kill studies involving methaciilin- ⁇ resistant Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli
  • lidocaine Several embodiments relate to methods and compositions for reducing the risk of thromboembolism by oral administration of lidocaine.
  • the bioavailability of orally administered lidocame is limited by rapid degradation of lidocaine by cytochrome P450 enzymes.
  • cytochrome P450 enzymes Several embodiments described herein relate to methods of reducing the risk of thromboembolism by oral administration of lidocaine in combination with an inhibitor of cytochrome P450 enzymes.
  • cytochrome P450 inhibitors include free bases or pharmacologically acceptable salts of: alpha- naphthoflavone, beta-naphthoflavone, apigemn, daralem, beta-myrcene, catechm, 3-phenylpropyl acetate, formononetin, gallic acid, hesperetin, hesperidin, isoquereitrin, lauryl alcohol, luteolm, luteolin-7-glycoside, narigin, nordihydroguaiaretic acid, quercitrin, swertiamarin, terpineol, and trans-cinnamaldehyde.
  • Lidocaine and one or more cytochrome P450 inhibitors may be administered simultaneously or sequentially.
  • TLAnti can be delivered using a disposable, plastic cannula as described in U.S. Patent Application Ser. No. 1 1 /800,355, the disclosures of which are incorporated herein in their entirety by reference thereto.
  • This device provides a method for relatively rapid fluid resuscitation and the administration of anesthesia and antibiotics in situations wherein establishing intravenous (IV) access is not feasible (e.g., in a remote area, an obese patient with poor venous access, burn/trauma victim, unavailable trained medical professional, etc.).
  • IV intravenous
  • a significant advantage of using the tumescent technique to deliver fluids and medications is that the infiltration procedure is relatively easy to perform.
  • tumescent antibiotic solution can be modified by eliminating a vasoconstrictor such as epinephrine, and instead adding a vasodilator such as methyl nieotinate. The resulting systemic absorption and redistribution of TLAnti into the intracellular and intravascular compartments could be life-saving.
  • the tumescent technique performed with disposable catheters and TLAnti provides a useful method of administering fluids and medications to patients when establishing an IV line is difficult or impossible. For example, it can be extremely difficult to obtain IV access among patients who are obese, elderly, have a history of IV drug abuse, or with severe dehydration. By contrast, the subcutaneous infiltration of medications using the tumescent technique can often be achieved relatively easily in many such cases. In such cases, the ability to administer IV fluids, anesthetic, and antibiotics through the alternative subcutaneous route can be invaluable and, at times, lifesaving.
  • the use of tumescent drug delivery for emergency fluid resuscitation when IV access is not feasible has been previously described in U.S. Patent 7,572,613 the disclosure of which is incorporated herein m their entirety by reference thereto.
  • the tumescent technique can also be useful in certain conditions where various aspects of the environment make IV insertion difficult or impractical . Such conditions could include the treatment of wounded soldiers in night-time combat conditions when establishing an IV access in total darkness is nearly impossible and the use of a flash light might attract enemy fire. It could also be useful in low gravity environments, such as on the International Space Station where a normal gravity-fed IV could not function, but injecting medications subcutaneously using the tumescent technique would not be affected. Cannula with pre-mixed dosages of TLAnti could be provided in emergency medical kits for use in such conditions if and when the need arises.
  • TISF interstitial space fluid
  • Several embodiments described herein relate to a novel method for conducting pharmakinetie measurements of ISF by sequential sampling of tumescent interstitial space fluid (TISF).
  • TISF tumescent interstitial space fluid
  • Several embodiments relate to a method of conducting pharmakinetie measurements of one or more drugs m ISF comprising obtaining from subcutaneous adipose tissue sequential samples of TISF by hand-held syringe liposuction for a period of time after tumescent delivery of the one or more drugs and measuring the amount of one or more drugs m each sample.
  • sequential sampling of TISF is conducted hourly, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, or every ten hours for up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,
  • the methods described herein may be used to investigate the absorption pharmacokinetics of antibiotics.
  • TISF subcutaneous adipose tissue by hand-held syringe liposuction for a period of time after tumescent delivery of TLAnti solution and measuring the amount of the one or more antibiotics in each sample.
  • a sample of TISF is obtained every 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 minutes after TAD.
  • a sample of TISF is obtained hourly after TAD.
  • a sample of TISF is obtained every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after TAD.
  • sequential samples of TISF are obtained for a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, or 68 hours after TAD.
  • One embodiment relates to a method of conducting pharmakinetic measurements of one or more antibiotics in ISF comprising obtaining a sample of TiSF hourly for a period of 10 hours after TAD and measuring the amount of one or more antibiotics m each sample.
  • the methods described herein may be utilized to measure important pharmacokinetic (PK) metrics for bioavailability of drugs, such as antibiotics, within subcutaneous adipose tissue, such PK metrics including: area under the curve of concentration as a function of time (AUC) and the maximum concentration (Cmax) of the drug.
  • PK metrics including: area under the curve of concentration as a function of time (AUC) and the maximum concentration (Cmax) of the drug.
  • AUC area under the curve of concentration as a function of time
  • Cmax maximum concentration
  • the magnitude of the cumulative tissue exposure a tissue over time to a given drug can be measured by determining the AUC of drug concentration within the interstitial fluid (ISF) as a function of time.
  • ISF interstitial fluid
  • the methods described herein may further be utilized to measure the duration of time that the antibiotic concentration exceeds the minimal inhibitory concentration (MIC) for a specific bacteria (T>MIC).
  • the methods described herein may be utilized to evaluate the effectiveness of tumescent drug delivery compared to other modes of delivery.
  • the methods described herein may be utilized to evaluate the effectiveness of tumescent antibiotic delivery (TAD) and intravenous antibiotic delivery (IV AD) for preventing surgical site infection (SSI).
  • TAD tumescent antibiotic delivery
  • IV AD intravenous antibiotic delivery
  • TAD is superior to IV AD for preventing SSIs where free[ISF]IVAD ⁇ free[TISF]TAD.
  • TAD is superior to IV AD for preventing SSIs where experimental data demonstrates total[Serum]IVAD ⁇ total[TISF]TAD.
  • Adit a small round hole in the skin (typically 1 mm, 1.5 mm or 2 mm diameter) made by a skin-biopsy punch, and intended to be an access port for percutaneous entry into the subcutaneous fat by a tumescent infiltration cannula and/or a liposuction cannula.
  • Infiltration an injection that causes a fluid to permeate or percolate through pores and/or interstices.
  • an infiltration refers to an injection directly into tissue.
  • Infusion an injection that pours a fluid into a place or into the lumen of a blood vessel.
  • an infusion refers to an intravascular injection
  • Injection The action of forcing a fluid, etc. into tissue or cavity, as by means of a syringe, or by some impulsive force.
  • Tumescent Technique is a method of subcutaneous drug delivery of large volumes of very dilute solution of a medication together with either a dilute vasoconstrictor such as epinephrine or a dilute vasodilator such a methyl mcotmate in an isotonic solution of crystalloid (e.g.
  • physiologic saline, lactated Ringer’s solution, Hartman’s solution infiltrated directly into subcutaneous fat or muscle or along the exterior of a length of vein or other tissue to produce either a vasoconstrictor-induced ver slow' systemic absorption or a vasodilator-induced rapid systemic absorption, as well as direct hydrostatic effect on capillaries, veins, and arterioles.
  • the tumescent technique can be used to deliver large volumes of very dilute medication together with dilute epinephrine in isotonic solution of crystalloid (e.g., physiologic saline, lactated Ringer’s solution, Hartman’s solution, etc). Inclusion of a vasoconstrictor in the tumescent solution produces very slow systemic absorption as a result of intense subcutaneous vasoconstriction, as well as direct hydrostatic compression of capillaries and veins.
  • Minimum Bactericidal Concentration is the lowest concentration of antibiotic required to kill a particular bacterial isolate in vitro. Antimicrobials are usually regarded as bactericidal if the MBC is no more than four times the MIC.
  • Minimum Inhibitory Concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a particular bacterial isolate. Measurements of MIC are used to confirm resistance of microorganisms to an antimicrobial agent and also to monitor the activity of new' antimicrobial agents. Clinically, the minimum inhibitory concentrations may be used not only to determine the amount of antibiotic that the patient will receive but also the type of antibiotic used, which prevents the development of microbial resistance to antimicrobial agents.
  • Tumescent drug delivery and synonyms refer to the tumescent technique for delivering a drug into the subcutaneous space.
  • tumescent delivery is a process of infiltration of very large volumes of very dilute solutions of therapeutic substances dissolved in a crystalloid solution with either a vasoconstrictor such as epinephrine or a vasodilator such as methyl mcotmate into subcutaneous tissue to the point of producing tumescence of the targeted tissue.
  • TLA Tumescent Local Anesthesia
  • Tumescent Local Anesthetic Solution is the local anesthetic solution used to produce TLA.
  • TLA Solution consists of a 10 to 20 fold dilution of commercially available concentration of lidocaine and epinephrine.
  • TLA Solution comprises very dilute lidocaine ⁇ 1 gram/liter) and epinephrine ( ⁇ 1 milligram/liter) with sodium bicarbonate (10 milliequivendings/iiter) in a crystalloid solution such as physiologic saline or lactated Ringer’s solution.
  • the volume of TLA Solution infiltrated into the target tissue is so large that the skin and subcutaneous tissue becomes tumescent, in other words swollen and firm.
  • the terms“tumescent local antibiotic solution,”“TLAnti solution,” “tumescent antibiotic delivery solution,” or “TAD solution,” may be used interchangeably to refer to a solution comprising an antibiotic component, an anesthetic component, a vasoconstrictor component and a solvent/pharmaceutically acceptable carrier.
  • Tumescent, tumescence swollen and firm.
  • Tumescent liposuction liposuction performed by local anesthesia using tumescent local anesthesia.
  • Tumescent fluid tumescent solution
  • dilute solutions of therapeutic substances dissolved in an aqueous solvent, such as crystalloid solution intended for tumescent delivery into subcutaneous tissue.
  • Tumescent “drug” the “drug” in the context as an ingredient in a tumescent solution and its pharmacokinetic behavior as a result of the pharmacokinetics of a tumescent solution; for example tumescent lidocaine, tumescent epinephrine, tumescent antibiotic.
  • Tumescent Pharmacokinetics The absorption pharmacokinetics (the pharmacologic and physiologic factors associated with the systemic absorption of a drug) after tumescent infiltration of a drug is either dramatically slower with a vasoconstrictor such as epinephrine or dramatically faster with a vasodilator such as methyl nicotinate than the rate of systemic absorption of routine injection of the drug.
  • a vasoconstrictor such as epinephrine
  • a vasodilator such as methyl nicotinate
  • the intense vasoconstriction induced by epinephrine slows the rate of drug absorption into the central circulation and prolongs the local effects of the drug.
  • the duration of routine local anesthesia with lidocaine is typically 2 hours; in contrast the duration of tumescent local anesthesia may be 12 to 18 hours or more.
  • a similar prolonged effect of tumescent antibiotic infiltration significantly improves the prophylactic effect of preoperative antibiotic therapy in the prevention of surgical site infections.
  • the term“[FLUIDjMODE” refers to the concentration of a drug (e.g., an antibiotic) in a specified FLUID, for example, interstitial fluid, blood serum, whole blood, ammotie fluid, aqueous humour, breast milk, cerebrospinal fluid, lymph, peritoneal fluid, pleural fluid, saliva, sweat, mucus, etc., after a specified MODE of drug delivery.
  • a drug e.g., an antibiotic
  • MODES of drug delivery include, but are not limited to ingestion, topical administration, transmuscosal administration, inhalation, injection, intravenous administration, intrartal administration, intramuscular administration, intraosseous administration, intrathecal administration, intraperitoneal administration, intravesical administration, intravitreal administration, intradermal administration, and tumescent administration.
  • ISFJIVAD and [SerurnjIVAD represent the antibiotic concentration in interstitial fluid (ISF) and serum, respectively, after IV AD.
  • TISFJTAD and [Serum] TAD refer to the antibiotic concentrations in TISF and serum after TAD.
  • bound[FLUID]MODE refers to the concentration of protein bound drug (e.g., antibiotic) in the specified FLUID after delivery by a specified MODE.
  • free[FLUID]MODE refers to the concentration of free drug (e.g., antibiotic) (not bound to protein) in the specified FLUID after delivery by a specified MODE.
  • pharmacodynamic quantity refers to a quantitative measure of drug effect in terms of drug concentration as a function of time.
  • area under the curve (AUC)” and “time to Cmax” refer to pharmacokinetic quantities.
  • the term“Cmax” refers to the peak drug (e.g., antibiotic) concentration in a tissue after drug delivery.
  • the term“Cmax[FLUID]MQDE” refers to the peak drug (e.g., antibiotic) concentration in a specified FLUID after delivery by a specified MODE.
  • T(Cmax) refers to the time from initiation of drug (e.g., antibiotic) delivery to the time when Cmax is achieved.
  • T>MIC refers to the length of time during which the drug concentration exceeds the Minimum Inhibitory Concentration (MIC) for a given pathogen.
  • T[TISF]TAD>MIC refers to the length of time the antibiotic concentration exceeds the MIC for a given bacteria in Tumescent Interstitial Space Fluid (TISF) after TAD.
  • ISF interstitial space fluid
  • the term“Tumescent Interstitial Space Fluid (TISF)” refers to a mixture of a small volume of ISF and a larger volume of tumescently-delivered solution, for example, TLA Solution, TLAnti Solution, TAD solution, etc., said mixture resulting from tumescent infiltration. Immediately after tumescent infiltration, TISF is chemically equivalent to the TAD solution.
  • the term“Minimum Inhibitory Concentration (MIC)” refers to the lowest concentration of a drug (e.g., an antimicrobial) that wall inhibit the visible growth of a pathogen (e.g., a microorganism) after overnight incubation. MIC is a function of both the pathogen and the drug under consideration.
  • the term“area under the curve (AUC)” is a pharmacokinetic term that refers to drug concentration as a function of time following drug delivery. AUC is calculated from the area under the plot of body fluid concentration of drug (not logarithm of the concentration) against time after drug administration. The AUC is of particular use in estimating hioavaiiabihty of drugs, and in estimating total clearance of drugs. Area under the curve (AUC) of drug concentration within blood or tissue as a function of time is a pharmacokinetic metric for measuring the magnitude of the cumulative tissue exposure over time to a given drug. Whenever drug concentration is measured continuously then AUC is
  • AUC can be estimated using the trapezoid rule:
  • the term“AUC[FLUID]MODE” refers to the AUC of the drug in a specified body FLUID by a specified MODE.
  • AUC[ISF]TAD refers to the AUC in interstitial space fluid of the drug administered by tumescent deliver ⁇ '
  • AUC [Serum] TAD refers to the AUC in serum of the drug administered by tumescent delivery
  • AUC[ISF]IVAD refers to the AUC in interstitial space fluid of the drug administered by IV delivery
  • AUC [Serum] TAD refers to the AUC in serum of the drug administered by IV delivery.
  • each antibiotic has a characteristic fraction of its total concentration which is bound to proteins. Only free antibiotic molecules interact with bacteria or diffuse across capillary walls between serum and ISF.
  • the term“freeAUC[TISF]TAD” refers to the AUC of free (unbound) antibiotic in ISF after TAD.
  • the term “totalAUC[Serum]XVAD” refers to the ALIC of total (bound and unbound) antibiotic in Serum after IV AD.
  • a fraction of an antibiotic in ISF is protein bound.
  • the term“patient” refers to the recipient of a therapeutic treatment and includes all organisms within kingdom animaha. In preferred embodiments, the animal is within the family of mammals, such as humans, bovine, ovine, porcine, feline, buffalo, canine, goat, equine, donkey, deer and primates. The most preferred animal is human.
  • the terms “treat” “treating” and “treatment” include “prevent”“preventing” and“prevention” respectively.
  • the use of the singular includes the plural unless specifically stated otherwise.
  • the use of “or” means“and/or” unless stated otherwise.
  • the use of the term“including”, as well as other forms, such as“includes” and“included”, is not limiting.
  • terms such as “element” or“component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.
  • the use of the term“portion” can include part of a moiety or the entire moiety.
  • the term“effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to prevent thromboembolism or infection.
  • An effective amount of TLAnti or other tumescent solution may vary according to factors such as the disease state, age, and weight of the subject, and the ability' of TLAnti or other tumescent solution to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of TLAnti or other tumescent solution are outweighed by the therapeutically beneficial effects.
  • the language“a prophylactically effective amount” of TLAnti refers to an amount of TLAnti which is effective, upon single or multiple dose administration to the subject, in preventing or treating infection or thromboembolism.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved.
  • an“increase” or“decrease” m a measurement is typically in comparison to a baseline value.
  • an increase in time to hospitalization for subjects undergoing treatment may be in comparison to a baseline value of time to hospitalization for subjects that are not undergoing such treatment.
  • an increase or decrease in a measurement can be evaluated based on the context m which the term is used.
  • TAD was achieved using blunt-tipped Monty infiltration cannula and peristaltic tumescent infiltration pump.
  • Treated areas included: abdomen (Patient 1 & Patient 4); female breasts (Patient 2); and hips-outer thighs (Patient 3).
  • Patient 4 received Cefazolin and Metronidazole.
  • Patient 1 was studied on 3 separate occasions with treatments occurring at least one week apart.
  • Patient 1 was treated with: TAD lOOOmg Cefazolin/Tl 1 1ml; TAD 500mg Cefazolin/1061ml; or IVAD l OOOmg Cefazolin.
  • the 10 hour Cefazolin AUC and Cmax for TAD (abdomen) and IV AD treatments for Patient 1 are shown in Table 1. Other patients studied gave similar results (not shown).
  • subcutaneous tissue fluid AUC for TAD 1000 mg Cefazoiin and TAD 500mg Cefazoiin yielded 15.2 and 7.2 times AUC, respectively, compared to IV AD 1000 mg Cefazoiin (assuming Cefazoiin concentration in subcutaneous tissue after IV AD is less than or equal to the concomitant Cefazoiin concentration in serum).
  • TAD yields reduced AUC & Cmax, while prolonging duration of serum Cefazoiin compared to IV AD.
  • antibiotic surgical site infection prophylaxis by TAD may be better and have fewer risks compared to the current standard of care, IV AD.
  • bactericidal properties of three antimicrobial compounds were evaluated by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration for Staphyloccus aureus (MRS A) ATCC 33592.
  • a standardized suspension of Staphyloccus aureus (MRS A) ATCC 33592 was prepared by culturing on tryptic soy agar for 3-5 days at 35° C. The agar slant was washed with sterile phosphate buffer solution and the organism concentration was adjusted. Innoculum levels of Staphyloccus aureus (MRS A) ATCC 33592 w3 ⁇ 4re between 4.4 x ! 0 5 to 4 7 x 1 O' CFlJ/ml.
  • Table 8 shows the results of the analysis of the Minimum Bactericidal Concentration (MBC) of Lidoeaine, Cefazolin, and Lidocaine + Cefazolin. Determinations of MBC followed the method described in “Report on the Working Party on Antibiotic Sensitivity Testing of the British Society of Antimicrobial Chemotherapy: A Guide to Sensitivity Testing.”
  • MBC Minimum Bactericidal Concentration
  • Endpoints were achieved for ail 3 test products, Lidocaine, Cefazoiin, and Lidocaine + Cefazoiin, evaluated in the MIC and MBC study.
  • the MIC endpoints are shown in Table 9 and the MBC endpoints are shown in Table 10.
  • the results of this evaluation indicate that the MIC for Cefazoiin is between 125 and 250 mg/L, Lidocaine was around 5,000 mg/L and the combination of both Cefazoiin and Lidocaine had an MIC of 100 mg/L.
  • a patient presenting with a localized infection characterized by a central abscess and inflammation is treated by tumescent antibiotic delivery to the affected area.
  • a solution of 250 mg of cetazoiin (150 mi from a solution consisting of 500 mg of cefazolin), 300 mg iidoeaine. 0.3 mg epinephrine, 3 meq sodium bicarbonate is dissolved in saline to a total volume of 280 ml. The solution is then infiltrated in the area of inflammation. The patient is examined approximately 12-24 hours after infiltration for visible evidence of inflammation and/or redness.
  • TLAnti is administered to the subcutaneous compartment of a surgical site in a 70 kg adult patient under general anesthesia. The patient is subsequently monitored for perioperative and postoperative thromboembolism.
  • TLAnti is administered to the subcutaneous compartment of a surgical site or site of other injury in a 70 kg adult patient without general anesthesia. The patient is subsequently monitored for perioperative and postoperative thromboembolism.
  • TLAnti is administered to the subcutaneous compartment at a site of infection in a 70 kg adult patient without general anesthesia.
  • concentrations of the antibiotic component and anesthetic component used in TLAnti for the treatment of infection exceed concentrations considered safe for systemic use.
  • the progress of the infection is subsequently monitored in the treated patient.
  • a catheter is inserted into the surgical site and the area infiltrated with a tumescent solution.
  • the tumescent solution comprising .9% normal saline, 500mg of cefazolin, 500mg Hdocaine 2%, Img epinephrine, and lOmEq bicarbonate. Once sufficient anesthesia is achieved, the surgeon removes cancerous tissue with sufficient margins to ensure complete removal of the tumor. The site can subsequently be closed and dressed.
  • TAD Tumescent Antibiotic Delivery
  • IV AD IV Antibiotic Delivery
  • mice Eighty rats are anesthetized and their backs shaved and cleansed. Groups of 20 rats each are given a 250 mg/kg dose of cefazolin either by subcutaneous tumescent administration (TAD), intraperitoneal injection (IVAD), or a combination of TAD and IVAD 15 to 35 minutes prior to making a 4 cm sterile vertical incision through the skin of the back into the subcutaneous tissue. The incisions are then immediately inoculated with Staphylococcus aureus at concentrations of I Q 2 , I Ok ! 0 4 or ! 0 5 organisms per ml and closed.
  • TAD subcutaneous tumescent administration
  • IVAD intraperitoneal injection
  • Staphylococcus aureus 15 to 35 minutes prior to making a 4 cm sterile vertical incision through the skin of the back into the subcutaneous tissue. The incisions are then immediately inoculated with Staphylococcus aureus at concentrations of I Q 2 , I Ok ! 0 4 or
  • one group of 10 rats is untreated prior to undergoing incision and inoculation as described above and one group of 10 rats is given a 250 mg/kg dose of cefazolin by a combination of TAD and IVAD prior to incision, but the incision is closed without inoculation.
  • the rats are euthanized and samples of 1 cnr of tissue from the lateral side of the incisions is collected for microbiological assessment.
  • the collected tissue is weighed and placed in individual sterile tubes containing 1ml of sterile tryptic soybean broth (TBS).
  • TBS sterile tryptic soybean broth
  • the tissue is homogenized and four 1 : 10 serial dilutions of each homogenate with 0.5-ml aliquots and diluted with 4.5 ml of sterile TSB: 10 to lO 4 are made.
  • Blood agar plates are inoculated with 0.1 mi of each dilution and the plates are incubated at 35 °C for 18 to 24 hours.
  • the Duke method of determining bleeding time is used to assess effect of tumescent administration of TLAnti comprising 0.5 mg/ml lidocaine on hemostatic function (platelet response to injury and functional capacity of vasoconstriction).
  • TLAnti comprising 0.9% normal saline, 500mg of cefazolin, 500mg lidocame 2%, I mg epinephrine, l OrnEq bicarbonate is infiltrated into the subcutaneous tissue of the left thigh until the skin becomes swollen and taught— tumescent.
  • Simultaneous 4 mm deep puncture wounds are made to the same area of the left and right thighs with disposable lancets.
  • the puncture sites are blotted with filter paper every 30 seconds, until bleeding stops and the bleeding time for each thigh is recorded.
  • the bleeding times of the left and right thigh are compared to determine if administration of TLAnti increases bleeding time. Normal bleeding time measured by the Duke method is 1 to 3 minutes.
  • the Center for Disease Control has defined 3 classes of surgical site infection (SSI): 1) Superficial Incisional SSI, an infection involving skin or subcutaneous tissue within 30 days of surgery; 2) Deep Incisional SSI, an infection involving fascia and muscle layers within 30 days after surger without an implant or 1 year if an implant is left in place and the infection appears to be related to the surgery and the incision; and 3) Organ/Space SSI, an infection involving any organ or spaces opened and manipulated during the surgery occurring within 30 days of surgery' without an implant or 1 year if an implant is left m place and the infection appears to be related to the surgery and the infection.
  • SSI surgical site infection
  • antibiotic concentration profile of the antibiotic depends upon the concentration profile of the antibiotic (magnitude and duration) within the interstitial space fluid (XSF) at the site of potential bacterial contamination.
  • antibiotic concentration m ISF depends upon the mode of antibiotic delivery and the total dose of antibiotic.
  • the area under the curve of concentration as a function of time (AUC), the maximum concentration (Crnax) and the duration of time that the antibiotic concentration exceeds the AUC for specific bacteria (T > MIC) are important pharmacokinetic (PK) metrics for bioavailability of antibiotics within subcutaneous adipose tissue.
  • the mode of antibiotic delivery with the greatest AUC, Cmax and T>MIC in subcutaneous tissue is expected to be the most effective at preventing surgical incision site infections.
  • IV AD intravenous antibiotic delivery
  • P penetration ratio
  • ISF freeAUC[ISF]IVAD/freeAUC[SERUM]IVAD.
  • Penetration ratios can be used to compare different drugs or different formulations of the same drug after IV AD.
  • Antibiotic penetration ratio varies widely between different patients and between different tissues and is decreased by surgery, diabetes and obesity. For example, the penetration of an antibiotic is quantitatively different after IV AD among obese patients compared to normal patients.
  • Peri -incisional or intra-incisionai injection of antibiotics has been found to reduce the risk of SSI compared to IV AD.
  • Such techniques for local delivery of antibiotics involve the infiltration of small volumes of antibiotic solution, resulting in a minimal reservoir effect and minimal dispersion into adjacent tissue.
  • Antibiotic solutions introduced by peri- incisionaf or intra-incisionai injection which do not contain a vasoconstrictor drug like epinephrine, are rapidly absorbed with rapid decline of antibiotic concentrations within the targeted tissue.
  • tumescent antibiotic delivery involves the infiltration of a relatively large volume of an antibiotic- containing solution into the subcutaneous compartment, such that the surrounding tissue becomes swOllen and firm, i.e., tumescent
  • a TAD solution comprises one or more antibiotics dissolved in tumescent local anesthesia (TLA), which comprises relatively large volumes of dilute lidocaine ( ⁇ 1 grams/L), epinephrine ( ⁇ 1 milligrams/L), sodium bicarbonate (10 milliequivalents/L) m physiologic saline or lactated Ringer’s solution.
  • TLA tumescent local anesthesia
  • TAD solution The physical and physiologic effects of infiltrating a TAD solution are identical to the effects of a solution of TLA and include prolonged and profound local anesthesia, extensive local epinephrine- induced capillary and venous constriction for surgical hemostasis, hydrostatic pressure- induced capillary and venous compression, inhibition of incisional-trauma-induced platelet activation and delayed systemic absorption of solution components, for example, lidocaine and antibiotics
  • the spread of tumescent fluid within subcutaneous tissue occurs by means of rapid bulk flow through the interstitial gel substance. Efficient infiltration of up to five liters of solution or more into subcutaneous fat may be facilitated by use of specialized infiltration cannulas, peristaltic infiltration pumps and tubing. Equilibration of ISF pressures results in a uniform distribution of tumescent fluid throughout the infiltrated tissues A process of detumescence occurs during 1 to 2 hours following infiltration. The rate of systemic absorption of antibiotics from tumescent subcutaneous tissue is slow as a result of wide spread tumescent vasoconstriction. TAD produces a prolonged large-volume subcutaneous reservoir of an antibiotic solution within a mass of vasoconsticted local tissues.
  • Tumescent techniques were developed for local delivery of to enable liposuction to be done totally by local anesthesia.
  • Tumescent local anesthesia produces profound surgical local anesthesia persisting for more than 6 to 8 hours with peak serum lidocaine concentrations occurring between 10 to 16 hours after completion of the subcutaneous infiltration.
  • 1% or 2% commercial concentrations of lidocaine with epinephrine reliably provide local anesthesia for 2 to 3 hours or less.
  • TLA tumescent local anesthesia
  • Intravenous antibiotic delivery' may not reliably achieve adequate subcutaneous antibiotic concentrations for prevention of surgical site infections (SSIs).
  • Tumescent antimicrobial delivery TAD
  • TLA dilute tumescent lidocaine anesthesia
  • the primary' aim of this research was to measure eefazolm and metronidazole concentrations as a function of time in subcutaneous interstitial fluid after TAD, in serum after TAD and m serum after IV AD.
  • TAD provides uniformly higher subcutaneous antibiotic concentrations compared to IV AD and that the area under the curve (AUC ⁇ ) of the concentration-time profile and the peak concentrations (Cmax) of concomitant TAD+IVAD are superior to IV AD alone for SSI prevention.
  • TAD of Igm of cefazolin resulted m AUG» and Cmax in subcutaneous interstitial fluid 16.5 and 5.6 times greater, respectively, than in serum after Igm by TV AD.
  • TAD of 500mg of metronidazole resulted in AUC ⁇ and Cmax in TISF that was 8.1 and 24.7 times greater, respectively, than in serum after 500mg by IV AD.
  • subcutaneous Cmax is approximately equal to the antibiotic concentration in the TAD solution.
  • Slow systemic absorption after subcutaneous infiltration by TAD resulted in serum antibiotic concentration-time profiles that resemble a slow IV infusion. There were no adverse events or evidence of tissue toxicity associated with TAD.
  • TAD+IVAD provides superior antibiotic bioavailability in both local subcutaneous tumescent interstitial fluid and serum, suggesting TAD+IVAD might improve SSI prevention.
  • tumescent antibiotic deliver alone may be superior to IV drug delivery alone.
  • tumescent interstitial fluid ISF
  • TISF tumescent interstitial fluid
  • TAD is the direct subcutaneous infiltration of antimicrobial drug(s) dissolved in a large volume of a TLA solution.
  • a TLA solution consists of lidocaine ( ⁇ I gm), epinephrine ( ⁇ lmg), and sodium bicarbonate (10 mEq) per liter bag of physiologic saline or lactated Ringer’s solution.
  • Sodium bicarbonate neutralizes the acidic pH of commercial local anesthetics thereby reducing the stinging-pain associated with subcutaneous infiltration of commercial solutions of lidocaine with epinephrine (McKay W, Morris R, Mushlin P.
  • a TLA solution consists of at least a 10-fold dilution of commercial 1% lidocaine with epinephrine 1 : 100,000.
  • Cefazoim and metronidazole were selected because they are water soluble and generally safe, effective and economical for prevention of SSIs (Meyer NL, Hosier KV, Scott K, Lipscomb GH.
  • 201 1 update endorsed by the Infectious Diseases Society of America and the Surgical Infection Society. J Trauma. 201 1 ;71 (2 Suppl 2): S210-34; Cho MJ, Kurtz RR, Lewis C, Machkovech SM, Houser DJ. Metronidazole phosphate— a water-soluble prodrug for parenteral solutions of metronidazole. J Pharm Sci. 1982;71 :410-4).
  • Cefazoim and metronidazole when mixed together in a saline solution for IV delivery, are both chemically stable for at least 72 hours at 8°C (Rivers TE, McBride HA, Trang JM. Stability of cefazolin sodium and metronidazole at 8 degrees C for use as an i.v. admixture. J Parenter Sci Technol. 1993;47: 135-7).
  • Diminishing surgical site infections after colorectal surgery with surgical care improvement project is it time to move on? Dis Colon Rectum. 201 1 ; 54:394-400; Serra-Aracil X, Garcia-Dommgo MI, Pares D, Espin-Basany E, Biondo S, Guirao X, Orrego C, Sitges-Serra A. Surgical site infection in elective operations for colorectal cancer after the application of preventive measures. Arch Surg. 2011 ; 146:606- 12; Owens PL, Barrett ML,Raetzman S, Maggard-Gihhons M, Steiner CA. Surgical site infections following ambulatory surgical procedures. JAMA 2014; 31 1 :709-716).
  • Anesthesiologists are most frequently responsible for administering perioperative antimicrobial prophylaxis (Sinha B, van Assen S, Friedrich AW. Important issues for perioperative systemic antimicrobial prophylaxis in surgery. Curr Opm Anaesthesiol. 2014;27:377-81 ; Roth JV. More reasons why anesthesiologists should administer preoperative antibiotics. Anesthesiology 2004; 101 :258-259).
  • SSI subcutaneous surgical site infections
  • IV AD antibiotic penetration from serum into subcutaneous interstitial fluid at a surgical incision site varies widely between different patients and between different tissues and is decreased by diabetes and obesity.
  • Surgical incision reduces local subcutaneous antibiotic bioavailability following IVAD as the result of capillary hypotension, vasoconstriction, capillary' thrombosis, tissue edema and tissue desiccation (Kennedy MJ, Van Riji A. Effects of surgery on the pharmacokinetic parameters of drugs.
  • TAD is a novel form of drug delivery'.
  • TAD has unexpected local and systemic effects. Wide spread subcutaneous vasoconstriction resulting from a large volume of dilute tumescent epinephrine produces in slow' steady systemic absorption of drugs dissolved in the TLA solution, persistent high local tissue concentrations of the drugs, prolonged local anesthesia and reduced surgical blood loss (Klein JA. Tumescent technique for local anesthesia improves safety in large volume liposuction. Plast Reconstr Surg 1993; 92: 1085- 1098).
  • the mean inhibitory' concentration (MIC) is an ex-vivo predictor of the susceptibility of a specific strain of bacteria to a specific antibiotic. In-vivo predictors of susceptibility of a specific bacterium to a specified antibiotic within a specified tissue depend on both the MIC as well as antibiotic access to the site of infection. Antibiotic access to the site of infection is measured by the area under the curve (AUC ⁇ ) of a drug’s concentration time profile, the drug’s peak concentration (Cmax) and the length of time that the MIC is exceeded by antibiotic concentration (T>MIC) AUC ⁇ , Cmax and T>MIC depend upon the antibiotic’s pharmacokinetic properties, formulation and mode of delivery. In this research AUCoo is used as the metric for bioavaiiability.
  • a second research aim was to determine the correlation between the antibiotic concentration (pg/ml) in a TAD solution and the resulting antibiotic concentration (mg/L) in TISF immediately after TAD. We hypothesized that the respective concentrations are highly correlated and nearly equal.
  • a third research aim was 1) to observe the concentration vs time profiles of cefazolin and metronidazole in serum after rapid IV AD and in TISF after TAD, at equal mg doses and equal mg/L concentrations in the TAD solution.
  • concentration time profiles of these two drugs are different in serum after IV AD and identical in TISF after TAD.
  • a fourth research aim was to document evidence of adverse effects of subcutaneous deliver ⁇ of large volumes of dilute cefazolin, metronidazole, !idocaine and epinephrine. We hypothesize that there would be no evidence of either systemic or local tissue toxicity associated with subcutaneous delivery of these drugs and therefore TAD represents a non-significant risk of harm to patients.
  • a fifth research aim was to observe the serum concentration-time profile of the antibiotics after TAD and subsequent systemic absorption. We hypothesize that, following TAD, the slow systemic absorption of the antibiotics from the subcutaneous TISF would produce a serum concentration-time profile of the antibiotics similar to that of a continuous slow IV infusion.
  • a sixth aim was to apply the present research results to generate new hypotheses that can be tested in future randomized clinical trials comparing tumescent antimicrobial delivery versus IV antimicrobial deliver ⁇ for surgical site infection prophylaxis or for other clinical applications.
  • Eligibility requirements were: good health (ASA I) and good candidate for liposuction, age at least 18, not pregnant, no history of allergy to lidocaine, cefazolin or metronidazole, and good venous access. Exclusion criteria were: current significant health problems, history' or evidence of HIV or Hepatitis C infection and no current use of drugs that block cytochrome P450 3A4 or 1A2 or impair hemostasis.
  • IV AD IV antibiotic delivery
  • TLA tumescent lidocaine anesthesia
  • TAD solution of cefazolin was prepared by withdrawing 10ml of TLA solution and injecting this 10ml into a vial containing lOOOmg of cefazolin powder. The solubilized cefazolin was then re-injected into the TLA solution. Metronidazole for IV delivery is available as 5QQmg in 100ml.
  • TAD with metronidazole was prepared by adding 500mg in 100ml to 1 1 10ml of a TLA solution.
  • a bag of TAD solution with lOOOmg of cefazolin and 500mg of metronidazole contained 1210ml. In other words the TAD solution contained 826mg/L of cefazolin (1000mg/1210ml), 423mg/L of metronidazole
  • TISF aqueous infranate tumescent interstitial fluid
  • the research cohort consisted of non-obese healthy adult females, age range 37-64 years. There were 5 separate studies. Each study consisted of 2 to 3 pharmacokinetic procedures involving an individual subject There were a total of 14 pharmacokinetic procedures.
  • cefazolin concentrations in the TAD solutions ranged from 225mg/L to 900mg/L.
  • metronidazole concentrations in the TAD solutions ranged from 345mg/L or 413mg/L.
  • TAD provides prolonged local subcutaneous antibiotic concentrations, prolonged systemic therapeutic concentrations of antibiotics and lidocaine, prolonged local anesthesia for intraoperative and postoperative analgesia, prolonged local vasoconstriction for surgical hemostasis and local tissue hydration to prevent incision site desiccation.
  • TAD+IVAD provides a pharmacokinetiea!ly superior AUC ⁇ and Cmax compared to TAD alone or IV AD alone with respect to preventing surgical site infections (SSI).
  • TAD alone is pharmacokinetically superior to IV AD alone or TAD+IVAD for preventing SSI while minimizing exposure of the gut microbiota to antibiotics.
  • TAD The antibiotic concentration in TISF immediately after TAD is virtually identical to the antibiotic concentration in the TAD solution. TAD can provides a predictable high initial subcutaneous antibiotic concentration at the site of a proposed surgical incision.
  • TISF tumescent interstitial fluid
  • other drugs for example lidocaine, antiviral, antifungal, or anti-tumor drugs may also demonstrate prolonged high subcutaneous concentrations in TISF after tumescent delivery.
  • TAD may provide safe prolonged extraordinary high concentrations of drugs in subcutaneous TISF where similar concentrations in serum following IVAD would result in significant systemic toxicity. In other words, TAD may be able to achieve localized therapeutic results that would be impossible with IVAD.
  • Inequality 1 Concentrations of cefazolin and metronidazole in ISF after IV AD are always less than, or equal to, their concentrations in serum after IVAD (Muller M, dela Pena A, Derendorf H Minireview: issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue. Antimicrob Agents Chemother, 2004; 48: 1441— 1453; van Kralingen S, Taks M, Diepstraten J, van de Garde EM, van Dongen EP, Wiezer MJ, van Ramshorst B, Vlaminckx B, Deneer VH, Knibbe CA. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients.
  • Inequality 2 Our data show that the concentrations of cefazolin and metronidazole in serum after IVAD are always less than their concentrations in subcutaneous TISF after TAD (within the range of antibiotic concentrations in TAD solution utilized in the present study).
  • Inequality 3 Concentrations of cefazolin and metronidazole in ISF after IVAD are always less than the antibiotic concentrations in TISF after TAD.
  • Dilute lidocame, epinephrine and sodium bicarbonate are essential components of the TAD solution.
  • Dilute epinephrine m a local tumescent antibiotic solution produces delayed systemic absorption of antibiotics, prolonged localized high concentrations of antibiotics, long-lasting local capillary vasoconstriction and incision-site hemostasis.
  • Dilute lidocaine eliminates the pain of subcutaneous antibiotic injection.
  • lidocaine Systemic administration of lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol-remifentanil-based anaesthesia. Eur J Anaesthesiol. 2010; 27: 41-46). Lidocaine is has bactericidal effects (Sakuragi T, ishino H, Dan K. Bactericidal activity of clinically used local anesthetics on Staphylococcus aureus. Reg Anesth. 21 : 239-42, 1996; Parr AM, Zoutman DE, Davidson JS. Antimicrobial activity of lidocaine against bacteria associated with nosocomial wound infection. Ann Plast Surg.
  • IV AD provides approximately 160 (10 x 16) times less subcutaneous bioavailability (of cefoxitin or cefazoim) than does TAD for a significant proportion of patients. Note that TAD produces such an extreme dilution of subcutaneous interstitial fluid that essentially all antibiotic in TISF can be regarded as unbound protein-free.
  • TAD tumescent antibiotic delivery
  • Table 16A Cefazolin, Abdomen Table 16B. Metronidazole, Abdomen
  • Table 17 Dose, concentration and volumes of cefazo!in, lidocaine in the TAD solutions.
  • Table 18 Dose, concentration and volumes of cefazoiin, metronidazole, lidocaine in the tumescent antimicrobial delivery (TAD) solutions and by intravenous antimicrobial delivery' (IVAD).
  • Subcutaneous TI of Acyclovir (lgm acyclovir in 1130ml of tumescent lidocaine solution) resulted in: 1) no stinging upon injection, 2) no ecchymosis and 3) no local tenderness upon palpation in 6 of 6 subjects.
  • Subcutaneous TI of Gentamicin (80mg in 1110ml of tumescent lidocaine solution) resulted in: 1) no stinging upon in j ection but with 9 to 12 hours of transient erythema and edema, 2) no ecchymosis and 3) no local tenderness upon palpation in 6 of 6 subjects.
  • Bacteriostatic saline 1% benzyl alcohol
  • Bacteriostatic saline is commonly used as a vehicle for intradermal and subcutaneous drug injections. It is known that 1% benzoyl alcohol is bacteriostatic and provides brief (30 seconds) of local anesthesia. It is not well recognized that 1% benzoyl causes relatively intense subcutaneous inflammation, ecchymosis and prolonged tenderness.
  • NP chronic neuropathic pain
  • TLA Tumescent lidocaine anesthesia
  • Precipitating factors for NP typically involve intense pain, or traumatic and inflammatory damage to peripheral nerves. (Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain; risk factors and prevention. Lancet. 2006; 367: 1618-25).
  • TLA provides local (peripheral nervous system) anesthetic effects by eliminating painful sensor ⁇ neural stimuli and acting as a potent local anti-inflammatory.
  • TLA concomitantly provides distant (central nervous system) effects as a result of slow steady systemic lidocaine absorption from tumescent subcutaneous tissues.
  • TLA provides preoperative intraoperative and prolonged postoperative local anesthesia all of which are important to treating postoperative pain.
  • TLA provides potent anti-inflammatory effects on immune cells and molecules involved in the pathophysiology of peripheral neuropathic pain.
  • TLA can attenuate the severity of neuropathic pain (traumatic wounds) and traumatic neural damage (spinal cord injury) by simultaneously treating the local (direct) inflammatory damage to peripheral sensory nerves and treating distant (central) neural inflammation.
  • Macrophages comprise the most important cellular component in inflammation-mediated neuropathic pain. (Thacker MA, Clark AK, Marchand F, McMahon SB. Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg. 2007; 105: 838-47).
  • Lidocaine inhibits macrophage function and inhibits macrophage mediated inflammation.
  • Inhibition of toll-like receptor-4, nuclear factor-kappaB and mitogen-activated protein kinase by iignocaine may involve voltage-sensitive sodium channels.
  • IV lidocaine for palliative care of opioid-refractory cancer pain with a neuropathic component is an effective therapeutic option. Tumescent infiltration of lidocaine is uniquely effective in providing both local anesthesia and systemic analgesia.
  • Tumescent Lidocaine Anesthesia produces both long lasting local anesthesia and prolonged slow systemic lidocaine absorption with serum lidocaine concentrations ranging from 1 to 4pg/ml.
  • serum lidocaine concentrations ranging from 1 to 4pg/ml.
  • systemic lidocaine absorption following TLA is clinically equivalent to a slow continuous IV infusion.
  • IV lidocaine infusion produces effective perioperative analgesia.
  • IV lidocaine provides effective postoperative analgesia after laparoscopic cholecystectomy.
  • Ram D Sistla SC, Karthikeyan VS, Ali SM, Badhe AS, Mahalakshmy T. Comparison of intravenous and intraperitoneal Iignocaine for pain relief following laparoscopic cholecystectomy: a double-blind, randomized, clinical trial. Surg Endosc. 2014; 28: 1291-7).
  • IV lidocaine significantly improves postoperative pain after complex spine surgery ' .
  • Drag E Ghobrial M, Sessler DI, Dalton JE, Liu I, Lee JH, Zaky S, Benzel E, Bingaman W, Kurz A. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery'. Anesthesiology. 2013; 119: 932-40).
  • lidocaine improves preoperative and intraoperative analgesia and reduces surgery-induced immune alterations.
  • Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H The effect of perioperative intravenous lidocaine on postoperative pain and immune function Anesth Analg. 2009; 109: 1464-9)
  • Serum lidocaine concentrations of 2 to 5 micrograms/ml are effective following subcutaneous infiltration of lidocaine for treatment of cancer neuropathic pain.
  • IV Lidocaine provided complete analgesia for neuropathic pain at a mean serum lidocaine concentration of 3.79 ⁇ 1.00 pg/ml. (Ferrante FM, Paggioli J, Cherukuri S, Arthur GR. The analgesic response to intravenous lidocaine in the treatment of neuropathic pam. Anesth Analg. 1996; 82: 91-7).
  • Tumescent Infiltration prevents systemic inflammation and sepsis.
  • Tumescent infiltration of lidocaine combined with tumescent antibiotics has potent any inflammatory effects.
  • Lidocaine has long been known to have significant anti-inflammatory properties.
  • Tumescent infiltration (TI) antibiotic delivery has the potential to significantly reduce the risk of sepsis and inappropriate systemic inflammatory response including organ failure and adult respiratory distress syndrome (ARDS).
  • ARDS adult respiratory distress syndrome
  • TLA delivers interstitial lidocaine concentrations (1000pg/ml) that are nearly 200 times greater than clinically safe serum lidocaine concentrations ( ⁇ 5 pg/ml).
  • TLA provides very high concentrations of subcutaneous lidocaine throughout a large volume of tissue at the site of a surgical incision and thus profoundly inhibits local platelet activation, neutrophil priming, platelet-leukocyte aggregation (PLA) and endothelial-platelet and endothelial-leukocyte inflammatory interactions.
  • TLA prevents the contents of cells that have been ruptured by infection, surgeiy, or trauma, including bum or combat injury, from flooding the systemic circulation and precipitating an excessive inflammatory response.
  • Lidocaine can reduce a systemic inflammatory response.
  • Tumescent antibiotic delivery provides local interstitial antibiotic bioavailability that can be 10 to 100 times grater than that provided by IV antibiotic delivery'. Tims TAD is more effective than IV delivery for preventing of surgical site infections and treating localized life-threatening cutaneous infections (e.g. cellulitis in a diabetic or necrotizing soft tissue infections in a traumatic combat injury), both of which are commonly associated with sepsis.
  • ⁇ antibiotic delivery produces a concentration-time profile that resembles that of a prolonged slow constant IV antibiotic infusion.
  • Seram antibiotic concentrations persist far longer following II antibiotic delivery than after a single rapid IV infusion of antibiotics.
  • T! antibiotic delivery by itself or II + IV antibiotic delivery' can achieve more effective systemic effects and better reduce the risk of sepsis than IV delivery alone.
  • Lidocaine reduces platelet activation, platelet aggregation and platelet- leukocyte aggregation in a concentration-dependent fashion. Recent evidence suggests there is a critical connection between infection, ceil damage, inflammation and coagulation.
  • Intracellular contents which are known to be potent triggers of systemic inflammation and thrombosis include mitochondria cell free DMA, chromatin DNA-histone complexes, extracellular RNA, neutrophil extracellular traps (NETs), polyphosphates secreted from platelet dense granules, and leukocyte contents.
  • mitochondria cell free DMA mitochondria cell free DMA
  • chromatin DNA-histone complexes extracellular RNA
  • neutrophil extracellular traps (NETs) polyphosphates secreted from platelet dense granules
  • leukocyte contents include mitochondria cell free DMA, chromatin DNA-histone complexes, extracellular RNA, neutrophil extracellular traps (NETs), polyphosphates secreted from platelet dense granules, and leukocyte contents.
  • NETs neutrophil extracellular traps
  • lidocaine Slow' constant IV infusion of lidocaine may decrease the inappropriate leukocyte activation, transmigration across capillary endothelium, interstitial positioning, and recruitment during sepsis.
  • Lidocaine inhibits platelet activation, platelet activation of neutrophils and neutrophil mediated inflammation. Inappropriate activation of neutrophils contributes to tissue damage during inflammatory diseases.
  • tumescence delays the systemic absorption of lidocaine and antibiotics
  • the physical isolation produced by tumescent infiltration can delay the systemic absorption of intracellular contents and prevent an excessively rapid systemic exposure to these inflammatory and thrombogenic molecules.
  • Lidocaine priming reduces ADP-induced P-seleetin expression and platelet-leukocyte aggregation. Acta Anaesthesiol Taiwan. 47:56-61,2009; Futosi Kl, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways hit Immunopharmacol. 2013;17:638-50; Berger C, Rossaint J, Van Aken H, Westphal M, Hahnenkamp K, Zarbock A.
  • Lidocaine reduces neutrophil recruitment by abolishing chemokine-induced arrest and transendothelial migration in septic patients.
  • Lidocaine Reduces Neutrophil Recruitment by Abolishing Chemokine-induced Arrest and Transendothelial Migration in Septic Patients. J Immunology , 2014;192:367-376; Kawasaki C, Kawasaki T, Ogata M, Sata T, Chaudry ⁇ H.
  • Lidocaine enhances apoptosis and suppresses mitochondrial functions of human neutrophils in vitro. J Trauma.
  • lidocaine on in vitro neutrophil and endothelial adhesion molecule expression induced by plasma obtained during tourniquet- induced ischaemia and reperfusion.
  • Lidocaine attenuates cytokine-induced cell injury in endothelial and vascular smooth muscle cells.
  • NETs Neutrophil extracellular traps
  • Platelet TLK4 activates NETs to ensnare bacteria in septic blood (Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen- Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P.
  • Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463-9; Sun H, Wang X, Degen JL, Ginsburg D.
  • IL-10 Interleukin- 10
  • Lidoeaine increases the anti-inflammatory cytokine IL-10 following mechanical ventilation in healthy mice. Acta Anaesthesiol Seand. 2015; 59: 47-55).
  • lidoeaine 100-fold higher than safe serum lidoeaine concentrations ( ⁇ 5pg/mi) effectively reduced reactive oxygen species (ROS) production by human neutrophils.
  • Therapeutic serum lidoeaine concentrations have no effect on ROS.
  • Concentration of lidoeaine in TLA solution and peak lidoeaine concentrations in tumescent subcutaneous interstitial fluid is between SOOpg/mi and 1000pg/ml (Mikawa K, Akamatsu H, Nishina K, Shiga M, Maekawa N, Obara H, Niwa Y. Inhibitory effect of local anaesthetics on reactive oxygen species production by human neutrophils. Acta Anaesthesiol Scand. 1997; 41: 524-8).
  • Pretreatment with intravenous lidoeaine attenuates the inflammatory lung injury induced by the pancreatic enzymes or hydrochloric acid (Kiyonari Y, Nishina K, Mikawa K, Maekawa N, Obara H. Lidoeaine attenuates acute lung injury induced by a combination of phospholipase A2 and trypsin. Crit Care Med. 2000; 28: 484-489; Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, Obara H. Intravenous lidoeaine attenuates acute lung injury induced by hydrochloric acid aspiration in rabbits. Anesthesiology. 1998; 88: 1300-9).
  • phrases“at least one of’ is intended to require at least one item from the subsequent listing, not one type of each item from each item in the subsequent listing.
  • “at least one of A, B, and C” can include A, B, C, A and B, A and C, B and C, or A, B, and C.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
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  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne une composition tumescente comprenant un cannabinoïde dissous dans une solution tumescente, la solution tumescente comprenant un anesthésique local ; un vasoconstricteur ; et un support pharmaceutiquement acceptable, une concentration tumescente du cannabinoïde étant de 1 à 2 000 mg/kg et étant simultanément : en dessous d'un seuil de toxicité locale, sous-cutanée de tissu, au-dessus d'un seuil pour un effet thérapeutique local positif, et au-dessus d'une concentration pouvant être obtenue en toute sécurité par administration intraveineuse (IV), intramusculaire (IM) ou orale (PO).
PCT/US2020/015963 2019-01-31 2020-01-30 Administration de cannabinoïdes par infiltration tumescente WO2020160328A1 (fr)

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Cited By (1)

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US20170360772A1 (en) * 2008-01-09 2017-12-21 Charleston Laboratories, Inc. Pharmaceutical compositions
US20160030387A1 (en) * 2011-07-11 2016-02-04 Full Spectrum Laboratories Limited Cannabinoid formulations
US20170100331A1 (en) * 2015-10-12 2017-04-13 Jeffrey Alan KLEIN Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11696890B2 (en) 2015-10-12 2023-07-11 Hk Pharma Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity
US11723859B2 (en) 2015-10-12 2023-08-15 Hk Pharma Tumescent infiltration drug delivery of high subcutaneous drug concentrations with prolonged local and systemic effects and minimal local or systemic toxicity

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