US20070248639A1 - Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures - Google Patents

Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures Download PDF

Info

Publication number
US20070248639A1
US20070248639A1 US11/378,618 US37861806A US2007248639A1 US 20070248639 A1 US20070248639 A1 US 20070248639A1 US 37861806 A US37861806 A US 37861806A US 2007248639 A1 US2007248639 A1 US 2007248639A1
Authority
US
United States
Prior art keywords
composition
ketoprofen
nifedipine
urinary tract
spasm
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/378,618
Other languages
English (en)
Inventor
Gregory Demopulos
Jeffrey Herz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Omeros Corp
Original Assignee
Omeros Medical Systems Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Omeros Medical Systems Inc filed Critical Omeros Medical Systems Inc
Priority to US11/378,618 priority Critical patent/US20070248639A1/en
Assigned to OMEROS CORPORATION reassignment OMEROS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEMOPULOS, GREGORY A., M.D., HERZ, JEFFREY M., PH.D.
Publication of US20070248639A1 publication Critical patent/US20070248639A1/en
Priority to US13/454,926 priority patent/US20120238940A1/en
Priority to US14/199,144 priority patent/US20140212460A1/en
Priority to US14/947,107 priority patent/US20160166555A1/en
Priority to US15/981,450 priority patent/US20190083477A1/en
Priority to US17/223,836 priority patent/US20210290605A1/en
Priority to US17/454,583 priority patent/US20220062252A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists

Definitions

  • the present invention relates to pharmaceutical compositions for administration to the urinary tract during urological diagnostic, interventional, surgical and other medical procedures and for therapeutic treatment of urologic structures.
  • urological procedures are now performed using minimally invasive endoscopic (e.g., cystoscopic or uteroscopic) techniques. These include examination of the urethra, bladder and ureters, therapeutic treatments for benign prostatic hypertrophy, removal or fragmentation of kidney and bladder stones, the placement of urethral or ureteral stents to facilitate the passage of stones, the performance of biopsies and the excision of tumors. While less invasive than open surgery, these techniques involve procedural irritation and trauma to the urinary tract leading to pain, inflammation and smooth muscle spasm. Postoperative lower urinary tract symptoms (LUTS) following urological procedures often include pain, hyperreflexia (unstable bladder contractions), urinary frequency, nocturia and urgency, and in some cases urinary retention requiring prolonged catheterization.
  • LUTS postoperative lower urinary tract symptoms
  • Urological procedures are often performed with concurrent irrigation of the urinary tract, to remove blood and tissue debris so that a clear endoscopic field of view is maintained.
  • Conventional irrigation solutions include saline, lactated Ringer's, glycine, sorbitol, manitol and sorbitol/manitol. These conventional irrigation solutions do not contain active pharmaceutical agents.
  • U.S. Pat. No. 5,858,017 to Demopulos, et al. discloses surgical irrigation solutions and methods for the inhibition of pain, inflammation and/or spasm.
  • the use of irrigation solutions containing pain/inflammation inhibitors and anti-spasm agents during urological procedures in general and during TURP specifically is disclosed, including five-drug and nine-drug combinations.
  • This reference does not teach optimized pairings of a pain/inflammation inhibitory agent with an anti-spasm agent for given urological procedures.
  • the present invention provides a locally deliverable composition for inhibiting pain/inflammation and spasm, comprising a combination of ketoprofen and a calcium channel antagonist in a carrier.
  • Ketoprofen and the calcium channel antagonist are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm at a site of local delivery.
  • a locally deliverable composition for inhibiting pain/inflammation and spasm comprises a combination of a cyclooxygenase inhibitor and a calcium channel antagonist, propyl gallate as a stabilizing agent and a liquid carrier.
  • Each active agent is included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm at a site of local delivery.
  • a locally deliverable composition for inhibiting pain/inflammation and spasm comprises a combination of a cyclooxygenase inhibitor and a calcium channel antagonist an aqueous liquid carrier, a cosolvent, at least one stabilizing agent and a buffer.
  • Each active agent is included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm at a site of local delivery.
  • a further aspect of the present invention provides a method of inhibiting pain/inflammation and spasm in the urinary tract, comprising delivering to the urinary tract a composition including a combination of ketoprofen and a calcium channel antagonist in a carrier.
  • Ketoprofen and the calcium channel antagonist are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain/inflammation and spasm in the urinary tract during a diagnostic, interventional, surgical or other medical urological procedure, comprising periprocedurally delivering to the urinary tract during a urological procedure a composition including a combination of ketoprofen and nifedipine in a carrier.
  • Ketoprofen and nifedipine are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to the urinary tract during a ureteroscopic procedure a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier.
  • the cyclooxygenase inhibitor and the calcium channel antagonist are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to the urinary tract during a procedure to remove, fragment or dislodge a kidney or bladder stone a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier.
  • the cyclooxygenase inhibitor and the calcium channel antagonist are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to a urologic structure during a procedure that causes thermal injury to urinary tract tissue a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier.
  • the cyclooxygenase inhibitor and the calcium channel antagonist are each included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to a urologic structure during a ureteroscopic procedure a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier. Each agent is included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to a urologic structure during a procedure to remove, fragment or dislodge a kidney or bladder stone a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier. Each agent is included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.
  • a still further aspect of the present invention provides a method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising periprocedurally delivering to a urologic structure during a procedure that causes thermal injury to urinary tract tissue a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier. Each agent is included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.
  • FIG. 1 provides a model for action of prostaglandin activity.
  • FIG. 2 illustrates the bradykinin and substance P cumulative concentration-response curves obtained from normal animals in Example I.
  • FIG. 3A illustrates bradykinin concentration-response curves produced in the presence of 0.25, 1.0, 2.5 and 10 ⁇ M ketoprofen from Example I;
  • FIG. 3B illustrates the Schild plot for pA2 analysis of ketoprofen from Example I.
  • FIG. 4A demonstrates that bradykinin rapidly induces the formation of PGE 2 in rat bladder tissue strips tested in Example I within the first minutes of stimulation and reaches a maximum within 30 minutes, with a t 1/2 for formation of about 7.5 minutes.
  • FIG. 4B illustrates the rapid kinetics of PGE 2 formation detected within minutes in Example I.
  • FIG. 5A illustrates that intravenous aspirin (10 mg/kg) produced a gradual time-dependent inhibition of the acetic acid induced reduction in the intercontraction interval (ICI), and FIG. 5B illustrates the parallel changes in bladder capacity, from Example I.
  • ICI intercontraction interval
  • FIG. 6 shows the effect of increasing concentrations of nifedipine on contractility of rat bladder strips from Example II.
  • FIG. 7 shows the combined effect of nifedipine (0.1 ⁇ M) and ketoprofen (0.3-3.0 ⁇ M) on bradykinin-stimulated contractility of rat bladder strips from Example III.
  • FIG. 8 shows the combined effect of nifedipine (0.3 ⁇ M) and ketoprofen (0.3-3.0 ⁇ M) on bradykinin-stimulated contractility of rat bladder strips from Example III.
  • FIG. 9 shows the combined effect of nifedipine (1.0 ⁇ M) and ketoprofen (0.3-3.0 ⁇ M) on bradykinin-stimulated contractility of rat bladder strips from Example III.
  • FIG. 10 illustrates the concentration-response surface (reduced model) of individual tension values from dose response curves corresponding to 30 ⁇ M bradykinin-induced tension in rat bladder strips from Example III.
  • FIG. 11 shows the effect of ketoprofen (10 ⁇ M) and nifedipine (1 ⁇ M), individually, on multiple agonist-stimulated tension in rat bladder tissue strips from Example IV.
  • FIG. 12 shows the effect of ketoprofen (10 ⁇ M) and nifedipine (1 ⁇ M), individually, on bradykinin-stimulated PGE 2 release from rat bladder tissue strips from Example IV.
  • FIG. 13 shows a rat bladder cystometry tracing demonstrating the effect of acetic acid perfused as described in Example V.
  • FIG. 14 demonstrates the effect of ketoprofen pretreatment on acetic acid-induced bladder hyperactivity from Example V.
  • FIG. 15 demonstrates the effect of nifedipine pretreatment on acetic acid-induced bladder hyperactivity from Example V.
  • FIG. 16 illustrates mean ketoprofen plasma levels for rats treated with ketoprofen or a combination of ketoprofen and nifedipine in the pharmacokinetic study of Example VI.
  • FIG. 17 illustrates mean nifedipine plasma levels for rats treated with nifedipine or a combination of ketoprofen and nifedipine in the pharmacokinetic study of Example VI.
  • FIG. 18 illustrates the effects of nifedipine, ketoprofen and a combination of nifedipine and ketoprofen on PGE 2 in rat bladders from the pharmacokinetic study of Example VI.
  • FIG. 19 shows a chromatogram of a nifedipine and ketoprofen formulation F 1 in accordance with Example VIII after having been stressed at 60° C. for 1 month.
  • the present invention provides methods and compositions for inhibiting pain, inflammation and/or spasm during urological procedures by locally delivering such compositions to structures of the urological tract during the procedure.
  • the compositions include at least one agent that is a pain/inflammation inhibitory agent or a spasm inhibitory agent, or that acts to inhibit both pain/inflammation and spasm.
  • the compositions and methods of the present invention include two or more pain/inflammation inhibitory or spasm inhibitory agents that act on different molecular targets (i.e., enzymes, receptors or ion channels) or that act through different mechanisms of action. More preferably, the compositions of the present invention include at least one pain/inflammation inhibitory agent and at least one spasm inhibitory agent.
  • pain/inflammation inhibitory agent includes analgesic agents (i.e., antinociceptive agents), non-steroidal agents that inhibit inflammation [including both “non-steroidal anti-inflammatory drugs” (i.e., NSAIDS or cyclooxygenase inhibitors) and other agents that are not steroidal that act to inhibit inflammation], corticosteroids and local anesthetics.
  • analgesic agents i.e., antinociceptive agents
  • non-steroidal anti-inflammatory drugs i.e., NSAIDS or cyclooxygenase inhibitors
  • spasm inhibitory agent includes agents that inhibit spasm or contraction of smooth muscle tissue and agents that inhibit spasm or contraction of other muscle tissue associated with the urinary tract (e.g., prostatic muscle tissue).
  • Another aspect of the present invention is directed to the periprocedural delivery to the urinary tract of a cyclooxygenase (COX) inhibitor, suitably a non-selective COX-1/COX-2 inhibitor, preferably a non-selective COX-1/COX-2 inhibitor that is a propionic acid derivative, more preferably ketoprofen, alone or with at least one additional agent that inhibits pain/inflammation and/or that inhibits spasm, such as a calcium channel antagonist.
  • COX cyclooxygenase
  • a calcium channel antagonist i.e., a calcium channel blocker
  • an L-type calcium antagonist preferably a dihydropyridine calcium channel antagonist, more preferably nifedipine, alone or with at least one additional agent that inhibits pain/inflammation and/or that inhibits spasm, such as a COX inhibitor.
  • Another aspect of the present invention is directed to the periprocedural delivery to the urinary tract of a combination of a COX inhibitor and a calcium channel antagonist, preferably a non-selective COX-1/COX-2 inhibitor in combination with an L-type calcium antagonist, more preferably ketoprofen in combination with nifedipine.
  • Ketoprofen and nifedipine have been found by the present inventors to provide greater than additive or synergistic results in the inhibition of bladder spasm, as described in the examples below.
  • One aspect of the present invention entails the local delivery of the compositions of the present invention to the bladder, ureter, urethra, or other urinary tract structures to inhibit pain, inflammation and/or smooth muscle spasm during urological therapeutic, diagnostic, interventional, surgical and other medical procedures.
  • urinary tract and “urinary system” refer to the kidneys, ureters, bladder, urethra and associated nerves, blood vessels and muscles.
  • lower urinary tract refers to the bladder and urethra and associated nerves, blood vessels and muscles.
  • a further aspect of the present invention entails the local delivery of the compositions of the present invention to urinary tract structures to reduce postoperative irritative voiding symptoms (e.g., void frequency, nocturia, urgency), pain and/or other lower urinary tract symptoms following such urological procedures.
  • postoperative irritative voiding symptoms e.g., void frequency, nocturia, urgency
  • a further aspect of the present invention entails the local delivery of the compositions of the present invention to urinary tract structures to improve postoperative urinary function (e.g., decrease undesirable urinary retention) following such urological procedures.
  • compositions of the present invention are suitably delivered to the urinary tract before, during and/or after urological procedures, i.e., before (pre-) procedurally, during (intra-) procedurally, after (post-) procedurally, pre- and intraprocedurally, pre- and postprocedurally, intra- and postprocedurally or pre-, intra- and postprocedurally.
  • the compositions of the present invention are locally delivered to the urinary tract “periprocedurally”, which as used herein means intraprocedurally, pre- and intraprocedurally, intra- and postprocedurally or pre-, intra- and postprocedurally.
  • Periprocedural delivery may be either continuous or intermittent during the procedure.
  • the compositions of the present invention are delivered “continuously” during the procedure, which as used herein means delivery so as to maintain an approximately constant concentration of active agent(s) at the local delivery site.
  • the term “perioperatively” may be used interchangeably with periprocedurally herein.
  • the compositions of the present invention are delivered periprocedurely during the period of time when surgical or other procedural trauma and irritation is being incurred by urinary tract tissue.
  • “Local” delivery of the compositions of the present invention to the urinary tract as used herein refers to delivery of the compositions directly to one or more structures of the urinary tract.
  • the therapeutic agent(s) contained in the locally delivered compositions are not subject to first and/or second pass metabolism before reaching the local site of intended therapeutic (e.g., inhibitory) effect, in contrast to systemically delivered drugs.
  • the trauma of urological procedures results in an acute, localized inflammatory response in the associated urological structures. Inflammation is associated with a complex pattern of biochemical and cellular processes occurring at the local site, involving positive-feedback interactions between the peripheral nervous system, immune cells, the local vasculature and the central nervous system.
  • the inflammatory response to procedural trauma in the urinary tract includes cytokine release, inflammatory cell migration, edema, pain and hyperalgesia.
  • inflammatory mediators that have been described in the lower urinary tract include tachykinins and ATP (from C-fibers) (Maggi, C., et al., Tachkykinin Antagonists and Capsaicin - Induced Contraction of the Rat Isolated Urinay Bladder: Evidence for Tachykinin - Mediated Cotransmission, Br. J. Pharmacol. 103:1535-41 (1991), CGRP (from C-fibers), serotonin (from mast cells and platelets), and endothelin.
  • tachykinins and ATP from C-fibers
  • CGRP from C-fibers
  • serotonin from mast cells and platelets
  • endothelin endothelin.
  • Capsaicin-sensitive afferent fiber stimulation elicits a local efferent response, which is characterized by release of neuropeptides (tachykinins and CGRP) from nerve endings. This release produces a number of local responses, which are part of the pathophysiological effects in the lower urinary tract.
  • the pathophysiologic response to procedural trauma of the urinary tract involves a complex cascade of molecular signaling and biochemical changes resulting in inflammation, pain, spasm and lower urinary tract symptoms. These are preferably addressed in accordance with the methods and compositions of the present invention by locally and periprocedurally delivering a combination of pharmacologic agents acting on multiple molecular targets to inhibit pain, inflammation and/or spasm.
  • Preferred agents include cyclooxygenase inhibitors and calcium channel antagonists, more preferably in combination.
  • Prostaglandins are produced throughout the lower urinary tract and play a role in neurotransmission, bladder contractility and inflammatory responses.
  • Human bladder mucosa has been found to contain several types of prostaglandins, which have been shown to contract the human detrusor.
  • Prostaglandin E 2 (PGE 2 ) is a potent mediator of pain and edema, and the exogenous administration of PGE 2 induces contractile responses in inflamed bladders.
  • Intravesical PGE 2 produces both urgency and involuntary bladder contractions.
  • Lepor, H. The Pathophysiology of Lower Urinary Tract Symptoms in the Ageing Male Population, Br.
  • Prostanoids may, via release of tachykinins, contribute to both urge and bladder hyperactivity seen in inflammatory conditions of the lower urinary tract. While not wishing to be limited by theory, these actions are most likely mediated through activation of specific prostanoid receptor subtypes (EP1R) located on C-fibers and on bladder smooth muscle ( FIG. 1 ).
  • EP1R prostanoid receptor subtypes
  • bradykinin is a well-established mediator of inflammation, and bradykinin receptor agonists stimulate greater PGE 2 production in inflamed bladders than in control bladders.
  • Topical application of bradykinin activates bladder sensory nerves. Lecci, A., et al., Kinin B 1 Receptor - Mediated Motor Responses in Normal or Inflamed Rat Urinary Bladder in Vivo, Regul. Pept.
  • Microvascular leakage induced by administration of substance P acting through the NK1 receptor also involves the release of cyclooxygenase metabolites of arachidonic acid.
  • Abelli, L., et al. Microvascular Leakage Induced by Substance P in Rat Urinary Bladder: Involvement of Cyclo - oxygenase Metabolites of Arachidonic Acid, J. Auton. Pharmacol. 12:269-76 (1992).
  • COX-2 is the major isoform that is rapidly expressed and dramatically up-regulated during bladder inflammation. It is believed to be responsible for the high levels of prostanoids released during acute and chronic inflammation of the bladder. COX-2 is up-regulated in response to proinflammatory cytokines and bladder treatment with either endotoxin or cyclophosphamide. Both COX isozymes are therefore suitable molecular targets for the drug compositions of the present invention.
  • An aspect of the present invention is directed to therapeutic compositions including a cyclooxygenase inhibitor in a carrier suitable for local delivery to urologic structures in the urinary tract. To achieve maximal inhibition of prostaglandin synthesis at sites of acute inflammation, it is believed desirable to inhibit both COX isoenzymes.
  • the COX inhibitor is therefore preferably non-selective with respect to activity at COX-1 and COX-2, which for purposes of the present invention may be defined as an agent for which the ratio of (a) the concentration of the agent effective for the inhibition of 50% (IC50) of the activity of COX-1 relative to (b) the IC50 for the inhibition of the activity of COX-2 is greater than or equal to 0.1 and less than or equal to 10.0, and more preferably is greater than or equal to 0.1 and less than or equal to 1.0.
  • Suitable assays for determining COX-1 and COX-2 inhibitory effect are disclosed in Riendau, D., et al., Comparison of the Cyclooxygenase -1 Inhibitory Properties of Nonsteroidal Anti - inflammatory Drugs (NSAIDs ) and Selective COX -2 Inhibitors, Using Sensitive Microsomal and Platelet Assays, Can. J. Physiol. Pharmacol. 75:1088-1095 (1997).
  • Suitable non-selective COX-1/COX-2 inhibitors include, for purposes of illustration, salicylic acid derivatives including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine, para-aminophenol derivatives such as acetaminophen, indole and indene acetic acids such as indomethacin and sulindac, heteroaryl acetic acids including tolmetin, diclofenac and keterolac, arylpropionic acids including ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin, anthranilic acids (fenamates) including mefanamic acid and meclofenamic acid, enolic acids including oxicams such as piroxicam and meloxicam and alkanones such as nabu
  • the non-selective COX-1/COX-2 inhibitor is an arylpropionic acid, i.e., a propionic acid derivative, such as ketoprofen, dexketoprofen, ibuprofen, naproxen, flurbiprofen, fenoprofen and oxaprozin.
  • the agent is ketoprofen.
  • the non-selective COX-1/COX-2 inhibitor used in the compositions and methods of the present invention is selected as having an IC50 for the inhibition of bradykinin-induced bladder smooth-muscle strip contractility (as determined by the bladder contractility model described herein below) of less than or equal to 100 ⁇ M, preferably less than or equal to 25 ⁇ M, more preferably less than or equal to 5 ⁇ M, still more preferably less than 2 ⁇ M.
  • the non-selective COX-1/COX-2 inhibitor used in the compositions and methods of the present invention is selected as having an IC50 for the inhibition of bradykinin-induced prostaglandin E 2 (PGE 2 ) (as determined by the PGE 2 bladder tissue analysis model described herein below) of less than or equal to 100 ⁇ M, preferably less than or equal to 25 ⁇ M, more preferably less than or equal to 5 ⁇ M, still more preferably less than 2 ⁇ M.
  • PGE 2 bradykinin-induced prostaglandin E 2
  • the non-selective COX-1/COX-2 inhibitor used in the compositions and methods of the present invention is selected as having (a) an IC50 for the inhibition of bradykinin-induced bladder smooth-muscle strip contractility (as determined by the bladder contractility model described herein below) of less than or equal to 100 ⁇ M , preferably less than or equal to 25 ⁇ M, more preferably less than or equal to 5 ⁇ M, still more preferably less than 2 ⁇ M, and (b) an IC50 for the inhibition of bradykinin-induced PGE 2 (as determined by the PGE 2 bladder tissue analysis model described herein below) of less than or equal to 100 ⁇ M, preferably less than or equal to 25 ⁇ M, more preferably less that or equal to 5 ⁇ M, still more preferably less than 2 ⁇ M.
  • IC50 concentrations are not to be interpreted as limitations on drug concentrations in the compositions of the present invention, which may suitably be determined by the concentrations needed to approach maximal effectiveness and thus may be higher than the IC50 levels.
  • the non-selective COX-1/COX-2 inhibitor used in the compositions and methods of the present invention is selected as having a pA 2 (antagonist potency) of greater than or equal to 7, wherein pA 2 is the negative logarithm of the concentration of antagonist that would produce a 2-fold shift in the concentration response curve for an agonist, and is a logarithmic measure of the potency of an antagonist.
  • This potency corresponds to an equilibrium dissociation constant K D of less than or equal to 100 nM.
  • the non-selective COX-1/COX-2 inhibitor used in the compositions and methods of the present invention exhibits 50% of maximal inhibitory response in less than or equal to 10 minutes in a kinetic study of bradykinin-stimulated PGE 2 response in the PGE 2 bladder tissue analysis model described herein below.
  • ketoprofen i.e., m-benzoylhydratropic acid or 3-benzoyl- ⁇ -methylbenzeneacetic acid
  • references herein to the use of ketoprofen i.e., m-benzoylhydratropic acid or 3-benzoyl- ⁇ -methylbenzeneacetic acid
  • ketoprofen in the present invention are to be understood to also include pharmaceutically acceptable isomers thereof, including its racemic S-(+)-enantiomer, dexketoprofen, pharmaceutically acceptable salts or esters thereof, and pharmaceutically acceptable prodrugs or conjugates thereof
  • Ketoprofen is a preferred COX inhibitor for use in the present invention.
  • Ketoprofen exhibits potent anti-inflammatory, analgesic, and antipyretic actions that are associated with the inhibition of prostaglandin synthesis and antagonism of the effects of bradykinin.
  • Ketoprofen non-selectively inhibits the activity of COX-1 and COX-2, which results in the blockade of prostaglandin production, particularly that of PGE 2 , preventing the development of hyperalgesia.
  • Ketoprofen has an IC 50 value of 4-8 nM in a non-selective COX assay, being functionally 6-12 times more potent than other NSAIDs evaluated (e.g., naproxen or indomethacin).
  • Ketoprofen A review of its Pharmacologic and Clinical Properties, Pharmacotherapy 6:93-103 (1986). Ketoprofen also has functional bradykinin antagonist activity, its effects being eight times greater than those seen with the classical NSAID, indomethacin. Julou, L., et al., Ketoprofen (19.583 R.P. ) (2-(3- Benzoylphenyl )- propionic acid ). Main Pharmacological Properties—Outline of Toxicological and Pharmacokinetic Data, Scand J Rheumatol Suppl. 0:33-44 (1976).
  • ketoprofen In addition to inhibiting cyclooxygenase, ketoprofen is believed to offer the additional anti-inflammatory benefit of inhibiting lipoxygenase. Ketoprofen has also been found to synergise with nifedipine in the inhibition of bladder spasm, as discussed in greater detail in the examples below.
  • inflammatory mediators including bradykinin
  • the tone of the urinary bladder smooth muscle is regulated by numerous contraction-promoting receptor systems. They include well established systems such as muscarinic, purinergic and tachykinin receptors [Anderson, K., et al., Pharmacolgy of the Lower Urinary Tract: Basis for Current and Future Treatments for Urinary Inumblece Pharmacol Rev.
  • L-type Ca 2+ channels has the potential to depress neural, urothelial and smooth muscle evoked contractions of bladder strips mediated by a multiplicity of endogenous GPCR agonists.
  • the L-type calcium channel represents a point of integration for the convergence of multiple inflammatory mediators that can lead to hyperactive smooth muscle contractility.
  • Ca 2+ channels located in afferent and efferent nerve terminals in the lower urinary tract are also important for regulation of neurotransmitter release.
  • de Groat, W., et al. Pharmacology of the Lower Urinary Tract, Annu. Rev. Pharmacol Toxicol. 41:691-721 (2001).
  • a number of active agents produce Ca 2+ influx and transmitter release from the peripheral nerve endings of capsaicin-sensitive afferent neurons through voltage-sensitive Ca 2+ channels.
  • L-type Ca 2+ channels can also contribute to transmitter release.
  • L-type Ca 2+ channel The significant role of the L-type Ca 2+ channel in the initiation of smooth muscle contraction makes this channel a potential therapeutic target for the treatment of lower urinary tract problems that involve hyperactivity or spasm of smooth muscle tissues. In the presence of inflammatory mediators, signaling through these same channels may mediate bladder hyperactivity and spasm.
  • An aspect of the present invention is thus directed to therapeutic compositions including a calcium channel antagonist in a carrier suitable for delivery to urologic structures in the urinary tract.
  • the calcium channel antagonist is preferably an L-type calcium channel antagonist, such as verapamil, diltiazem, bepridil, mibefradil, nifedipine, nicardipine, isradipine, amlodipine, felodipine, nisoldipine and nimodipine, as well as pharmaceutically effective esters, salts, isomers, conjugates and prodrugs thereof.
  • the calcium channel antagonist is a dihydropyridine, such as nifedipine, nicardipine, isradipine, amlodipine, felodipine, nisoldipine and nimodipine, as well as pharmaceutically effective esters, salts, isomers, conjugates and prodrugs thereof.
  • the agent is nifedipine.
  • Nifedipine is a preferred calcium channel antagonist for use in the present invention.
  • Nifedipine is a member of the dihydropyridine class of calcium channel antagonists with pharmacological specificity for the L-type channel (alternatively termed the Cav1.2 ⁇ -subunit). Nifedipine has a rapid onset of action (less than 10 minutes), which is desirable for use in urological procedures, and as such is more preferred than certain closely related dihydropryidine calcium channel antagonists (e.g., amlodipine) that require longer periods for initial action. The time to response for steady-state inhibition of muscle contraction ideally occur within 10-15 minutes of initial local drug delivery, and nifedipine fulfills this criterion.
  • the pain/inflammation and/or spasm agents of the present invention are suitably delivered in solution or in suspension in a liquid carrier, which as used herein is intended to encompass biocompatible solvents, suspensions, polymerizable and non-polymerizable gels, pastes and salves.
  • the carrier is an aqueous irrigation solution that may or may not include physiologic electrolytes, such as saline, distilled water, lactated Ringer's solution, glycine solutions, sorbitol solutions, manitol solutions or sorbital/manitol solutions.
  • the carrier may also include a sustained release delivery vehicle, such as microparticles, microspheres or nanoparticles composed of proteins, liposomes, carbohydrates, synthetic organic compounds, or inorganic compounds.
  • compositions of the present invention may also be coated on ureteral and urethral stents, catheters, radioactive seeds, seed spacers and other implantable devices and on surgical instruments, for local delivery from such devices and instruments into the urinary tract as further described below.
  • Polymers that may be suitably employed to form a drug impregnated stent or other implantable device include, by way of non-limiting example, poly(D,L-lactic acid) (PDLLA), poly(lactide-co-glyocide) (PLGA), poly(L-lactic acid) (PLLA), poly(glycolic acid), poly(6-hydroxycaproic acid), poly(5-hydroxyvaleric acid), poly(4-hydroxybutyric acid), poly(ethylene glycol), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO—PPO—PEO, PluronicsTM) block copolymers, and copolymers and blends of the above.
  • PLLA poly(D,L-lactic acid)
  • PLGA poly(lactide-co-glyocide)
  • PLA poly(L-lactic acid)
  • PLLA poly(glycolic acid)
  • poly(6-hydroxycaproic acid) poly(6-hydroxycaproic acid
  • Suitable materials for use in producing drug coated stents, catheters, other implantable devices and instruments include biodegradable polymers and polymeric hydrogels, such as by way of nonlimiting example, PluronicsTM triblock copolymers, PLLAs or their copolyesters, poly(glycolic acid) or their copolyesters, poly(ethylene oxide)-cyclodextrin(polyrotaxan)hydrogels, poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide)-cyclodextrin hydrogels, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, and cellulose nitrate; polyurethane resins, including the reaction product of 2,4-tolylene diisocyanate, 4,4′-diphenylmethane diisocyanate, polymethylenepolyphenyl isocyanate, or 1,5-napthylene diisocyanate with 1,2-polypropylene glycol, polyte
  • suitable non-biodegradable polymers include polyacrylates, polystyrenes, polyvinyl chloride, ethylene-vinyl acetate copolymers, polyvinyl fluoride, poly(vinyl imidazole) and chlorosulphonated polyolefins.
  • the pain/inflammation and/or spasm inhibitory compositions of the present invention can also include excipients or adjuvants for enhanced uptake, release, solubility and stability. Aspects of formulating the compositions of the present invention are discussed below.
  • the cyclooxygenase inhibitor, calcium channel antagonist or combination cyclooxygenase inhibitor plus calcium channel antagonist compositions of the present invention may include alternate or additional agents that inhibit pain, inflammation and/or spasm. Suitable agents include those disclosed in U.S. Pat. No. 5,858,017 to Demopulos.
  • suitable alternate or additional anti-inflammation/anti-pain agents include serotonin receptor antagonists, (e.g., amitriptyline, imipramine, trazodone, desipramine, ketanserin, tropisetron, metoclopramide, cisapride, ondansetron, yohimbine, GR127935, methiothepin), serotonin receptor agonists (e.g., buspirone, sumatriptan, dihydroergotamine, ergonovine), histamine receptor antagonists (e.g., promethazine, diphenhydramine, amitriptyline, terfenadine, mepyramine (pyrilamine), tripolidine), bradykinin receptor antagonists (e.g., [Leu 8 ] des-Arg 9 -BK, [des-Arg 10 ] derivative of HOE 140, [leu 9 ] [des-Arg 10 ] kalliden, [D-Phe
  • Suitable alternate or additional spasm inhibitory agents include serotonin receptor antagonists (e.g., amitriptyline, imipramine, trazodone, desipramine, ketanserin, tropisetron, metoclopramide, cisapride, ondansetron, yohimbine, GR127935, methiothepin, oxymetazoline), tachykinin receptor antagonists including neurokinin 1 receptor subtype antagonists (e.g., GR 82334, CP 96.345, RP 67580) and neurokinin 2 receptor subtype antagonists (e.g., MEN 10.627, L 659.877, ( ⁇ )-SR 48968), adenosine triphosphate (ATP)-sensitive potassium channel openers, (e.g., cromakalim, nicorandil, minoxidil, P 1075, KRN 2391, ( ⁇ )pinacidil), nitric-oxide donors, (e.g.,
  • compositions of the present invention are expected to preemptively inhibit pain, inflammation and smooth muscle spasm otherwise associated with urological procedures.
  • the compositions of the present invention act on molecular targets, i.e., receptors, enzymes and ion channels, that initiate pain, inflammation and spasm pathways and mechanisms.
  • the present invention employs local periprocedural delivery to inhibit these pathophysiologic processes at the time they are initiated. For example, multiple proinflammatory peptides stimulate the release of PGE 2 from bladder tissue within the first five minutes of exposure, as shown in the examples below. Solely postprocedurally administered therapeutic agents can only take effect after these processes have commenced.
  • Local delivery of drugs in accordance with the present invention permits the utilization of a much lower dosage than would be needed if the same drugs were administered systemically (e.g., orally, intravenously, intramuscularly, subcutaneously) to achieve the same predetermined local level of inhibitory effect in the urinary tract.
  • the focused, local delivery of the present invention results in a significantly lower plasma level of the drug than would result from systemic delivery of the drug to achieve the same predetermined local level of inhibitory effect in the urinary tract, thereby reducing the potential for undesirable systemic side effects.
  • Local delivery permits the inclusion in the compositions of the present invention of drugs such as peptides that are not susceptible to systemic delivery due to degradation during first- and second-pass metabolism.
  • Local delivery of drug compositions in accordance with the present invention provides for an immediate and certain therapeutic concentration at the local urinary tract site, which is not dependent on variations in metabolism or organ function.
  • a constant concentration of the drugs can be maintained during the period of delivery of the composition during the procedure.
  • compositions of the present invention can be locally delivered before, during and/or after cystoscopy, i.e., the endoscopic examination of the urethra and bladder through a cystoscope inserted into the lower urinary tract for purposes of examining the urinary tract structures, preferably periprocedurally during such procedures.
  • compositions of the present invention may also be used before, during and/or after (preferably periprocedurally during) other diagnostic, interventional, medical and surgical procedures performed in conjunction with cystoscopy, by insertion of surgical instruments through the cystoscope, such as for the removal of tissue for biopsy, removal of growths, removal of foreign bodies, bladder or kidney stone removal, placement, removal and manipulation of urethral stents, transurethral resection of bladder tumors (TURBT), treatment of tumors with electrocautery or laser or local chemotherapeutics, treatment of bleeding in the bladder or to relieve obstructions in the urethra.
  • TURBT transurethral resection of bladder tumors
  • compositions of the present invention can be locally delivered to the urinary tract before, during and/or after ureteroscopy, i.e., the endoscopic examination of the ureters and renal tissues through an ureteroscope inserted through the urethra and bladder and into a ureter for purposes of examining the urinary tract structures, preferably periperatively during such procedures.
  • ureteroscopy i.e., the endoscopic examination of the ureters and renal tissues through an ureteroscope inserted through the urethra and bladder and into a ureter for purposes of examining the urinary tract structures, preferably periperatively during such procedures.
  • Ureteroscopy is often performed for the drawing of urine samples from each kidney, the placement, removal and manipulation of ureteral stents, as part of the treatment for kidney stones, or to place a catheter in the ureter for a retrograde pyelography, and the compositions of the present invention can be delivered before, during and/or after such procedures, preferable periprocedurally during such procedures.
  • a basket or other instrument employed via the ureteroscope can be used to capture the stone, the stone may be broken up by laser or shock wave lithotripsy through the ureteroscope, or the ureteroscope may be employed to displace a lodged stone back into the kidney for subsequent breaking up and passage, such as by using a laser or extracorporeal shock wave lithotripsy (ESWL).
  • ESWL extracorporeal shock wave lithotripsy
  • compositions of the present invention are suitably locally delivered to the urinary tract before, during and/or after procedures that typically result in ureteral spasm, such as kidney stone removal using laser treatment, cystoscopy, ureteroscopy or lithotripsy, and preferably periprocedurally during such stone removal procedures.
  • compositions of the present invention may also be locally delivered to the urinary tract before, during and/or after (preferably periprocedurally) urological procedures that cause thermal trauma to tissue in and/or associated with the urinary tract.
  • urological procedures include laser treatment to fragment stones or ablate tissue, microwave ablation of tissue (e.g., transurethral microwave thermotherapy (TUMT) to remove prostatic tissue), radiofrequency ablation of tissue (e.g., transurethral needle ablation (TUNA) to remove prostatic tissue), electrocauterization or vaporization of tissue or cryoblation of tissue.
  • compositions of the present invention may also be locally delivered to the urinary tract before, during and/or after (preferably periprocedurally) urological procedures employing a laser for tissue resection, including Holmium: yttrium-aluminum-garnet (Ho:YAG), neodymium:yttrium-aluminum-garnet (Nd:YAG) and potassium-titanyl-phosphate (KTP) “green light” laser therapies.
  • laser procedures may include the treatment of benign prostatic hyperplasia (BPH) and bladder tumors, by way of non-limiting example.
  • ketoprofen composition, calcium channel antagonist and ketoprofen combination composition and the preferred ketoprofen and nifedipine combination composition of the present invention may also be locally delivered to the urinary tract before, during and/or after (preferably periprocedurally) transurethral resection of the prostate (TURP).
  • compositions of the present invention may also be suitably employed for local delivery during other minimally invasive urological procedures.
  • these include, by way of example, the transrectal or transperitoneal delivery of the compositions of the present invention to the prostate and surrounding anatomic structures during implantation of radioactive seeds and seed spacers to treat prostate cancer or prostatitis, and the transrectal or transperitoneal delivery of the compositions of the present invention to the prostate to treat prostatitis.
  • compositions of the present invention are suitably locally delivered to the urinary tract before, during and/or after (preferably periprocedurally) procedures that standardly include irrigation, such as TURP, transurethral incision of the prostate (TUIP), laser prostatectomy, cystoscopy, ureteroscopy and other procedures in which irrigation is used to aid visualization by removing blood and tissue debris from the operative field.
  • irrigation solution standardly used in such procedures, e.g., saline, distilled water, lactated Ringer's solution, glycine, sorbitol, manitol, sorbital/manitol, at dilute levels, with no change to the urologist's standard procedure being required.
  • compositions of the present invention can also be locally delivered by coating ureteral stents, uretheral stents, catheters, radioactive seeds, seed spacers or other implantable devices or surgical instruments, or impregnating or otherwise incorporating the therapeutic agents into the body of stents, catheters, radioactive seeds, seed spacers or other implantable devices or surgical instruments constructed from a polymeric material or mesh.
  • Techniques for coating devices with drugs and impregnating devices with drugs are well known to those of ordinary skill in the art, and coatings or polymeric materials may be designed to permit the drugs (e.g., a COX inhibitor and a calcium channel antagonist) to begin releasing into the urinary tract upon implantation and continuing for a period of time following implantation.
  • One aspect of the invention is directed to a composition including a cyclooxygenase inhibitor and a calcium channel antagonist, preferably ketoprofen and nifedipine, which are dissolved in an aqueous solution for parenteral delivery, preferably for intravesicular delivery.
  • a cyclooxygenase inhibitor and a calcium channel antagonist preferably ketoprofen and nifedipine
  • such compositions can be manufactured in a lyophilized form and then reconstituted with an aqueous solvent prior to administration.
  • cyclooxygenase inhibitor and calcium channel antagonist are suitably included in a molar ratio (cyclooxygenase inhibitor:calcium channel antagonist) of from 10:1 to 1:10, preferably from 5:1 to 1:5, more preferably from 4:1 to 1:1, and most preferably 3:1.
  • ketoprofen and nifedipine are suitably included in a molar ratio (ketoprofen:nifedipine) of from 10:1 to 1:10, preferably from 5:1 to 1:5, more preferably from 4:1 to 1:1, and most preferably approximately (i.e., ⁇ 20%) 3:1.
  • the cyclooxygenase inhibitor such as ketoprofen is suitably included at a concentration (as diluted for local delivery) of no more than 500,000 nanomolar, preferably no more than 300,000 nanomolar, more preferably no more than 100,000 nanomolar and most preferably less than 50,000 nanomolar.
  • the calcium channel antagonist such as nifedipine is suitably included at a concentration (as diluted for local delivery) of no more than 200,000 nanomolar, preferably no more than 100,000 nanomolar, more preferably no more than 50,000 nanomolar and most preferably less than 25,000 nanomolar.
  • compositions of the present invention may be formulated in an aqueous or organic solvent, but preferably are formulated in an aqueous solvent.
  • an additional solvent or solvents i.e., cosolvents or solubilizing agents
  • cosolvents or solubilizing agents may suitably be included to aid in dissolution of the drugs.
  • suitable solvents include polyethylene glycol (PEG) of various molecular weights (e.g., PEG 200, 300, 400, 540, 600, 900, 1000, 1450, 1540, 2000, 3000, 3350, 4000, 4600, 6000, 8000, 20,000, 35,000), propylene glycol, glycerin, ethyl alcohol, oils, ethyl oleate, benzyl benzoate, and dimethyl sulfoxide (DMSO).
  • PEG polyethylene glycol
  • a preferred cosolvent for the compositions of the present invention is PEG, most preferably PEG 400.
  • the composition includes ketoprofen and nifedipine in an aqueous solution including at least one stabilizing agent.
  • stabilizing agent is used herein to refer to an agent that inhibits degradation of the active pharmaceutical ingredients and/or extends the duration of stability of the solution when stored under either refrigerated (e.g., 2-8° C.) or ambient temperature conditions, and includes both anti-oxidants and chelating agents.
  • the solution may also suitably include one or more cosolvents or buffering agents.
  • the aqueous ketoprofen and nifedipine solution includes one or more antioxidants as stabilizing agent(s), a cosolvent and a buffering agent.
  • the preferred ketoprofen and nifedipine solution formulation is stable when stored at between 2° C. and 25° C. for a period of at least six months, preferably one year, more preferably two years, most preferably longer than two years, and can be readily diluted with standard urologic irrigation solutions for local intravesicular delivery during urological procedures.
  • Suitable antioxidants for use as stabilizing agents in the compositions of the present invention include water soluble antioxidants such as sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulphoxylate, ascorbic acid, acetylcysteine, cysteine, thioglycerol, thioglycollic acid, thiolactic acid, thiourea, dithithreitol, and glutathione, or oil soluble antioxidants such as propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, nordihydroguaiaretic acid and ⁇ -tocopherol.
  • water soluble antioxidants such as sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulphoxylate, ascorbic acid, acetylcysteine
  • a preferred stabilizing agent for the present invention is propyl gallate.
  • a cosolvent is included solubilizing oil soluble antioxidants such as propyl gallate.
  • a preferred aqueous ketoprofen and nifedipine composition of the present invention includes PEG 400 as a cosolvent and propyl gallate as a stabilizing agent, and may more preferably also include a second stabilizing agent such as a water soluble antioxidant, most preferably sodium metabisulfite.
  • a suitable range of concentrations for antioxidant(s) is typically about 0.001% to about 5%, preferably about 0.002% to about 1.0%, and more preferably about 0.01% to about 0.5%, by weight of the composition.
  • a chelating agent as a stabilizing agent may be useful in the compositions of the present invention.
  • suitable chelating agents include the various salts of ethylenediamine tetraacetic acid salts (EDTA), ⁇ -hydroxyethylenediaminetriacetic acid (HEDTA), diethylenetriamine-pentaacetic acid (DTPA) and nitrilotriacetate (NTA).
  • compositions of the present invention suitably include a buffering agent to maintain pH.
  • suitable buffering agents for inclusion in the compositions of the present invention include acetic acid and its salts, citric acid and its salts, glutamic acid and its salt and phosphoric acid and its salts.
  • Citric acid also has the ability to chelate divalent cations and can thus also prevent oxidation, thereby serving two functions as both a buffering agent and an antioxidant stabilizing agent.
  • a preferred aqueous ketoprofen and nifedipine composition of the present invention includes citric acid (such as in the form of sodium citrate) as a buffering agent and antioxidant, and in a more preferred composition also includes PEG 400 as a cosolvent and propyl gallate and sodium metabisulfite as stabilizing agents.
  • compositions of the present invention may also include additional excipients and adjuvants.
  • Excipients may include a preservative to protect against microbial growth, especially for multiple-dose containers. Suitable excipients include antimicrobial agents such as benzyl alcohol, chlorobutanol, thimiserol, methyl paraben and propyl paraben.
  • Excipients may also include a surfactant to reduce surface tension and thereby facilitate wetting for dissolution. Examples of suitable surfactants include polyoxyethylene sorbitan monooleate and sorbitan monooleate. Excipients may also include tonicity adjustment agents to render the solution iso-osmotic with physiologic fluids.
  • Suitable tonicity agents include sodium chloride, sodium sulfate, mannitol, glucose, sucrose, trehalose, and sorbitol. Additional excipients may include a colorant to impart color, such as FD& C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black, and indigo tar pigments.
  • the above concentrated solution is diluted, such as at a ratio of 1:1,000 (v:v) with standard irrigation solution such as saline or lactated Ringer's solution.
  • the final dilute solution from the above exemplary formulation thus includes 0.06% PEG40, 0.00005% sodium metabisulfite and 0.00001% propyl gallate (all by volume).
  • the active ingredients are present in the final dilute solution at concentrations of 0.00763 mg/ml (30,000 nM) for ketoprofen and 0.00346 mg/ml (10,000 nM) for nifedipine.
  • the present invention may be illustrated by the following studies demonstrating the effects of ketoprofen and other cyclooxygenase inhibitors, nifedipine and combinations of these agents in urological models, and demonstrating the stability of certain formulations of such compositions.
  • bradykinin induces immediate prostaglandin E 2 (PGE 2 ) production in the bladder, and demonstrate the effects of cyclooxygenase inhibitors on this process.
  • PGE 2 immediate prostaglandin E 2
  • Bradykinin was chosen as the activating agonist for testing in this system because its actions on the rat bladder tissue system have been well characterized and because its role as a proinflammatory agent in acute pathophysiology has been studied. Bradykinin is also known to stimulate contraction of smooth muscle of the bladder when delivered intravesically by activation of B1 and B2 receptor subtypes.
  • multiple inflammatory mediators including bradykinin and Substance P (SP) are released into the bladder.
  • SP bradykinin and Substance P
  • Exogenous application of these pro-inflammatory peptides or activation of bladder nerves can trigger the production of prostaglandins (PGs) in the bladder.
  • PGs prostaglandins
  • the rat bladder tissue strip system represents a well established system for characterization of the pharmacological actions on numerous agents on smooth muscle bladder contractility [Edwards, G., et al., Comparison of the Effects of Several Potassium - Channel Openers on Rat Bladder and Rat Portal Vein In Vitro, Br. J. Pharmacol. 102:679-80 (1991); Birder, L., et al., ⁇ - adrenoceptor Agonists Stimulate Endothelial Nitric Oxide Synthase in Rat Urinary Bladder Urothelial Cells, J. Neurosci. 22:8063-70 (2002)].
  • Isolated bladder smooth muscle strips of 1 ⁇ 2 ⁇ 15 mm dimension were obtained from Wistar derived male or female rats weighing 275 ⁇ 25 g that were sacrificed by CO 2 overexposure. Each strip was placed under 1 g tension in a 10 ml bath containing Krebs solution with 1 ⁇ M enalaprilic acid (MK-422), composition (g/l): NaCl 6.9, KCl 0.35, KH 2 PO 4 0.16, NaHCO 3 2.1, CaCl 2 0.28, MgSO 4.7, H 2 O 0.29, (+)Glucose 1.8, pH 7.4 bubbled with 95% O 2 /5% CO 2 at 32° C.
  • MK-422 1 ⁇ M enalaprilic acid
  • Each strip was connected to an isometric transducer (Harvard, # 50-7293) and two-pen recorder and allowed to equilibrate for 60 minutes.
  • mounted tissues were validated for acceptance by challenge with 100 ⁇ M of methoxamine to obtain a minimum of 1 g tension, which was considered as 100%. Qualified tissues were washed repeatedly every 15 minutes for 60 minutes.
  • a cumulative contraction-response curve to bradykinin was then generated through application of 3 concentrations of bradykinin (0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M) at 1 minute intervals for a total of 3 minutes.
  • the tissue was subsequently washed periodically until tension returned to baseline value. Two hours later, the ability to inhibit the bradykinin cumulative dose response (0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M) after a 10 minute pretreatment with ketoprofen was determined.
  • Each concentration of test substance was tested in four separate preparations.
  • FIG. 2 illustrates the cumulative concentration-response curves of normal animals to the agonists bradykinin and SP.
  • the EC 50 for bradykinin was 8.5 nM and for SP was 6.5 nM. This provided a validated system for testing the effects of the inhibitory activity of NSAIDs (COX inhibitors).
  • FIG. 3A illustrates bradykinin concentration-response curves produced in the presence of 0.25, 1.0, 2.5 and 10 ⁇ M ketoprofen.
  • the maximal agonist response could not be determined experimentally for all concentrations of ketoprofen, although curve-fitting using a standard Hill equation revealed no change in maximal response at saturating agonist concentrations.
  • Schild analysis was used to calculate the pA 2 value of 7.26 for ketoprofen, equivalent to a K D for ketoprofen at its site of action of 5.52 ⁇ 10 ⁇ 8 M (see FIG. 3B ). This finding demonstrates that the potency for inhibition in this tissue assay system is quite comparable to values obtained from direct enzyme inhibition assays.
  • the release of PGE 2 from urinary bladder strips into 10 ml of tissue bath was measured using a specific enzyme immunoassay (EIA) according to the manufacturer's instructions (Amersham Pharmacia Biotech) for the basal, bradykinin-induced and COX inhibitor treatment plus bradykinin-induced samples.
  • EIA enzyme immunoassay
  • the COX inhibitors tested were ketoprofen, flurbiprofen, 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl)thiophene (i.e., DUP-697) and 1-[(4-methysufonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl)pyrazole (i.e., SC-58125).
  • One mL of fluid was collected from the 10 mL tissue bath after 10 minutes of bradykinin challenge for PGE 2 determination. Samples were frozen immediately and stored at ⁇ 4° C. until assay. The bladder strips were dried gently by blotting and were then weighed. Results are expressed as picograms of PGE 2 released per milligram tissue.
  • FIG. 4A illustrates that bradykinin rapidly induces the formation of PGE 2 in rat bladder tissue strips within the first minutes of stimulation and reaches a maximum within 30 minutes. The t 1/2 for formation was about 7.5 minutes.
  • FIG. 4B illustrates the rapid kinetics of PGE 2 formation detected within the first ten minutes.
  • Ketoprofen inhibition of bradykinin-induced bladder strip contraction was closely correlated with inhibition of PGE 2 formation, as shown in Table 2.
  • Non-selective COX-1/COX-2 inhibitors were found to be effective in blocking bradykinin-stimulated PGE 2 , while COX-2 selective agents were not effective. This corresponds to a lack of COX-2 inhibitor activity under bradykinin-induced normal cystometry parameters.
  • FIG. 1 provides a model for action of prostaglandin activity.
  • Activation of bradykinin receptors on urothelial cells may produce PGs in the urothelium, which in turn may activate bladder nerves (C-fiber and A ⁇ fibers) to affect bladder contractility and control micturition reflexes.
  • Ketoprofen inhibits formation of PGE 2 .
  • the rats were anesthetized with urethane at 1.2 g/kg i.p. in 5 ml/kg.
  • a polyethylene catheter (PE50) was implanted into the bladder for saline or acetic acid infusion through a 3-way stopcock.
  • a pressure transducer was connected for measurements of intravesical pressure.
  • Warm (37° C.) saline was infused into the bladder at a constant rate of 16.7 ml/min (1 ml/hour) until cystometry became stable (no less than 60 minutes). Thereafter, 0.2% acetic acid was infused into the urinary bladder.
  • Aspirin (10 mg/kg i.v.) and vehicle were administered intravenously via a PE-10 catheter in the femoral vein at 5 minutes after infusion of acetic acid was started and at the end of first micturition cycle.
  • Dunnett's test was applied for comparison between the time before and after test substance or vehicle treatment. To ascertain differences between the test substance and the vehicle control group, an unpaired Student's t test was used. Differences are considered significant at p ⁇ 0.5.
  • FIG. 5A illustrates that intravenous aspirin (10 mg/kg) produced a gradual time-dependent inhibition of the acetic acid induced reduction in the intercontraction interval (ICI), and FIG. 5B illustrates the parallel changes in bladder capacity. Threshold pressure and micturition pressure were not affected by aspirin treatment (data not shown).
  • ketoprofen a non-selective COX-1/COX-2 inhibitor, and nifedipine, an L-type Ca 2+ channel antagonist, on agonist-stimulated rat bladder contractility using bradykinin as a stimulating agonist.
  • Ketoprofen USP and nifedipine USP were dissolved in DMSO prior to dilution to the final concentration.
  • Bladder tissue strips from Wistar derived rats were prepared, transduced and equilibrated using the bladder strip contractility method described in Example I above. Assayed tissue was incubated with the test drugs for 10 minutes before activities were determined.
  • bradykinin concentrations were generated through application of 7 bradykinin concentrations in 3-fold increments ranging from 0.001 ⁇ M to 1 ⁇ M at 1 minute intervals for a total of 7 minutes to establish the maximal 100% control response.
  • the tissue was subsequently washed periodically until tension returned to baseline value.
  • similar bradykinin concentration-responses were carried out in the presence of each respective test compound (ketoprofen: 0.25 ⁇ M, 1 ⁇ M, 2.5 ⁇ M and 10 ⁇ M; nifedipine: 0.125 ⁇ M, 0.5 ⁇ M, 1.25 ⁇ M and 5 ⁇ M) following a 10 min incubation period.
  • Tissue strips were always used in pairs for the study of the action of the antagonist (bradykinin) alone and in the presence of a concentration of antagonist (ketoprofen or nifedipine). Schild plots were obtained using computer software (Pharmacology Cumulative System, Version 4) and pA 2 values were determined.
  • Nifedipine was found to exhibit a noncompetitive type of antagonism upon bradykinin-induced contractile responses in the in vitro rat bladder preparation. This was shown by a depression of the maximum agonist response and a small non-parallel rightward shift of the agonist concentration response curves ( FIG. 6 ).
  • increasing concentrations of ketoprofen (0.25-10 ⁇ M) produced a series of concentration-response curves (see FIG. 3A ) in which the EC 50 agonist response moved progressively to higher concentrations of bradykinin (shift to the right of over 2 orders of magnitude) with no apparent effect on maximal tension. This pattern of inhibition is consistent with a competitive mechanism for ketoprofen and was further analyzed by Schild regression analysis.
  • nifedipine For nifedipine, the criteria for application of the Schild regression analysis were not met due to the noncompetitive pattern of inhibition. Even the lowest concentration of nifedipine (0.125 ⁇ M) resulted in a large reduction in the agonist response (to about 50% of maximum). These studies of ketoprofen and nifedipine reveal two very different patterns of inhibition of bradykinin-stimulated contractile tension.
  • the present study evaluated the effects of nifedipine and ketoprofen administered in combination on the contractile tension response in a rat bladder tissue strip model.
  • Bladder tissue strips from Wistar derived rats were prepared, transduced and equilibrated using the bladder strip contractility method described in Example I above with transduced strips being allowed to equilibrate for 45 minutes.
  • two tissue strips were collected from each animal. The control group consisted of 12 strips and 54 strips were used for the treatment groups.
  • the concentration range that was chosen for each of the active agents was based upon results from prior in vitro pharmacological studies of each single agent described in Examples I and II above. Those studies showed that ketoprofen in the 0.3-3 ⁇ M range had measurable effects on the EC 50 for bradykinin activation. Ketoprofen at 3 ⁇ M was near maximal in its ability to shift the EC 50 of the bradykinin activated response curves on muscle contractility. Similarly, prior testing of nifedipine identified a range of concentrations (0.05-5 ⁇ M) effective at inhibiting bradykinin induced tension.
  • a factorial design characterized the effects of nine different two-drug combinations of ketoprofen and nifedipine at the following concentrations of (i) ketoprofen: 0.3, 1.0, or 3.0 ⁇ M; and (ii) nifedipine: 0.1, 0.3 or 1.0 ⁇ M.
  • the treatment groups (groups 2-10) tested are summarized in Table 3 below: TABLE 3 Ketoprofen-Nifedipine Combinations Tested Group Ketoprofen Conc. ( ⁇ M) Nifedipine Conc. ( ⁇ M) 1 (Control) — — 2 0.3 0.1 3 0.3 0.3 4 0.3 1.0 5 1.0 0.1 6 1.0 0.3 7 1.0 1.0 8 3.0 0.1 9 3.0 0.3 10 3.0 1.0
  • the bradykinin concentration-response data was fit to a variable slope sigmoidal equation, also known as the 3-parameter logistic response (3PL) function, to obtain the maximal tension, EC 50 , and Hill slope in which the bottom of the curve was fixed at 0.
  • the force of contraction in the presence of inhibitors was expressed as a percentage of the maximum bradykinin effects observed within the same strip before addition of an inhibitor.
  • the concentrations of the two agents (nifedipine and ketoprofen) used in this combination experiment represent independent variables.
  • the maximal tension is an effect that results from the combination and is the response variable of primary interest for the response surface analysis.
  • the relationship between the drug combinations and the response variable can be represented in a three-dimensional plot in which the concentrations are plotted as Cartesian coordinates in the x-y-plane, and the response variable (e.g., maximal tension) is plotted as the vertical distance above the planar point.
  • the collection of spatial points plotted in this way provides a view that represents the combined concentration-response relationship.
  • the advantages of this experimental design method include the fact that the biological response measured is not limited to a specific response (effect) level of the system. In this way, a number of fixed-ratio concentration combinations can be tested over a wide range of concentrations to define the interaction efficacy of the two drugs.
  • a smooth surface may be fit to the data in a three-dimensional plot of a two-drug combination concentration-response relationship. This surface represents the additivity or interaction of the combination.
  • the graph of this response surface becomes the reference surface for viewing actual combination effects and allows the visualization and prediction of effects in regions of the curve for which no data could be generated.
  • FIG. 10 shows the fitted response surface for the reduced model as a function of ketoprofen and nifedipine concentration.
  • the combination response curve drops steeply with increasing concentrations of both ketoprofen and nifedipine.
  • the surface becomes fairly flat as the maximal response is obtained as concentrations approach 1 ⁇ M nifedipine +3 ⁇ M ketoprofen.
  • the concentration combination that results in 90% maximal inhibition of the effect of bradykinin is 3 ⁇ M of ketoprofen +1 ⁇ M of nifedipine.
  • Example III evaluated the effects of nifedipine in combination with ketoprofen using bradykinin as an agonist to stimulate smooth muscle contraction.
  • Bradykinin was used in the rat bladder tissue strip assay system (Examples I-III) to serve as an endogenous mediator of contraction.
  • the overall pattern of inhibition seen with all combinations of nifedipine and ketoprofen concentrations was characteristic of non-competitive antagonism.
  • Nifedipine which prevents the influx of calcium ions through the cell membrane by acting on L-type voltage-dependent channels, attenuates the bradykinin receptor activated contraction of smooth muscle without directly inhibiting the receptor.
  • nifedipine inhibition was shown above (Example II) to cause a reduction in the maximum bradykinin responses that were not accompanied by statistically significant changes in the agonist potency of the remaining response.
  • bradykinin the proinflammatory agonist
  • this effect may be due to a positive feedback loop that operates at a cellular and tissue level.
  • Prostaglandins generated intracellularly as a result of bradykinin receptor activation may move to the extracellular environment, where they may interact and in turn activate prostanoid receptors subtypes.
  • prostanoid receptor subtypes There are at least four known prostanoid receptor subtypes, termed EP1, EP2, EP3 and EP4.
  • EP1 receptors are believed to be coupled through G proteins to stimulation of phophoinositide hydrolysis and/or PLC-independent influx of calcium.
  • EP1 receptors have been previously identified in smooth muscle, where they can function to mediate contractile activity.
  • the discovery of the combined synergistic actions of ketoprofen and nifedipine on contractile activity may be a result of simultaneous blockade of calcium mobilization and the concurrent inhibition of a positive-feedback loop involving PGE 2 driven activation of prostanoid receptors.
  • each combination of nifedipine and ketoprofen showed a greater inhibition of maximal bradykinin-induced contraction compared to either drug alone in the rat bladder tissue strip assay. Furthermore, the multiple combinations of nifedipine and ketoprofen tested allowed a response surface analysis to define optimal concentrations. A fixed ratio combination containing 3.0 ⁇ M ketoprofen and 1.0 ⁇ M nifedipine was identified that produced 90% inhibition.
  • Bradykinin, substance P, histamine and ATP are endogenous mediators that can be released as part of the acute inflammatory response and activate bradykinin receptors (B1 and B2 subtypes), tachykinin receptors (NK 1-3 ) and histamine receptors (all subtypes) and purinergic P2X and P2Y receptors, respectively.
  • Carbamylcholine is an agonist that may activate muscle and neuronal nicotinic acetylcholine subtypes or muscarinic acetylcholine receptors subtypes (M 1-5 ) present in the bladder, while methoxamine is specific for a,-adrenergic receptors.
  • the first objective was to evaluate the effect of ketoprofen (10 ⁇ M) and nifedipine (1 ⁇ M) individually, each at a fixed concentration, on contractile tension induced by each of the six agonists (bradykinin, substance P, carbamylcholine, methoxamine, histamine and ATP) in the rat bladder tissue strip model.
  • the second objective was to determine the amount of PGE 2 released from the bladder tissue in response to stimulation by each agonist in the presence of either ketoprofen or nifedipine during the same test conditions employed to measure contractile smooth muscle tension.
  • Bladder tissue strips from Wistar derived rats were prepared, transduced and equilibrated using the bladder strip contractility method described in Example I above. Either 10 ⁇ M ketoprofen or 1.0 ⁇ M nifedipine was pre-incubated individually with the tissue for a period of 10 minutes prior to stimulation with the following agonists at a concentration equivalent to its respective ED 75 for stimulation of tension: 0.03 ⁇ M bradykinin; 0.03 ⁇ M substance P; 3.0 ⁇ M carbochol; 30 ⁇ M methoxamine; 25 ⁇ M histamine; and 20 ⁇ M ATP.
  • Antagonist activity for a given concentration of an antagonist was determined as the ability of that concentration of the antagonist to reduce the noted agonist-induced (e.g., 0.03 ⁇ M bradykinin-induced) response by 50 percent or more ( ⁇ 50%).
  • concentration of antagonist was tested in four separate tissue preparations.
  • the effects of the two drugs on PGE 2 release in response to multiple agonists was compared using the same 10 min pre-incubation protocol and a subsequent 30 min incubation period with agonist in the presence of the test compound.
  • PGE 2 produced after 30 minutes of treatment with each agonist (e.g., 0.03 ⁇ M bradykinin) in the absence and presence of the test compounds was determined.
  • An initial 1.0 ml sample was taken from the tissue bath after a 30 minute incubation with the agonist. Subsequently, the tissue was washed using 10 ml of Krebs solution every 15 minutes for a 2 hour period. The test compound was added and pre-incubated for a period of 10 minutes prior to re-challenge with the same agonist.
  • Bradykinin evoked the largest increase in PGE 2 relative to the other agonists tested. This evoked release was effectively inhibited by ketoprofen (81%) but minimally affected by pre-treatment with nifedipine (12%) ( FIG. 12 ). Thus, the extent of inhibition of smooth muscle tension by nifedipine was not linked to agonist-induced PGE 2 responses and was distinct from the effect of ketoprofen.
  • the absolute bladder levels of PGE 2 produced in response to stimulation by other GPCR agonists were about 10-fold less than those seen with bradykinin.
  • nifedipine and ketoprofen act through distinct mechanisms to inhibit smooth muscle contractile tension and release of pro-inflammatory prostaglandins in bladder tissue.
  • the primary objective of this study was to measure the effect of ketoprofen and nifedipine during intravesical, local delivery to female rats with overactive bladder function caused by perfusion with saline containing 0.2% acetic acid (acidified saline). Perfusion of 0.2% acetic acid through the bladder is known to rapidly induce an acute inflammatory state that is reflected in functional changes in bladder cystometry.
  • the method used in the current study represents an adaptation of a widely used acetic acid-triggered rat model of hyperactive bladder.
  • acute inflammation of the bladder is produced by using 0.2% acetic acid in saline as the bladder perfusion fluid and cystometry under anesthesia is performed after a recovery period from the surgical procedure.
  • a regular interval of voiding cycles can be seen for several hours after the initial stabilization period occurs.
  • a bladder catheter connected to an infusion pump was used to deliver the drug solutions directly to the bladder at a constant, defined rate.
  • the animals were anesthesized and bladder catheters were surgically implanted to allow irrigation of the test agents.
  • the following cystometry parameters were monitored: intercontraction interval (ICI), trigger pressure (TP), micturition pressure (MP) and micturition volume (MV) using a Med Associates Cystometry Station and software program.
  • ICI intercontraction interval
  • TP trigger pressure
  • MP micturition pressure
  • MV micturition volume
  • rats that displayed normal and stable cystometry profiles during the preliminary saline-infusion stage (not less than 15 min of baseline stabilization followed by 7 regular representative ICI intervals) were included in the study.
  • the rat bladder was infused with test agent in saline containing 0.2% acetic acid for 20 min followed by the collection of 7 representative ICI intervals for analysis. Due to the fixed concentrations of the irrigation solutions employed in the study and the use of constant perfusion rates for fixed constant times, a fixed, uniform dose of each agent was delivered to all animals.
  • Groups of female rats were administered ketoprofen at selected concentrations (0.01-25 ⁇ M) alone or nifedipine at selected concentrations (0.1-10 ⁇ M) alone. Five to seven animals were normally tested in each group. Acidified saline served as the control. All infusion solutions were prepared fresh on the day of the experiment before use. For each of the test agents, three distinct bladder irrigation periods were employed: 1) baseline (saline only) for 1 hour; 2) drug in saline only for 15 minutes; and 3) drug in 0.2% acidified saline for 1 hour.
  • ketoprofen in the irrigation buffer leads to a concentration-dependent inhibition of the shortening of the ICI ( FIG. 14 ). Complete inhibition was seen at approximately 3 ⁇ M ketoprofen and higher concentrations tended to go above 100% (data not shown).
  • the primary objective of this study was to measure systemic plasma levels of ketoprofen and nifedipine during and after the intravesical, local delivery of a combination of these drugs to rats.
  • a secondary objective of this study was to determine the rate of appearance of ketoprofen and nifedipine when administered individually or in combination.
  • a third objective of this study was to evaluate the effects of local drug delivery on the rat bladder tissue content of the pro-inflammatory mediator, PGE 2 , following surgical trauma to the bladder and subsequent intravesical perfusion of each agent or the combination.
  • a bladder catheter connected to an infusion pump was used to deliver the drug solutions directly to the bladder at a constant, defined rate.
  • bladder irrigation periods were employed that were defined by the bladder perfusion solution for each period: 1) baseline (saline only) for 1 hour; 2) drug in saline only for 1 hour; and 3) post-drug saline period for 30 minutes (min).
  • the animals were anesthetized and the dome of the bladders were surgically implanted with a catheter to allow perfusion of the test agents with an infusion pump at a constant flow rate of 100 ⁇ M/min.
  • saline was the perfusion fluid used and no plasma samples were collected.
  • plasma samples were collected at time points of 0, 15, 30, 45 and 60 min following perfusion of test agents.
  • ketoprofen and nifedipine were formulated in accordance with an aspect of the invention to include ketoprofen (10 mM), and nifedipine (10 mM) in a 60% polyethylene glycol 400 (PEG 400):40% water solvent base, including 50 mM sodium citrate buffer for a pH 7.5 solution in a 5 mL glass vial.
  • the combination solution was diluted in the standard irrigation fluid at a ratio of 1:1000 such that the final concentrations of the active drugs delivered directly to the bladder were each 10 ⁇ M.
  • a fixed concentration ratio of 1:1 nifedipine:ketoprofen was chosen, and final concentrations of 10 ⁇ M for each agent were maintained in the irrigation buffer.
  • a narrow range of C max between 4.3-5.8 ng/ml was seen at 60 min.
  • the perfusion with 10 ⁇ M ketoprofen was stopped and normal saline irrigation was continued for an additional 30 min period.
  • plasma levels decreased at 75 and 90 minutes following cessation of ketoprofen perfusion. Delayed absorption during the 75-90 minute interval was observed in the other two animals in the ketoprofen-only group.
  • ketoprofen levels were also determined for the combination of ketoprofen and nifedipine.
  • the perfusion with the combination was stopped and normal saline irrigation was continued for an additional 30 minute period.
  • FIG. 16 A comparison of the mean plasma ketoprofen results are presented graphically in FIG. 16 for the ketoprofen-only group and the combination group.
  • the mean values (and standard error of the means, SEMs) clearly show the constant plasma levels for the combination after 60 minutes. Although small differences are apparent in the earliest phase of the time-course, no significant differences were observed either in the peak levels or in the absorption kinetics for the ketoprofen plasma levels in the combination group versus the ketoprofen alone group after 30 minutes, or in the peak levels, indicating that no apparent ketoprofen-nifedipine drug interactions were present.
  • nifedipine The overall kinetic profile observed for nifedipine was similar to that observed for ketoprofen.
  • nifedipine-only plasma group nifedipine plasma levels increased linearly in 5 ⁇ 6 animals and some delayed absorption was observed in only 1 ⁇ 6 animals.
  • the C max plasma level in the nifedipine group was in the range of 10.6-16.0 ng/ml at 60 minutes for 5 ⁇ 6 animals.
  • the mean peak plasma levels observed at 60 minutes were below the acceptable mean peak levels of 79 ⁇ 44 ng/ml that are obtained in man as a result of an oral therapeutic daily dose of nifedipine.
  • nifedipine systemic plasma levels from the combination of ketoprofen and nifedipine also exhibited a linear increase with increasing time for the initial 60 minute drug perfusion period.
  • the C max plasma levels in the combination group had a mean value of 18.2 ng/ml and values ranged from 8.2-34.6 ng/ml at 60 minutes for all six animals.
  • the mean peak plasma levels observed at 60 minutes are about one fourth the mean peak levels that are obtained as a result of oral therapeutic daily dose of nifedipine.
  • nifedipine As shown in FIG. 17 , a comparison of the mean peak plasma concentrations of nifedipine (and plotted SEMs) shows the similar linear increase that occurs during the initial perfusion phase of intravesical delivery. No significant differences in nifedipine plasma levels were seen in the nifedipine only group when compared with the nifedipine and ketoprofen combination drug product group.
  • bladders were harvested from the animals and subsequently the entire bladder was analyzed for PGE 2 content using an enzyme immunoassay system. Data shown in FIG. 18 are expressed as the mean of PGE 2 using units of pg/mg protein +the standard error of the mean from six animals per treatment group.
  • the drugs tested in this study were directly in contact with the absorptive site within the bladder.
  • the continuous perfusion maintained constant drug concentrations of either ketoprofen, nifedipine or the combination within the bladder during the period of drug delivery.
  • minimal systemic exposure to the drugs occurred in female rats during a 1 hour intravesical perfusion.
  • Low levels of each drug were detectable within the first 15 min interval measured, and absorption progressed gradually as an approximately linear function over time of drug perfusion for each agent.
  • the locally delivered drugs and drug combination were exposed to the structures of the bladder, including the uroepithelium, C-fiber afferents, efferents and smooth muscle.
  • the data obtained in the study show that this action is local and cannot be ascribed to systemic effect that could be mediated through central nervous system mechanisms because the initial levels in the plasma for both drugs tested are so low.
  • ketoprofen rat mean ketoprofen plasma level of 9.29 ⁇ 2.13 ng/ml at 60 min.
  • C max peak plasma levels
  • the accepted daily mean peak C max for a single 200 mg ketoprofen tablet (a single oral dose) is 3900 ng/ml.
  • peak levels observed for nifedipine were approximately 15 ng/ml to 25 ng/ml.
  • C max The maximal levels typically occurred at the end of 60 min drug perfusion period or within the following 30 min sampling period.
  • C max The maximal levels (C max ) typically occurred at the end of 60 min drug perfusion period or within the following 30 min sampling period.
  • C max the accepted daily C max for a single 10 mg immediate release nifedipine tablet is reported to be 79 ⁇ 44 ng/ml.
  • Systemic exposure was comparable for ketoprofen plasma levels whether administered alone or with nifedipine.
  • nifedipine plasma levels were comparable whether administered alone or with ketoprofen.
  • ketoprofen demonstrated an extended period of anti-inflammatory activity in this model of local, intravesical drug delivery.
  • ketoprofen and nifedipine combo liquid formulations identified as F3/1, F10/3, and F30/10, were prepared according to the composition shown in Table 8 below. In all three test formulations, 50 mM sodium citrate aqueous buffer was used. The target solubility of ketoprofen/nifidipine for F3/1, F10/3, and F30/10 were 3 mM/1 mM, 10 mM/3 mM, and 30 mM/10 mM respectively.
  • ketoprofen and nifedipine in the formulatins, different percentages of PEG 400, 35% v/v PEG 400 (F3/1), 50% v/v PEG 400 (F10/3), 60% v/v PEG 400 (F30/10), were used as a cosolvent.
  • PEG 400 as a solubilizing agent
  • the approximate saturation solubility of ketoprofen and nifedipine in all three formulations was approximately 1.5 ⁇ of their respective target solubility.
  • the solubility results in Table 8 clearly indicate that PEG 400 is a suitable solubility enhancing agent for both drugs when it is desired to prepare highly concentrated combination solution formulations.
  • ketoprofen and nifedipine combination solution formulations were prepared according to the composition shown in Table 9.
  • concentrations of the active drugs were 3 mM for Ketoprofen and 1 mM for Nifedipine.
  • All four formulations employed sodium citrate buffer (pH 5.5) with a 35% v/v of PEG 400. The ionic strength of the buffer used was 50 mM for F1 and F2, and 20 mM for F3 and F4.
  • HPLC high performance liquid chromatograph
  • Chromatographic conditions for the related substances assay were as follows: (1) detection wave length: UV 241 nm; (2) column: Zorbax SB-C18, 5 ⁇ M, 4.6 ⁇ 150 mm; (3) column temperature: 30 ⁇ 1° C.; (4) flow rate: 1.0 mL/min; (5) injection volume: 20 ⁇ L; (6) run time: 27 minutes.
  • FIG. 19 shows an example chromatogram of the combination solution formulation F1 after stressing by storing at 60° C. for 1 month.
  • the two active ingredients, ketoprofen and nifedipine have a retention time of 24.19 minutes and 19.31 minutes respectively.
  • RRT relative retention times
  • the stability data in Table 10 indicates that the chemical stability of ketoprofen and nefidipine, especially nifedipine, is significantly improved in the presence of a small amount of either propyl gallate (0.05% w/v) or sodium metabisulfite (0.02% w/v) at elevated temperatures such as 40° C. and 60° C., with this effect being unexpectedly pronounced for propyl gallate.
US11/378,618 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures Abandoned US20070248639A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US11/378,618 US20070248639A1 (en) 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US13/454,926 US20120238940A1 (en) 2005-05-20 2012-04-24 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US14/199,144 US20140212460A1 (en) 2005-05-20 2014-03-06 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US14/947,107 US20160166555A1 (en) 2005-05-20 2015-11-20 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US15/981,450 US20190083477A1 (en) 2005-05-20 2018-05-16 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US17/223,836 US20210290605A1 (en) 2005-05-20 2021-04-06 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US17/454,583 US20220062252A1 (en) 2005-05-20 2021-11-11 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68348805P 2005-05-20 2005-05-20
US11/378,618 US20070248639A1 (en) 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/454,926 Continuation US20120238940A1 (en) 2005-05-20 2012-04-24 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Publications (1)

Publication Number Publication Date
US20070248639A1 true US20070248639A1 (en) 2007-10-25

Family

ID=37452511

Family Applications (10)

Application Number Title Priority Date Filing Date
US11/384,235 Active 2029-07-15 US8790696B2 (en) 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US11/378,618 Abandoned US20070248639A1 (en) 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US13/454,926 Abandoned US20120238940A1 (en) 2005-05-20 2012-04-24 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US14/199,144 Abandoned US20140212460A1 (en) 2005-05-20 2014-03-06 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US14/316,008 Abandoned US20150031728A1 (en) 2005-05-20 2014-06-26 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US14/947,107 Abandoned US20160166555A1 (en) 2005-05-20 2015-11-20 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US15/145,453 Active US9855256B2 (en) 2005-05-20 2016-05-03 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US15/981,450 Abandoned US20190083477A1 (en) 2005-05-20 2018-05-16 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US17/223,836 Abandoned US20210290605A1 (en) 2005-05-20 2021-04-06 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US17/454,583 Abandoned US20220062252A1 (en) 2005-05-20 2021-11-11 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/384,235 Active 2029-07-15 US8790696B2 (en) 2005-05-20 2006-03-17 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Family Applications After (8)

Application Number Title Priority Date Filing Date
US13/454,926 Abandoned US20120238940A1 (en) 2005-05-20 2012-04-24 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US14/199,144 Abandoned US20140212460A1 (en) 2005-05-20 2014-03-06 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US14/316,008 Abandoned US20150031728A1 (en) 2005-05-20 2014-06-26 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US14/947,107 Abandoned US20160166555A1 (en) 2005-05-20 2015-11-20 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US15/145,453 Active US9855256B2 (en) 2005-05-20 2016-05-03 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US15/981,450 Abandoned US20190083477A1 (en) 2005-05-20 2018-05-16 Cyclooxygenase Inhibitor and Calcium Channel Antagonist Compositions and Methods for Use in Urological Procedures
US17/223,836 Abandoned US20210290605A1 (en) 2005-05-20 2021-04-06 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US17/454,583 Abandoned US20220062252A1 (en) 2005-05-20 2021-11-11 Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Country Status (11)

Country Link
US (10) US8790696B2 (ja)
EP (1) EP1881821B1 (ja)
JP (1) JP5008206B2 (ja)
KR (3) KR20080014056A (ja)
CN (1) CN101180040B (ja)
AU (2) AU2006249684A1 (ja)
CA (1) CA2608486C (ja)
ES (1) ES2614474T3 (ja)
HK (1) HK1111911A1 (ja)
MX (1) MX2007014496A (ja)
WO (1) WO2006127096A2 (ja)

Cited By (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090264477A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc., An Indiana Corporation Beta adrenergic receptor agonists for treatment of pain and/or inflammation
US20090263463A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of pain and/or inflammation
US20090263321A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Compositions and Methods for Treating Post-Operative Pain Using Clonidine and Bupivacaine
US20090263443A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedics, Inc. Methods for treating post-operative effects such as spasticity and shivering with clondine
US20090263454A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation
US20110184037A1 (en) * 2010-01-28 2011-07-28 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US20110182849A1 (en) * 2010-01-28 2011-07-28 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
US8231891B2 (en) 2009-07-31 2012-07-31 Warsaw Orthopedic, Inc. Implantable drug depot for weight control
US8404268B2 (en) 2010-10-26 2013-03-26 Kyphon Sarl Locally targeted anti-fibrotic agents and methods of use
US8617583B2 (en) 2009-07-17 2013-12-31 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis
US8623396B2 (en) 2010-12-03 2014-01-07 Warsaw Orthopedic, Inc. Compositions and methods for delivering clonidine and bupivacaine to a target tissue site
US8629172B2 (en) 2008-04-18 2014-01-14 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising clonidine
US8722079B2 (en) 2008-04-18 2014-05-13 Warsaw Orthopedic, Inc. Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine
US8740982B2 (en) 2010-10-26 2014-06-03 Kyphon Sarl Devices containing a chemonucleolysis agent and methods for treating an intervertebral disc or spinal arachnoiditis
US8846068B2 (en) 2008-04-18 2014-09-30 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising a local anesthetic
US8880185B2 (en) 2010-06-11 2014-11-04 Boston Scientific Scimed, Inc. Renal denervation and stimulation employing wireless vascular energy transfer arrangement
US8939970B2 (en) 2004-09-10 2015-01-27 Vessix Vascular, Inc. Tuned RF energy and electrical tissue characterization for selective treatment of target tissues
US8951251B2 (en) 2011-11-08 2015-02-10 Boston Scientific Scimed, Inc. Ostial renal nerve ablation
US8956636B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprosing ketorolac
US8956641B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of inflammatory diseases
US8974451B2 (en) 2010-10-25 2015-03-10 Boston Scientific Scimed, Inc. Renal nerve ablation using conductive fluid jet and RF energy
US9023034B2 (en) 2010-11-22 2015-05-05 Boston Scientific Scimed, Inc. Renal ablation electrode with force-activatable conduction apparatus
US9028485B2 (en) 2010-11-15 2015-05-12 Boston Scientific Scimed, Inc. Self-expanding cooling electrode for renal nerve ablation
US9028472B2 (en) 2011-12-23 2015-05-12 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9050106B2 (en) 2011-12-29 2015-06-09 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
US9060761B2 (en) 2010-11-18 2015-06-23 Boston Scientific Scime, Inc. Catheter-focused magnetic field induced renal nerve ablation
US9060978B2 (en) 2011-01-24 2015-06-23 Warsaw Orthopedic, Inc. Method for treating an intervertebral disc disorder by administering a dominant negative tumor necrosis factor antagonist
US9066853B2 (en) 2013-01-15 2015-06-30 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable fiber
US9072727B2 (en) 2008-04-18 2015-07-07 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of degenerative disc disease
US9079000B2 (en) 2011-10-18 2015-07-14 Boston Scientific Scimed, Inc. Integrated crossing balloon catheter
US9084609B2 (en) 2010-07-30 2015-07-21 Boston Scientific Scime, Inc. Spiral balloon catheter for renal nerve ablation
US9089350B2 (en) 2010-11-16 2015-07-28 Boston Scientific Scimed, Inc. Renal denervation catheter with RF electrode and integral contrast dye injection arrangement
US9119632B2 (en) 2011-11-21 2015-09-01 Boston Scientific Scimed, Inc. Deflectable renal nerve ablation catheter
US9119600B2 (en) 2011-11-15 2015-09-01 Boston Scientific Scimed, Inc. Device and methods for renal nerve modulation monitoring
US9125667B2 (en) 2004-09-10 2015-09-08 Vessix Vascular, Inc. System for inducing desirable temperature effects on body tissue
US9125666B2 (en) 2003-09-12 2015-09-08 Vessix Vascular, Inc. Selectable eccentric remodeling and/or ablation of atherosclerotic material
US9155589B2 (en) 2010-07-30 2015-10-13 Boston Scientific Scimed, Inc. Sequential activation RF electrode set for renal nerve ablation
US9162046B2 (en) 2011-10-18 2015-10-20 Boston Scientific Scimed, Inc. Deflectable medical devices
US9173696B2 (en) 2012-09-17 2015-11-03 Boston Scientific Scimed, Inc. Self-positioning electrode system and method for renal nerve modulation
US9186210B2 (en) 2011-10-10 2015-11-17 Boston Scientific Scimed, Inc. Medical devices including ablation electrodes
US9186209B2 (en) 2011-07-22 2015-11-17 Boston Scientific Scimed, Inc. Nerve modulation system having helical guide
US9192790B2 (en) 2010-04-14 2015-11-24 Boston Scientific Scimed, Inc. Focused ultrasonic renal denervation
US9192435B2 (en) 2010-11-22 2015-11-24 Boston Scientific Scimed, Inc. Renal denervation catheter with cooled RF electrode
US9220561B2 (en) 2011-01-19 2015-12-29 Boston Scientific Scimed, Inc. Guide-compatible large-electrode catheter for renal nerve ablation with reduced arterial injury
US9220558B2 (en) 2010-10-27 2015-12-29 Boston Scientific Scimed, Inc. RF renal denervation catheter with multiple independent electrodes
US9265969B2 (en) 2011-12-21 2016-02-23 Cardiac Pacemakers, Inc. Methods for modulating cell function
US9277955B2 (en) 2010-04-09 2016-03-08 Vessix Vascular, Inc. Power generating and control apparatus for the treatment of tissue
US9297845B2 (en) 2013-03-15 2016-03-29 Boston Scientific Scimed, Inc. Medical devices and methods for treatment of hypertension that utilize impedance compensation
US9301946B2 (en) 2010-12-03 2016-04-05 Warsaw Orthopedic, Inc. Clonidine and GABA compounds in a biodegradable polymer carrier
US9326751B2 (en) 2010-11-17 2016-05-03 Boston Scientific Scimed, Inc. Catheter guidance of external energy for renal denervation
US9327100B2 (en) 2008-11-14 2016-05-03 Vessix Vascular, Inc. Selective drug delivery in a lumen
US9358365B2 (en) 2010-07-30 2016-06-07 Boston Scientific Scimed, Inc. Precision electrode movement control for renal nerve ablation
US9358223B2 (en) 2009-10-26 2016-06-07 Warsaw Orthopedic, Inc. Formulation for preventing or reducing bleeding at a surgical site
US9364284B2 (en) 2011-10-12 2016-06-14 Boston Scientific Scimed, Inc. Method of making an off-wall spacer cage
US9408661B2 (en) 2010-07-30 2016-08-09 Patrick A. Haverkost RF electrodes on multiple flexible wires for renal nerve ablation
US9414930B2 (en) 2010-10-26 2016-08-16 Kyphon SÀRL Activatable devices containing a chemonucleolysis agent
US9420955B2 (en) 2011-10-11 2016-08-23 Boston Scientific Scimed, Inc. Intravascular temperature monitoring system and method
US9433760B2 (en) 2011-12-28 2016-09-06 Boston Scientific Scimed, Inc. Device and methods for nerve modulation using a novel ablation catheter with polymeric ablative elements
US9463062B2 (en) 2010-07-30 2016-10-11 Boston Scientific Scimed, Inc. Cooled conductive balloon RF catheter for renal nerve ablation
US9486355B2 (en) 2005-05-03 2016-11-08 Vessix Vascular, Inc. Selective accumulation of energy with or without knowledge of tissue topography
US9486500B2 (en) 2010-01-28 2016-11-08 Warsaw Orthopedic, Inc. Osteoimplant and methods for making
US9511018B2 (en) 2012-04-05 2016-12-06 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable matrix
US9511077B2 (en) 2011-04-25 2016-12-06 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for wound healing
US9579030B2 (en) 2011-07-20 2017-02-28 Boston Scientific Scimed, Inc. Percutaneous devices and methods to visualize, target and ablate nerves
US9592243B2 (en) 2011-04-25 2017-03-14 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for treatment of an injury
US9636174B2 (en) 2002-04-08 2017-05-02 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US9649156B2 (en) 2010-12-15 2017-05-16 Boston Scientific Scimed, Inc. Bipolar off-wall electrode device for renal nerve ablation
US9668811B2 (en) 2010-11-16 2017-06-06 Boston Scientific Scimed, Inc. Minimally invasive access for renal nerve ablation
US9687166B2 (en) 2013-10-14 2017-06-27 Boston Scientific Scimed, Inc. High resolution cardiac mapping electrode array catheter
US9693821B2 (en) 2013-03-11 2017-07-04 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9707036B2 (en) 2013-06-25 2017-07-18 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation using localized indifferent electrodes
US9713730B2 (en) 2004-09-10 2017-07-25 Boston Scientific Scimed, Inc. Apparatus and method for treatment of in-stent restenosis
US9713483B2 (en) 1995-10-13 2017-07-25 Medtronic Vascular, Inc. Catheters and related devices for forming passageways between blood vessels or other anatomical structures
US9770606B2 (en) 2013-10-15 2017-09-26 Boston Scientific Scimed, Inc. Ultrasound ablation catheter with cooling infusion and centering basket
US9808311B2 (en) 2013-03-13 2017-11-07 Boston Scientific Scimed, Inc. Deflectable medical devices
US9808300B2 (en) 2006-05-02 2017-11-07 Boston Scientific Scimed, Inc. Control of arterial smooth muscle tone
US9814873B2 (en) 2002-04-08 2017-11-14 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for bilateral renal neuromodulation
US9827039B2 (en) 2013-03-15 2017-11-28 Boston Scientific Scimed, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9833283B2 (en) 2013-07-01 2017-12-05 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
US9855256B2 (en) 2005-05-20 2018-01-02 Omeros Corporation Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US9895194B2 (en) 2013-09-04 2018-02-20 Boston Scientific Scimed, Inc. Radio frequency (RF) balloon catheter having flushing and cooling capability
US9907609B2 (en) 2014-02-04 2018-03-06 Boston Scientific Scimed, Inc. Alternative placement of thermal sensors on bipolar electrode
US9919144B2 (en) 2011-04-08 2018-03-20 Medtronic Adrian Luxembourg S.a.r.l. Iontophoresis drug delivery system and method for denervation of the renal sympathetic nerve and iontophoretic drug delivery
US9925001B2 (en) 2013-07-19 2018-03-27 Boston Scientific Scimed, Inc. Spiral bipolar electrode renal denervation balloon
US9943365B2 (en) 2013-06-21 2018-04-17 Boston Scientific Scimed, Inc. Renal denervation balloon catheter with ride along electrode support
US9956033B2 (en) 2013-03-11 2018-05-01 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9962223B2 (en) 2013-10-15 2018-05-08 Boston Scientific Scimed, Inc. Medical device balloon
US9968611B2 (en) 2002-04-08 2018-05-15 Medtronic Ardian Luxembourg S.A.R.L. Methods and devices for renal nerve blocking
US9974607B2 (en) 2006-10-18 2018-05-22 Vessix Vascular, Inc. Inducing desirable temperature effects on body tissue
US10022182B2 (en) 2013-06-21 2018-07-17 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation having rotatable shafts
US10034708B2 (en) 2002-04-08 2018-07-31 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for thermally-induced renal neuromodulation
US10085799B2 (en) 2011-10-11 2018-10-02 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
WO2018191607A1 (en) * 2017-04-14 2018-10-18 Massachusetts Institute Of Technology Formulations, methods, and systems for treating genitourinary conditions
US10124195B2 (en) 2002-04-08 2018-11-13 Medtronic Ardian Luxembourg S.A.R.L. Methods for thermally-induced renal neuromodulation
US10130792B2 (en) 2002-04-08 2018-11-20 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation using neuromodulatory agents or drugs
US10265122B2 (en) 2013-03-15 2019-04-23 Boston Scientific Scimed, Inc. Nerve ablation devices and related methods of use
US10271898B2 (en) 2013-10-25 2019-04-30 Boston Scientific Scimed, Inc. Embedded thermocouple in denervation flex circuit
US10321946B2 (en) 2012-08-24 2019-06-18 Boston Scientific Scimed, Inc. Renal nerve modulation devices with weeping RF ablation balloons
US10342609B2 (en) 2013-07-22 2019-07-09 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
US10350004B2 (en) 2004-12-09 2019-07-16 Twelve, Inc. Intravascular treatment catheters
US10384048B2 (en) 2014-07-25 2019-08-20 Warsaw Orthopedic, Inc. Drug delivery device and methods having an occluding member
US10398464B2 (en) 2012-09-21 2019-09-03 Boston Scientific Scimed, Inc. System for nerve modulation and innocuous thermal gradient nerve block
US10413357B2 (en) 2013-07-11 2019-09-17 Boston Scientific Scimed, Inc. Medical device with stretchable electrode assemblies
US10478603B2 (en) 2014-07-25 2019-11-19 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10549081B2 (en) 2016-06-23 2020-02-04 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10549127B2 (en) 2012-09-21 2020-02-04 Boston Scientific Scimed, Inc. Self-cooling ultrasound ablation catheter
US10653619B2 (en) 2009-03-23 2020-05-19 Medtronic, Inc. Drug depots for treatment of pain and inflammation
US10660703B2 (en) 2012-05-08 2020-05-26 Boston Scientific Scimed, Inc. Renal nerve modulation devices
US10660698B2 (en) 2013-07-11 2020-05-26 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation
US10695124B2 (en) 2013-07-22 2020-06-30 Boston Scientific Scimed, Inc. Renal nerve ablation catheter having twist balloon
US10722300B2 (en) 2013-08-22 2020-07-28 Boston Scientific Scimed, Inc. Flexible circuit having improved adhesion to a renal nerve modulation balloon
US10737123B2 (en) 2012-03-08 2020-08-11 Medtronic Ardian Luxembourg S.A.R.L. Neuromodulation and associated systems and methods for the management of pain
US10835305B2 (en) 2012-10-10 2020-11-17 Boston Scientific Scimed, Inc. Renal nerve modulation devices and methods
US10945786B2 (en) 2013-10-18 2021-03-16 Boston Scientific Scimed, Inc. Balloon catheters with flexible conducting wires and related methods of use and manufacture
US10952790B2 (en) 2013-09-13 2021-03-23 Boston Scientific Scimed, Inc. Ablation balloon with vapor deposited cover layer
US11000679B2 (en) 2014-02-04 2021-05-11 Boston Scientific Scimed, Inc. Balloon protection and rewrapping devices and related methods of use
US11116561B2 (en) 2018-01-24 2021-09-14 Medtronic Ardian Luxembourg S.A.R.L. Devices, agents, and associated methods for selective modulation of renal nerves
US11202671B2 (en) 2014-01-06 2021-12-21 Boston Scientific Scimed, Inc. Tear resistant flex circuit assembly
US11246654B2 (en) 2013-10-14 2022-02-15 Boston Scientific Scimed, Inc. Flexible renal nerve ablation devices and related methods of use and manufacture
USRE48948E1 (en) 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
US11478587B2 (en) 2016-11-08 2022-10-25 Warsaw Orthopedic, Inc. Drug depot delivery system and method
US11759614B2 (en) 2015-11-23 2023-09-19 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080188830A1 (en) * 2007-02-06 2008-08-07 Arrow International, Inc. Selectively reinforced medical devices
JP5805369B2 (ja) * 2007-03-20 2015-11-04 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． 治療薬を放出するための泌尿器科学的医療機器
JP5340823B2 (ja) * 2008-06-24 2013-11-13 ナガセ医薬品株式会社 医療用潤滑剤
WO2010039828A1 (en) * 2008-10-01 2010-04-08 Teleflex Medical Incorporated Article containing segregated biguanide and lewis acid
TWI556849B (zh) 2010-10-21 2016-11-11 美敦力阿福盧森堡公司 用於腎臟神經協調的導管裝置
KR101951064B1 (ko) * 2011-08-04 2019-02-21 오메로스 코포레이션 주사를 위한 안정한 항-염증성 용액
US9044575B2 (en) 2012-10-22 2015-06-02 Medtronic Adrian Luxembourg S.a.r.l. Catheters with enhanced flexibility and associated devices, systems, and methods
US10548663B2 (en) 2013-05-18 2020-02-04 Medtronic Ardian Luxembourg S.A.R.L. Neuromodulation catheters with shafts for enhanced flexibility and control and associated devices, systems, and methods
WO2015113034A1 (en) 2014-01-27 2015-07-30 Medtronic Ardian Luxembourg S.A.R.L. Neuromodulation catheters having jacketed neuromodulation elements and related devices, systems, and methods
EP3134018A1 (en) 2014-04-24 2017-03-01 Medtronic Ardian Luxembourg S.à.r.l. Neuromodulation catheters having braided shafts and associated systems and methods
TWI618535B (zh) * 2014-09-24 2018-03-21 魏斯理製藥公司 減少膀胱痙攣之醫藥調配物及其使用方法
KR20170049613A (ko) * 2014-09-24 2017-05-10 웰즐리 파마슈티컬스 엘엘씨 방광경련을 감소시키기 위한 약학적 제형과 이의 사용법
WO2017068532A1 (en) * 2015-10-23 2017-04-27 Ftf Pharma Private Limited Oral solution of dihydropyridine derivatives
WO2017094029A2 (en) * 2015-12-01 2017-06-08 Sun Pharmaceutical Industries Ltd. Parenteral dosage form of diltiazem
CA3064154A1 (en) * 2017-05-26 2018-11-29 Church & Dwight Co., Inc. Oral care composition
CN107260735A (zh) * 2017-07-25 2017-10-20 合肥华方医药科技有限公司 生物利用度提高的二氢吡啶类药物组合物
CN107375283A (zh) * 2017-07-26 2017-11-24 合肥华方医药科技有限公司 生物利用度提高的硝苯地平组合物
CN107308158A (zh) * 2017-07-28 2017-11-03 合肥华方医药科技有限公司 一种提高非洛地平生物利用度的药物组合物
CN107308159A (zh) * 2017-07-28 2017-11-03 合肥华方医药科技有限公司 一种提高伊拉地平生物利用度药物组合物
JP2019069991A (ja) * 2018-12-27 2019-05-09 ウェルズリー ファーマスーティカルズ、エルエルシー 膀胱痙攣を低減するための医薬製剤およびその使用の方法
CN112891631B (zh) * 2021-01-29 2021-12-03 江南大学 一种植物源导管及其在修复神经损伤中的应用

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4593044A (en) * 1983-08-05 1986-06-03 Merckle Gmbh Injectable solution for the treatment of inflammations
US4724266A (en) * 1986-07-31 1988-02-09 Godecke Aktiengesellschaft Pharmaceutical composition with antithrombotic activity
US4867985A (en) * 1987-03-04 1989-09-19 Euroceltique S.A. Spheroids
US4932936A (en) * 1988-01-29 1990-06-12 Regents Of The University Of Minnesota Method and device for pharmacological control of spasticity
US4966890A (en) * 1986-04-04 1990-10-30 Angiogenics, Ltd. Method and composition for arresting angiogenesis and capillary, cell or membrane leakage
US5019601A (en) * 1987-12-29 1991-05-28 Cuno, Incorporated Elastomeric composition containing therapeutic agents and articles manufactured therefrom
US5409955A (en) * 1993-05-13 1995-04-25 Bockow; Barry I. Compositions and methods for inhibiting uterine contractility
US5512055A (en) * 1991-02-27 1996-04-30 Leonard Bloom Anti-infective and anti-inflammatory releasing systems for medical devices
US5536241A (en) * 1990-12-05 1996-07-16 The General Hospital Corporation Methods and devices for relaxing smooth muscle contractions
US5610184A (en) * 1994-01-14 1997-03-11 Shahinian, Jr.; Lee Method for sustained and extended corneal analgesia
US5698549A (en) * 1994-05-12 1997-12-16 Uva Patent Foundation Method of treating hyperactive voiding with calcium channel blockers
US5779661A (en) * 1995-12-11 1998-07-14 Physion, S.R.L. Method of treating dysfunctional bladder syndromes by electromotive drug administration
US5800385A (en) * 1994-12-12 1998-09-01 Omeros Medical Systems, Inc. Vascular irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis
US5843016A (en) * 1996-03-18 1998-12-01 Physion S.R.L. Electromotive drug administration for treatment of acute urinary outflow obstruction
US5912006A (en) * 1996-08-28 1999-06-15 Eboc, Inc. Compositions and methods for alleviating discomforting menstrual pain
US5962522A (en) * 1997-09-05 1999-10-05 Avmax, Inc. Propyl gallate to increase bioavailability of orally administered pharmaceutical compounds
US6242447B1 (en) * 1995-12-12 2001-06-05 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US20020077328A1 (en) * 2000-07-13 2002-06-20 Fred Hassan Selective cyclooxygenase-2 inhibitors and vasomodulator compounds for generalized pain and headache pain
US20020114838A1 (en) * 1996-04-05 2002-08-22 Ayer Atul D. Uniform drug delivery therapy
US20020198136A1 (en) * 2001-03-06 2002-12-26 Cellegy Pharmaceuticals, Inc. Compounds and methods for the treatment of urogenital disorders
US20030181426A1 (en) * 2002-02-11 2003-09-25 Eisenach James C. Compositions and methods for treating pain using cyclooxygenase-1 inhibitors
US20040142034A1 (en) * 2002-12-20 2004-07-22 Dynogen Pharmaceuticals, Inc. Methods of treating non-painful bladder disorders using alpha2delta subunit calcium channel modulators
US20040198775A1 (en) * 2003-03-10 2004-10-07 Dynogen Pharmaceuticals, Inc. Methods for treating lower urinary tract disorders and the related disorders vulvodynia and vulvar vestibulitis using Cav2.2 subunit calcium channel modulators
US20050159403A1 (en) * 2003-04-22 2005-07-21 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of central nervous system damage

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4557255A (en) * 1983-08-22 1985-12-10 Goodman Tobias M Ureteroscope
US7341737B2 (en) * 1997-06-11 2008-03-11 Kimberly-Clark Worldwide, Inc. Medicated tampon
US7973068B2 (en) * 1998-10-20 2011-07-05 Omeros Corporation Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation
US7179798B2 (en) 2001-11-16 2007-02-20 Russell R. Roby Methods and compositions for the treatment of pain and other hormone-allergy-related symptoms using dilute hormone solutions
ITMI20020798A1 (it) 2002-04-15 2003-10-15 F T Holding S A Cerotti transdermici a matrice adesiva siliconica stabilizzati con copolimeri metacrilici
US8790696B2 (en) 2005-05-20 2014-07-29 Omeros Corporation Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4593044A (en) * 1983-08-05 1986-06-03 Merckle Gmbh Injectable solution for the treatment of inflammations
US4593044B1 (ja) * 1983-08-05 1988-06-21
US4966890A (en) * 1986-04-04 1990-10-30 Angiogenics, Ltd. Method and composition for arresting angiogenesis and capillary, cell or membrane leakage
US4724266A (en) * 1986-07-31 1988-02-09 Godecke Aktiengesellschaft Pharmaceutical composition with antithrombotic activity
US4867985A (en) * 1987-03-04 1989-09-19 Euroceltique S.A. Spheroids
US5019601A (en) * 1987-12-29 1991-05-28 Cuno, Incorporated Elastomeric composition containing therapeutic agents and articles manufactured therefrom
US4932936A (en) * 1988-01-29 1990-06-12 Regents Of The University Of Minnesota Method and device for pharmacological control of spasticity
US5536241A (en) * 1990-12-05 1996-07-16 The General Hospital Corporation Methods and devices for relaxing smooth muscle contractions
US5512055A (en) * 1991-02-27 1996-04-30 Leonard Bloom Anti-infective and anti-inflammatory releasing systems for medical devices
US5409955A (en) * 1993-05-13 1995-04-25 Bockow; Barry I. Compositions and methods for inhibiting uterine contractility
US5610184A (en) * 1994-01-14 1997-03-11 Shahinian, Jr.; Lee Method for sustained and extended corneal analgesia
US5698549A (en) * 1994-05-12 1997-12-16 Uva Patent Foundation Method of treating hyperactive voiding with calcium channel blockers
US5800385A (en) * 1994-12-12 1998-09-01 Omeros Medical Systems, Inc. Vascular irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis
US5858017A (en) * 1994-12-12 1999-01-12 Omeros Medical Systems, Inc. Urologic irrigation solution and method for inhibition of pain, inflammation and spasm
US5860950A (en) * 1994-12-12 1999-01-19 Omeros Medical Systems, Inc. Arthroscopic irrigation solution and method for inhibition of pain and inflammation
US5779661A (en) * 1995-12-11 1998-07-14 Physion, S.R.L. Method of treating dysfunctional bladder syndromes by electromotive drug administration
US6261279B1 (en) * 1995-12-12 2001-07-17 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US6645168B2 (en) * 1995-12-12 2003-11-11 Omeros Corporation Arthroscopic irrigation solution and method for inhibition of pain and inflammation
US6420432B2 (en) * 1995-12-12 2002-07-16 Omeros Corporation Surgical irrigation solution and method for inhibition of pain and inflammation
US6242447B1 (en) * 1995-12-12 2001-06-05 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US5843016A (en) * 1996-03-18 1998-12-01 Physion S.R.L. Electromotive drug administration for treatment of acute urinary outflow obstruction
US20020114838A1 (en) * 1996-04-05 2002-08-22 Ayer Atul D. Uniform drug delivery therapy
US5912006A (en) * 1996-08-28 1999-06-15 Eboc, Inc. Compositions and methods for alleviating discomforting menstrual pain
US5962522A (en) * 1997-09-05 1999-10-05 Avmax, Inc. Propyl gallate to increase bioavailability of orally administered pharmaceutical compounds
US20020077328A1 (en) * 2000-07-13 2002-06-20 Fred Hassan Selective cyclooxygenase-2 inhibitors and vasomodulator compounds for generalized pain and headache pain
US20020198136A1 (en) * 2001-03-06 2002-12-26 Cellegy Pharmaceuticals, Inc. Compounds and methods for the treatment of urogenital disorders
US20030181426A1 (en) * 2002-02-11 2003-09-25 Eisenach James C. Compositions and methods for treating pain using cyclooxygenase-1 inhibitors
US20040142034A1 (en) * 2002-12-20 2004-07-22 Dynogen Pharmaceuticals, Inc. Methods of treating non-painful bladder disorders using alpha2delta subunit calcium channel modulators
US20040198775A1 (en) * 2003-03-10 2004-10-07 Dynogen Pharmaceuticals, Inc. Methods for treating lower urinary tract disorders and the related disorders vulvodynia and vulvar vestibulitis using Cav2.2 subunit calcium channel modulators
US20050159403A1 (en) * 2003-04-22 2005-07-21 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of central nervous system damage

Cited By (159)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9713483B2 (en) 1995-10-13 2017-07-25 Medtronic Vascular, Inc. Catheters and related devices for forming passageways between blood vessels or other anatomical structures
US10124195B2 (en) 2002-04-08 2018-11-13 Medtronic Ardian Luxembourg S.A.R.L. Methods for thermally-induced renal neuromodulation
US10850091B2 (en) 2002-04-08 2020-12-01 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for bilateral renal neuromodulation
US10441356B2 (en) 2002-04-08 2019-10-15 Medtronic Ardian Luxembourg S.A.R.L. Methods for renal neuromodulation via neuromodulatory agents
US10179027B2 (en) 2002-04-08 2019-01-15 Medtronic Ardian Luxembourg S.A.R.L. Catheter apparatuses having expandable baskets for renal neuromodulation and associated systems and methods
US9814873B2 (en) 2002-04-08 2017-11-14 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for bilateral renal neuromodulation
US9968611B2 (en) 2002-04-08 2018-05-15 Medtronic Ardian Luxembourg S.A.R.L. Methods and devices for renal nerve blocking
US10034708B2 (en) 2002-04-08 2018-07-31 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for thermally-induced renal neuromodulation
US9636174B2 (en) 2002-04-08 2017-05-02 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US10376516B2 (en) 2002-04-08 2019-08-13 Medtronic Ardian Luxembourg S.A.R.L. Methods and devices for renal nerve blocking
US10130792B2 (en) 2002-04-08 2018-11-20 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation using neuromodulatory agents or drugs
US10179235B2 (en) 2002-04-08 2019-01-15 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for bilateral renal neuromodulation
US9510901B2 (en) 2003-09-12 2016-12-06 Vessix Vascular, Inc. Selectable eccentric remodeling and/or ablation
US10188457B2 (en) 2003-09-12 2019-01-29 Vessix Vascular, Inc. Selectable eccentric remodeling and/or ablation
US9125666B2 (en) 2003-09-12 2015-09-08 Vessix Vascular, Inc. Selectable eccentric remodeling and/or ablation of atherosclerotic material
US9125667B2 (en) 2004-09-10 2015-09-08 Vessix Vascular, Inc. System for inducing desirable temperature effects on body tissue
US8939970B2 (en) 2004-09-10 2015-01-27 Vessix Vascular, Inc. Tuned RF energy and electrical tissue characterization for selective treatment of target tissues
US9713730B2 (en) 2004-09-10 2017-07-25 Boston Scientific Scimed, Inc. Apparatus and method for treatment of in-stent restenosis
US11272982B2 (en) 2004-12-09 2022-03-15 Twelve, Inc. Intravascular treatment catheters
US10350004B2 (en) 2004-12-09 2019-07-16 Twelve, Inc. Intravascular treatment catheters
US9486355B2 (en) 2005-05-03 2016-11-08 Vessix Vascular, Inc. Selective accumulation of energy with or without knowledge of tissue topography
US9855256B2 (en) 2005-05-20 2018-01-02 Omeros Corporation Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
US9808300B2 (en) 2006-05-02 2017-11-07 Boston Scientific Scimed, Inc. Control of arterial smooth muscle tone
US9974607B2 (en) 2006-10-18 2018-05-22 Vessix Vascular, Inc. Inducing desirable temperature effects on body tissue
US10213252B2 (en) 2006-10-18 2019-02-26 Vessix, Inc. Inducing desirable temperature effects on body tissue
US10413356B2 (en) 2006-10-18 2019-09-17 Boston Scientific Scimed, Inc. System for inducing desirable temperature effects on body tissue
US8629172B2 (en) 2008-04-18 2014-01-14 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising clonidine
US20090264477A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc., An Indiana Corporation Beta adrenergic receptor agonists for treatment of pain and/or inflammation
US8420114B2 (en) 2008-04-18 2013-04-16 Warsaw Orthopedic, Inc. Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation
US9351959B2 (en) 2008-04-18 2016-05-31 Warsaw Orthopedic, Inc. Alpha adreneric receptor agonists for treatment of degenerative disc disease
US9387197B2 (en) 2008-04-18 2016-07-12 Warsaw Orthopedic, Inc. Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine
USRE48948E1 (en) 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
US9072727B2 (en) 2008-04-18 2015-07-07 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of degenerative disc disease
US8722079B2 (en) 2008-04-18 2014-05-13 Warsaw Orthopedic, Inc. Methods for treating conditions such as dystonia and post-stroke spasticity with clonidine
US9833548B2 (en) 2008-04-18 2017-12-05 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising clonidine
US8956641B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of inflammatory diseases
US8956636B2 (en) 2008-04-18 2015-02-17 Warsaw Orthopedic, Inc. Methods and compositions for treating postoperative pain comprosing ketorolac
US9775800B2 (en) 2008-04-18 2017-10-03 Warsaw Orthopedic, Inc. Compositions and methods for treating post-operative pain using clonidine and bupivacaine
US20090263454A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation
US8889173B2 (en) 2008-04-18 2014-11-18 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of pain and/or inflammation
US9211285B2 (en) 2008-04-18 2015-12-15 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising clonidine
US20090263443A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedics, Inc. Methods for treating post-operative effects such as spasticity and shivering with clondine
US9132085B2 (en) 2008-04-18 2015-09-15 Warsaw Orthopedic, Inc. Compositions and methods for treating post-operative pain using clonidine and bupivacaine
US8846068B2 (en) 2008-04-18 2014-09-30 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising a local anesthetic
US20090263321A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Compositions and Methods for Treating Post-Operative Pain Using Clonidine and Bupivacaine
US9549920B2 (en) 2008-04-18 2017-01-24 Warsaw Orthopedic, Inc. Methods and compositions for treating post-operative pain comprising a local anesthetic
US20090263463A1 (en) * 2008-04-18 2009-10-22 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for treatment of pain and/or inflammation
US9327100B2 (en) 2008-11-14 2016-05-03 Vessix Vascular, Inc. Selective drug delivery in a lumen
US10653619B2 (en) 2009-03-23 2020-05-19 Medtronic, Inc. Drug depots for treatment of pain and inflammation
US8617583B2 (en) 2009-07-17 2013-12-31 Warsaw Orthopedic, Inc. Alpha adrenergic receptor agonists for prevention or treatment of a hematoma, edema, and/or deep vein thrombosis
US8231891B2 (en) 2009-07-31 2012-07-31 Warsaw Orthopedic, Inc. Implantable drug depot for weight control
US9358223B2 (en) 2009-10-26 2016-06-07 Warsaw Orthopedic, Inc. Formulation for preventing or reducing bleeding at a surgical site
US9125902B2 (en) 2010-01-28 2015-09-08 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US20110182849A1 (en) * 2010-01-28 2011-07-28 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
US9486500B2 (en) 2010-01-28 2016-11-08 Warsaw Orthopedic, Inc. Osteoimplant and methods for making
US20110184037A1 (en) * 2010-01-28 2011-07-28 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US9050274B2 (en) 2010-01-28 2015-06-09 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
US9277955B2 (en) 2010-04-09 2016-03-08 Vessix Vascular, Inc. Power generating and control apparatus for the treatment of tissue
US9192790B2 (en) 2010-04-14 2015-11-24 Boston Scientific Scimed, Inc. Focused ultrasonic renal denervation
US8880185B2 (en) 2010-06-11 2014-11-04 Boston Scientific Scimed, Inc. Renal denervation and stimulation employing wireless vascular energy transfer arrangement
US9155589B2 (en) 2010-07-30 2015-10-13 Boston Scientific Scimed, Inc. Sequential activation RF electrode set for renal nerve ablation
US9463062B2 (en) 2010-07-30 2016-10-11 Boston Scientific Scimed, Inc. Cooled conductive balloon RF catheter for renal nerve ablation
US9358365B2 (en) 2010-07-30 2016-06-07 Boston Scientific Scimed, Inc. Precision electrode movement control for renal nerve ablation
US9408661B2 (en) 2010-07-30 2016-08-09 Patrick A. Haverkost RF electrodes on multiple flexible wires for renal nerve ablation
US9084609B2 (en) 2010-07-30 2015-07-21 Boston Scientific Scime, Inc. Spiral balloon catheter for renal nerve ablation
US8974451B2 (en) 2010-10-25 2015-03-10 Boston Scientific Scimed, Inc. Renal nerve ablation using conductive fluid jet and RF energy
US8740982B2 (en) 2010-10-26 2014-06-03 Kyphon Sarl Devices containing a chemonucleolysis agent and methods for treating an intervertebral disc or spinal arachnoiditis
US8404268B2 (en) 2010-10-26 2013-03-26 Kyphon Sarl Locally targeted anti-fibrotic agents and methods of use
US9414930B2 (en) 2010-10-26 2016-08-16 Kyphon SÀRL Activatable devices containing a chemonucleolysis agent
US9220558B2 (en) 2010-10-27 2015-12-29 Boston Scientific Scimed, Inc. RF renal denervation catheter with multiple independent electrodes
US9028485B2 (en) 2010-11-15 2015-05-12 Boston Scientific Scimed, Inc. Self-expanding cooling electrode for renal nerve ablation
US9848946B2 (en) 2010-11-15 2017-12-26 Boston Scientific Scimed, Inc. Self-expanding cooling electrode for renal nerve ablation
US9089350B2 (en) 2010-11-16 2015-07-28 Boston Scientific Scimed, Inc. Renal denervation catheter with RF electrode and integral contrast dye injection arrangement
US9668811B2 (en) 2010-11-16 2017-06-06 Boston Scientific Scimed, Inc. Minimally invasive access for renal nerve ablation
US9326751B2 (en) 2010-11-17 2016-05-03 Boston Scientific Scimed, Inc. Catheter guidance of external energy for renal denervation
US9060761B2 (en) 2010-11-18 2015-06-23 Boston Scientific Scime, Inc. Catheter-focused magnetic field induced renal nerve ablation
US9023034B2 (en) 2010-11-22 2015-05-05 Boston Scientific Scimed, Inc. Renal ablation electrode with force-activatable conduction apparatus
US9192435B2 (en) 2010-11-22 2015-11-24 Boston Scientific Scimed, Inc. Renal denervation catheter with cooled RF electrode
US8623396B2 (en) 2010-12-03 2014-01-07 Warsaw Orthopedic, Inc. Compositions and methods for delivering clonidine and bupivacaine to a target tissue site
US9968572B2 (en) 2010-12-03 2018-05-15 Warsaw Orthopedic, Inc. Clonidine and GABA compounds in a biodegradable polymer carrier
US9301946B2 (en) 2010-12-03 2016-04-05 Warsaw Orthopedic, Inc. Clonidine and GABA compounds in a biodegradable polymer carrier
US9649156B2 (en) 2010-12-15 2017-05-16 Boston Scientific Scimed, Inc. Bipolar off-wall electrode device for renal nerve ablation
US9220561B2 (en) 2011-01-19 2015-12-29 Boston Scientific Scimed, Inc. Guide-compatible large-electrode catheter for renal nerve ablation with reduced arterial injury
US9060978B2 (en) 2011-01-24 2015-06-23 Warsaw Orthopedic, Inc. Method for treating an intervertebral disc disorder by administering a dominant negative tumor necrosis factor antagonist
US9616104B2 (en) 2011-01-24 2017-04-11 Warsaw Orthopedic, Inc. Method for treating osteoarthritis using dominant negative tissue necrosis factor
US9919144B2 (en) 2011-04-08 2018-03-20 Medtronic Adrian Luxembourg S.a.r.l. Iontophoresis drug delivery system and method for denervation of the renal sympathetic nerve and iontophoretic drug delivery
US9511077B2 (en) 2011-04-25 2016-12-06 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for wound healing
US9592243B2 (en) 2011-04-25 2017-03-14 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for treatment of an injury
US9579030B2 (en) 2011-07-20 2017-02-28 Boston Scientific Scimed, Inc. Percutaneous devices and methods to visualize, target and ablate nerves
US9186209B2 (en) 2011-07-22 2015-11-17 Boston Scientific Scimed, Inc. Nerve modulation system having helical guide
US9186210B2 (en) 2011-10-10 2015-11-17 Boston Scientific Scimed, Inc. Medical devices including ablation electrodes
US10085799B2 (en) 2011-10-11 2018-10-02 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
US9420955B2 (en) 2011-10-11 2016-08-23 Boston Scientific Scimed, Inc. Intravascular temperature monitoring system and method
US9364284B2 (en) 2011-10-12 2016-06-14 Boston Scientific Scimed, Inc. Method of making an off-wall spacer cage
US9079000B2 (en) 2011-10-18 2015-07-14 Boston Scientific Scimed, Inc. Integrated crossing balloon catheter
US9162046B2 (en) 2011-10-18 2015-10-20 Boston Scientific Scimed, Inc. Deflectable medical devices
US8951251B2 (en) 2011-11-08 2015-02-10 Boston Scientific Scimed, Inc. Ostial renal nerve ablation
US9119600B2 (en) 2011-11-15 2015-09-01 Boston Scientific Scimed, Inc. Device and methods for renal nerve modulation monitoring
US9119632B2 (en) 2011-11-21 2015-09-01 Boston Scientific Scimed, Inc. Deflectable renal nerve ablation catheter
US9265969B2 (en) 2011-12-21 2016-02-23 Cardiac Pacemakers, Inc. Methods for modulating cell function
US9186211B2 (en) 2011-12-23 2015-11-17 Boston Scientific Scimed, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9174050B2 (en) 2011-12-23 2015-11-03 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9402684B2 (en) 2011-12-23 2016-08-02 Boston Scientific Scimed, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9028472B2 (en) 2011-12-23 2015-05-12 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9037259B2 (en) 2011-12-23 2015-05-19 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9072902B2 (en) 2011-12-23 2015-07-07 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9592386B2 (en) 2011-12-23 2017-03-14 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US9433760B2 (en) 2011-12-28 2016-09-06 Boston Scientific Scimed, Inc. Device and methods for nerve modulation using a novel ablation catheter with polymeric ablative elements
US9050106B2 (en) 2011-12-29 2015-06-09 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
US10737123B2 (en) 2012-03-08 2020-08-11 Medtronic Ardian Luxembourg S.A.R.L. Neuromodulation and associated systems and methods for the management of pain
US11515029B2 (en) 2012-03-08 2022-11-29 Medtronic Ardian Luxembourg S.A.R.L. Neuromodulation and associated systems and methods for the management of pain
US9511018B2 (en) 2012-04-05 2016-12-06 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable matrix
US10660703B2 (en) 2012-05-08 2020-05-26 Boston Scientific Scimed, Inc. Renal nerve modulation devices
US10321946B2 (en) 2012-08-24 2019-06-18 Boston Scientific Scimed, Inc. Renal nerve modulation devices with weeping RF ablation balloons
US9173696B2 (en) 2012-09-17 2015-11-03 Boston Scientific Scimed, Inc. Self-positioning electrode system and method for renal nerve modulation
US10549127B2 (en) 2012-09-21 2020-02-04 Boston Scientific Scimed, Inc. Self-cooling ultrasound ablation catheter
US10398464B2 (en) 2012-09-21 2019-09-03 Boston Scientific Scimed, Inc. System for nerve modulation and innocuous thermal gradient nerve block
US10835305B2 (en) 2012-10-10 2020-11-17 Boston Scientific Scimed, Inc. Renal nerve modulation devices and methods
US9867910B2 (en) 2013-01-15 2018-01-16 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable fiber
US9066853B2 (en) 2013-01-15 2015-06-30 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable fiber
US9956033B2 (en) 2013-03-11 2018-05-01 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9693821B2 (en) 2013-03-11 2017-07-04 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9808311B2 (en) 2013-03-13 2017-11-07 Boston Scientific Scimed, Inc. Deflectable medical devices
US9827039B2 (en) 2013-03-15 2017-11-28 Boston Scientific Scimed, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
US10265122B2 (en) 2013-03-15 2019-04-23 Boston Scientific Scimed, Inc. Nerve ablation devices and related methods of use
US9297845B2 (en) 2013-03-15 2016-03-29 Boston Scientific Scimed, Inc. Medical devices and methods for treatment of hypertension that utilize impedance compensation
US9943365B2 (en) 2013-06-21 2018-04-17 Boston Scientific Scimed, Inc. Renal denervation balloon catheter with ride along electrode support
US10022182B2 (en) 2013-06-21 2018-07-17 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation having rotatable shafts
US9707036B2 (en) 2013-06-25 2017-07-18 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation using localized indifferent electrodes
US9833283B2 (en) 2013-07-01 2017-12-05 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
US10660698B2 (en) 2013-07-11 2020-05-26 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation
US10413357B2 (en) 2013-07-11 2019-09-17 Boston Scientific Scimed, Inc. Medical device with stretchable electrode assemblies
US9925001B2 (en) 2013-07-19 2018-03-27 Boston Scientific Scimed, Inc. Spiral bipolar electrode renal denervation balloon
US10342609B2 (en) 2013-07-22 2019-07-09 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
US10695124B2 (en) 2013-07-22 2020-06-30 Boston Scientific Scimed, Inc. Renal nerve ablation catheter having twist balloon
US10722300B2 (en) 2013-08-22 2020-07-28 Boston Scientific Scimed, Inc. Flexible circuit having improved adhesion to a renal nerve modulation balloon
US9895194B2 (en) 2013-09-04 2018-02-20 Boston Scientific Scimed, Inc. Radio frequency (RF) balloon catheter having flushing and cooling capability
US10952790B2 (en) 2013-09-13 2021-03-23 Boston Scientific Scimed, Inc. Ablation balloon with vapor deposited cover layer
US11246654B2 (en) 2013-10-14 2022-02-15 Boston Scientific Scimed, Inc. Flexible renal nerve ablation devices and related methods of use and manufacture
US9687166B2 (en) 2013-10-14 2017-06-27 Boston Scientific Scimed, Inc. High resolution cardiac mapping electrode array catheter
US9962223B2 (en) 2013-10-15 2018-05-08 Boston Scientific Scimed, Inc. Medical device balloon
US9770606B2 (en) 2013-10-15 2017-09-26 Boston Scientific Scimed, Inc. Ultrasound ablation catheter with cooling infusion and centering basket
US10945786B2 (en) 2013-10-18 2021-03-16 Boston Scientific Scimed, Inc. Balloon catheters with flexible conducting wires and related methods of use and manufacture
US10271898B2 (en) 2013-10-25 2019-04-30 Boston Scientific Scimed, Inc. Embedded thermocouple in denervation flex circuit
US11202671B2 (en) 2014-01-06 2021-12-21 Boston Scientific Scimed, Inc. Tear resistant flex circuit assembly
US9907609B2 (en) 2014-02-04 2018-03-06 Boston Scientific Scimed, Inc. Alternative placement of thermal sensors on bipolar electrode
US11000679B2 (en) 2014-02-04 2021-05-11 Boston Scientific Scimed, Inc. Balloon protection and rewrapping devices and related methods of use
US11464958B2 (en) 2014-07-25 2022-10-11 Warsaw Orthopedic, Inc. Drug delivery methods having an occluding member
US10478603B2 (en) 2014-07-25 2019-11-19 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11504513B2 (en) 2014-07-25 2022-11-22 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10384048B2 (en) 2014-07-25 2019-08-20 Warsaw Orthopedic, Inc. Drug delivery device and methods having an occluding member
US11759614B2 (en) 2015-11-23 2023-09-19 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector
US11413442B2 (en) 2016-06-23 2022-08-16 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10549081B2 (en) 2016-06-23 2020-02-04 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US11478587B2 (en) 2016-11-08 2022-10-25 Warsaw Orthopedic, Inc. Drug depot delivery system and method
EP3621606A4 (en) * 2017-04-14 2021-04-14 Massachusetts Institute of Technology FORMULATIONS, METHODS AND SYSTEMS FOR TREATING GENITOURINARY CONDITIONS
WO2018191607A1 (en) * 2017-04-14 2018-10-18 Massachusetts Institute Of Technology Formulations, methods, and systems for treating genitourinary conditions
US11523985B2 (en) 2017-04-14 2022-12-13 Massachusetts Institute Of Technology Formulations, methods, and systems for treating genitourinary conditions
US11116561B2 (en) 2018-01-24 2021-09-14 Medtronic Ardian Luxembourg S.A.R.L. Devices, agents, and associated methods for selective modulation of renal nerves

Also Published As

Publication number Publication date
MX2007014496A (es) 2008-02-11
WO2006127096A3 (en) 2007-02-08
WO2006127096A2 (en) 2006-11-30
US20160317515A1 (en) 2016-11-03
US20060263393A1 (en) 2006-11-23
JP5008206B2 (ja) 2012-08-22
EP1881821A4 (en) 2012-08-29
US20220062252A1 (en) 2022-03-03
ES2614474T3 (es) 2017-05-31
KR20120099730A (ko) 2012-09-11
CN101180040B (zh) 2012-10-10
US8790696B2 (en) 2014-07-29
CA2608486A1 (en) 2006-11-30
US9855256B2 (en) 2018-01-02
EP1881821A2 (en) 2008-01-30
US20140212460A1 (en) 2014-07-31
HK1111911A1 (zh) 2008-08-22
JP2008540646A (ja) 2008-11-20
AU2011200026A1 (en) 2011-01-27
US20150031728A1 (en) 2015-01-29
KR20100133511A (ko) 2010-12-21
US20160166555A1 (en) 2016-06-16
AU2006249684A1 (en) 2006-11-30
EP1881821B1 (en) 2016-11-09
CN101180040A (zh) 2008-05-14
AU2011200026B2 (en) 2012-02-09
KR20080014056A (ko) 2008-02-13
US20210290605A1 (en) 2021-09-23
CA2608486C (en) 2011-08-23
US20120238940A1 (en) 2012-09-20
KR101398903B1 (ko) 2014-06-19
US20190083477A1 (en) 2019-03-21

Similar Documents

Publication Publication Date Title
US20220062252A1 (en) Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures
EP2301562B1 (en) Irrigation solution and method for inhibition of pain, inflammation and spasm
Villégier et al. Monoamine oxidase inhibitors allow locomotor and rewarding responses to nicotine
Hama et al. Centrally mediated antinociceptive effects of cannabinoid receptor ligands in rat models of nociception
US11369685B2 (en) Compositions and methods for wound treatment
Akasaka et al. Glycyrrhetinic acid prevents cutaneous scratching behavior in mice elicited by substance P or PAR-2 agonist
Palamaras et al. Calcium antagonists in dermatology: a review of the evidence and research-based studies
Anacak et al. Lacidipine has antiatherosclerotic effects independent of its actions on lipid metabolism and blood pressure
Antonopoulos et al. Novel therapeutic strategies targeting vascular redox in human atherosclerosis
Bertrand et al. The role of EP2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1
Holtman Jr et al. The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain
Palea et al. Netupitant, a potent and highly selective NK1 receptor antagonist, alleviates acetic acid-induced bladder overactivity in anesthetized guinea-pigs
Zhao et al. Role of mitochondria in pathogenesis and therapy of renal fibrosis
Moukhariq Is GALA solution (DuraGraft®) the optimal preservation solution to protect the endothelial function of saphenous vein grafts used in coronary artery bypass grafting surgery?
Richebé et al. Néfopam et hyperalgésie périopératoire
AU6307699A (en) Irrigation solution and method for inhibition of pain, inflammation and spasm

Legal Events

Date Code Title Description
AS Assignment

Owner name: OMEROS CORPORATION, WASHINGTON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEMOPULOS, GREGORY A., M.D.;HERZ, JEFFREY M., PH.D.;REEL/FRAME:018002/0345

Effective date: 20060607

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION