US20080139641A1 - Use Of Resiniferatoxin (Rtx) For Producing An Agent For Treating Joint Pains And Method For Applying Said Agent - Google Patents

Use Of Resiniferatoxin (Rtx) For Producing An Agent For Treating Joint Pains And Method For Applying Said Agent Download PDF

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US20080139641A1
US20080139641A1 US11/722,779 US72277904A US2008139641A1 US 20080139641 A1 US20080139641 A1 US 20080139641A1 US 72277904 A US72277904 A US 72277904A US 2008139641 A1 US2008139641 A1 US 2008139641A1
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pain
injection
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Dominik Meyer
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Mestex AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to the use of resiniferatoxin (RTX) for producing an agent for treating joint pains in accordance with the introductory portion of claim 1 and to a method for applying said agent in the intracapsular space or joint capsule of the introductory portion of claim 22 .
  • RTX resiniferatoxin
  • many analogies may come into consideration, such as arthrotic or arthritic forms of a disease, mechanical or other irritation of bone surfaces in the vicinity of a joint, irritation or injury to the ligament structures of joints, infections, autoimmune processes, etc.
  • the resulting pain emanates from nociceptive nerve fibers in the region near the joint. Nociceptive fibers are also referred to as C fibers and A delta fibers.
  • an analgesic substance such as a local anesthetic or morphine
  • the symptoms of the patient are alleviated.
  • the substances, customary at the present time act for only a limited period, so that the symptoms generally return.
  • the known method of synoviorthesis has the disadvantage of destroying the molecular structures, especially of denaturing the proteins, which act as initiators of inflammation in the process of arthritis and, partly also in the development of arthroses. Moreover, a fibrosis of the joint capsules is formed, which is less likely to become inflamed and accordingly also is less painful. At the same time, due to the fibrosis of the joint, which occurs during the synoviorthesis, the hyperemia, which is generally present and also to be treated, is decreased, resulting also in therapeutic benefit. However, the fibrotic scarring after synoviorthesis may lead to decreased mobility of the joint, as well as to a decreased production of synovial fluid and to a destruction of the joint cartilage. This undesirable fibrosis of the joint capsule should be avoided and only the sensitive innervation of the joint should be switched off.
  • the EP-B 0 998 288 of CAMPBELL discloses the use of capsaicin and analogues thereof (simultaneously or sequentially) with a local anesthetic.
  • Local anesthetics are intended to prevent the burning pain during the injection of RTX. If the local anesthetics have an antagonistic effect with respect to capsaicins, the concentration of capsaicins, when used in combination with local anesthetics, must be higher than when capsaicin is used alone, in order to achieve the desired pain therapy. As side effects, capsaicins bring about hyperemia and inflammation reactions of the tissue.
  • U.S. Pat. No. 4,997,853 of BERNSTEIN discloses the use of capsaicin together with a local anesthetic having topical activity for the treatment of topical pain syndromes.
  • capsaicins without local anesthetics is known for systemic use (intraperitoneal, subcutaneous, intravenous, etc. administration) or for regional use (epidural, intrathecal, transcutaneous administration or as a regionally selective nerve block), however, always in combination with general anesthesia of the experimental animals.
  • systemic use intraperitoneal, subcutaneous, intravenous, etc. administration
  • regional use epidural, intrathecal, transcutaneous administration or as a regionally selective nerve block
  • capsaicins in the bladder (intravesical) without local anesthesia is also known.
  • the agent is used here only topically and is not injected through a skin barrier.
  • the invention is to provide a remedy. It is an object of the invention to make available an agent for the treatment of joint pain in accordance with the introductory portion of claim 1 and a method for the local injection of this agent, which, for long-lasting analgesia, permanently damage the nerve ends, responsible for nociception, without endangering the structures remote from the joint.
  • RTX resiniferatoxin
  • the inventive method consists therein that resiniferatoxin (RTX) is injected locally into a painful or diseased joint of the human or animal body.
  • the RTX may be left there or, after a certain period of action, drawn off once again partly or completely.
  • the RTX diffuses to the sensitive nerve endings, which innervate the region of the joint directly or indirectly, inhibits on damages this region predominately and, with that, leads to a decrease in the perception of joint pain.
  • the joint capsule is used for concentrating the effect of the RTX on the place where the pain originates and, by these means, permits a higher concentration of RTX than would be possible without the protective joint capsule at the same concentration and compatibility and, at the same time, to look after the vascular, nerve and other structures in the vicinity of the joint. Accordingly, a long-term amelioration of the sensation of pain, emanating from the diseased disk-capsule-joint complex, is achieved by inhibiting or switching off the conduction. This method may be used preventatively or therapeutically.
  • the invention is described in the following for use in man, the dosages given referring particularly to human applications. However, the invention is also suitable for the veterinary sector, in which dosages would have to be adapted depending on the bodyweight of the respective animal.
  • the use of resiniferatoxin (RTX), without the simultaneous administration of further pharmacologically active substances relates to the preparation of an agent for the treatment of local pain, especially of
  • RTX resiniferatoxin
  • the concentration of RTX advis is between 100 nmolar and 10 nmolar and preferably between 500 nmolar and 1 ⁇ nmolar.
  • the agent does not contain any alcohol and especially not any ethanol.
  • Ethanol has the disadvantage that it can bring about a local inflammation and lead to painful neuritis.
  • an x-ray contrasting agent preferably substances containing gadolinium, iodine or barium, such as a barium addition or an MRI contrasting agent are used in addition to the RTX, so that an imaging control of the distribution of the RTX in the intracapsular space is possible.
  • the following substances can be used as contrasting agents:
  • an antibiotic, disinfecting and/or sterilizing substance is additionally added to the RTX.
  • a viscous additive such as hyaluronic acid, preferably in a concentration of 0.1-10 mg/milliliter of injections solution, is used in addition to the RTX. This leads to an improvement in the mechanical sliding of the joint.
  • a vasoconstrictor preferably adrenaline, noradrenaline, phenylephrin or omipressin or other, similar, preferably alpha-adrenergic vasoconstrictors are used in addition to the RTX.
  • adrenaline the total dose of neurotoxin (that is, of the substance toxic for the peripheral nervous system) can be increased by the factor of 2, since the systemic action is reduced by the decreased absorption.
  • the adrenaline concentration may amount to 1:10,000 to 1 80,000 to 1 200,000.
  • the total dose of adrenaline is less than 0.25 mg.
  • a 50 mL solution of 1:200,000 adrenaline contains 0.25 mg of adrenaline.
  • glycerin is used as solvent in addition to the RTX.
  • Glycerin also has neurotoxic properties (especially, however, if it is injected intraneurally).
  • glycerin can lubricate the joint, so that there is also a physical effect here.
  • the concentration of glycerin preferably is between 10 and 95%.
  • water, a salt solution, sodium iothalamates, iophenylate, ricin, polyethylene glycol or polypropylene glycol may be used as solvent medium.
  • glycerin has the advantage that it is hyperbaric and, in itself, also already somewhat neurotoxic.
  • Betamethasone has proven to be particularly suitable, for example, in the form of 5 mg of betamethasone as dipropionate (crystalline suspension) and 2 mg of betamethasone as disodium phosphate (solution in 1 mL can be added to the total amount that is to be injected). This solution is equivalent to 45/23 mg of prednisone/prednisolone.
  • the agent is used for denervation or neurolysis in degeneratively diseased joints.
  • the agent may be dissolved in a carrier liquid (carrier), a pharmacologically acceptable vehicle, especially from the group of sodium chloride injection solution, Ringier's injections solution, isotonic dextrose, sterile water, lactated Ringer's injections solution, distilled water or mixtures thereof, for local injection.
  • carrier liquid carrier liquid
  • pharmacologically acceptable vehicle especially from the group of sodium chloride injection solution, Ringier's injections solution, isotonic dextrose, sterile water, lactated Ringer's injections solution, distilled water or mixtures thereof, for local injection.
  • the agent may contain additionally a permeation-promoting substance, such as ethoxyethylene diglycol, purified phosphatidyl cholines, propylene glycol dipelargonates (DPPG) or with glycosylated, ethoxylated glycerides.
  • a permeation-promoting substance such as ethoxyethylene diglycol, purified phosphatidyl cholines, propylene glycol dipelargonates (DPPG) or with glycosylated, ethoxylated glycerides.
  • the agent may also contain additionally a substance, preferably glucosamininoglycans or hyaluronic acid, which enables the release of the RTX to be retarded or prolonged.
  • a different pH is produced at the site of action, preferably by mixing RTX with a suitably buffered medium.
  • a different activity profile can be produced by shifting the pH. The effect of RTX is enhanced at a pH below 7.4 and the painfulness of the injection is reduced clearly at a pH above 7.4.
  • the mixture is dissolved in a buffer solution with a pH above 7.6 and preferably above 8.5.
  • the agent may be dissolved in a buffer solution with a pH below 7.2 and preferably below 6.5.
  • the pH at first is adjusted to a value higher than 7.4 for the application or injection by means of suitable buffer media, which can also be released with delay by microencapsulation or in solid form, for example, as a powder or as an implant, such as a bone-replacement material. Subsequently, the pH drops, preferably within minutes to hours, to a value below 7.4.
  • suitable buffer media such as a powder or as an implant, such as a bone-replacement material.
  • the pH drops, preferably within minutes to hours, to a value below 7.4.
  • solvent glycerin has the advantage that it is hyperbaric and also already somewhat neurotoxic.
  • calcium Ca 2+ or comparable ions are used in a solvent in addition to RTX at a concentration, higher than that physiologically present and are released simultaneously or with delay. Calcium is necessary for the action of RTX and improves the effect of the latter if present at a concentration above the physiological one.
  • concentration of calcium exceeds 2 mmolar and particularly 4 mmolar.
  • RTX RTX
  • magnesium antioxidants, preservatives and excipients, especially sodium bisulfite (>0.2%), NaHSO 3 , ammonium compounds, such as ammonium sulfate (NH 4 ) 2 SO 4 , 2-10 ( ⁇ 30%) and polysorbate 80 (PS80) 0.025 mg/milliliter.
  • antioxidants especially sodium bisulfite (>0.2%), NaHSO 3 , ammonium compounds, such as ammonium sulfate (NH 4 ) 2 SO 4 , 2-10 ( ⁇ 30%) and polysorbate 80 (PS80) 0.025 mg/milliliter.
  • PS80 polysorbate 80
  • the concentration of salts and ions, dissolved in the solution medium preferably is higher than the normal physiological concentration (for example, in Ringer lactate).
  • RTX is dissolved in a solvent, which is compatible with the body, and advisably is injected in an amount, which corresponds to the available space in the joint, which is to be treated, so that this space is filled barely to firmly.
  • a solvent which is compatible with the body
  • advisably is injected in an amount, which corresponds to the available space in the joint, which is to be treated, so that this space is filled barely to firmly.
  • the advantage of an optimum local distribution of the RTX is achieved. It is, however, also possible to inject less liquid. In that case, however, the joint must be moved well in order to improve the distribution of the substance combination.
  • the liquid volume, to be injected into the intracapsular region may vary from 0.1 to 150 mL.
  • a maximum of about 1 mL is sufficient, for the shoulder joint, a maximum of 10 mL, for the knee joint, a maximum of 30 to 50 mL and preferably of not more than 2 mL.
  • the dosage of the combination of substances depends on the localization and indication.
  • the dosage of RTX depends on the absolute solubility of the latter in the solution medium selected.
  • the thickness of the capsule of the joint affected has a decisive effect on the dosage. The thicker the capsule, the higher is the concentration or amount of RTX, which is required.
  • the method for treating pain with the agent, used pursuant to the invention consists therein that resiniferatoxin (RTX) is dissolved in a suitable solvent, which is compatible with the body, and a volume, preferably of 0.12150 mL, thereof
  • the nociceptive nerve fibers are made insensitive to pain by the resiniferatoxin (RTX) for at least 14 days and preferably for at least 8 weeks.
  • the resiniferatoxin (RTX) is used advantageously at such a concentration, that neurolysis occurs.
  • concentration of RTX advisably is between approximately 10 nmolar (nM) and 100 ⁇ molar ( ⁇ M).
  • the advantage of this method consists therein that it permits local administration without a local anesthetic. As a result, a lower concentration of RTX is possible, so that fewer local side effects of RTX, such as swelling or inflammation, arise.
  • the agent is injected into a synovial cavity, which is not lined with urothel.
  • the injection into a synovial cavity has proven to be particularly advantageous, because an optimum residence time for developing the effect is achieved here in combination with minimum side effects, such as inflammation or pain.
  • the therapist brought an injection needle into the joint space of a knee joint and injected 9 mL of a 500 nmolar solution (approximately 0.003 mg) of resiniferatoxin into the intracapsular space.
  • the patient noted a clear alleviation of his symptoms already 14 hours after the intervention. This alleviation lasted for more than 6 months.
  • the therapist brought an injection needle into the joint space of a knee joint and injected 20 mL of a 500 nmolar solution (approximately 0.006 mg) of resiniferatoxin into the intracapsular space.
  • the patient noted a clear alleviation of his symptoms already a few days after the intervention. This alleviation lasted for more than 6 months.
  • the injected solution corresponded to that of Example 1 with the difference that, for the imaging method to be used, 5 mL of a visible contrasting agent (lopamidol) was added at a concentration of 50 g/100 mL. After the injection, this contrasting agent spread out within the joint capsule and documented the position of the injection needle and the distribution of the RTX within the joint capsule.
  • the injected solution, containing RTX was drawn off again directly after the injection. It could, however, also be drawn off after a defined, substance-dependent time of action or not be drawn off at all. The patient noted a clear alleviation of his symptoms already 15 hours after the intervention. This alleviation lasted for more than 8 months.
  • the therapist placed a thin infusion catheter, similar to an epidural catheter, into the affected joint and, with a perfuser, injected a solution of 1 liter of 100 nmolar of resiniferatoxin into the affected joint at a rate of 1-10 mL/h for 12 hours.
  • he also placed a drainage catheter with an optionally defined drainage resistance (such as 20 mm Hg), in order to achieve a liquid turnover.
  • an optionally defined drainage resistance such as 20 mm Hg
  • the therapist injected 50 mL of a solution of 100 nmolar (approximately 0.001 mg) solution of resiniferatoxin into the joint capsule, which had been closed off once again. It was possible to minimize postoperative pain by these means.
  • the therapist injected 50 mL of a solution of 100 nmolar (approximately 0.001 mg) solution of resiniferatoxin into the periprosthetic region without a capsule. It was possible to minimize postoperative pain by these means.
  • a solution of 5 ⁇ molar (approximately 0.03 mg) solution of resiniferatoxin was injected into the (neo)-capsule about the prosthesis of a patient with a painful, septic loosening of a total hip endoprosthesis. Subsequently, the patient experienced a permanent (more than one year) alleviation of pain within a few (6-12) hours.
  • the infection about the prosthesis was brought very much under control by the diffusion of the RTX (which also had antiseptic activity) along the shaft of the prosthesis and about the socket and, in some cases, was even eliminated completely.
  • this treatment may be supported with systemically administered antibiotics (such as 450 mg of Rifampicin, 750 mg of ciproflaxacin). It was possible to show radiologically that the bone substance had consolidated about the prosthesis.
  • the therapist brought an injection needle into the joint space of a knee joint and injected 9 mL of a 500 nM (approx. 0.003 mg) solution of resiniferatoxin, buffered with a buffer to a pH of 8.5, together physiological salt solution into the intracapsular space.
  • a 500 nM (approx. 0.003 mg) solution of resiniferatoxin buffered with a buffer to a pH of 8.5, together physiological salt solution into the intracapsular space.
  • the patient noted a clear alleviation of his symptoms already a few minutes after the intervention. This alleviation lasted for more than 6 months.
  • the therapist Under the optionally simultaneous (image converter, CT, sonography, MRI, etc.) or subsequent (x-ray, CT, MRI, sonography, arthroscopy, etc.) imaging control, the therapist, brought an injection needle into the joint space of a knee joint and injected 9 mL of a 500 nmolar solution (approximately 0.003 mg) of resiniferatoxin, buffered to a pH of 6.5 with a buffer, together with a physiological salt solution into the intracapsular space. Within minutes of the intervention, the patient already noted a clear alleviation of his symptoms, which lasted for more than 6 months.
  • the therapist Under the optionally simultaneous (image converter, CT, sonography, MRI, etc.) or subsequent (x-ray, CT, MRI, sonography, arthroscopy, etc.) imaging control, the therapist, brought an injection needle into the joint space of a knee joint and injected 9 mL of a 500 nmolar solution (approximately 0.003 mg) of resiniferatoxin, in a physiological Ringer solution with 10 mmolar Ca 2+ into the intracapsular space. Within minutes of the intervention, the patient already noted a clear alleviation of his symptoms, which lasted for more than 6 months.
  • the shoulder joint of a patient with painful capsulitis of joints was injected with 9 mL of a 100 nmolar (approximately 0.001 mg) solution of resiniferatoxin in physiological salt solution.
  • a substance with antiphlogistic activity was admixed.
  • the pain was alleviated permanently, so that the patient was able to regain the mobility, lost due to capsulitis, by undergoing physiotherapy.
  • only a temporary analgesia (2-3 weeks) is desired. For this reason, the concentration of the neurotoxic substances, if anything, was kept low.
  • the shoulder joint of a patient with painful capsulitis of joints was injected with 3 mL of a 500 nmolar (approximately 0.001 mg) solution of resiniferatoxin in physiological salt solution. A few minutes after the injection, the pain had abated permanently, so that the patient, with physiotherapy, regained the mobility lost due to capsulitis.
  • the therapist injected 5 mL of a solution of a 500 nmolar (approximately 0.001 mg) solution of resiniferatoxin, buffered to a pH of 8.5 with a buffer, together with physiological salt solution as solvent, into a chronically inflamed bursa (Bursa trochenterica) over the greater trochanter of the hip.
  • a chronically inflamed bursa (Bursa trochenterica)
  • the therapist injected 50 mL of a 100 nmolar (approximately 0.001 mg) solution of resiniferatoxin in glycerin or Ringer lactate as solvent. Within 60 minutes, the symptoms of the patient disappeared and the patient remained asymptomatic at this place for several years.

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Cited By (13)

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WO2010011597A3 (en) * 2008-07-22 2010-04-29 Mayo Foundation For Medical Education And Research Treatment of obesity and related disorders
US8277459B2 (en) 2009-09-25 2012-10-02 Tarsus Medical Inc. Methods and devices for treating a structural bone and joint deformity
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US8277459B2 (en) 2009-09-25 2012-10-02 Tarsus Medical Inc. Methods and devices for treating a structural bone and joint deformity
US8795286B2 (en) 2009-09-25 2014-08-05 Tarsus Medical Inc. Methods and devices for treating a structural bone and joint deformity
US8652141B2 (en) 2010-01-21 2014-02-18 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US8696719B2 (en) 2010-06-03 2014-04-15 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US9949948B2 (en) 2011-06-10 2018-04-24 Queen Mary University Of London Artemisinin and its derivatives for use in the treatment of trauma haemorrhage and associated conditions
US9623005B2 (en) 2011-06-10 2017-04-18 Queen Mary University Of London Artemisinin and its derivatives for use in the treatment of trauma haemorrhage and associated conditions
US9603831B2 (en) 2012-12-12 2017-03-28 Queen Mary & Westfield College, University Of London Artemisinin and its derivatives for use in the treatment of kidney disease
US10076384B2 (en) 2013-03-08 2018-09-18 Symple Surgical, Inc. Balloon catheter apparatus with microwave emitter
CN111315360A (zh) * 2017-09-11 2020-06-19 索伦托治疗有限公司 树脂毒素制剂
CN113490745A (zh) * 2018-12-21 2021-10-08 索伦托药业有限公司 神经周施用树脂毒素治疗适应不良性疼痛
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US12029725B2 (en) 2019-01-22 2024-07-09 Vivasor, Inc. Method for treating osteoarthritis pain by administering resiniferatoxin
CN115551480A (zh) * 2020-04-15 2022-12-30 格吕伦塔尔有限公司 树脂毒素组合物
WO2025153516A1 (en) 2024-01-15 2025-07-24 Grünenthal GmbH Ethanolic resiniferatoxin concentrate
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CA2594202C (en) 2013-12-03
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US20100196281A1 (en) 2010-08-05
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