EP1353659A1 - Use of neurotoxic substances in producing a medicament for treating joint pains - Google Patents

Use of neurotoxic substances in producing a medicament for treating joint pains

Info

Publication number
EP1353659A1
EP1353659A1 EP20010900365 EP01900365A EP1353659A1 EP 1353659 A1 EP1353659 A1 EP 1353659A1 EP 20010900365 EP20010900365 EP 20010900365 EP 01900365 A EP01900365 A EP 01900365A EP 1353659 A1 EP1353659 A1 EP 1353659A1
Authority
EP
Grant status
Application
Patent type
Prior art keywords
characterized
use according
preferably
neurotoxic
concentration
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.)
Withdrawn
Application number
EP20010900365
Other languages
German (de)
French (fr)
Inventor
Dominik Meyer
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.)
MESTEX AG
Original Assignee
MESTEX AG
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

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05Phenols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05Phenols
    • A61K31/055Phenols the aromatic ring being substituted by halogen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/075Ethers or acetals
    • A61K31/085Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245Amino benzoic acid types, e.g. procaine, novocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/28Compounds containing heavy metals
    • A61K31/282Platinum compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/475Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine

Abstract

The invention relates to the use of neurotoxic substances that are particularly toxic for the axon and the nociceptive nerve endings. These neurotoxic substances are used for producing a medicament for treating joint pains.

Description

USE OF NEUROTOXISCHΞN SUBSTANCES FOR THE PRODUCTION OF A MEANS FOR TREATING GELENKSCHMERZΞN

The invention relates to the use of neurotoxic substances for the preparation of an agent for the treatment of joint according to the preamble of claim 1 and a method for application of this agent in the intracapsular compartment or in the synovial bag of joints according to the preamble of claim 30th

emanating from joints pain often have their roots in the joint capsule or near the joint area of ​​the bone. However, many analogies may come into question, for example, arthritic or arthritic disease forms, mechanical or other irritation of the periarticular bone surface, irritation or injury of the articular ligaments, infections, autoimmune processes, etc. In all cases, which are within the scope of this invention of interest, go resulting pain from nociceptive nerve fibers near the joint area. Nociceptive nerve fibers are also known as C-fibers and A-delta fibers. Is injected into a diseased joint as an analgesic substance (eg, local anesthetics or morphine), the patient's symptoms are alleviated. However, the use today substances have for only a limited time, which is why the complaints return often.

For the treatment of painful, diseased joints in general the following methods are used today:

• Physiotherapy / movement therapy

• systemic analgesic / anti-inflammatory therapy (etc.)

• Local analgesic / anti-inflammatory process (etc.)

• Surgical procedures:

• Arthroscopically: debridement, joint toilet, etc.

• Open / mini-open: joint replacement, joint stiffness, etc. a number of known substances were in the literature also been proposed for the treatment of painful, inflamed joints, in particular:

• osmic acid, radioactive substances such as technetium 99, which lead to a synoviorthesis;

• injection of local anesthetics, hyaluronic acid preparations (etc.)

• injection of anti-inflammatory drugs

• injection of contrast agents for joint diagnostics

• joint flushing for joint toilette

• Chemical, thermal, electrical or surgical ablation of the nerves supplying joint.

All substances and methods used so far only lead to a relatively brief or incomplete freedom from pain or cause permanent damage to the joint.

Thus, for example, the known method of synoviorthesis the disadvantage of denaturation of the structures, in particular of the proteins, which also act as a trigger of inflammation arthritis development in the process of arthritis and in some cases. This creates a fibrous joint capsule which is less flammable and therefore less painful. Same time, the occurring in the synoviorthesis fibrosis of the joint which is generally present and also reduced hyperemia to be treated, from which also therapeutic benefit. but the fibrotic scarring after synoviorthesis can lead to decreased mobility of the joint, as well as decreased production of synovial fluid. This undesirable fibrosis of the joint capsule should be avoided and only the sensitive innervation of the joint off.

The invention aims to provide a remedy. The invention has for its object to look for suitable substances and to develop a method for injecting such substances that damage the nerve endings responsible for nociception for prolonged analgesia lasting, without compromising the hinge remote structures. The invention solves this problem by the use of neurotoxic substances according to claim 1 and a method according to the features of claim 30th

The invention will be described below for use in humans, in particular the doses indicated refer to the human application. However, the invention is also suitable for veterinary use, where there adjustments in dosage must be made depending on the body weight of the animal.

As a particular substances suitable for the preparation of an agent for the treatment of joint pain have phenol and phenol derivatives, including proven analog and pharmacologically acceptable salts thereof. Of the phenol derivatives have especially the cresols, especially ortho, meta and para cresols and their derivatives proved to be effective. Of the cresol derivatives are suitable especially the chloro-cresols, in particular the 2-chloro-m-cresol, 3-chloro-p-cresol, 4-chloro-m-cresol, 3-chloro-o-cresol, 6-chloro-o -cresol 2-chloro-p-cresol, 5-chloro-o-cresol, 6-chloro-m-cresol, and 4-chloro-o-cresol. Also, eugenol and thymol and its derivatives have been shown to be effective.

As a further preferred group of neurotoxic substances, the alcohols, particularly ethyl alcohol have been found.

As a further preferred group of neurotoxic substances have the cytostatic drugs, especially those with neuropathic side effects proved. the so-called Tubulus- and spindle poisons to the disruption of axonal transport and to reduce the Wallerian degeneration of particular effectiveness are. As a special efficient cytostatics, the taxanes have been shown, such as paclitaxel (> 200 mg / m 2 body surface area), taxol (> 200 mg / m 2 body surface area) as well as the vinca alkaloids such as vincristine (1, 4 mg / m 2 body surface area) , vinblastine (6 mg / m 2 body surface area), vindesine (3 mg / m 2 body surface area), vinorelbine (30 mg / m 2 body surface area), and finally also the marine cytostatics Aplidine, didemnin B, isohomohalichondrin B (IHB). Another effective set of Zytostaktika consisting of alkylating agents, in particular platinum complexes such as cisplatin (DDP) 50-75 (up to 120) mg / m 2 body surface area, or 2 mg per kg of body weight / week, or carboplatin (50 to 450 mgl ).

As a further preferred group of neurotoxic substances, the nitrites have been found, preferably 1, 3-butenenitrile (allyl cyanide) in an amount of> 20-40 mg / kg body weight; cis / trans-2-Buntennitrile (Crotonitrile) in an amount of> 50-100 mg / kg body weight; and 3,3'-lminodipropionitrile in an amount of 50-100 mg / kg body weight.

As a further preferred group of neurotoxic substances have the

Local anesthetics proved. As a particularly efficient effect is highly concentrated, but normal-dose local anesthetics have shown, for example,

Lidocaine, preferably in a concentration of about 6%, max. Dose of 500 mg;

Prilocaine, preferably in a concentration of over 3%, max. Dose of 600 mg;

Mepivacaine, preferably in a concentration of about 5%, max. Dose of 500 mg; Bupivacaine, preferably in a concentration of more than 1, 5%, max. dose of

150 mg;

Levobupivacaine, preferably in a concentration of about 5%;

Ropivacaine in a concentration of about 2%;

Etidocaine, preferably in a concentration of about 2%, max. Dose of 300 mg;

Procaine, preferably in a concentration of over 3%, max. Dose of 600 mg;

Chloroprocaine, preferably in a concentration of over 3%, max. Dose of 800 mg.

Tetracaine, preferably in a concentration of about 2%, max. Dose of 100 mg.

Furthermore, the lidocaine-compounds, eg lidocaine (8%) and its

Compounds such as N-beta-phenylethyl-lidocaine at a high concentration.

The used total amounts of local anesthetic are approximately equal to the amounts indicated for phenols and cresols.

In the use of local anesthetics as a neurotoxic substance is acidic additives have proven to be effective reinforcing, such as NaHSO 3 to chloroprocaine. Thus, the pH is lowered to about 3, which enhances the inventive effects of the local anesthetic.

The novel substance groups listed above are characterized by the following advantageous properties:

Long-term effect

One-stage use

Systemic non-toxic at effective dose

Predominantly neurotoxic / -lytisch for sensitive fibers, less for proprioceptive

Fibers and motor fibers

fast acting

Non-toxic to synovial

Non-toxic to bone

Non-toxic to ligaments

Non-toxic to cartilage

Non-toxic to blood vessels

Not painful when injected

Little or reversibly harmful upon leaving the joint capsule

Soluble and injectable

miscible with the desired additives

In lesion of motor neurons recovery possible

Non-inflammatory

germicidal

The inventive method is a neurotoxic, neurolytic, neuroparalytic or long term analgesic substance (hereinafter, and particularly in the claims referred to as "neurotoxic" substance) to be injected into a painful or diseased joints of the body in humans or animals. The substance can either be left in place or completely or partly drawn off again after a certain contact time. The therapeutic substance now diffuses to the sensory nerve endings that innervate directly or indirectly to the region of the joint, inhibits, or damaging these predominant and therefore leads to reduced perception of joint pain. A novel feature of this method is that the joint capsule, or synovial bag is used to concentrate the effect of the therapeutic substance to the site of pain generation and thereby allow a higher concentration of the therapeutic substance locally than without the protective capsule or synovial bag in same concentration and compatibility would be possible while protecting the vascular / nerve structures and other structures in the vicinity of the joint relatively. Thus, a long-term relief of emanating from the diseased intervertebral joint capsule complex pain sensation is obtained by inhibiting or eliminating the conduction. This method can be used preventatively or therapeutically. At the same potential infectious agents are killed by the disinfecting effect of the neurotoxic substance, a fact which can be used therapeutically.

The advantages of the inventive use of neurotoxic substances, and the inventive method for its injection into the joint capsule or in the synovial pouch are as follows:

• Intra-articular injection of selectively neurotoxic substances for analgesic therapy of joints leads to a substantial preservation of the capsule-ligament structures, the synovium and cartilage-bone structures and thus to maintain the physiological conditions.

• The use of the capsule as a natural boundary of the distribution of a neurotoxic substance.

• The effect of development of neurotoxic substances is not dependent on specific neuronal epitopes.

• The procedure can be performed by non-specialists.

• The method can be implemented with a thin, non-arthroscopic needle.

• The process is not hazardous infection, in contrast to the popular method of cortisone injection, which is strong locally promote infection since cortisone inhibits the immune system locally. • The process results in a sensitive denervation, that is the elimination of pain-transmitting nerves.

• Expansion of joint mobility by eliminating the painful limitation of movement, in contrast to synoviorthosis, wherein by the resulting capsule fibrosis movement limitation.

• Positive preparation for a later arthroplasty. By skierotisierende effect of the neurotoxic substance (the one hand as a result of chemical biological reaction on the other hand by the mechanical load at the joint pain-free use) near the joint bone obtains a more favorable for the later maintenance of a prosthesis structure.

• No local Fettgeweberesorption (lipolysis)

• No weakening of collagenous tendon / ligament / capsule structures.

In a preferred embodiment of the invention, an X-ray contrast agent, for example a Bariumzusatz or a MRI contrast agent is used in addition to the neurotoxic substance so that an imaging control the distribution of the neurotoxic substance in the intracapsular space is possible. As a contrast agent, the following substances can be used depending on the process: X-ray, CT: Iodine-containing substances, such as triiodinated benzoates or iopamidol, ideally 30 - 80g / 100ml or z. B. 5 - 10% of another contrast agent, such as barium. MRI: eg gadolinium, for example, per 1 ml: 469,01mg Gadopentat Dimeglumid,

0,99mg meglumine, 0.4 mg Diethylene pentaacetät.

In a further preferred embodiment of the invention, an antibiotic, disinfecting and / or sterilizing substance is added in addition to the neurotoxic substance.

In a further preferred embodiment of the invention is preferably in addition to the neurotoxic substance a viscous additive, such as hyaluronic acid, used at a concentration of 0.1-10.0 mg / ml solution for injection, which leads to a mechanical sliding of the joint. In a further preferred embodiment of the invention, a vasoconstrictor, in addition to the neurotoxic substance used, preferably adrenaline, noradrenaline, or other, similar, preferably alpha-adrenergic vasoconstrictors. Epinephrine, the total dose of the neurotoxin can be increased (dg for the peripheral nervous system toxic substance) and about a factor of 2, since the systemic

Effect is reduced by the decreased absorption. The adrenaline concentration (1: 10,000 to) be 1: 200,000: 80,000 to first The total dose of adrenaline is <0.25 mg. A 50 ml solution of 1: 200,000 epinephrine containing 0.25 mg epinephrine.

In a further preferred embodiment of the invention, an anti-inflammatory active substances, in addition to the neurotoxic substance used, for example, non-steroidal anti-inflammatory drugs such as COX-2 inhibitors, Acetylsalycylsäure, etc.

In a further preferred embodiment of the invention, a steroid, in addition to the neurotoxic substance used to control this at any possible occurrence of an inflammatory reaction. Leaves can also be add more causal treatment of painful, inflammatory joint diseases, which supports the symptomatic, neurolytic therapy. Particularly suitable betamethasone has been shown; for example, 5 mg of betamethasone dipropionate as a (crystalline suspension) and 2 mg of betamethasone as disodium phosphate (solution in 1 ml, can be added to the total amount to be injected). This solution is equivalent to 45/23 mg of prednisone / prednisolone.

In a further preferred embodiment of the invention glycerol is used as a solvent in addition to the neurotoxic substance. Glycerin also has neurotoxic properties (but especially when it is injected intraneural). In other glycerin can lubricate the joint, so that even a physical effect occurs. The concentration of glycerin is preferably between 10 and 95%.

In a further preferred embodiment of the invention is an analgesic in addition to the neurotoxic substance used to cause a short-time analgesia, for the case that the neurolytic effect is delayed and a painful first period occurs. As a particularly efficient effect is highly concentrated, but normal-dose local anesthetics have shown, for example, the substances listed above.

As dissolution medium Instead of glycerin, water, saline solution, sodium, iophendylate, ricin, polyethylene glycol or polypropylene glycol can be used. The advantage of glycerol as a solvent which is hyperbaric and also already somewhat neurotoxic.

Some substances have been shown to be effective strengthening of the neurotoxic substances, such as antioxidants, Preservative and excipients, especially sodium bisulfite (> 0.2%), NaHSO 3, ammonium compounds such as ammonium sulfate (NH) 2 SO, 2 - (10 - 30%), polysorbate 80 (PS80) 0.025 mg / ml.

The neurotoxic substance is preferably dissolved in a biocompatible solvent and is advantageously injected in a volume amount which corresponds to the available space in the joint to be treated, so that it is well filled. This has the advantage of an optimal distribution of neurolytic substance is achieved. but it is also possible to inject less fluid, but then must the joint are good moves for better distribution of neurolytic substance. To be injected into the intracapsular region liquid volume may be from 0.1 to 150 ml. For a finger joint enough about max. 1ml, for the shoulder joint max. 10 ml, for the knee joint about 30 - 50 ml.

The dosage of the neurolytic substance depends on its absolute solubility in the selected solvent medium. A significant impact on the dosage has the capsule thickness of the affected joint. The thicker the capsule, the more neurolytic substance is necessary.

When using chlorocresol as neurolytic substance in glycerol as a biocompatible solvent should expediently a ratio of Chorokresol: glycerol in the range 1: 5 to 1: 70, preferably from 1: 50 are selected: 40 to first In one use of phenol in glycerin should advantageously a concentration range of 0.5 - 40.0%, preferably from 3 - 12% are chosen.

To illustrate the invention better, several examples of advantageous embodiments are described below.

Example 1 :

After optional, directly or longer preceding diagnostic injection of local anesthetics of Under the optionally simultaneous (image converter, CT, ultrasound, MRI, etc.) or subsequent (X-ray, CT, MRI, ultrasound, etc.) imaging control, a syringe needle into the joint space of a knee joint and injected 40 ml of a solution of m-chloro-cresol in glycerol in the intracapsular region. The patient already felt 14 hours after the procedure clear alleviation of his symptoms. This lasted for more than 6 months.

Example 2:

The injected solution was similar to that of Example 1 with the difference that for to be used in imaging procedures 5 ml of a visible contrast medium (Iopamidol in a concentration of 50 g / 100 ml) was added, which spread after injection within the joint capsule and so the Location of the injection needle and the distribution of the therapeutic substance within the capsule documented. The neurotoxic substance contained in the injected solution was again aspirated immediately after injection. But it can be drawn off again after a defined substance-dependent action or not. The patient already felt 15 hours after the procedure clear alleviation of his symptoms. This lasted for more than 8 months.

Example 3:

The therapist placed a thin infusion catheter similar to an epidural into the affected joint and injected with a syringe pump, the low-concentration in this case neurotoxic substance (2-5% chlorocresol, 5% hydrocortisone (optional), 80-95% glycerol, 0- 10% contrast agent) in the affected joint at a rate of 1 10 ml / h during 12 h. Optionally, he also placed a drainage catheter with an optionally defined drainage resistance (eg, 20 mm Hg) to achieve a liquid turnover. With this method, the therapist achieved a uniform infiltration of the painful joint, without large concentration peaks. In addition to the exposure time could be better defined.

In a subsequent arthroscopy after 1, 2, 7, 14 and 28 d has been shown that very little inflammatory tissue was present. The patient already felt 12 hours after the procedure clear alleviation of his symptoms. This lasted for more than one year.

Example 4:

After implantation of an artificial joint (. Eg knee), the therapist injected 50 ml of the neurotoxic substance in the resealed joint capsule (in a further embodiment: in the periprosthetic area without capsule). Thus, the post-operative pain could be minimized. The neurotoxic substance was aueh in this case, low concentration (5% chlorocresol in glycerol as a solvent) in order to allow later reinnervation.

Example 5:

(5% Chorkresol in glycerine highly concentrated here) into the (neo) capsule to be injected around the prosthesis, which meant that the patient on a permanent (more than a year in a patient with painful septic loosening of a total hip replacement, the neurotoxic substance could ) relief of pain within a few (6-12) hours learned. In addition, the infection to the prosthesis by the diffusion of the neurotoxic substance (which also acted antiseptic) along the prosthesis shaft and are strongly restrained to the pan and in some cases even completely eliminated. Optionally, this treatment can with systemically administered antibiotics (eg rifampicin 450 mg, 750 mg ciprofloxacin) are supported.

Radiological a consolidation of the bone around the prosthesis was shown. Example 6:

In a patient with painful capsulitis of joints (eg. As "frozen shoulder") the neurotoxic substance was injected into the joint. Again, could the distribution of the substance can be controlled by imaging with the addition of the corresponding contrast agent. Optionally, was added an anti-inflammatory active substance . a few minutes after the injection Hesse the pain permanently to, so that the patient with physiotherapy regained the lost by the capsulitis mobility. In this application, sometimes only a temporary analgesia (2-3 weeks) is desired, therefore, here, the concentration of the neurotoxic substance was kept low (2-3% chlorocresol).

Example 7:

The therapist injected in a chronically inflamed bursa (Bursa trochanterica) practicing the greater trochanter of the hip 5 ml of a neurotoxic substance consisting of 8% phenol and 5% cortisone in glycerol as a solvent.

Within 60 minutes disappeared, the patient's symptoms, the more

remained symptom-free years at this point.

Example 8:

The therapist injected 1 ml of a neurotoxic substance consisting of 15% lidocaine, epinephrine (1: 80000) and 5% contrast agent in a physiological saline solution as a solvent in a painful, arthrotic finger joint. After about 15 minutes, the patient's symptoms disappeared for several months. The correct position of the needle could be documented by the contrast agent.

Example 9:

The therapist injected a mixture of 5% chlorocresol, 10% lidocaine and vincristine in an amount of 0.7 mg / m 2 body surface area in glycerol as a solvent. This blend showed a particularly sustained efficacy, as their components hurt to damaging nerves in different ways. The effect of the Chlorkresols is that it dissolves the nerve membrane, that of lidocaine that it destroys the nerve via irreversible Rezeptoblockierung, as well as toxic intracellular Ca release and that of vincristine, that it is the

Nerve regeneration permanently prevents and inhibits axonal transport.

In a variant, the mixture contained additional epinephrine 1: 80,000 and 10%

Contrast agents as excipients.

All variants of this mixture proved to be particularly effective for the permanent nerve damage.

Claims

claims
1. The use of neurotoxic substances for the preparation of an agent for the treatment of joint pain.
2. Use according to claim 1, characterized in that the neurotoxic substances nerve fibers are predominant toxic to pain conductive (nociceptive).
3. Use according to claim 1 or 2, characterized in that the neurotoxic substances from that group are selected, which are nontoxic to the axon and the nociceptive nerve endings.
4. Use according to one of claims 1 to 3, characterized in that the neurotoxic substances for motor and for propioceptive nerve fibers are less neurotoxic than for sensitive nerve fibers.
5. Use according to one of claims 1 to 4, characterized in that the neurotoxic substances belong to the group comprising: phenol and phenol derivatives, including analogues and pharmacologically acceptable salts thereof.
6. Use according to claim 5, characterized in that the phenol derivatives of the group of cresols, in particular ortho-, meta-, and para-cresols and their derivatives belong.
7. Use according to claim 6, characterized in that said cresol derivatives include the chloro-cresols, in particular 2-chloro-m-cresol, 3-chloro-p-kresoI, 4-chloro-m-cresol, 3-chloro-o- cresol, 6-chloro-o-cresol, 2-chloro-p-cresol, 5-chloro-o-cresol, 6-chloro-m-cresol, and 4-chloro-o-cresol.
8. Use according to claim 6, characterized in that the phenol derivatives belong to the group of Eugenole and its derivatives.
9. Use according to claim 6, characterized in that the phenol derivatives belong to the group of thymols and its derivatives.
10. Use according to one of claims 1 to 4, characterized in that the neurotoxic substances belong to the group comprising: alcohols, preferably ethyl alcohol.
11. Use according to one of claims 1 to 4, characterized in that the neurotoxic substances belonging to the following group: local anesthetics, preferably together with an acid, lowering the pH additive.
12. Use according to claim 11, characterized in that the local anesthetic is lidocaine, preferably in a concentration of about 6%.
13. Use according to claim 11, characterized in that the local anesthetic is prilocaine, preferably in a concentration of about 3%.
14. Use according to claim 11, characterized in that the local anesthetic is mepivacaine, preferably in a concentration of about 5%.
15. Use according to claim 11, characterized in that the local anesthetic is bupivacaine, preferably in a concentration of more than 1, 5%.
16. Use according to claim 11, characterized in that the local anesthetic levobupivacaine, preferably in a concentration of about 5%.
17. Use according to claim 11, characterized in that the local anesthetic ropivacaine is, preferably in a concentration of about 2%.
18. Use according to claim 11, characterized in that the local anesthetic is etidocaine, preferably in a concentration of about 2%.
19. Use according to claim 11, characterized in that the local anesthetic is procaine, preferably in a concentration of about 3%.
20. Use according to claim 11, characterized in that the local anesthetic is chloroprocaine, preferably in a concentration of about 3%.
21. Use according to claim 11, characterized in that the local anesthetic tetracaine is, preferably in a concentration of about 2%.
22. Use according to any one of claims 1 to 4, characterized in that the neurotoxic substances belonging to the following group: cytostatic agents, preferably paclitaxel, taxol, vincristine, vinblastine, vindesine, vinorelbine, Aplidine, didemnin B, isohomohalichondrin B (IHB), cisplatin or carboplatin.
23. Use according to any one of claims 1 to 4, characterized in that the neurotoxic substances belong to the group comprising: nitriles, vorzugseise 1, 3- butenenitrile (allyl cyanide), cis / trans-2-Buntennitrile (Crotonitrile), 3,3 ' - Iminodipropionitrile.
24. Use according to any one of claims 1 to 23, characterized in that in addition to the neurotoxic substances an X-ray contrast agent is used, preferably gadolinium, iodine-containing or barium-containing substances.
25. Use according to any one of claims 1 to 24, characterized in that in addition to the neurotoxic substances glycerin is used preferably in a concentration of 10 to 95 weight percent.
26. Use according to any one of claims 1 to 25, characterized in that in addition to the neurotoxic substances steroids are used.
27. Use according to any one of claims 1 to 26, characterized in that in addition to the neurotoxic substances a vasoconstrictor is used, preferably adrenaline, noradrenaline, phenylephrine or Omipressin.
28. Use according to any one of claims 1 to 27, characterized in that the neurotoxic substances are dissolved in a biocompatible solvent, preferably glycerol, iophendylate or propylene glycol.
29. Use according to any one of claims 1 to 28, characterized in that the neurotoxic substances are used for the denervation in the degenerative diseased joints.
30. A method for the treatment of joint pain, characterized in that a neurotoxic substance is injected into the intracapsular region or in the synovial bag joint affected by pain.
31. A method for the treatment of joint pain according to claim 30, characterized in that the neurotoxic substance is dissolved in a biocompatible solvent and preferably a liquid volume of 0.1 to 150 ml in the intracapsular region or in the synovial pouch of the joint affected by pain is injected ,
32. The method of claim 30 or 31, characterized in that the nociceptive nerve fibers are made insensitive to pain by the neurotoxic substance for at least 14 days.
EP20010900365 2001-01-24 2001-01-24 Use of neurotoxic substances in producing a medicament for treating joint pains Withdrawn EP1353659A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CH2001/000053 WO2002058688A1 (en) 2001-01-24 2001-01-24 Use of neurotoxic substances in producing a medicament for treating joint pains

Publications (1)

Publication Number Publication Date
EP1353659A1 true true EP1353659A1 (en) 2003-10-22

Family

ID=4358170

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20010900365 Withdrawn EP1353659A1 (en) 2001-01-24 2001-01-24 Use of neurotoxic substances in producing a medicament for treating joint pains

Country Status (5)

Country Link
US (1) US20040047807A1 (en)
EP (1) EP1353659A1 (en)
JP (1) JP2004521112A (en)
CA (1) CA2435418A1 (en)
WO (1) WO2002058688A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005538983A (en) * 2002-07-19 2005-12-22 メステックス アクチエンゲゼルシャフト How to apply the use and the drug neurotoxic substances for the manufacture of a medicament for the treatment of joint pain
US20050019436A1 (en) 2002-12-18 2005-01-27 Algorx Injectable capsaicin
RU2341283C2 (en) * 2003-03-12 2008-12-20 Фарма Мар, С.А. Advanced treatment of tumours
JP5775246B2 (en) * 2004-12-28 2015-09-09 メステックス アクチェンゲゼルシャフトMestex Ag How to apply to death methods and the drugs used in Blow toxin (rtx) for producing of a medicament for the treatment of joint pain
US20070099882A1 (en) * 2005-10-27 2007-05-03 Gurney Harry C Methods and compositions for prolonged alleviation of articular joint pain
ES2575518T3 (en) 2006-02-28 2016-06-29 Pharma Mar S.A. improved treatment of multiple myeloma
US20070270971A1 (en) * 2006-03-14 2007-11-22 Sdgi Holdings, Inc. Intervertebral prosthetic disc with improved wear resistance
US20070270970A1 (en) * 2006-03-14 2007-11-22 Sdgi Holdings, Inc. Spinal implants with improved wear resistance
US20070233246A1 (en) * 2006-03-31 2007-10-04 Sdgi Holdings, Inc. Spinal implants with improved mechanical response
US20080021462A1 (en) * 2006-07-24 2008-01-24 Warsaw Orthopedic Inc. Spinal stabilization implants
US20080021557A1 (en) * 2006-07-24 2008-01-24 Warsaw Orthopedic, Inc. Spinal motion-preserving implants
US20110112511A1 (en) * 2009-11-09 2011-05-12 Singer Jonathan E Method and apparatus for administering anesthetics to peripheral nerve regions
EP3246035A1 (en) 2010-01-26 2017-11-22 Michael A. Evans Devices and agents for denervation
US8986283B2 (en) 2011-05-18 2015-03-24 Solo-Dex, Llc Continuous anesthesia nerve conduction apparatus, system and method thereof
CA2835354A1 (en) 2011-05-18 2012-11-22 Solodex Llc Continuous anesthesia nerve conduction apparatus, system and method

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3046196A (en) * 1959-05-25 1962-07-24 Craig Pharmaceutical Company I Therapeutic compositions
US4170656A (en) * 1977-05-31 1979-10-09 American Cyanamid Company Compositions containing cis-2-benzoyl-3-hydroxy-crotononitrile used to treat inflammation and joint deterioration
US4208414A (en) * 1978-06-05 1980-06-17 Eli Lilly And Company Vinblastine in rheumatoid arthritis
US5073366A (en) * 1989-05-30 1991-12-17 Fred Beck Analgesic composition useful in providing a temporary relief from symptoms of arthritis
US5994341A (en) * 1993-07-19 1999-11-30 Angiogenesis Technologies, Inc. Anti-angiogenic Compositions and methods for the treatment of arthritis
US5583153A (en) * 1994-10-06 1996-12-10 Regents Of The University Of California Use of taxol in the treatment of rheumatoid arthritis
EP1683520B1 (en) * 1996-03-12 2013-11-20 PG-TXL Company, L.P. Water-soluble prodrugs
US6248345B1 (en) * 1997-07-02 2001-06-19 Euro-Celtique, S.A. Prolonged anesthesia in joints and body spaces
US6063768A (en) * 1997-09-04 2000-05-16 First; Eric R. Application of botulinum toxin to the management of neurogenic inflammatory disorders
ES2212038T3 (en) * 1997-09-30 2004-07-16 D &amp; W TRADING B.V. Use of pharmaceutical compositions comprising carvacrol and / or thymol against histomoniasis.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02058688A1 *

Also Published As

Publication number Publication date Type
WO2002058688A1 (en) 2002-08-01 application
JP2004521112A (en) 2004-07-15 application
CA2435418A1 (en) 2002-08-01 application
US20040047807A1 (en) 2004-03-11 application

Similar Documents

Publication Publication Date Title
Amid et al. Local anesthesia for inguinal hernia repair step-by-step procedure.
Bianconi et al. Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery
Bowersox et al. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain.
US5352683A (en) Method for the treatment of chronic pain
Chirwa et al. Intraarticular bupivacaine (Marcaine) after arthroscopic meniscectomy: a randomized double-blind controlled study
Ruetsch et al. From cocaine to ropivacaine: the history of local anesthetic drugs
Troncy et al. Results of preemptive epidural administration of morphine with or without bupivacaine in dogs and cats undergoing surgery: 265 cases (1997–1999)
US5145852A (en) Vaso-active medicament to treat impotence
Lindsey et al. Fissurectomy-botulinum toxin: a novel sphincter-sparing procedure for medically resistant chronic anal fissure
US5063060A (en) Compositions and method for treating painful, inflammatory or allergic disorders
Andersen et al. Postoperative analgesia in total hip arthroplasty: a randomized double-blinded, placebo-controlled study on peroperative and postoperative ropivacaine, ketorolac, and adrenaline wound infiltration
North et al. Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience
Shetter et al. Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain
Andersen et al. Reduced hospital stay and narcotic consumption, and improved mobilization with local and intraarticular infiltration after hip arthroplasty: a randomized clinical trial of an intraarticular technique versus epidural infusion in 80 patients
NlEMI Effects of intrathecal clonidine on duration of bupivacaine spinal anaesthesia, haemodynamics, and postoperative analgesia in patients undergoing knee arthroscopy
Ticker et al. Recognition and treatment of refractory posterior capsular contracture of the shoulder
Kerr et al. Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients
Krames et al. Intrathecal infusional analgesia for nonmalignant pain: analgesic efficacy of intrathecal opioid with or without bupivacaine
Andersen et al. A randomized, controlled trial comparing local infiltration analgesia with epidural infusion for total knee arthroplasty
Scott Wound infiltration for surgery
Toftdahl et al. Comparison of peri-and intraarticular analgesia with femoral nerve block after total knee arthroplasty: a randomized clinical trial
Essving et al. Reduced hospital stay, morphine consumption, and pain intensity with local infiltration analgesia after unicompartmental knee arthroplasty: A randomized double–blind study of 40 patients
Borison et al. Emetic action of nitrogen mustard (mechlorethamine hydrochloride) in dogs and cats
von REIS et al. Intra‐articular injections of osmic acid in painful joint affections
Fu et al. Efficacy of a multimodal analgesia protocol in total knee arthroplasty: a randomized, controlled trial

Legal Events

Date Code Title Description
AX Extension or validation of the european patent to

Countries concerned: ALLTLVMKROSI

AK Designated contracting states:

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

17P Request for examination filed

Effective date: 20030704

RIN1 Inventor (correction)

Inventor name: MEYER, DOMINIK

17Q First examination report

Effective date: 20041021

18D Deemed to be withdrawn

Effective date: 20060618