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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
• • 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
  • A61K31/4415—Pyridoxine, i.e. Vitamin B6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
  • A61K31/51—Thiamines, e.g. vitamin B1
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7135—Compounds containing heavy metals
  • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/76—Salicaceae (Willow family), e.g. poplar
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • 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
  • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the use of flupirtine or its pharmaceutically acceptable salts for the treatment of pain and prevention of pain chronification in degenerative joint diseases of dogs and cats, which can be associated with inflammation.
• Degenerative joint diseases are understood as non-inflammatory joint diseases. In English-speaking countries, these diseases are referred to as “degenerative joint diseases” (DJD). Degenerative joint diseases occur particularly in dogs and also in many old cats. The slowly progressing loss of the articular cartilage creates an increasing and pain-related restriction in the mobility of the affected joint. As a preliminary stage of these joint diseases in dogs and cats, e.g. Hip dysplasia (growth disorder), patellar dislocation (dislocation of the kneecap or kneecap prolapse). These preliminary stages of degenerative joint diseases are also painful, even if there is no damage to the cartilage. In dogs, ligament stretching, ligament tears (e.g. torn ligament rupture) or meniscus damage often occur, which on the one hand go hand in hand with pain and on the other hand promote a renewed kneecap.
• DJD degenerative joint diseases
• the degenerative joint diseases are generally accompanied by pain. Acute inflammatory flare-ups occur occasionally. However, there are differences in this regard between humans and dogs, because these inflammatory reactions take place in dogs in a clearly softened form (e.g. swellings which are hardly detectable in dogs, very pronounced swellings in humans). There are other painful diseases in animals that are partially accompanied by degenerative changes in the joints. These include, for example, Dachshund paralyzes or Cauda equina syndrome. The latter is the so-called "horse tail syndrome", which mainly affects dogs of large breeds (such as German shepherd). The cause of the pain is the narrowing of the spinal canal due to the partial collapse of the cartilaginous spinal disc.
• corticosteroids are also used, which, according to their mechanism of action, also trigger serious side effects in animals.
• NSAIDs non-steroidal anti-inflammatory drugs
• cartilage protective / protective (chondroprotective) drugs are most often used.
• the cartilage-protective substances include polysulfated glycosaminoglycan and the combination of chondroitin and glucosamine. polysulphated
• Glycosaminoglycan is given intramuscularly or intra-articularly (directly into the joint).
• Chondroitin and glucosamine are used either as monosubstances (glucosamine) or in combination orally. To date, their effectiveness is none controlled clinical study in both humans and animals (Leffler, CT, AF Philippi, SG Leffler, JC Mosure, PD Kim. Glucosamine, chondroitin, and magnesium ascorbate for degenerative Joint disease of the knee or low back: A randomized, double -blind, placebo-controlled pilot study. Military medicine 164: 85-91, 1999).
• TNF ⁇ tumor necrosis factor ⁇
• TNF ⁇ vascular endothelium in the inflammatory response: insights from the clinical trial of anti-TNF ⁇ antibody in rheumatoid arthritis. Mol. Pathol. 50: 225 -233, 1997).
• Clinical studies have clearly demonstrated that neutralization of TNF ⁇ either by monoclonal antibodies directed against TNF ⁇ (anti-TNF mABs) or by the use of soluble TNF ⁇ receptors (soluble TNF receptor fusion proteins: sTNFR-lgGs) is not only the acute one Symptoms (e.g. swelling of the joints) but also the continuously progressing cartilage and bone destruction can be suppressed (Fenner, H. Immunopharmacological profile and therapeutic perspectives of anti-TNF ⁇ therapies. Journal. Rheumatol.
• Veterinary medicine primarily prescribes NSAIDs for the treatment of chronic pain.
• the following active ingredients are currently used in particular: aspirin, carprofen, ketoprofen, piroxicam, naproxen and meclofenamic (Papich, G. M., Hardie E. M., Management of chronic pain).
• the non-steroidal anti-inflammatories can alleviate the pain, but rather promote cartilage destruction (Wang, B, Yao, YY, Chen MZ. Effects of indometacin on Joint damage in rat and rabbit.
• NSAIDs as inhibitors of cyclooxyeganase, cause an increase in leukotrienes by shifting the arachidonic acid metabolism, which are able to promote the degenerative processes
• Bennette, K, Aehringhaus, U, Peskar BA Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages, Agents Actions 14: 729-34, 1984; Achterrath-Tuckermann, U., Th.Simmet, W. Luck, I. Szelenyi, BA Peskar. Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance.
• NSAIDs have serious gastrointestinal and other potentially life-threatening side effects (Forsyth, SF, Guilford, WG, Haslett, SJ, Godfrey, J. Endoscopy of the gastrduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J. Small Animal Practice 39: 421-4, 1998).
• COX-1 cyclooxygenases
• Enzyme whose job it is, among other things, to protect the gastrointestinal mucosa and to maintain the necessary renal blood flow and to maintain adequate blood circulation.
• COX-2 enzyme is only induced by various factors and is responsible for the inflammatory processes.
• NSAIDs cause gastrointestinal side effects.
• NSAIDs such as acetylsalicylic acid, ibuprofen, ketoprofen, naproxen, carprofen,
• diclofenac, meclofenamic acid, piroxicam, meloxicam are not selective
• gastrointestinal side effects can occur when using such NSAIDs (Forsyth, SF, WG Guilford, SJ Haslett, J Godfrey. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J. Small Animal Pract. 39: 421-424 , 1998; Tjalve, H. Adverse reactions to veterinary drugs reported in Sweden during 1991-1995. J. Vet. Pharmacol. Therap. 20: 105-10, 1997)).
• analgesics can also cause other undesirable reactions that cannot be explained by the inhibition of the enzyme COX. They are substance-specific and occur with certain medications. For example, liver damage has occasionally been observed with diclofenac, naproxen, nimesuli and piroxicam (Helfgott SM, et al. Diclofenac-associated hepatotoxicity. JAMA 264: 2660-2662, 1990; Andrejak, M, et al. Cross hepatotoxicity between non-steroidal anti -inflammatory drugs. Br. Med. J. 295: 180-181, 1987; McCormick, PA, et al. COX-2 inhibitor and fulminant hepatic failure, Lancet 353: 40-41, 1990; Paterson D, et al. Piroxicam induced submassive necrosis of the liver. Gut 33: 1456-1458, 1992).
• Organism loaded with 50% fiber may also contribute to drug interactions (Szelenyi, I, G Geisslinger, E Polymeropoulos, W Paul, M Herbst, K Brune. The real Gordian knot: Racemic mixtures versus pure enantiomers. Drug News & Perspectives 11: 139-160, 1998).
• NSAIDs such as diciofenac
• aspirin are incomparably better tolerated in human therapy than in dogs.
• Pain treatment and the prevention of pain chronification in degenerative joint diseases in dogs and cats are becoming increasingly important.
• the corresponding pharmaceutical preparations must be in a form that is easily ingestible for dogs and cats and that is well tolerated in terms of taste.
• flupirtine or its pharmaceutically acceptable salts can be used for the treatment of pain and for the prevention of pain chronification in degenerative joint diseases in dogs and cats with little potential for side effects.
• Flupirtin has not yet been used in veterinary medicine.
• Flupirtine is a triaminopyridine derivative with the chemical name 2-amino-3-ethoxycarbonyl-amino-6- (p-fluoro-benzylamino) pyridine.
• flupirtine is a centrally acting analgesic, but without addictive potential and without side effects typical of other central analgesics such as constipation, respiratory depression, development of tolerance and withdrawal symptoms. It is known from the literature that flupirtine can be used in human therapy for the treatment of various diseases.
• flupirtine has muscle-relaxing properties, so that flupirtine can also be used for the treatment of muscle tension or for diseases based on muscle tension (DE 40 22 442, US 5 162 346, US 5 284 861).
• flupirtine is also suitable for the treatment of NMDA-mediated CNS diseases, such as, for example, cerebral ischemia, neurodegenerative diseases and epilepsy (DE 43 27 516, US 5 721 258) ,
• WO 97/17072 shows the use of flupirtine for the treatment of diseases of the hematopoietic cell system, such as AIDS.
• flupirtine can be used for the treatment of diseases which are associated with an unphysiologically high cell death rate (WO 97/49398).
• flupirtine also opens the so-called voltage-independent K + channels in the central nervous system.
• flupirtine is also able to prevent the chronification of pain (Kornhuber, J. A pain reliever that differs from all known analgesics. Med. Week 64:10, 1999).
• the analgesic effect of flupirtine is most likely due to the combination of the above effects. For example, it was shown that the opening of the central ATP-dependent K + channels not only has an antinociceptive effect per se, but that it also activates the noradrenergic descending pain-modulating pathways in the spinal cord (Narita, M, Takamori, K, Kawashima, N , Funada, M, Kamei, J, Suzuki, T, Misawa, M, Nagase, H. Activation of central ATP-sensitive potassium Channels produces the antinociception and spinal noradrenaline tumover-enhancing effect in mice. Psychopharmacol. 113: 11-14, 1993).
• flupirtin thus clearly differs from that of the so-called peripheral analgesics such as aspirin, ibuprofen, diciofenac, which develop their analgesic effect by inhibiting cyclooxygenase. Since flupirtine does not inhibit prostaglandin synthesis, there is no damage to the gastrointestinal mucous membranes.
• Renal function is also not affected by flupirtine. In chronic toxicological studies (6-12 months), no evidence of a liver-damaging effect was found.
• the animals were tested a week after the silver wire was implanted.
• the silver wire was made with a
• Pulse generator connected, with the help of which the current levels could be regulated continuously.
• Flupirtine was administered orally to the dogs in a capsule. 30 minutes later, the current was ramped up at a steady rate. At the first sign of pain sensation, the power generator was switched off immediately. The current that was observed at the first sign of pain was considered the pain threshold. Symptoms such as salivation, lip licking, and twitching of the facial muscles were considered signs of pain sensation.
• Table 1 nu: not examined
• flupirtine is both in dogs
• Ibuprofen as well as diciofenac clearly superior.
• Buprenorphine is a very potent analgesic with a very low oral bioavailability and is one of the classic morphine derivatives.
• buprenorphine had a significantly stronger analgesic effect than flupirtine after intravenous administration.
• flupirtine has a very strong analgesic potential in dogs. Due to the mechanism of action and the available toxicological results, gastrointestinal, renal or hepatic damage is not expected with acute or long-term use. Flupirtine can preferably be administered orally, parenterally or rectally to treat pain in degenerative diseases in dogs and cats. Suitable dosage forms can be: granules, pellets, capsules, microcapsules, dragees, film-coated tablets, chewable tablets, prolonged-release tablets, two-layer tablets, prolonged-release capsules, bolus, powder, suppositories or injection solutions.
• Tablet formulations with a single or double break notch can be advantageous here in order to be able to better administer the individually required amount to the animals.
• taste enhancers such as Trigarol Digest P (Haarmann & Reimer GmbH) or artificial meat flavors, for example consisting of vegetable protein and oil from soybeans and dried pork liver powder, can be added to the tablet granules in proportions of between 5 and 10%.
• Flupirtine maleate 0.1 to 20 mg / kg, preferably 1 to 5 mg / kg.
• Capsules containing 100 mg flupirtine maleate can be administered two to three times a day.
• the maximum daily dose should not exceed 600 mg.
• Suppositories can contain 0.1 to 30 mg / kg, preferably 2.5 to 7.5 mg / kg, of flupirtine maleate as a single dose.
• Parenteral dosage forms preferably injection solutions for intramuscular administration, preferably contain 1.5 to 5 mg / kg of flupirtine gluconate (because of the better local tolerance).
• ampoules containing 164.5 mg of flupirtine gluconate in 3 ml solution can be administered once a day.
• the breaking strength of the tablets is 80 N to 100 N (Schleuniger breaking strength tester).
• the disintegration time according to DAB 8 is 5 minutes.
• Each tablet contains 100 mg of active ingredient.
• a capsule filling is produced in hard gelatin capsules of the appropriate size is filled. Filling quantity per capsule: 200 mg. One capsule contains 100 mg of active ingredient.
• solution 1 8000.0 g of polyethylene glycol molecular weight 380 to 420 are weighed in and the solution is heated to 70 ° C. while gassing with nitrogen.
• Solution 5 is cooled and made up to 20 liters with nitrogen-gassed water.
• Solution 6 is sterile filtered through a membrane filter with a pore size of 0.2 ⁇ m and a glass fiber pre-filter.
• Solution 7 is filled under aseptic conditions and under nitrogen gassing into colorless ampoules, content 3 ml.
• One ampoule contains 164.5 mg flupirtine gluconate in 3 ml solution.
• flupirtine or its pharmaceutically usable salts can also be used in combination with other active substances for treating pain in degenerative joint diseases in dogs and cats.

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