IE922467A1 - Use of 1,4-dihydropyridines for the preparation of medicaments for treating neuropathy caused by diabetes - Google Patents
Use of 1,4-dihydropyridines for the preparation of medicaments for treating neuropathy caused by diabetesInfo
- Publication number
- IE922467A1 IE922467A1 IE246792A IE922467A IE922467A1 IE 922467 A1 IE922467 A1 IE 922467A1 IE 246792 A IE246792 A IE 246792A IE 922467 A IE922467 A IE 922467A IE 922467 A1 IE922467 A1 IE 922467A1
- Authority
- IE
- Ireland
- Prior art keywords
- nimodipine
- preparation
- diabetes
- medicaments
- caused
- Prior art date
Links
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title claims abstract description 8
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 201000001119 neuropathy Diseases 0.000 title claims description 11
- 230000007823 neuropathy Effects 0.000 title claims description 11
- 208000033808 peripheral neuropathy Diseases 0.000 title description 6
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims abstract description 42
- 229960000715 nimodipine Drugs 0.000 claims abstract description 42
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 210000000578 peripheral nerve Anatomy 0.000 abstract description 12
- 230000002213 calciumantagonistic effect Effects 0.000 abstract description 3
- 210000005036 nerve Anatomy 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 11
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 11
- 229960001052 streptozocin Drugs 0.000 description 11
- 230000001953 sensory effect Effects 0.000 description 10
- 230000007830 nerve conduction Effects 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 241000700157 Rattus norvegicus Species 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003288 aldose reductase inhibitor Substances 0.000 description 2
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000035987 intoxication Effects 0.000 description 2
- 231100000566 intoxication Toxicity 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- -1 -isopropyl ester Chemical class 0.000 description 1
- NCHLDZALJLMLPJ-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine Chemical compound C1=C(C)NC(C)=CC1C1=CC=CC([N+]([O-])=O)=C1 NCHLDZALJLMLPJ-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the use of 1,4-dihydropyridines with a calcium-antagonistic action, especially of nimodipine, for the preparation of a medicament for controlling damage to peripheral nerves caused by diabetes.
Description
The invention relates to the use of 1,4-dihydropyridines having calcium antagonistic action, in particular of nimodipine, for the preparation of medicaments for controlling damage to peripheral nerves which is caused by diabetes.
The dihydropyridines which can be employed according to the invention, their preparation and their use as circulatory and cerebrally active agents have been disclosed (compare German Patent Specification 2,117,571, EPB 4650). For the active compound nimodipine (1,4dihydro-2,6-dimethyl-4-(3'-nitrophenyl)pyridine 3-βmethoxyethyl ester 5-isopropyl ester), in addition to the cerebral effects such as improvements in memory, learning behaviour and the motor field, certain neuroprotective effects are also known (compare Steen P.A. et al., Anesthesiology, 62. 406-411 (1985)). In addition to these cerebral effects of nimodipine, effects on peripheral nerves are also described. The publication by R.E. Sporel-Ozakat et al., Nimodipine and central nervous system function: New Vistas, Schattauer Verlag Stuttgart, 71-85 (1989) describes that, after administration of nimodipine to rats, the peripheral nerves are better protected, in particular with respect to cis-platin neuropathy. In this publication, reference is also made to the fact that the mechanism of action of nimodipine is not_ known and further investigations regarding this are urgently needed.
A TP 98 The publication of C.E.E.M. van der Zee et al., Neuroscience Letters, 83 (1987) 143-148 describes the positive effect of nimodipine on mechanically damaged peripheral nerves. The prior art contains no indication that 1,45 dihydropyridines having calcium antagonistic action, in particular nimodipine, can be employed in the therapy and prophylaxis of damage to the peripheral nerves which is caused by diabetes.
One of the most frequent types of late damage in diabetes 10 mellitus is peripheral neuropathy. The prevalence rate for this is over 60% of the patients suffering from diabetes mellitus. The symptoms include pains in the extremities, muscle weakness up to paralysis symptoms and diverse dysfunctions of the autonomic nervous system such as diarrhoea or impotence. Owing to this damage caused by diabetes, there is a consistent decrease in the nerve conduction rate of both sensory and motor nerves. This nerve conduction rate is thus a readily measurable parameter for determining this damage.
To date, there is no established method for treating such neuropathies and an urgent need thus exists for a therapeutically active agent.
It has already been attempted to employ aldose reductase inhibitors for this therapy. These substances inhibit the enzyme which catalyses the conversion of glucose to sorbitol. In diabetes mellitus, such a glucose oversupply TP 98 is present, as a result of which an excess of sorbitol is formed which can lead, for example, to cloudiness of the lens of the eye, and which is regarded as a reason for the neuropathy which is caused by diabetes. Aldose reductase inhibitors have already been clinically tested in this indication. The expectations placed on them, however, have not been fulfilled.
As already indicated above, it is also known for the calcium antagonist nimodipine that it has certain neuro10 protective effects. For example, it accelerates the regeneration of the function of peripheral nerves after mechanical lesion. Additionally, it is described that nimodipine in the rat after a specific intoxication with the cytostatic cis-platin antagonises selective disorders of the nerve conduction rate of sensory peripheral nerves. The nerve conduction rate of motor peripheral nerves is not affected by cis-platin.
A corresponding intoxication with acrylamide likewise leads to a reduction of the conduction rate of sensory and motor nerves. It is known that nimodipine does not antagonise this damage to peripheral nerves (compare R.E. Sporel-0zakat, Dissertation, University of Utrecht, 1990, pages 93-98). These results show that the nerve protective action of nimodipine is not of the general type and can thus not be derived from the prior art. The person skilled in the art would not expect that nimodipine has a therapeutic effect on the specific peripheral neuropathy which is induced by diabetes mellitus.
TP 98 Surprisingly, it has now been found that nimodipine antagonises damage to sensory and motor peripheral nerves which is caused by chronic excess of sugar. This effect occurs both after prophylactic administration and after therapeutic administration. Thus, the person skilled in the art is for the first time able to treat therapeutically peripheral neuropathies which are caused by diabetes mellitus. It was unforeseeable for the person skilled in the art that calcium antagonists of the nimodipine type would have such specific therapeutic effects on peripheral nerves.
The invention relates to the use of calcium antagonists from the 1,4-dihydropyridine family, in particular nimodipine, for controlling neuropathies which are caused by diabetes mellitus. Of particular importance is the control of those neuropathies which occur in the peripheral nervous system.
The preparation of the active compound nimodipine and the preparation of medicaments containing nimodipine for the treatment of such neuropathies is carried out by customary methods, for example by extending the active compound with solvents and/or excipients and then converting into customary formulations such as tablets, coated tablets, granules, syrups, emulsions, suspensions and solutions using inert, non-toxic pharmaceutically suitable auxiliaries.
TP 98 Administration is carried out in a customary manner, preferably orally. On oral administration, the dosage is about 0.05 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
The surprising therapeutic effect of the present invention is confirmed by the following use examples: In male Wistar rats, the insulin-producing pancreas cells are damaged by a single administration of streptozotocin (50 mg/kg i.v.), which leads to chronically increased glucose levels. In the diabetic rats damaged in this way, the nerve conduction rates are distinctly reduced (compare A.K. Sharma et al.. Diabetic neuropathy (1987), 237-252 and Y. Harati, Ann. Intern. Med. 107 (1987) 546-559). The results of the test are to be inferred from the curves of Figs. 1 to 4. The curves a in each case represent the nerve conduction rate of the control groups, the curves c those in damaged diabetic rats which have received no nimodipine and the curves b the nerve conduction rate in diabetic rats treated with nimodipine. Whereas in the healthy control animals the nerve conduction rate of both sensory (Figs. 1 and 3, curves a) and motor nerves (Figs. 2 and 4, curves a) rises continuously over time, the nerve conduction rate in the diabetic animals not treated with nimodipine is virtually unchanged (in each case curves c for sensory nerves in Figs. 1 and 3, and for motor nerves in Figs. 2 and 4).
After administration of nimodipine (20 mg/kg i.p. every TP 98 hours), the disorder induced by the excess of sugar is significantly compensated. This applies both for prophylactic nimodipine treatment (curves b in Figs. 1 and 2) and for therapeutic nimodipine treatment (curves b in Figs. 3 and 4).
Fig. 1: Prophylactic effect of nimodipine on the conduction rate of sensory nerves In each case, the average values (± SEM) for the conduction rates of sensory nerves (CRSN) 0, 2, 4, 6, 8 and 10 weeks after streptozotocin administration (50 mg/kg i.v.) are shown. Group 1 (curve b, n = 11) was treated with nimodipine (20 mg/kg i.p. every 48 h in 1 ml/kg of polyethylene glycol), group 2 (curve c, n = 11) only with the solvent (1 ml/kg i.p.). Group 3 (curve a, n - 11) is a non-diabetic control group treated neither with streptozotocin nor with nimodipine, but only with 1 ml/kg of polyethylene glycol. All experiments were carried out on male Wistar rats (11-12 weeks old at the start of the experiment).
The statistical analysis showed that in streptozotocintreated diabetic animals the nimodipine treatment led to a significant increase in the CRSN (p < 0.001). The CRSN of untreated non-diabetic control animals was significantly higher than that of the solvent- or nimodipine25 treated diabetic rats (p < 0.001).
TP_2£ Fig. 2: Prophylactic effect of nimodipine on the conduction rate of motor nerves In each case, the average values (± SEM) for the conduction rates of motor nerves (CRMN) 0, 2, 4, 6, 8 and 10 weeks after streptozotocin administration (50 mg/kg i.v.) are shown. Group 1 (curve b, n = 11) was treated with nimodipine (20 mg/kg i.p. every 48 h in 1 ml/kg of polyethylene glycol), group 2 (curve c, n = 11) only with the solvent (1 ml/kg i.p.). Group 3 (curve a, n = 11) is a non-diabetic control group treated neither with streptozotocin nor with nimodipine, but only with 1 ml/kg of polyethylene glycol. All experiments were carried out on male Wistar rats (11-12 weeks old at the start of the experiment).
The statistical analysis showed that in streptozotocintreated diabetic animals the nimodipine treatment led to a significant increase in the CRMN (p < 0.001). The CRMN of untreated non-diabetic control animals was significantly higher than that of the solvent- or nimodipine20 treated diabetic rats (p < 0.001).
Fig. 3: Therapeutic effect of nimodipine on the conduction rate of sensory nerves In each case, the average values (± SEM) for the conduction rates of sensory nerves (CRSN) 0, 4, 6, 8 and 10 weeks after streptozotocin administration (50 mg/kg i.v.) are shown. Group 1 (curve b, n = 12) was treated with TP 98 nimodipine (20 mg/kg i.p. every 46 h in 1 ml/kg of polyethylene glycol), group 2 (curve c, n - 12) only with the solvent (1 ml/kg i.p.). The treatment of the diabetic rats with nimodipine or solvent was carried out 4 weeks after the start of streptozotocin administration, a time at which a significant decrease in the CRSN in comparison with non-diabetic control animals not treated with streptozotocin was measurable (group 3, curve a, n = 12). All experiments were carried out on male Wistar rats (11-12 weeks old at the start of the experiment).
The statistical analysis showed that in streptozotocintreated diabetic animals the nimodipine treatment led to a significant increase in the CRSN (p < 0.001). The CRSN of untreated non-diabetic control animals was signifi15 cantly higher than that of the solvent- or nimodipinetreated diabetic rats (p < 0.001).
Fig. 4: Therapeutic effect of nimodipine on the conduction rate of motor nerves In each case, the average values (± SEM) for the conduc20 tion rates of motor nerves (CRMN) 0, 4, 6, 8 and 10 weeks after streptozotocin administration (50 mg/kg i.v.) are shown. Group 1 (curve b, n = 12) was treated with nimodipine (20 mg/kg i.p. every 48 h in 1 ml/kg of polyethylene glycol), group 2 (curve c, n = 12) only with the solvent (1 ml/kg i.p.). The treatment of the diabetic rats with nimodipine or solvent was carried out 4 weeks after the start of streptozotocin administration, a time TP 98 at which a significant decrease in the CRMN in comparison with non-diabetic control animals not treated with streptozotocin was measurable (group 3, curve a, n = 12). All experiments were carried out male Wistar rats (11-12 weeks old at the start of the experiment).
The statistical analysis showed that in streptozotocintreated diabetic animals the nimodipine treatment led to a significant increase in the CRMN (p < 0.001). The CRMN of untreated non-diabetic control animals was signifi10 cantly higher than that of the solvent- or nimodipinetreated diabetic rats (p < 0.001).
Claims (9)
1. Use of calcium antagonists from the 1,4-dihydropyridine family for controlling neuropathies which are caused by diabetes mellitus. 5
2. Use of calcium antagonists according to Claim 1 for controlling neuropathies in the peripheral nervous system.
3. Use of calcium antagonists from the 1,4-dihydropyridine family in the preparation of medicaments for 10 controlling neuropathies which are caused by diabetes mellitus.
4. Use according to Claims 1 to 3, characterised in that nimodipine is employed as the active compound.
5. Process for the preparation of medicaments for 15 controlling neuropathies which are caused by diabetes mellitus, characterised in that calcium antagonists from the 1,4-dihydropyridine family are converted into a suitable administration form, if appropriate using customary auxiliaries and 20 excipients. TP 98
6. Use according to Claim 1, substantially as hereinbefore described.
7. Use according to Claim 3, substantially as hereinbefore described.
8. A process according to Claim 5 for the preparation of a medicament, substantially as hereinbefore described.
9. A medicament whenever prepared by a process claimed in a preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4125116A DE4125116A1 (en) | 1991-07-30 | 1991-07-30 | USE OF 1,4-DIHYDROPYRIDINE IN DIABETES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE922467A1 true IE922467A1 (en) | 1993-02-10 |
| IE65109B1 IE65109B1 (en) | 1995-10-04 |
Family
ID=6437256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE922467A IE65109B1 (en) | 1991-07-30 | 1992-07-29 | Use of 1,4-dihydropyridines for the preparation of medicaments for treating neuropathy caused by diabetes |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0525537B1 (en) |
| JP (1) | JP3381198B2 (en) |
| KR (1) | KR930001908A (en) |
| AT (1) | ATE111732T1 (en) |
| AU (1) | AU659177B2 (en) |
| CA (1) | CA2074709A1 (en) |
| CZ (1) | CZ281712B6 (en) |
| DE (2) | DE4125116A1 (en) |
| DK (1) | DK0525537T3 (en) |
| ES (1) | ES2059181T3 (en) |
| HU (1) | HU208632B (en) |
| IE (1) | IE65109B1 (en) |
| IL (1) | IL102648A (en) |
| MX (1) | MX9204423A (en) |
| NO (1) | NO300253B1 (en) |
| RU (1) | RU2043102C1 (en) |
| SK (1) | SK238692A3 (en) |
| TW (1) | TW202388B (en) |
| ZA (1) | ZA925686B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4863360A (en) * | 1988-01-15 | 1989-09-05 | Rogers Industrial Products | Bag control mechanism for tire press |
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1991
- 1991-07-30 DE DE4125116A patent/DE4125116A1/en not_active Withdrawn
-
1992
- 1992-07-07 TW TW081105356A patent/TW202388B/zh active
- 1992-07-15 NO NO922795A patent/NO300253B1/en unknown
- 1992-07-17 ES ES92112201T patent/ES2059181T3/en not_active Expired - Lifetime
- 1992-07-17 EP EP92112201A patent/EP0525537B1/en not_active Expired - Lifetime
- 1992-07-17 DK DK92112201.6T patent/DK0525537T3/en active
- 1992-07-17 DE DE59200530T patent/DE59200530D1/en not_active Expired - Fee Related
- 1992-07-17 AT AT92112201T patent/ATE111732T1/en not_active IP Right Cessation
- 1992-07-22 AU AU20484/92A patent/AU659177B2/en not_active Ceased
- 1992-07-27 IL IL102648A patent/IL102648A/en not_active IP Right Cessation
- 1992-07-27 CA CA002074709A patent/CA2074709A1/en not_active Abandoned
- 1992-07-29 KR KR1019920013561A patent/KR930001908A/en not_active Withdrawn
- 1992-07-29 RU SU925052306A patent/RU2043102C1/en active
- 1992-07-29 MX MX9204423A patent/MX9204423A/en not_active IP Right Cessation
- 1992-07-29 ZA ZA925686A patent/ZA925686B/en unknown
- 1992-07-29 JP JP22094392A patent/JP3381198B2/en not_active Expired - Fee Related
- 1992-07-29 IE IE922467A patent/IE65109B1/en not_active IP Right Cessation
- 1992-07-30 HU HU9202484A patent/HU208632B/en not_active IP Right Cessation
- 1992-07-30 CZ CS922386A patent/CZ281712B6/en unknown
- 1992-07-30 SK SK2386-92A patent/SK238692A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2043102C1 (en) | 1995-09-10 |
| CA2074709A1 (en) | 1993-01-31 |
| ATE111732T1 (en) | 1994-10-15 |
| SK238692A3 (en) | 1995-11-08 |
| DE4125116A1 (en) | 1993-02-04 |
| AU659177B2 (en) | 1995-05-11 |
| ES2059181T3 (en) | 1994-11-01 |
| NO922795D0 (en) | 1992-07-15 |
| DE59200530D1 (en) | 1994-10-27 |
| HUT63330A (en) | 1993-08-30 |
| NO922795L (en) | 1993-02-01 |
| CZ281712B6 (en) | 1996-12-11 |
| CZ238692A3 (en) | 1994-01-19 |
| EP0525537B1 (en) | 1994-09-21 |
| EP0525537A1 (en) | 1993-02-03 |
| KR930001908A (en) | 1993-02-22 |
| AU2048492A (en) | 1993-02-04 |
| IL102648A0 (en) | 1993-01-14 |
| NO300253B1 (en) | 1997-05-05 |
| JPH06157314A (en) | 1994-06-03 |
| HU9202484D0 (en) | 1992-10-28 |
| ZA925686B (en) | 1993-04-28 |
| JP3381198B2 (en) | 2003-02-24 |
| TW202388B (en) | 1993-03-21 |
| DK0525537T3 (en) | 1995-02-20 |
| MX9204423A (en) | 1993-01-01 |
| IL102648A (en) | 1997-03-18 |
| HU208632B (en) | 1993-12-28 |
| IE65109B1 (en) | 1995-10-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |