US20060258732A1 - Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors - Google Patents
Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors Download PDFInfo
- Publication number
- US20060258732A1 US20060258732A1 US11/415,428 US41542806A US2006258732A1 US 20060258732 A1 US20060258732 A1 US 20060258732A1 US 41542806 A US41542806 A US 41542806A US 2006258732 A1 US2006258732 A1 US 2006258732A1
- Authority
- US
- United States
- Prior art keywords
- pindolol
- dyspepsia
- treatment
- 5ht1a
- 5ht1a receptors
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
Definitions
- the present invention provides a method for preventing and treating gastrointestinal diseases such as dyspepsia, irritable bowel disease and chemotherapy-associated nausea by administering an antagonist or partial agonist of 5HT1a receptors.
- Dyspepsia is a common symptom ranging in prevalence from 26% in the United States to 41% in England (1). Whilst only 1 in 4 patients seek medical help (2) the condition results in significant health care costs (3) and an organic cause is found in only 40% of patients.
- the Rome criteria for diagnosing idiopathic or nonulcer dyspepsia (NUD) were put forward in 1991 and consist of chronic or recurrent upper abdominal pain or discomfort in the absence of obvious pathology (4).
- the Rome group suggested subcategorising NUD into ulcer-like, reflux-like, dysmotility-like and non-specific dyspepsia. This classification has been questioned on the grounds that there is a marked overlap of symptoms and an overlap between the symptoms and those of the irritable bowel syndrome (5).
- Serotonin (5HT) is a neurotransmitter both in the enteric nervous system (8) and in the brain (9). It plays a key role in regulating gut physiology, including peristalsis and intestinal tone (10). Animal studies have shown that intracerebroventricular injection of fenfluramine (a serotonin releasing agent) inhibits gastric emptying (11). Selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are widely used in the treatment of depression and produce a transient syndrome similar to NUD in up to 30% of patients treated (12).
- the present invention provides a means for prevention and treatment of gastrointestinal disease by administration of a substance that reduces the sensitivity of 5HT1a receptors.
- a preferred means is the administration of RS pindolol or a salt thereof.
- An especially preferred means is the administration of S ( ⁇ ) pindolol or a salt thereof.
- this invention can use any substance that is an antagonist or a partial agonist of 5HT1a receptors such that the sensitivity of 5HT1a receptors described above is reduced.
- Pindolol is a beta adrenergic antagonist, used in the treatment of hypertension and angina. It also has affinity for 5HT1a receptors of a similar magnitude as its affinity for beta adrenergic receptors. Until now, no therapeutic applications of this phenomenon have been discovered. Pindolol is used therapeutically in hypertension and angina as the racemic substance, RS pindolol. Most or all of the pharmacological effects of pindolol are possessed by the isomer S ( ⁇ ) pindolol.
- the present invention utilizes pindolol to reduce the sensitivity of 5HT1a receptors and as a result to provide the means for prevention and treatment certain gastrointestinal diseases, including non-ulcerative dyspepsia.
- a preferred embodiment of the invention is the isomer S ( ⁇ ) pindolol or salts thereof.
- Another method utilizes the administration of cyproheptadine, described in U.S. Pat. Nos. 5,324,738 and 5,403,848. The latter also describes a method for diagnosis of non-ulcerative dyspepsia by measuring the responsiveness of 5HT1a receptors.
- RS pindolol has an advantage over cyproheptadine of greater selectivity for the 5HT1a receptor and S ( ⁇ ) pindolol has further advantages of greater potency and specificity.
- the invention is likely to be effective in various presentations of gastrointestinal disease in which there is altered sensitivity of 5HT1a receptors.
- compositions for oral use including (but not limited to) tablets, capsules, oral solutions and suspensions and parenteral solutions. Included are also pharmaceutical formulations for oral use in which the active substance is released in a controlled and slower fashion such that the treatment may be administered less frequently.
- RS pindolol and S ( ⁇ ) pindolol will be in the range of 2.5 mg to 50 mg daily in single or divided doses, depending upon the therapeutic response and the pharmaceutical form.
- S ( ⁇ ) pindolol will be lesser than those of RS pindolol since the former will be more potent because it is responsible for most or all of the pharmacological effects.
- the invention is intended for the treatment of mammals, including humans.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides a method for preventing and treating gastrointestinal diseases such as dyspepsia, irritable bowel disease and chemotherapy associated nausea by administering an antagonist or partial agonist of 5HT1A receptors.
Description
- This application claims the priority of Provisional Application 60/161,117 filed Oct. 22, 1999.
- The present invention provides a method for preventing and treating gastrointestinal diseases such as dyspepsia, irritable bowel disease and chemotherapy-associated nausea by administering an antagonist or partial agonist of 5HT1a receptors.
- Dyspepsia is a common symptom ranging in prevalence from 26% in the United States to 41% in England (1). Whilst only 1 in 4 patients seek medical help (2) the condition results in significant health care costs (3) and an organic cause is found in only 40% of patients. The Rome criteria for diagnosing idiopathic or nonulcer dyspepsia (NUD) were put forward in 1991 and consist of chronic or recurrent upper abdominal pain or discomfort in the absence of obvious pathology (4). The Rome group suggested subcategorising NUD into ulcer-like, reflux-like, dysmotility-like and non-specific dyspepsia. This classification has been questioned on the grounds that there is a marked overlap of symptoms and an overlap between the symptoms and those of the irritable bowel syndrome (5).
- Conventional diagnostic evaluation (endoscopy, ultrasonography, 24 h ambulatory pH monitoring) does not reveal a structural or biochemical abnormality to explain NUD Attempts at elucidating the pathophysiology of the condition have produced inconsistent findings (6) and a wide array of theories are currently put forward (7).
- Serotonin (5HT) is a neurotransmitter both in the enteric nervous system (8) and in the brain (9). It plays a key role in regulating gut physiology, including peristalsis and intestinal tone (10). Animal studies have shown that intracerebroventricular injection of fenfluramine (a serotonin releasing agent) inhibits gastric emptying (11). Selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are widely used in the treatment of depression and produce a transient syndrome similar to NUD in up to 30% of patients treated (12).
- Studies indicate that a central 5HT1a receptor hypersensitivity may be involved in the pathophysiology of NUD (13,14). The release of prolactin from the anterior pituitary is under dopamine inhibition and under 5HT stimulation, probably at the level of the hypothalamus (15). Buspirone is an azaspirodecanedione, which acts as a partial agonist at the 5HT1a receptor (16) and stimulates prolactin release. We have established that prolactin release following buspirone challenge is enhanced in NUD indicating 5HT1a receptor supersensitivity in this condition.
- We have demonstrated this in a clinical study that extends our previous findings reported in U.S. Pat. No. 5,403,848.
- A total of 109 subjects, 50 NUD patients (39 female/11 male) and 59 healthy comparison subjects (32 female/28 male) gave fully informed consent to take part in the study, which had Ethics Committee approval. The mean±SD age of the patients was 35.6±12.2 years (Range 20-62) and of the comparison group 27.2±7.6 years (Range 20-52). At 0830 h subjects had a cannula inserted in a forearm vein. Buspirone (30 mg) or matching placebo was administered orally at 0900 h (Time 0). Blood was taken at 0, 30, 60. 90, 120 and 180 min. Prolactin levels rose in all subjects challenged with buspirone. The mean±SD AUC in patients was 46±35 and in healthy subjects 24±35. A 2-way repeated measures ANOVA yields a significant group X time interaction, with differences significant at 60 min (p<0.05), 90 min (p<0.01) and 120 min (p<0.05). Prolactin concentration at 90 min provided the best discrimination between the two groups.
- According to the present invention, what is required to treat non-ulcerative dyspepsia is the administration of effective amounts of a substance that reduces the sensitivity of 5HT1a receptors and we have discovered that pindolol, which has affinity for 5HT1a receptors has beneficial effects in subjects suffering from non-ulcerative dyspepsia.
- The present invention provides a means for prevention and treatment of gastrointestinal disease by administration of a substance that reduces the sensitivity of 5HT1a receptors. A preferred means is the administration of RS pindolol or a salt thereof. An especially preferred means is the administration of S (−) pindolol or a salt thereof.
- As noted earlier, this invention can use any substance that is an antagonist or a partial agonist of 5HT1a receptors such that the sensitivity of 5HT1a receptors described above is reduced.
- Pindolol is a beta adrenergic antagonist, used in the treatment of hypertension and angina. It also has affinity for 5HT1a receptors of a similar magnitude as its affinity for beta adrenergic receptors. Until now, no therapeutic applications of this phenomenon have been discovered. Pindolol is used therapeutically in hypertension and angina as the racemic substance, RS pindolol. Most or all of the pharmacological effects of pindolol are possessed by the isomer S (−) pindolol. The present invention utilizes pindolol to reduce the sensitivity of 5HT1a receptors and as a result to provide the means for prevention and treatment certain gastrointestinal diseases, including non-ulcerative dyspepsia. A preferred embodiment of the invention is the isomer S (−) pindolol or salts thereof. Another method utilizes the administration of cyproheptadine, described in U.S. Pat. Nos. 5,324,738 and 5,403,848. The latter also describes a method for diagnosis of non-ulcerative dyspepsia by measuring the responsiveness of 5HT1a receptors. RS pindolol has an advantage over cyproheptadine of greater selectivity for the 5HT1a receptor and S (−) pindolol has further advantages of greater potency and specificity.
- The invention is likely to be effective in various presentations of gastrointestinal disease in which there is altered sensitivity of 5HT1a receptors. We have specific demonstration of the role of 5HT1a receptors in non-ulcerative dyspepsia, but there is likely to be also benefit in certain cases of irritable bowel syndrome, especially that occurring in the upper intestinal region and in certain cases of motility disorders (including nausea) caused by cancer chemotherapy.
- Various pharmaceutical presentations are possible, including (but not limited to) tablets, capsules, oral solutions and suspensions and parenteral solutions. Included are also pharmaceutical formulations for oral use in which the active substance is released in a controlled and slower fashion such that the treatment may be administered less frequently.
- The usual doses of RS pindolol and S (−) pindolol will be in the range of 2.5 mg to 50 mg daily in single or divided doses, depending upon the therapeutic response and the pharmaceutical form. The usual doses of S (−) pindolol will be lesser than those of RS pindolol since the former will be more potent because it is responsible for most or all of the pharmacological effects.
- The invention is intended for the treatment of mammals, including humans.
- The ability of the invention to treat gastrointestinal disease has been demonstrated in a clinical study.
- Eleven patients suffering from non-ulcerative dyspepsia were recruited to a clinical study and gave informed consent. All were treated with pindolol 2.5 mg three times daily. Seven of the 11 patients showed a significant improvement in symptoms within 1 week of commencing treatment. A further patient improved in the second week. Their responses were quantified using a standard rating scale (GSRS scores). The results demonstrated a substantial improvement with a reduction in average symptom severity of approximately 68% in three weeks, with the greatest improvement observed within one week.
TABLE 1 Mean symptom score (average of 11 patients) Week Mean GSRS Score 0 9 1 4.2 2 3.5 3 2.9 - T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,324,783
- T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,403,848
- 1. Fisher R S, Parkman H P. Management of nonulcer dyspepsia. N Engl J Med 1998; 339:13-6-81.
- 2. Brown C, Rees E W E. Dyspepsia in general practice. BMJ 1990; 300:829-30.
- 3. Nyren O, Adami H O, Gustavsson S, Loof L. Excess sick-listing in nonulcer dyspepsia. J Clin Gastroenterol 1986; 8:339-45.
- 4. Talley N J, Colin-Jones D, Koch K I, Koch M, Nyren O, Stranghellini V. Functional dyspepsia: a classification with guidelines of diagnosis and management. Gastroenterol Int 1991; 4:145-60.
- 5. Talley N J, Zinsmeister A R, Schleck C D, Melton L J. Dyspepsia and dyspepsia subgroupings: a population-based study. Gastroenterology 1992; 102:1259-68.
- 6. Talley N J, Philips S F. Non-ulcer dyspepsia: potential causes and pathophysiology. Ann Intern Med 1988; 108:865-79.
- 7. Dotevall G. Psychosomatic gastroenterology today and some ideas for tomorrow. Gastroenterol Int 1989; 2:96-100.
- 8. Gershon M D. Erde S M. The nervous system of the gut. Gastroenterology 1981; 80; 1571-94.
- 9. Baumagarten H G, Grozdanovic Z. Neuroanatomy and neurophysiology of central serotonergic systems. J Serotonin Res 1994; 1:171-81.
- 10. Lundgren O, Svanvik J, Jivegard L. Enteric nervous system: 1. Physiology and pathophysiology of the intestinal tract. Digest Dis Sci 1989; 34:264-83.
- 11. Rowland N, Carlton J. Inhibition of gastric emptying by peripheral and central fenfluramine in rats: correlation with anorexia. Life Sci 1984; 34:2495-9.
- 12. Thakore J H, Berti C, Dinan T G. Treating depression with specific serotonergic acting agents. J Serotonin Res 1996; 3:145-160.
- 13. Dinan T G, Yatham L N, Barry S, Chua A, Keeling P W N. Serotonin supersensitivity: the pathophysiologic basis of non-ulcer dyspepsia? A preliminary report of buspirone/prolactin responses. Scand J Gastroenterol 1990; 25:541-44.
- 14. Chua K, Keating J, Hamilton D, Keeling P W N, Dinan T G, Central serotonin receptors and delayed gastric emptying in in-ulcer dyspepsia. BMJ 1992; 305:280-2.
- 15. Lamberts S W J, Macleod R M. Regulation of prolactin secretion at the level of the lactrotroph. Physiol Rev. 1990; 70:279-318.
- 16. Meltzer H Y, Maes M. Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. Biol Psychiat. 1994; 35:316-323.
Claims (6)
1. A method for preventing and treating gastrointestinal disease by means of administration of an effective amount of an antagonist or partial agonist of 5HT1a receptors.
2. A method according to claim 1 employing an effective amount of the racemic substance RS pindolol or a salt thereof.
3. A method according to claim 1 employing an effective amount of one of the enantiomers, S (−) pindolol of claim 2 or a salt thereof.
4. A method according to claim 1 in which effective amounts of RS-pindolol or S(−) pindolol or their salts are administered in a pharmaceutical dosage form that permits rapid release of the active substances.
5. A method according to claim 1 in which effective amounts of RS pindolol or S(−) pindolol or their salts are administered in a pharmaceutical dosage form that releases the active substances in a slow or controlled fashion that in turn permits administration of the active substances at lesser frequency than in claim 4 .
6. A method according to claim 1 in which the gastrointestinal diseases are characterised as non-ulcerative dyspepsia or irritable bowel syndrome or chemotherapy-associated disorders of motility, including nausea.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/415,428 US20060258732A1 (en) | 1999-10-22 | 2006-05-02 | Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16111799P | 1999-10-22 | 1999-10-22 | |
US09/687,384 US7098232B1 (en) | 1999-10-22 | 2000-10-13 | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
US11/415,428 US20060258732A1 (en) | 1999-10-22 | 2006-05-02 | Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/687,384 Continuation US7098232B1 (en) | 1999-10-22 | 2000-10-13 | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060258732A1 true US20060258732A1 (en) | 2006-11-16 |
Family
ID=36915522
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/687,384 Expired - Fee Related US7098232B1 (en) | 1999-10-22 | 2000-10-13 | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
US11/415,428 Abandoned US20060258732A1 (en) | 1999-10-22 | 2006-05-02 | Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/687,384 Expired - Fee Related US7098232B1 (en) | 1999-10-22 | 2000-10-13 | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
Country Status (1)
Country | Link |
---|---|
US (2) | US7098232B1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9132134B2 (en) | 2012-12-24 | 2015-09-15 | Neurogastrx, Inc. | Methods for treating GI tract disorders |
US9844554B2 (en) | 2014-06-24 | 2017-12-19 | Neurogastrx, Inc. | Prodrugs of metopimazine |
US10836757B1 (en) | 2020-04-02 | 2020-11-17 | Neurogastrx, Inc. | Polymorphic forms of metopimazine |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7098232B1 (en) * | 1999-10-22 | 2006-08-29 | Athpharma Limited | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5403848A (en) * | 1989-09-20 | 1995-04-04 | Earlow Limited | Diagnosis and treatment of a disorder of the gastrointestinal tract |
US5859065A (en) * | 1990-12-17 | 1999-01-12 | University Of Manitoba | Treatment method for cancer |
US6159979A (en) * | 1997-04-18 | 2000-12-12 | Smithkline Beecham P.L.C. | Bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5HT1A, 5HT1B and 5HT1D receptor antagonistic activity |
US7098232B1 (en) * | 1999-10-22 | 2006-08-29 | Athpharma Limited | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RO92436B1 (en) | 1985-04-19 | 1987-10-01 | Ioan Puscas | Synergetic medicinal composition for treating gastritis, gastroduodenitis, gastroduodenal ulcer |
-
2000
- 2000-10-13 US US09/687,384 patent/US7098232B1/en not_active Expired - Fee Related
-
2006
- 2006-05-02 US US11/415,428 patent/US20060258732A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5403848A (en) * | 1989-09-20 | 1995-04-04 | Earlow Limited | Diagnosis and treatment of a disorder of the gastrointestinal tract |
US5859065A (en) * | 1990-12-17 | 1999-01-12 | University Of Manitoba | Treatment method for cancer |
US6159979A (en) * | 1997-04-18 | 2000-12-12 | Smithkline Beecham P.L.C. | Bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5HT1A, 5HT1B and 5HT1D receptor antagonistic activity |
US7098232B1 (en) * | 1999-10-22 | 2006-08-29 | Athpharma Limited | Treatment and prevention of gastrointestinal disease using antagonists of partial agonists of 5HT1a receptors |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9132134B2 (en) | 2012-12-24 | 2015-09-15 | Neurogastrx, Inc. | Methods for treating GI tract disorders |
US9808467B2 (en) | 2012-12-24 | 2017-11-07 | Neurogastrx, Inc. | Methods for treating GI tract disorders |
US11147820B2 (en) | 2012-12-24 | 2021-10-19 | Neurogastrx, Inc. | Methods for treating GI tract disorders |
US9844554B2 (en) | 2014-06-24 | 2017-12-19 | Neurogastrx, Inc. | Prodrugs of metopimazine |
US10836757B1 (en) | 2020-04-02 | 2020-11-17 | Neurogastrx, Inc. | Polymorphic forms of metopimazine |
US11390620B2 (en) | 2020-04-02 | 2022-07-19 | Neurogastrx, Inc. | Polymorphic forms of metopimazine |
US11834445B2 (en) | 2020-04-02 | 2023-12-05 | Neurogastrx, Inc. | Polymorphic forms of metopimazine |
Also Published As
Publication number | Publication date |
---|---|
US7098232B1 (en) | 2006-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Mozaffari et al. | Implications of melatonin therapy in irritable bowel syndrome: a systematic review | |
M Richey et al. | Pharmacological advances in the treatment of insomnia | |
Manocha et al. | Serotonin and GI disorders: an update on clinical and experimental studies | |
Chouinard | Severe cases of neuroleptic-induced supersensitivity psychosis: Diagnostic criteria for the disorder and its treatment | |
US6395705B2 (en) | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists | |
Srinivasan et al. | Melatonin agonists in primary insomnia and depression-associated insomnia: are they superior to sedative-hypnotics? | |
Wein | Pharmacological agents for the treatment of urinary incontinence due to overactive bladder | |
Callahan | Irritable bowel syndrome neuropharmacology: a review of approved and investigational compounds | |
JP2009539800A (en) | Treatment of gastrointestinal disorders with CGRP antagonists | |
US6833383B2 (en) | Methods for treating patients suffering from drug dependencies which lead to plasma melatonin deficiencies | |
US20140271890A1 (en) | Controlled-release pharmaceutical composition | |
US20060258732A1 (en) | Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors | |
Coon et al. | My treatment approach to multiple system atrophy | |
PL204075B1 (en) | Tramadol containing pharmacological compositions | |
Tahmaz et al. | Combination therapy of imipramine with oxybutynin in children with enuresis nocturna | |
AU2007330607A1 (en) | Treatment of cachexia | |
US6855729B2 (en) | Treatment of fibromyalgia and related fatigue syndromes using antagonists or partial agonists of 5HT1a receptors | |
BG62876B1 (en) | The application of melatonin for the treatment of patients with medicament addiction | |
PICHEL WARNER | Hyperserotoninemia in functional gastrointestinal disease | |
KR100692235B1 (en) | New use of angiotensin ii antagonists | |
WO2004026296A1 (en) | Composition against stress-related diseases | |
CA2425910A1 (en) | Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5ht1a receptors | |
CA1320133C (en) | Analgesic drug comprising l-tryptophan | |
Oh | Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome | |
Dépôt | Acute and chronic role of the 5-HT3 [souscrit] neurotransmission on cholecystokinin tetrapeptide-induced panic symptoms in humans |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |