[go: up one dir, main page]

WO1998005321A1 - Therapeutic utilities of verapamil enantiomers - Google Patents

Therapeutic utilities of verapamil enantiomers Download PDF

Info

Publication number
WO1998005321A1
WO1998005321A1 PCT/GB1997/002094 GB9702094W WO9805321A1 WO 1998005321 A1 WO1998005321 A1 WO 1998005321A1 GB 9702094 W GB9702094 W GB 9702094W WO 9805321 A1 WO9805321 A1 WO 9805321A1
Authority
WO
WIPO (PCT)
Prior art keywords
verapamil
treatment
single enantiomer
enantiomers
substantially single
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.)
Ceased
Application number
PCT/GB1997/002094
Other languages
French (fr)
Inventor
Deborah Phyllis Harding
Jane Lizbeth Greaves
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.)
Chirotech Technology Ltd
Darwin Discovery Ltd
Original Assignee
Darwin Discovery Ltd
Chiroscience Ltd
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
Priority claimed from GBGB9616550.1A external-priority patent/GB9616550D0/en
Priority claimed from GBGB9616504.8A external-priority patent/GB9616504D0/en
Application filed by Darwin Discovery Ltd, Chiroscience Ltd filed Critical Darwin Discovery Ltd
Priority to AU37784/97A priority Critical patent/AU3778497A/en
Priority to JP10507726A priority patent/JP2000515539A/en
Priority to EP97934642A priority patent/EP0925062A1/en
Publication of WO1998005321A1 publication Critical patent/WO1998005321A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to improved treatment of patients having conditions which are .susceptible to treatment with racemic verapamil, but who are disposed to constipation as a side effect thereof.
  • Verapamil (1) is presently in clinical use as a racemate for the treatment of hypertension, angina, atrial fibrillation and paroxysmal supraventricular tachycardia.
  • constipation is a well known and undesirable side effect of this drug, with a reported incidence up to 38% of .all patients treated; see C. Yedinak, American Pharmacy (1993) NS 33:8; 49-66. This can result in reduced compliance or even cessation of treatment.
  • the opposite enantiomers of verapamil have different biological activities and different potencies.
  • the ph-armacological profile is determined by stereoselectivity of pharmacodynamics and pharmacokinetics.
  • the (R)-enantiomer may be of benefit for the reversal of multi-drug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113).
  • the (S)-enantiomer may be of benefit in the treatment of atrial fibrillation (see Raschack, Naunyn-Schmiedeburg's Arch. Pharmacol. (1976) 294: 285-297). It may also be of benefit in the treatment of angina (see Curtis et al., Br. J. Pharmac. (1986) 89: 137-147), although dose-limiting side effects are reported to be associated with its use, such as depression in myocardial activity (see Satoh et al, Journal of Cardiovascular Pharmacology (1980) 2 : 309-318) and atrioventricular (AV) conduction block (see Raschack, as above). Summary of the Invention
  • a patient disposed to constipation typically we mean a patient who suffers from a difficult or infrequent p.assage of faeces after treatment with a standard treatment dosage, eg. 360 mg per day, of verapamil racemate; a patient whose colon does not respond to the usual stimuli providing evacuation of the colon; or a patient in whom accessory stimuli normally provided by eating or physical exercise are lacking, eg. a bedridden patient.
  • a standard treatment dosage eg. 360 mg per day
  • verapamil racemate eg. 360 mg per day
  • the use of drugs for medical conditions usually associated with constipation frequently compounds the problem, eg. opiates and anti-depressants.
  • patients suffering from neurological diseases, such as Parkinson's disease frequently suffer from constipation..
  • substantially single enantiomer typically we mean that the desired enantiomer is in an enantiomeric excess of at least 70% by weight as compared to the other enantiomer, preferably at least 95%, or higher.
  • the enantiomer may be enantiopure. It may be used in the form of any suitable salt, eg. the hydrochloride.
  • the utility of the present invention lies in the trr ⁇ tment of any condition susceptible to treatment by verapamil racemate. Patients for which it may have particular utility include tho.se who are cardiac-compromised, and therefore ill-equipped to cope with strain that may result from constipation.
  • cardiac-compromised typically we mean a patient suffering from any form of heart disease, and in particular from any of the following conditions: atrial fibrillation, angina, hypertension, and paroxysmal supraventricular t hycardia. It may also have utility in non-vascular conditions, for instance in multi-drug resistance reversal, eg. in chemotherapy, and any other condition for which verapamil racemate may have utility.
  • (.S)-verapamil has been suggested for the treatment of atrial fibrillation and angina. Accordingly, urther embodiments of the present invention utilise ( ⁇ verapamil for the treatment of patients suffering either from atrial fibrillation or angina, and who are disposed to constipation.
  • Administration of the single enantiomer may be by any of the conventional routes, for instance oral and sublingual. Conventional formulations may be used, including sustained-release formulations where appropriate.
  • the single enantiomer will be formulated for oral administration.
  • the dosage of the single enantiomer will typically depend upon the condition to be treated and/or the particular patient to be treated. Typically, however, the dosage will be lower than that usually used with the racemate, for instance up to 240 mg per day, and preferably not exceeding 200 mg per day. This is particul.arly true in the case of administration of (S)- verapamil for the treatment of angina, where side effects reported to be associated with this enantiomer may be particularly harmful at high dosages.
  • verapamil racemate and the individual enantiomers of verapamil on gastrointestinal transit were studied in 13 male volunteers in a four-way double blind cross-over study. All volunteers consumed a standard balanced diet throughout the period. In each phase of the study, each volunteer was assigned to one of four groups which received the following treatments, three times a day, over a period of 7 days.
  • Group A 120 mg racemic verapamil hydrochloride (a total of 360 mg drug per day).
  • Group B 60 mg (S)-verapamiI hydrochloride (a total of 180 mg drug per day).
  • Group C 60 mg (R)- verapamil hydrochloride (a total of 180 mg drug per day).
  • Group D - 320 mg Placebo (a total of 960 mg per day).
  • the volunteers were also administered a capsule containing ⁇ n In-labelled ion-exchange resin, to act as a marker of gastrointestinal transit. The minimum time interval between separate study periods was 7 days.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Substantially single enantiomer R or S verapamil, or a pharmaceutically-acceptable salt thereof, provides an improved treatment for patients having a condition susceptible to treatment with racemic verapamil and who are disposed to constipation.

Description

THERAPEUTIC UTILITIES OF VERAPAMIL ENANTIOMERS
Field of the Invention
This invention relates to improved treatment of patients having conditions which are .susceptible to treatment with racemic verapamil, but who are disposed to constipation as a side effect thereof. Background to the Invention
Verapamil (1) is presently in clinical use as a racemate for the treatment of hypertension, angina, atrial fibrillation and paroxysmal supraventricular tachycardia. However, constipation is a well known and undesirable side effect of this drug, with a reported incidence up to 38% of .all patients treated; see C. Yedinak, American Pharmacy (1993) NS 33:8; 49-66. This can result in reduced compliance or even cessation of treatment.
Figure imgf000003_0001
Verapamil (1)
The opposite enantiomers of verapamil have different biological activities and different potencies. The ph-armacological profile is determined by stereoselectivity of pharmacodynamics and pharmacokinetics.
The (R)-enantiomer may be of benefit for the reversal of multi-drug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113).
The (S)-enantiomer may be of benefit in the treatment of atrial fibrillation (see Raschack, Naunyn-Schmiedeburg's Arch. Pharmacol. (1976) 294: 285-297). It may also be of benefit in the treatment of angina (see Curtis et al., Br. J. Pharmac. (1986) 89: 137-147), although dose-limiting side effects are reported to be associated with its use, such as depression in myocardial activity (see Satoh et al, Journal of Cardiovascular Pharmacology (1980) 2 : 309-318) and atrioventricular (AV) conduction block (see Raschack, as above). Summary of the Invention
Surprisingly, it has now been found that administration of either of the individual enantiomers (R or S) of verapamil, at a dosage less than the standard treatment dosage of verapamil racemate, eg. 360 mg per day, does not delay large bowel transit, thereby removing the risk of constipation often experienced on treatment with the racemate. It may, therefore, prove beneficial to administer a substantially single enantiomer of verapamil for the treatment of a condition susceptible to treatment by the racemate, and for which the respective enantiomer has the majority of the therapeutic activity for treatment of that condition, thereby allowing a reduction in dosage compared with the racemate, in patients disposed to constipation. Description of the Invention
For the purposes of the present invention, by a patient disposed to constipation typically we mean a patient who suffers from a difficult or infrequent p.assage of faeces after treatment with a standard treatment dosage, eg. 360 mg per day, of verapamil racemate; a patient whose colon does not respond to the usual stimuli providing evacuation of the colon; or a patient in whom accessory stimuli normally provided by eating or physical exercise are lacking, eg. a bedridden patient. The use of drugs for medical conditions usually associated with constipation frequently compounds the problem, eg. opiates and anti-depressants. In addition, patients suffering from neurological diseases, such as Parkinson's disease, frequently suffer from constipation.. Furthermore, by substantially single enantiomer typically we mean that the desired enantiomer is in an enantiomeric excess of at least 70% by weight as compared to the other enantiomer, preferably at least 95%, or higher. The enantiomer may be enantiopure. It may be used in the form of any suitable salt, eg. the hydrochloride. The utility of the present invention lies in the trrøtment of any condition susceptible to treatment by verapamil racemate. Patients for which it may have particular utility include tho.se who are cardiac-compromised, and therefore ill-equipped to cope with strain that may result from constipation. By cardiac-compromised typically we mean a patient suffering from any form of heart disease, and in particular from any of the following conditions: atrial fibrillation, angina, hypertension, and paroxysmal supraventricular t hycardia. It may also have utility in non-vascular conditions, for instance in multi-drug resistance reversal, eg. in chemotherapy, and any other condition for which verapamil racemate may have utility.
As discussed above, (.S)-verapamil has been suggested for the treatment of atrial fibrillation and angina. Accordingly, urther embodiments of the present invention utilise (^verapamil for the treatment of patients suffering either from atrial fibrillation or angina, and who are disposed to constipation.
Administration of the single enantiomer may be by any of the conventional routes, for instance oral and sublingual. Conventional formulations may be used, including sustained-release formulations where appropriate. Typically, the single enantiomer will be formulated for oral administration. The dosage of the single enantiomer will typically depend upon the condition to be treated and/or the particular patient to be treated. Typically, however, the dosage will be lower than that usually used with the racemate, for instance up to 240 mg per day, and preferably not exceeding 200 mg per day. This is particul.arly true in the case of administration of (S)- verapamil for the treatment of angina, where side effects reported to be associated with this enantiomer may be particularly harmful at high dosages.
The data upon which the present invention is based are summarised below.
The effects of verapamil racemate and the individual enantiomers of verapamil on gastrointestinal transit were studied in 13 male volunteers in a four-way double blind cross-over study. All volunteers consumed a standard balanced diet throughout the period. In each phase of the study, each volunteer was assigned to one of four groups which received the following treatments, three times a day, over a period of 7 days.
Group A - 120 mg racemic verapamil hydrochloride (a total of 360 mg drug per day). Group B - 60 mg (S)-verapamiI hydrochloride (a total of 180 mg drug per day).
Group C - 60 mg (R)- verapamil hydrochloride (a total of 180 mg drug per day). Group D - 320 mg Placebo (a total of 960 mg per day). On day four of each study, the volunteers were also administered a capsule containing ιnIn-labelled ion-exchange resin, to act as a marker of gastrointestinal transit. The minimum time interval between separate study periods was 7 days.
Statistical analysis of the large bowel transit data at 36 hours post dosing gave the following mean geometric centre readings for the four treatment groups: 3.79 (A), 4.43 (B), 4.53 (C), and 4.51 (D). The smaller the geometric centre reading, the slower the bowel transit. The mean geometric centre analysis utilised is described by Krevsky et alt Dig. Dis. Sci. (1992) 37: 919-924.
The results clearly demonstrate that at a daily dose of 360 mg racemic verapamil is capable of having a significant constipating effect on large bowel transit. No significant differences in large bowel transit were observed for either of the individual verapamil enantiomers or the placebo control. It is, therefore, believed that at a daily dose of 180 mg of either of the individual verapamil enantiomers no constipating effect should be observed, but that at the same time the same therapeutic benefit will be achieved, at half the dosage of the racemate.

Claims

1. Use of substantially single enantiomer (R or S) verapamil, or a pharmaceutically- .acceptώle salt thereof, for the manufacture of a medicament for the treatment of a patient having a condition susceptible to treatment with racemic verapamil, and also disposed to constipation.
2. Use according to claim 1, wherein the substantially single enantiomer of verapamil is (-5)-verapamiI.
3. U.se according to claim 1, wherein the substantially single enantiomer of verapamil is (R)-verapamil.
4. Use according to any preceding claim, wherein the patient is cardiac-compromised.
5. Use according to claim 1, wherein the condition is selected from atrial fibrillation, angina, hypertension, paroxysmal supraventricular tachycardia, and multi-drug resistance eg. in chemotherapy.
6. Use according to claim 5, wherein the substantially single enantiomer is (S)- verapamil and the condition is atrial fibrillation.
7. Use according to claim 5, wherein the substantially single enantiomer is (S)- verapamil and the condition is angina.
PCT/GB1997/002094 1996-08-06 1997-08-06 Therapeutic utilities of verapamil enantiomers Ceased WO1998005321A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU37784/97A AU3778497A (en) 1996-08-06 1997-08-06 Therapeutic utilities of verapamil enantiomers
JP10507726A JP2000515539A (en) 1996-08-06 1997-08-06 Therapeutic use of verapamil enantiomers
EP97934642A EP0925062A1 (en) 1996-08-06 1997-08-06 Therapeutic utilities of verapamil enantiomers

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9616504.8 1996-08-06
GBGB9616550.1A GB9616550D0 (en) 1996-08-06 1996-08-06 Therapeutic product and its use
GBGB9616504.8A GB9616504D0 (en) 1996-08-06 1996-08-06 Therapeutic product and its use
GB9616550.1 1996-08-06

Publications (1)

Publication Number Publication Date
WO1998005321A1 true WO1998005321A1 (en) 1998-02-12

Family

ID=26309825

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/002094 Ceased WO1998005321A1 (en) 1996-08-06 1997-08-06 Therapeutic utilities of verapamil enantiomers

Country Status (4)

Country Link
EP (1) EP0925062A1 (en)
JP (1) JP2000515539A (en)
AU (1) AU3778497A (en)
WO (1) WO1998005321A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032919A1 (en) * 2002-09-27 2004-04-22 John Kelly Use of (r)-verapamil for the treatment of abnormal increases in gastrointestinal motility

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9616549D0 (en) * 1996-08-06 1996-09-25 Chiroscience Ltd Therapeutic product and its use
US8403882B2 (en) 2005-11-22 2013-03-26 Omrix Biopharmaceuticals, S.A. Applicator device for applying a multi-component fluid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995009150A1 (en) * 1993-09-27 1995-04-06 Chiroscience Limited Chiral nitriles, their preparation and their use for the manufacture of verapamil and analogues

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995009150A1 (en) * 1993-09-27 1995-04-06 Chiroscience Limited Chiral nitriles, their preparation and their use for the manufacture of verapamil and analogues

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
F.T.THANDROYEN ET AL.: "The influence of Verapamil and its Isomers on Vulnerability to Ventricular Fibrillation During Acute Myocardial Ischemia and Adrenergic Stimulation in Isolated Rat Heart", J.MOL.CELL CARDIOL., vol. 18, June 1986 (1986-06-01), pages 645 - 649, XP002045987 *
H.WATANABE ET AL.: "EFFECTS OF IMIPRAMINE ON FREQUENCY-FORCE RELATIONSHIP IN ISOLATED RIGHT ATRIAL MUSCLE OF THE DOG", JPN.J.PHARMACOL., vol. 31, no. 2, 1981, pages 289 - 291, XP000673131 *
J.E.F.REYNOLDS, EDITOR: "MARTINDALE The Extra Pharmacopoeia", April 1996, ROYAL PHARMACEUTICAL SOCIETY, LONDON, XP002046406 *
M.ARITA ET AL.: "Modification of "Depressed Fast Channel Dependent Slow Conduction" by Lidocaine and Verapamil in the Presence or Absence of Catecholamines - Evidence for Alteration of Preferential Ionic Channels for Slow Conduction - "", JPN.CIRC.J., vol. 47, no. 1, 1983, pages 68 - 81, XP000673130 *
M.ARITA ET AL.: "Nature of "Residual Fast Channel" Dependent Action Potentials and Slow Conduction in Guinea Pig Ventricular Muscle and Its Modification by Isoproterenol", AM.J.CARDIOL., vol. 51, no. 8, 1983, pages 1433 - 1440, XP000673127 *
M.J.CURTIS ET AL.: "THE CALCIUM ANTAGONIST POTENCY RATIO OF THE OPTICAL ENANTIOMERS OF VERAPAMIL IN A VARIETY OF PREPARATIONS", PROC. WEST. PHARMACOL. SOC., vol. 29, 1986, pages 295 - 297, XP000673133 *
M.J.CURTIS ET AL.: "The mechanism of action of the optical enantiomers of verapamil against ischaemia-induced arrhythmias in the conscious rat", BR.J.PHARMAC., vol. 89, no. 1, 1986, pages 137 - 147, XP000673132 *
M.RASCHACK ET AL.: "Calcium Antagonistic Activity and Myocardial Ischemic Protection by Both Stereoisomers of Verapamil", ADV.MYOCARDIOL., vol. 4, 1983, pages 505 - 512, XP002045984 *
M.RASCHACK: "Relationship of Antiarrhythmic to Inotropic Activity and Antiarrhythmic Qualities of the Optical Isomers of Verapamil", NAUNYN-SCHMIEDEBERG'S ARCH. PHARMACOL., vol. 294, no. 3, 1976, pages 285 - 291, XP000673129 *
P.SIMAMORA ET AL.: "COMPATIBILITY STUDIES OF INTRAVENOUS DEXVERAPAMIL FORMULATIONS", PHARMACEUTICAL RESEARCH, vol. 11, no. 10 suppl., 1994, NEW YORK, pages S277, XP000673128 *
R.J.MOTZER ET AL.: "Phase I/II Trial of Dexverapamil Plus Vinblastine for Patients With Advanced Renal Cell Carcinoma", JOURNAL OF CLINICAL ONCOLOGY, vol. 13, no. 8, 1995, pages 1958 - 1965, XP000673126 *
S. CHIBA ET AL.: "Effects of Optical Isomers of Verapamil on SA Nodal Pacemaker Activity and Contractility of the Isolated Dog Heart", JPN. HEART J., vol. 19, no. 3, May 1978 (1978-05-01), pages 409 - 414, XP002045985 *
S.W.RABKIN: "Verapamil Has Antiarrhythmic Effects That are Mediated in Brain Through Endogenous Opioids", J.CARDIOVASC.PHARMACOL., vol. 23, no. 5, May 1994 (1994-05-01), pages 814 - 821, XP002045986 *
W.G.NAYLER ET AL.: "An Inhibitory Effect of Verapamil and Diltiazem on the Release of Noradrenaline from Ischaemic and Reperfused Hearts", J. MOL. CELL. CARDIOL., vol. 16, 1984, pages 331 - 344, XP000673125 *
Y.SURAKITBANHARN ET AL.: "Self-Association of Dexverapamil in Aqueous Solution", J.PHARM.SCI., vol. 84, no. 6, 1995, pages 720 - 723, XP002030305 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032919A1 (en) * 2002-09-27 2004-04-22 John Kelly Use of (r)-verapamil for the treatment of abnormal increases in gastrointestinal motility
US6849661B2 (en) 2002-09-27 2005-02-01 Agi Therapeutics, Ltd. Treatment of abnormal increases in gastrointestinal motility with (R)-verapamil
EP1891947A3 (en) * 2002-09-27 2008-03-05 AGI Therapeutics Research Limited Use of (r)-verapamil for the treatment of abnormal increases in gastrointestinal motility

Also Published As

Publication number Publication date
EP0925062A1 (en) 1999-06-30
JP2000515539A (en) 2000-11-21
AU3778497A (en) 1998-02-25

Similar Documents

Publication Publication Date Title
DiBianco et al. Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin
US5538992A (en) Potentiation of drug response
Kebabian et al. A-77636: a potent and selective dopamine D1 receptor agonist with antiparkinsonian activity in marmosets
Brocks Anticholinergic drugs used in Parkinson’s disease: an overlooked class of drugs from a pharmacokinetic perspective
US6110973A (en) Methods for treating obesity and weight gain using optically pure (-)-bupropion
JP3041954B2 (en) Terfenadine metabolites and their optically pure isomers for the treatment of allergic diseases
US20240238276A1 (en) Method of maintaining remission of depressive symptoms
EP0663828A1 (en) Compositions for treating allergic disorders using (-) cetirizine
US5627183A (en) Methods for treating urticaria using optically pure (+) cetirizine
CA2318960A1 (en) Pharmaceutical uses of optically pure (+)-bupropion
JP3410109B2 (en) Antiarrhythmic compositions and methods of treatment
US5932246A (en) Therapeutic uses of verapamil enantiomers
WO1998005321A1 (en) Therapeutic utilities of verapamil enantiomers
Bigger Jr The interaction of mexiletine with other cardiovascular drugs
ROSSMAN et al. Depression in the elderly: Pharmacologic considerations in treatment
JP3982889B2 (en) Pharmaceutical preparations containing ibuprofen
CN102512389B (en) Fexofenadine hydrochloride oral disintegrating drug composition
KR0136787B1 (en) Long lasting composition of propafenone and quinidine for treatment of cardiac conditions
US6552087B1 (en) Therapeutic agent comprising (+)-sibutramine
Glassman et al. Cardiovascular effects of antidepressant drugs
US3505451A (en) Compositions and methods for alleviating schizophrenia employing one of haloperidol,trifluperidol or an acid addition salt thereof and one of desipramine,imipramine and an acid addition salt thereof
GB1573580A (en) Pharmaceutical cardioactive compositions containing pteridine derivatives
JPH05506642A (en) Drugs and their use
JP2002524510A (en) New composition
Brorson et al. Effects of concentration and steric configuration of propranolol on AV conduction and ventricular repolarization in the dog

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LV MD MG MK MN MW MX NO NZ PL RO RU SD SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997934642

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1997934642

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1997934642

Country of ref document: EP