MXPA99001294A - Verapamil as a medicament for the treatment of angina - Google Patents

Abstract

(R)-verapamil, or a pharmaceutically acceptable salt thereof, is useful in the treatment of angina.

Description

VERAPAMILO AS A MEDICINE FOR THE TREATMENT OF ANGINA FIELD OF THE INVENTION The present invention relates to the use of verapamil in the treatment of angina.

BACKGROUND OF THE INVENTION Angina is a common indication of myocardial ischemia, either as a result of coronary artery disease or post-acute myocardial infarction. Verapamil (1) is currently in clinical use for the treatment of angina as a racemate.

Verapamil (1) The opposite enantiomers of verapamil have different biological activities and different potencies. The pharmacological profile is determined for the tereoselectivity of pharmacodynamics and pharmacokinetics. Satoh et al Journal of Cardiovascular Pharmacology (1980) 2: 309-318 describe details of a study of the vasodilator and cardiodepressant effects of the two enantiomers of verapamil. The authors report that at equiefective doses in terms of increased coronary sinus flow, (R) -verapamil is significantly less cardiodepressant than (S) -verapamil. They conclude from this that (R) -verapamil may provide a safer means to treat angina than (S) -verapamil, but they add that it is not known which of the verapamil enantiomers is of the highest therapeutic value in the treatment of angina To reach this conclusion, the authors considered only two properties of verapamil, that is, the decrease in the consumption of oxygen by the myocardium and the increase in coronary blood flow. The reduction in oxygen consumption was attributed to the negative inotropic action and negative chronotropic and hypotensive effects. The authors considered that the coronary vasodilator effect was more important for the anti-anginal action of verapamil, and they cited nifedipine as a coronary vasodilator with a virtual lack of cardiodepressive action. However, coronary vasodilation is only one possible component, and certainly not the most important component of the angina treatment mechanism. Consequently, several compounds tested in the treatment of angina on the basis of their coronary vasodilator action alone have failed in clinical practice. This illustrates that the model used in the study by Satoh et al. Is not a true model of angina. Therefore, no conclusion based on that study can be given confidence. Curtís and collaborators Proc. West Pharmacol. Soc. (1986) 29_: 295-297 describes the use of a rat preparation with the medulla obliterated to evaluate the peripheral vasodilatory potencies of the different verapamil enantiomers. Their study illustrated a 23-fold power difference in favor of (S) -verapamil compared to (R) -verapamil. In a conscious rat model, however, they found a power difference of 4 times, again in favor of (S) -verapamil, to lower blood pressure. These data are, in their own right, disconcerting, and when viewed together with the data reported by Satoh and collaborators it is very difficult to predict the total vasodilator profile of (R) -verapamil, and therefore if it will have any significant therapeutic activity in the treatment of angina. Consequently, it is not known which, if one or the other, of the enantiomers of verapamil will be effective in the treatment of angina in clinical practice. An objective profile of a therapy is sought once a day, giving 24 hours of control and protection of the symptoms of angina, without the undesirable side effects limiting the dose experienced with the racemate, for example, depression of myocardial contractility (see Satoh et al.) and atrioventricular (AV) conduction block (see Raschack, Naunuyn-Schiedeberg's Arch. Pharmacol. (1976) 294: 285-291).

BRIEF DESCRIPTION OF THE INVENTION Surprisingly, it has now been found that (R) -verapamil significantly suppresses the increase in ventricular filling pressure that occurs during ischemia, and that it is one of the main components of transient myocardial insufficiency characteristic of an attack of angina. It is believed that this is a result of a Venodilator effect associated with the (R) -verapamil, which, coupled with its known arterial vasodilator effect, will directly affect the anti-angina activity of this enantiomer. This discovery is based on data from a study that closely mimics angina in a clinical situation, and that demonstrates, surprisingly, that as little as, or less than, twice the dose of the verapamil racemate, (R) -verapamil gave at least an equivalent and significant reduction in the degree of angina induced by ischemia, including the left ventricular end diastolic pressure. Whereupon, (R) -verapamil may be useful in the treatment of angina, and may be administered in amounts greater than those currently used with the racemate, without the adverse effects normally associated with higher doses of the drug, and reported to be associated with (S) -verapamil (see Satoh et al. and Raschack, above).

DESCRIPTION OF THE INVENTION The (R) -verapamil that is used in the present invention is substantially free of (S) -verapamil, for example in an enantiomeric excess of at least 70%, preferably at least 95% excess, or greater. The (R) -verapamil can be substantially enantiopuro. It can be used in the form of any suitable salt, for example the hydrochloride. There is an indication that (R) ~ verapamil is metabolized more slowly by the liver than (S) -verapamyl, and therefore it may not be necessary to administer (R) -verapamil at twice the dose of the racemate to achieve a similar therapeutic effect; see Longstreth, J.A., Clin. Pharmacol. (1993) 1_8_ (2nd Edition): 315-336. The administration of (R) -verapamil can be by any of the conventional routes, for example oral, intravenous, sublingual, topical and rectal. Conventional formulations may be used, including sustained release formulations when appropriate. Typically, (R) -verapamil will be formulated for oral administration. Typically, a suitable dosage of the active component is up to 500 mg per day, but any of the standard dosages for the racemate can be used, as is given in the Monthly Index of Medical Specialties, published by Haymarket Press. These parameters are, however, given as a guide only, and will depend on the usual considerations, such as age, weight, etc. of the patient, as it is within the experience of the doctor in charge. The data on which the present invention is based are summarized below. Myocardial ischemia was induced in four groups of 6 to 8 anesthetized mestizo dogs, of either sex, and having a body weight of more than 17 kg, by complete occlusion of the left anterior descending coronary artery (LAD) in the presence of of critical constriction of the circumflex coronary artery. The methodology used was in principle that described by Vegh et al., Europ. J. Pharmacol. (1987) 144: 15-27. The four test groups were as follows: Group 1 (vehicle control) - 1 ml of saline, given as a rapid bolus injection, followed by an intravenous infusion of 1 ml min-1 saline over a period of 30 minutes . Group 2 - racemic verapamil was given, in a total dose of 0.15 mg kg_1. First, a bolus injection of 0.1 mg kg "1 was given, followed by an intravenous infusion of 0.05 mg kg" 1 for 30 minutes. Group 3 - (S) -verapamil was given in one dose total of 0.075 mg kg-1. First, a bolus injection of 0.05 mg kg "1 was given, followed by an intravenous infusion of 0.025 mg kg" 1 for 30 minutes. Group 4 - (R) -verapamil was given in a total dose of 0.3 mg kg "1. First, a bolus injection of 0.2 mg kg" 1 was given, followed by an intravenous infusion of 0.1 mg kg "1 for 30 minutes Among the measurements taken were the standard ischemic parameters, the elevation of the ST segment of the epicardium and the non-homogeneity of the electrical activation, during a period of 5 minutes in the area provided by the coronary artery LAD. left ventricular pressure, including the left ventricular diastolic pressure (LVEDP) .The average values of the data obtained are given in Table I below.

Table 1 The data obtained illustrate that the three drugs (the racemate and the separated enantiomers) have the capacity to suppress ischemic changes in a model relevant to the clinical situation. In particular, the increase in filling pressure, inhomogeneity and ST elevation that occurred during ischemia were all markedly reduced by verapamil in each of its forms. Consequently, it is believed that (R) _ verapamil can provide an effective treatment for angina, and at the same time a safer treatment, due to the elimination of cardiodepressive effects and AV conduction block that are reported to be associated with (S) -verapamil.

Claims (2)

1. The use of (R) -verapamil, or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament for the treatment of angina.

2. The use according to claim 1, characterized in that it is for oral administration.