DE4308504A1 - New use of a combination of verapamil and trandolapril - Google Patents

Description

It is already known that the Ca antagonist Verapamil (Merck Index 1989, No. 9851) and the ACE inhibitor trandolapril (= N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aS-octa hydroindole-2-carboxylic acid, US Pat. No. 4,933,361) hypotensive Possess properties. The same applies to a combination of two substances (DE 41 09 134).

The present invention relates to the use of a station wagon nation of verapamil and trandolapril in a ratio of 670: 1 to 20: 1 for the manufacture of medicines for prevention and treatment Insulin resistance syndrome.

The ratio given relates to parts by weight. A ratio of 300: 1 to 50: 1 is preferred.

In combination, the verapamil can be in the form of a physiological compatible salt. For salt formation with verapamil come in particular hydrochloric acid, sulfuric acid, phosphoric acid, Acetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Citric acid, tartaric acid, lactic acid, amidosulfonic acid and oxal acid into consideration. The preferred salt is the hydrochloride.

The combination of trandolapril can also be used as a salt lie. Because trandolapril is both an acidic and basic Group, it can be used both with the acids mentioned above also with physiologically compatible bases, such as alkali or earth alkali hydroxide, salts. Free Trando is preferred lapril.

Cardiovascular disease, which remains the majority of the Cause deaths in western countries are subject to Traditionally the following three main risk factors: Hyper tonia, hypercholesterolemia and smoking. In addition, in the last insulin resistance syndrome (synonym: Syndrome X, meta bolic cardiovascular syndrome with hyperinsulinemia) as fourth Risk factor has been identified [Diabetes 37, 1595 (1988), J. Cardio vasc. Pharmac. 20 (Suppl. 8) p. 5-p. 10 (1992)]. Insulin resistance stenz is defined as a pathophysiological situation in that the skeletal muscle only responds to insulin to a reduced extent, d. H. only absorbs reduced glucose. This leads to compensatory an increased insulin production, so that hyperinsulinemia results. From this state there is a transition to  the non-insulin dependent diabetes with individually strong changing progression. It is now considered scientific ensured that the hyperinsulin occurring in this syndrome anemia due to the mitogenic effect of insulin an atherogenic Represents potential that morphological changes in the Vessel wall (e.g. coronary occlusion) [J. Cardiovasc. Pharmac. 20 (Suppl. 11) pp. 1-p. 16 (1992) as part of Thera Pie comes special attention to this metabolic syndrome Importance because it is now known that pharmaco therapeutically used diuretics and β-blockers the insulin resi Encourage tendon, while calcium antagonists are metabolically neutral and ACE inhibitors even weaken insulin resistance assets [J. Cardiovasc. Pharmac. 20 (Suppl. 11), pp. 77-S. 84 (1992)]. Preclinical findings now indicate that a Combination of an ACE inhibitor and a calcium channel blocker surprisingly not only improve insulin resistance, but even to produce the normal insulin sensitivity lead vity.

The combination can be used in the usual way for the new indication administered orally.

The dosage depends on the age, condition and weight of the patient as well as on the type of application. As a rule, the daily is dose between 50 and 480 mg verapamil and 0.2 to 4 mg tran dolapril.

The combination can be found in the usual galenical applications tion forms are applied solid or liquid, e.g. B. as a tablet film-coated tablets, prolonged-release tablets, capsules, powders, granules, Dragees, pellets, slow release pellets or solutions. These are in manufactured in the usual way. The active ingredients can with the usual pharmaceutical auxiliaries such as tablet binders, filling substances, preservatives, tablet disintegrants, flow regulating agents, plasticizers, wetting agents, dispersing agents, Emulsifiers, solvents, retardants and / or anti oxidants are processed (see H. Sucker et al: Pharma zeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The so Application forms obtained contain the active ingredient more normally in an amount of 10 to 90 wt .-%.

In combination, both Verapamil alone and both can Individual substances are in delayed form. The verapamil lies preferably as a sustained release form and the trandolapril in one Instant release form.  

The pharmacological study of the combination was carried out on two various model diseases of the rat, namely on the above sugar rat as well as on the spontaneously hypertensive Stroke-prone strain (SHRSP) rat. The SUGAR rat was used as a model for human insulin resistance, and it is characterized by the typical characteristics of hyperinsulinemia and redu graced glucose uptake in the skeletal muscle in the presence of Labeled insulin. High-pressure rats show as an expression of Glucose metabolism disorder is an increased excretion of glucose with the urine (glucosuria).

The experiments were carried out as follows:

1. Obese sugar rats were given on 14 consecutive Days orally trandolapril (1 mg / kg / day po) or verapamil (20 mg / kg / day p.o.) or the combination of both substances in the aforementioned dosages. Placebo served as a control treated animals of the same tribe. Of the so pretreated Animals became a skeletal muscle of the extremity (Musculus trochlearis) and in vitro 20 min in the presence of Insulin (2 ml units / ml) and metabolically stable deoxygly incubated. It was measured in the muscles per time amount of 2 deoxyglucose ingested. The findings are in shown in Table 1 and show that the combination of Verapamil and Trandolapril to a significantly stronger Glucose uptake in the skeletal muscles leads than when Trandolapril or verapamil alone. Glucose uptake under the combination treatment even exceeds that of healthy control animals (lean sugar rats).

2. SHRSP were taken daily with verapamil (20 mg / kg / Day p.o.) or trandolapril (0.03 mg / kg / day p.o.) or the Combination of both treated in the above dosages. At the end of the treatment, renal excretion of glucose of these animals compared to placebo-treated controls measured for 24 h. The results shown in Table 2 Nisse show that the combination made glucosuria significant more reduced than with treatment with calcium antago nest or the ACE inhibitor alone.

Prolonged use of a combination of calcium antago nest verapamil and the ACE inhibitor trandolapril Rats with glucose metabolism disorder (insulin resistance) to a surprising protective effect, the effect of Administration of the individual substance significantly exceeded. That about these Models found synergistic behavior of both active ingredients suggests that this combination is successful in the treatment  insulin resistance syndrome in humans can be set and is able to develop from latent to overt diabetes, for example insulinresi constant forms of hypertension and especially arteriosclerotic ones Consequences, and the mortality rate of these Lower disease.

Table 1

Effect of verapamil, trandolapril and the combination on the insulin-stimulated uptake of 2-deoxyglucose (DG) into the skeletal muscles of the sugar rat (mean values)

Table 2

Effect of verapamil, trandolapril and the combination on the glucosuria of SHRSP (mean values)

example

A Verapamil-HCl-Retard was placed in a hard gelatin capsule tablet with 120 mg of active ingredient and a trandolapril granulate with 0.5 mg trandolapril not reared and then filled the capsule closed.

Claims (1)

Use of a combination of verapamil and trandolapril in Ratio 670: 1 to 20: 1 for the production of drugs for Prevention and treatment of insulin resistance syndrome.