JPH0665089A - Vasodilator - Google Patents

Abstract

PURPOSE:To provide a vasodilator easy to use, causing no side effects such as excessive hypotension. CONSTITUTION:The objective vasodilator contains, as active ingredient, tuftsin of the formula H-Thr-Lys-Pro-Arg-OH, or a pharmaceutically permissible salt thereof.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a vasodilator useful for treating diseases such as heart failure, acute myocardial infarction, hypertension and the like.

[0002]

2. Description of the Related Art It is known that a therapy using a vasodilator is useful for cardiovascular diseases such as heart failure, acute myocardial infarction and hypertension.

Vasodilators are roughly classified into the following three types depending on the vasculature that acts. (1) Drugs that mainly expand the arterial system. For example, hydralazine, phentolamine, calcium channel blockers (nifedipine, verapamil, etc.). (2) Drugs that mainly dilate the venous system. For example, nitro compounds such as nitroglycerin and isosorbide dinitrate, or nitrites. (3) A drug that dilates both arteries and veins almost equally. For example, nitroprusside, α ₁ blocker (prazosin, etc.), angiotensin converting enzyme inhibitor.

The mechanism of action of these drugs is as follows: direct action on peripheral vascular smooth muscle (hydralazine, nitro compound, nitroprusside), inhibition of vasoconstriction via sympathetic nervous system (α ₁
Blocker), suppression of inflow of calcium ions into vascular smooth muscle cells (calcium antagonist), etc.

The above drugs are used properly according to the symptoms and changes in hemodynamics, and each has a high clinical value.

On the other hand, tuftsin represented by H-Thr-Lys-Pro-Arg-OH is 28 of the H chain of immunoglobulin IgG.
It is known that it is a tetrapeptide existing at the 9th to 292nd positions and has actions such as binding to phagocytic cells to enhance phagocytosis and enhancing immune response. It is also known that the IgG fraction (called leucokinin) that promotes phagocytosis when bound to leukocytes is due to tuftsin.

[0007]

Among the above-mentioned vasodilators, nitroprusside has a strong vasodilator effect and has a fast-acting effect, but since it has a short half-life, it must be administered by careful infusion by a constant volume infusion device. There is inconvenience. In addition, there is a problem that blood pressure sometimes falls excessively.

The present invention is intended to provide a vasodilator which has a vasodilator effect similar to nitroprusside, but has no side effects such as causing excessive hypotension and is easy to use.

[0009]

Means for Solving the Problems The present inventors have studied the vasodilatory action of various peptides, and surprisingly found that tuftsin has a vasodilatory action similar to nitroprusside, and completed the present invention.

That is, the present invention is H-Thr-Lys-Pro-Arg-OH.
A vasodilator that contains tuftsine represented by or a pharmaceutically acceptable salt thereof as an active ingredient (however, Thr
Represents an L-threonine residue, Lys represents an L-lysine residue, Pro represents an L-proline residue, and Arg represents an L-arginine residue).

[0011] Tuftsin can be obtained as a commercial product, or can be synthesized by a solid phase method or a liquid phase method usually used for peptide synthesis.

As pharmaceutically acceptable salts of tuftsin, inorganic salts such as hydrochloride, sulfate and phosphate, acetate,
Organic acid salts such as citrate, fumarate, tartrate, lactate, etc., alkali metal salts such as sodium salt, potassium salt, etc.
Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts and the like.

The above-mentioned pharmaceutically acceptable salts are equivalent to those obtained by removing the protecting group in the final step of the synthesis and then adding an acid such as hydrochloric acid or acetic acid or a base such as sodium hydroxide or potassium hydroxide. It is also possible to prepare a salt thereof, or after isolating tuftsin, a salt can be prepared by adding an acid or a base in the same manner as above.

The vasodilator of the present invention may take any form for oral or parenteral administration. As a typical administration method, it can be administered by various routes including oral, rectal, skin permeation, subcutaneous, intravenous, intramuscular, inhalation or intranasal routes.

In these administration methods, the vasodilator of the present invention can be administered in the form of various pharmaceutical preparations. The form of these pharmaceutical preparations includes tablets, hard capsules, soft capsules, granules, powders, troches, suppositories, syrups, creams, ointments, musts, injections, suspensions,
There are inhalants and aerosols. Further, it can be made into a double-layer tablet, a multi-layer tablet, etc. together with other vasodilators and other drugs. Further, in the case of tablets, a usual coating may be applied, if necessary, to give, for example, sugar-coated tablets and enteric-coated tablets.

In the case of preparing solid preparations such as tablets, granules and powders, known additives for formulation, such as lactose, sucrose, glucose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, Hydroxypropyl cellulose, gum arabic, polyvinylpyrrolidone, polyethylene glycol, magnesium stearate, talc and the like can be added.

In the case of a semisolid preparation, vegetable wax, microcrystalline wax, fat such as tallow,
Materials such as lanolin can be added.

In the case of a liquid preparation, additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, ethylene glycol and ethyl alcohol can be added.

The dose of tuftsin can be appropriately increased or decreased depending on the age, body weight, symptom of the patient, etc., but the dose for oral administration is 0.01 to 10 mg / kg per day, and the amount for parenteral administration is Is 10 to 1,000 μg / kg per day.

[0020]

[Examples] In the following examples, the effects of tuftsin on the vasodilator action and the circulatory system such as blood pressure and heart rate are shown, and it is demonstrated that this peptide is used as a vasodilator having an action similar to nitroprusside. To do.

Example 1 Vasodilatory effect of tuftsin The thoracic aorta of a male rabbit with a body weight of 2.5 to 3 kg was excised and its width was 4 m.
An aortic spiral strip specimen with a length of 25 to 30 mm was prepared. T
Aortic spiral streak specimens were prepared by aerating a mixed gas of 95% by volume oxygen and 5% by volume carbon dioxide at 37 ± 1 ° C in 10 ml of yrode solution.
It was suspended by applying a load of 2 g and kept stable for 1 h. Then potassium chloride was added to a final concentration of 104 mM, or norepinephrine was added to a final concentration of 10 ^-6 M to induce vasoconstriction, and tuftsin was cumulatively administered to each, and the relaxation reaction of blood vessels was observed. . In addition, nitroprusside (sodium salt) and verapamil were used as comparative drugs.

Tables 1 and 2 show the vasodilatory effects of tuftsin and the comparative drug in terms of relaxation rate when a blood vessel contracted with potassium chloride and a blood vessel contracted with norepinephrine were used, respectively.

[Table 1] Table 1 Effects of tuftsin and comparative drugs on vasoconstriction induced by potassium ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ slack slow rate compound ─────────────────────── of compound concentration ^{(M) 10 -8 10 -7 10} -6 10 -5 10 - ⁴ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ (%) (%) (%) (%) (%) Tuftsin 0 0 4.6 12.3 14.6 Nitroprusside 0 1.4 11.4 24.3 35.7 Verapamil 7.1 68.3 97.1 100 100 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0023]

[Table 2] Table 2 Effect of tuftsin and comparative drug on vasoconstriction induced by norepinephrine ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━ slack slow rate compound ─────────────────────── of compound concentration ^{(M) 10 -8 10 -7 10} -6 10 -5 10 - ⁴ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ (%) (%) (%) (%) (%) Tuftsin 0 0 13.6 23.2 51.3 Nitroprusside 16.1 59.4 86.0 93.8 98.8 Verapamil 0 4.6 20.6 47.1 68.6 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

From the results shown in Tables 1 and 2, tuftsin showed almost no relaxing action on potassium-induced vasoconstriction, but showed a dose-dependent relaxing action on norepinephrine-induced vasoconstriction, It can be seen that its action is more similar to nitroprusside than verapamil.

Example 2 Effect of tuftsin on circulatory system In order to examine the effect of tuftsin on the circulatory system, it was intravenously administered to rats and blood pressure, heart rate and electrocardiogram were observed.

Male Wistar rats weighing 300 to 350 g were anesthetized with urethane (1.5 g / Kg intravenous injection), arterial pressure was measured via a transducer from a cannula inserted in the left femoral artery, and heart rate was determined by electrocardiogram. The measurement was performed by a heart rate meter using the R wave of (lead II) as a trigger.

Tuftsin is 3 per 1 kg of rat body weight.
0 mg was dissolved in physiological saline and administered through the femoral vein. Figure 1
FIG. 3 is a graph showing blood pressure (mean blood pressure) and heart rate of rats after administration of tuftsin.

The blood pressure decreased immediately after the administration, and after 5 minutes, the blood pressure showed a minimum value (8% decrease from the average blood pressure before administration). However, 10 minutes after the administration, the blood pressure before administration was recovered. On the other hand, the heart rate decreased by 5% immediately after the administration, and the decrease lasted for 60 minutes. On the ECG, Q immediately after administration
Although a slight prolongation between T was observed, the width of QRS did not change.

[0029]

INDUSTRIAL APPLICABILITY Tuftsin exhibits a vasodilatory action similar to nitroprusside. According to the present invention, it is possible to provide a vasodilator which has no side effects such as excessive blood pressure reduction and is easy to use.

[Brief description of drawings]

FIG. 1 is a graph showing the effect of tuftsin on the circulatory system (blood pressure and heart rate).

Claims (1)

[Claims] 1. A vasodilator containing tuftsin represented by H-Thr-Lys-Pro-Arg-OH or a pharmaceutically acceptable salt thereof as an active ingredient.