Herbesser 30/Herbesser 60 are benzothiazepine-type calcium-antagonist products originally developed by Tanabe Seiyaku Co., Ltd. They are useful for the treatment of angina pectoris, variant angina and essential hypertension, which are due to the dilation of coronary blood vessels, relief of coronary spasms and dilation of peripheral blood vessels, etc, which are attributable to the calcium-antagonistic action of diltiazem HCl.
Pharmacology: The therapeutic benefits achieved with diltiazem HCl eg, improvement of myocardial ischemia and hypotensive effect are related to the ability to dilate blood vessels by inhibiting the influx of calcium ions into blood vessel smooth muscle cells eg, the coronary and peripheral blood vessels.
1. Effects on Myocardial Ischemia:
a. Effects of Improving the Balance of Myocardial Oxygen Demand and Supply:
1) To increase coronary blood flow into myocardial ischemic region by dilating the collateral channels and large coronary artery (dogs).
2) To suppress coronary artery spasms (monkeys, humans).
3) To decrease myocardial oxygen-consumption, without decreasing cardiac output, by decreasing afterload due to peripheral vasodilating effect and the heart rate (dogs).
b. Effect of Myocardial Protection: To retain cardiac function and myocardial energy metabolism and reduce the infarct size by inhibiting excess calcium ion influx into cells under myocardial ischemia (rats).
2. Action on Blood Pressure:
a. To lower elevated blood pressure gradually although they hardly affect normal blood pressure (rats, humans).
To suppress the elevation of blood pressure induced by exercise load (humans).
b. To lower blood pressure without decreasing cerebral and renal blood flow (dogs, humans).
c. To suppress myocardial and vascular hypertrophy together while lowering blood pressure (rats).
3. Action on Sinus Rhythms and the Cardiac Conduction System: To prolong slightly spontaneous sinus rhythm intervals and AV node conduction times. Not to affect the His-Purkinje conduction time (dogs, humans).
Pharmacokinetics: Plasma Level: When 2 tabs of Herbesser 30 (60 mg as diltiazem HCl) were orally administered to healthy adult men, its plasma level reached the peak 3-5 hrs after administration. The elimination half-life was about 4.5 hrs. In the long-term repeated oral administration of 90 mg (30 mg x 3)/day of diltiazem HCl to patients, plasma level at 2-4 hrs after administration was about 40 ng/mL.
Metabolism: When Herbesser 30 was orally administered to healthy adult men, diltiazem HCl was mainly metabolized by oxidative deamination, oxidative demethylation, deacetylation and conjugation.
Clinical Studies:
Angina Pectoris and Variant Angina: The usefulness of Herbesser 30 and Herbesser 60 in the treatment of angina pectoris was demonstrated by double-blind comparative studies, single-blind comparative studies and open studies. Their usefulness in the treatment of variant angina was demonstrated by open studies, including investigation with the Holter ECG.
Hypertension: The usefulness of Herbesser 30 and Herbesser 60 in the treatment of essential hypertension was demonstrated by 4 double-blind comparative studies with a placebo, reserpine and propranolol as control drugs.
Adverse Reactions: 442 cases (4.6%) of adverse reactions were reported out of total 9630 cases. The most common occurrences as well as their frequency were:
Gastrointestinal System: 1.4% (stomach discomfort 0.2%, constipation 0.2%, abdominal pain 0.1%, etc).
Cardiovascular System: 1.4% (dizziness 0.5%, bradycardia 0.4%, flush 0.2%, AV block 0.2%, etc).
Hypersensitivity: 1.2%.
Headache: 0.2%, etc.
Toxicology: Preclinical Studies:
Single-Dose Toxicity (LD
50 mg/kg): See table.
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Repeated-Dose Toxicity: When 2, 10, 25 and 125 mg/kg/day and 10, 20 and 40 mg/kg/day of diltiazem HCl were orally given respectively to SD-strain rats and beagle dogs for 6 successive months, the mortal cases in the 125 mg/kg/day group and hepatic and renal impediments in the 25 and 12.5 mg/kg/day groups were observed in rats, but no influences were observed in the 2 and 10 mg/kg/day group. The mortal cases and abnormalities in ECG in the 40 mg/kg group were observed in beagle dogs and the transient increase in GOT and GPT in the 20 mg/kg/day group was observed.
Reproductive and Developmental Toxicity:
Administration Before Mating and During Pregnancy and Lactation: 12.5, 25, 50 and 100 mg/kg/day of diltiazem HCl were orally given to CFY strain rats. Adverse effects on reproductive function in parents and lethality, teratogenicity and growth retardation in fetuses and pups were not observed.
Administration during the period of fetal organogenesis 10, 25, 50, 100, 200 and 400 mg/kg/day and 10, 50, 100, 200 and 400 mg/kg/day of diltiazem HCl were orally given respectively to ICR-JCL strain mice and Wistar strain rats. The feticidal effects were observed in all groups of mice and in the 200 and 400 mg/kg/day groups of rats. Teratogenicity was observed in the 50, 100, 200 and 400 mg/kg/day groups of mice, but it was not observed even in the 400 mg/kg/day group of rats.
Administration During the Peri- and Postnatal Periods: 10, 50, 100, 200 and 400 mg/kg/day of diltiazem HCl were orally given to Wistar strain rats. As general conditions in dams changed for the worse, decreases in the birth rate and nursing rate and decreases in the viability rate and body weight gain of pups were observed in the 200 and 400 mg/kg/day group, but no remarkable change was observed in the 10, 50 and 100 mg/kg/day groups.
Antigenicity: The antigenicity of diltiazem HCl was not observed in guinea pigs, mice and rats.
Mutagenicity: The mutagenicity of diltiazem HCl was not observed either by the repair and reverse mutation test with bacteria, the chromosomal aberration test with cultured cells of mammalia or the micronucleus test with mice.
Carcinogenicity: The carcinogenicity of diltiazem HCl was not observed by the test with mice.
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