The therapeutic benefits achieved with Herbesser 180 SR eg, improvement of myocardial ischemia and hypotensive effect are believed to be related to its ability to dilate vessels by inhibiting the influx of calcium ion into smooth muscle cells of the coronary and peripheral vessels, etc.
Action on Blood Pressure: Lowers the elevated blood pressure gradually although hardly affects the normal blood pressure (rat, human). Suppresses the elevation of blood pressure induced by exercise load (human). Lowers blood pressure without decreasing cerebral and renal blood flow (dog, human). Suppresses myocardial and vascular hypertrophy together with lowering blood pressure (rat).
Effects on Myocardial Ischemia: Increases coronary blood flow into myocardial ischemic region by dilating the collateral channels and large coronary artery (dog). Suppresses coronary artery spasms (monkey, human). Decreases myocardial oxygen consumption without decreasing cardiac output by decreasing afterload and heart rate due to peripheral vasodilating effect (dog). Retains cardiac function and myocardial energy metabolism and reduces the infarct size by inhibiting extra calcium ion influx during myocardial ischemia (rat).
Action on Sinus Rhythm and Cardiac Conduction System: Slightly prolongs spontaneous sinus rhythm interval and AV node conduction time. Does not affect His-Purkinje conduction time (dog, human).
Plasma Level: When 1 capsule (180 mg as diltiazem HCl) of Herbesser 180 SR was orally administered to healthy adult men, its plasma level reached the peak (about 74 ng/mL) about 8 hrs after administration. The plasma elimination half-life was about 9.7 hrs. In case of repeated administration of Herbesser 180 SR twice a day to healthy adult men, plasma level at 4-12 hrs after administration was about 95 ng/mL.
Metabolism: When Herbesser 180 SR was administered to healthy adult men, deacetyl diltiazem, deacetyl-N-monodemethyl diltiazem, deacetyl-O-demethyl diltiazem, deacetyl-N,O-demethyl diltiazem and N-monodemethyl diltiazem were detected in urine as metabolites. A part of these metabolites are conjugated with glucuronic acid or sulfuric acid in body.
Hypertension: Usefulness of Herbesser 180 SR in the treatment of essential hypertension was proved by 4 double-blind comparative studies with placebo, reserpine and propranolol as control drugs.
Adverse Reactions: 432 cases (4.5%) of adverse reactions were reported out of total 9347 cases. The most common occurrences as well as their frequency of presentation are: Gastrointestinal system 1.3% (stomach discomfort 0.2%, constipation 0.2%, abdominal pain 0.1%, etc), cardiovascular system 1.3% (bradycardia 0.4%, dizziness 0.4%, hot flush of face 0.2%, A-V block 0.2%, etc), hypersensitivity 1.2%, headache 0.2%, etc.
Preclinical Studies: Acute Toxicity (LD50
mg/kg): See table.
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Chronic Toxicity: When 2, 10 and 25 mg/kg/day each of diltiazem HCl were given orally to SD-strain rats and 5, 10 and 20 mg/kg/day to beagle dogs, for successive 6 months, respectively, general state as well as urinary and histopathological findings of these animals were not significantly different from those of the control. Hematological findings in dogs given orally 20 mg/kg of diltiazem HCl revealed a rise of GPT but it was transient and tended to recover the normal level at the end of experiment.
Teratogenicity: The effect of diltiazem HCl on the fetus was examined by the method as specified in "Policy for Assurance of Drug Safety" notified by the Ministry of Health and Welfare of Japan. At the oral dose level of >10 mg/kg in ICR-JCL-strain mice and >200 mg/kg in Wistar-strain rats, diltiazem HCl caused death of the fetus. At the oral dose level of >50 mg/kg in ICR-JCL-strain mice, diltiazem HCl provoked teratogenic effect. At an oral dose of 400 mg/kg in Wistar-strain rats, diltiazem HCl did not provoke teratogenic effect.