Naoteru Hashimoto

Pharmacokinetics of famotidine, a new H2-receptor antagonist, in relation to renal function

SummaryThe pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.14 l/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CLCR 90–60 ml/min/1.48 m2) but was increased to 4.72 h in moderate renal failure (CLCR 60–30 ml/min/1.48 m2), and to 12.07 h in severe renal failure (CLCR below 30 ml/min/1.48 m2). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CLCR above 60 ml/min/1.48 m2 the normal daily dose of famotidine can be employed, but in those with a CLCR between 60 and 30 ml/min/1.48 m2 the dose should be reduced by half, and in patients with a CLCR below 30 ml/min/1.48 m2 a reduction by three quarters of the normal dose is recommended.

Pharmacokinetics of SUN 1165, a new antiarrhythmic agent, in renal dysfunction

SummaryThe pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg.The apparent volume of distribution at steady state was 1.48 1 · kg−1, the absorption rate constant was 2.2 h−1, and plasma protein binding was 26.8% in subjects with normal renal function.These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration.The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml · min−1 · 1.48 m−2).Dosage adjustment of SUN 1165 is necessary in renal failure.

Blood Pressure Variability and Hemodynamic Response to Stress in Patients with Paroxysmal Elevation of Blood Pressure

Blood pressure variability during 24 hours and hemodynamic response to stress were studied in essential hypertensive patients, displaying paroxysmal hypertension and pheochromocytoma-type symptoms (PH). Hemodynamics at rest, in response to mental arithmetic, bicycle ergometer exercise or the cold together with baroreflex sensitivity were not different between these patients and other essential hypertensives (EH). Average waking systolic blood pressure was lower but variabilities of both systolic and diastolic blood pressure were greater in PH than in EH. During sleep, these differences disappeared. Thus, the greater variability in blood pressure seen only in waking PH patients cannot be estimated from the hemodynamic patterns at rest and is not likely to be related to an excessive response to stress or impaired baroreflex.

Effect of the calcium antagonist nilvadipine on haemodynamics at rest and during cold stimulation in essential hypertension

SummaryThe immediate haemodynamic effects of the calcium antagonist nilvadipine have been studied in ten patients with established mild essential hypertension.Nilvadipine 4 mg p.o. reduced both the systolic and diastolic blood pressures within 60 min, associated with a fall in total peripheral resistance and an increase in heart rate and cardiac index. The peak of blood pressure and total peripheral resistance reached during a cold pressor test were reduced by nilvadipine, but it did not affect the haemodynamic responsiveness to cold stimulation.Plasma renin activity was unaltered and the plasma noradrenaline concentration was increased only slightly.Thus, nilvadipine lowered blood pressure at rest and during cold stimulation as a result of arteriolar dilatation. The hypotensive effect at rest was associated with a reflex increase in heart rate and cardiac index.

Combination Therapy with Carvedilol and Nicardipine in Essential Hypertension

Although ,B-blockers and diuretics are widely used first-choice agents in the treatment of hypertension, as recommended in a stepped-care approach (Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure 1984), calcium antagonists have been shown to be effective in most cases of mild to moderate essential hypertension. Patients who do not respond to a calcium antagonist should be treated by adding other drugs, preferably with a different mechanism of action . ,B-Blockers in combination with calcium antagonists have been shown to exhibit synergistic effectsand cause fewer side effects than either agent alone (Anderton et al. 1988; Daniels & Opie 1986). In this study we have evaluated the efficacy and safety of combination treatment with the calcium antagonist nicardipine and a new ,B-blocking agent, carvedilol, in the treatment of mild to moderate essential hypertension. Nicardipine, a calcium antagonist with a dihydropyridine skeleton, is widely used in Japan. Carvedilol is a potent, non-selective ,B-blocking agent with a vasodilating property, and lacks intrinsic sympathomimetic activity (Sponer et al. 1986). 1. Methods 1.1 Patients

Effect of nicardipine on haemodynamic response to stress in hypertension

SummaryThe effects of the calcium antagonist nicardipine on the pressor response to mental arithmetic, cold pressor and exercise tests have been studied in fifteen patients with established mild to moderate essential hypertension.Nicardipine 20 mg p.o. showed a hypotensive effect within 60 min, associated with a fall in total peripheral resistance and an increase in heart rate. As the pressor response to each stress was not affected by nicardipine, the peak blood pressure reached during each stress was lower.Nicardipine lowers blood pressure at rest as a result of arteriolar dilatation, associated with reflex tachycardia. The pressor responsiveness to various stresses was not affected by nicardipine.

The Long Term Effects of Percutaneous Transluminal Angioplasty for Treating Patients with Renovascular Hypertension: Case Studies

Percutaneous transluminal angioplasty was performed on 10 patients with unilateral renovascular hypertension (7 with atheromatous and 3 with fibro muscular stenoses) who were then followed for an average of 42 months (range, 24 to 67 months). Dilatation of the stenosis was initially successful in all patients except one who had severe atheromatous stenosis. Among patients with ather omatous disease, normotension was attained for 40, 25 and 24 months in 3 patients given no antihypertensive medication and for 67 and 55 months in 2 patients given only nicardipine. The remaining one patient had a recurrent stenosis 3 months after angioplasty. All patients with fibromuscular dysplasia have been normotensive without any hypotensive medication for more than 4 years. Plasma renin activity declined within one week after angioplasty and remained unchanged thereafter in all patients except the one case suffering from a recurrent stenosis. Renal blood flow and glomerular filtration rate re mained increased after angioplasty. These results suggest that hypertension can be controlled and renal dysfunction in patients with renal artery stenosis caused by atheroma or fibromuscular dysplasia improved for long periods by percuta neous transluminal angioplasty. The antihypertensive effect obtained by this procedure was more valuable for the patients with fibromuscular dysplasia than in those with atheromatous disease.

A Case of One-Kidney Hypertension: Contrasting Effects of Angioplasty and Treatment with Captopril

A patient with hypertension is shown to have both a renal artery stenosis due to fibromuscular dysplasia and a hypoplastic contralateral kidney, a condition comparable to that of the one-kidney Goldblatt hypertension. Both blood volume and plasma renin activity were increased. Blood pressure was lowered either by an angiotensin II analog or by captopril. Secretion of excess renin was observed only from the stenotic kidney. A 4-week period of captopril treatment was accompanied by an acute, reversible deterioration of renal function. Transluminal angioplasty corrected the abnormalities in renin and in blood volume and has kept blood pressure and renal function normal for over 2 years.