Hiromoto Hara

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.

Effects of long-term prazosin therapy on lipoprotein metabolism in hypertensive patients

Prazosin administration caused a significant and continuous antihypertensive effect when given as a single agent for 12 months. The daily dose was stabilized after three months at 6.0 mg per day. After 12 months of prazosin treatment, high-density lipoprotein cholesterol increased by 17 percent (p less than 0.005) and the cholesterol ratio increased by 19 percent (p less than 0.05), but total cholesterol was not significantly changed. There were no statistically significant changes in triglycerides, plasma renin activity, and plasma aldosterone concentration following treatment when compared with baseline levels. Prazosin monotherapy is concluded to have favorable effects on serum lipids and can be considered suitable for long-term antihypertensive therapy.

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.

Pharmacokinetics of TZU-0460, a new H2-receptor antagonist, in patients with impaired renal function

SummaryWe have studied pharmacokinetics of a new H2-receptor antagonist, TZU-0460, in patients with varying degrees of renal impairment. The apparent volume of distribution at steady-state was 1.70 l/kg, and the plasma protein binding of TZU-0460 or its active metabolite, desacetyl TZU-0460 was less than 10% in normal subjects. These variables were not altered with renal impairment. Sixty percent of TZU-0460 given orally was excreted via the kidney, mainly by tubular secretion. The half-time of elimination was 3.94 h in normal subjects, and was prolonged to 12.13 h in severe renal failure (creatinine clearance below 30 ml/min/1.48 m2). Dosage adjustment of TZU-0460 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.

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 Angiotensin Blockade and Converting Enzyme Inhibition on Renovascular Hypertension: Comparison Between Unilateral and Bilateral Renal Artery Stenosis

The response to angiotensin II analog infusion during sodium deletion and the effects of a one-month captopril treatment were compared between 15 re novascular hypertensive patients with unilateral and 6 with bilateral renal ar tery stenosis. Plasma renin activity, its response to sodium depletion, and the renal vein renin ratio during sodium depletion were greater in unilateral than in bilateral stenosis. A fall in diastolic blood pressure induced by analog infusion during sodium depletion was correlated with the preinfusion plasma renin ac tivity and with the renal vein renin ratio. Treatment with captopril showed a comparable hypotensive effect in unilateral and bilateral stenosis. The reduc tion in blood pressure was not correlated with the pretreatment renin levels or changes in blood pressure observed during analog infusion. Plasma renin activ ity rose and plasma aldosterone level fell in all patients. These results indicate that the mechanism maintaining high blood pressure is more renin dependent in unilateral than in bilateral stenosis and that the long-term effect of captopril does not not depend solely on the suppression of the renin-angiotensin-aldoster one system.

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.

Activation of Tubuloglomerular Feedback in Rat Nephrons by Sera from Rabbits with Fulminant Hepatic Failure

Experiments were designed to determine whether substance(s) other than electrolytes might activate tubuloglomerular feedback in experimental fulminant hepatic failure. Severe hepatic damage and renal dysfunction were induced by intravenous administration of D-galactosamine. Sera from normal or D-galactosamine-treated rabbits were dialyzed against glucose solution to reduce electrolyte concentrations. Tubuloglomerular feedback response was evaluated in rat nephrons by measuring the early proximal flow rate (EPFR) during orthograde perfusion of the loop of Henle. EPFR was reduced by 28 and 48% with Ringers solution and sera from D-galactosamine-treated rabbits, respectively, but was not altered by normal sera. Substance(s) other than electrolytes in the sera from D-galactosamine-treated rabbits might activate the tubuloglomerular feedback to reduce glomerular filtration.