Takuyuki Ise

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.

Renal effects of manidipine hydrochloride : a new calcium antagonist in hypertensive patients

SummaryThe renal effects of manidipine hydrochloride were investigated in ten hospitalised patients with mild-to-moderate essential hypertension. After a one-week placebo period, manidipine was given for 1 week in a dose rising from 5 mg to 10 mg or 20 mg daily to normalise the mean blood pressure measured after 2 h.Blood pressure had decreased from 171/101 to 147/86 mm Hg at the end of manidipine treatment. The pulse rate was unaltered. Renal vascular resistance decreased from 1.90 to 1.33 dyn · s · cm−5/1.48 m2 × 104, and renal blood flow and glomerular filtration rate increased from 522 to 662 ml · min−1 · 1.48 m−2 and from 81 to 93 ml · min−1 · 1.48 m−2, respectively, in spite of a fall in renal perfusion pressure. Manidipine reduced the filtration fraction from 0.260 to 0.243, suggesting a preferential reduction in efferent arteriolar resistance. The fractional excretion of sodium and potassium did not change. Manidipine did not produce any significant alteration in plasma renin activity or in the plasma aldosterone concentration.The results indicate that manidipine has favourable renal effects and a concomitant hypotensive action in patients with mild-to-moderate essential hypertension.

Juxtaglomerular Cell Tumor of the Kidney Treated with Nephron-Sparing Surgery

A case of juxtaglomerular cell tumor of the right kidney is reported. A 30-year-old woman visited us with a complaint of headaches. Severe hypertension and an elevated level of plasma renin activity was seen at the initial evaluation. Computerized tomographic angiography revealed tumor vessels in the low-density mass in the right kidney. The preoperative diagnosis was renin-secreting tumor of the kidney, and nephron-sparing surgery was performed. The pathological findings showed a juxtaglomerular cell tumor. Postoperatively, prompt normalization of blood pressure and a reduced plasma renin activity level were observed.

Effect of calcium antagonist, manidipine hydrochloride, on renal hemodynamics and tubuloglomerular feedback in spontaneously hypertensive rats

The effects of a calcium antagonist, manidipine, on renal hemodynamics and the tubuloglomerular feedback (TGF) mechanism were examined in 7- to 8-week-old spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar-Kyoto rats (WKYs). Manidipine, 10 micrograms/kg intravenously, reduced blood pressure only in SHRs. A greater increase in renal plasma flow occurred in SHRs, but effects on GFR were observed in both SHR and WKY rats. Filtration fraction decreased only in SHRs. The TGF response curve in SHRs was shifted to the left compared with that in WKY rats, indicating a more active TGF in hypertensive rats. Manidipine infusion produced a right and upward shift of the feedback curve in SHRs and only an upward shift in WKY rats. We conclude that manidipine corrects hyperactivity of the TGF mechanism in SHRs.

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

A chimeric CYP11B1/CYP11B2 gene in glucocorticoid-insuppressible familial hyperaldosteronism

Although a chimeric gene combining the 11β‐hydroxylase gene (CYP11B1) and the aldosterone synthase gene (CYP11B2) explains the pathophysiology of familial hyperaldosteronism (FH) type I, the contribution of this abnormality to FH type II has not been tested. We screened genomic DNA from a Japanese family with FH type II for the CYP11B1/CYP11B2 gene. The index patient was a 27‐year‐old woman with hypertension. Hypokalaemia, elevated plasma aldosterone and suppressed plasma renin activity suggested primary aldosteronism. Though computed tomography failed to reveal an adrenal tumour, left adrenalectomy was indicated due to a high aldosterone concentration in left adrenal venous blood. The resected adrenal gland contained an adenoma. As her mother had also been diagnosed with primary aldosteronism due to an adenoma, we administered oral dexamethasone to our patient before the operation and observed the response of the blood pressure and plasma aldosterone concentration for 2 weeks. Both parameters remained elevated during the treatment period, confirming the diagnosis of FH type II. Total DNA was isolated from blood cells of the index patient, her mother, and an unaffected brother. Samples were amplified by polymerase chain reaction using specific primers from CYP11B1 and CYP11B2. Unique DNA fragments of 1·4 kb were obtained from the index patient and her mother, but not from the healthy subject. The CYP11B1/CYP11B2 chimeric gene was found in a Japanese family with FH type II.

Unilateral Stent Implantation for Renal Function in Bilateral Atherosclerotic Renovascular Hypertension A Case Report

Renal artery stenting improves or preserves renal function in patients with bilateral renovas cular disease and chronic renal insufficiency. An 80-year-old male was admitted to the hospital for elevated blood pressure accompanied by congestive heart failure. He had renal insufficiency and severe hypertension secondary to bilateral atherosclerotic renal artery stenosis. Unilateral renal artery stenting in the left kidney resulted in the recovery of renal function, whereas renal artery stenting in the right kidney was technically difficult due to a tortuous aorta. After the left unilateral stent implantation, the serum creatinine concentration decreased from 2.0 to 1.3 mg/dL, and control of his blood pressure required fewer antihypertensive drugs, namely a calcium antagonist, an angiotensin-converting enzyme inhibitor, and diuretics. Fifteen months after stenting, renal scintigraphy demonstrated improved function of the right kidney, despite severe renal artery stenosis, as well as improved function of the left kidney. Renal angioplasty or stenting should be attempted in bilateral atherosclerotic renovascular hypertension with renal insufficiency, even though it may only be successful unilaterally.