Rapamune: a novel macrolide immunosuppressant for transplantation.
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Biomedical subjects
Publications and source records attributed to D Latta.
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Medroxyprogesterone acetate (MPA) has been administered to rats and dogs. Dogs received single oral doses of 2.5, 5, and 10 mg MPA and a single intravenous dose of 1 mg MPA. Rats received single oral doses of 0.2, 1, 5, and 20 mg kg-1 MPA and multiple oral doses (14 daily doses) of 0.2, 5, and 20 mg kg-1 MPA. Dog plasma MPA levels from the intravenous dose were characterized by a triexponential decay with disposition half-lives of 0.3, 1.8, and 21.6 h. A Loo-Riegelman analysis of the dog plasma MPA levels from oral doses indicated absorption was not a simple first-order process. The Weibull Function was used to characterize the absorption kinetics of MPA. The oral absorption of MPA in dogs appears to be dose-linear over the dosage range studied, and the absolute bioavailability was estimated at 27 per cent. Rat plasma MPA levels from single and multiple oral doses were analyzed by a non-compartmental approach. AUC and Cmax values were not dose-linear over the dosage range studied; indicative of the self-induced metabolism of MPA. Exposure of similar dosages of MPA to both the rat and the dog resulted in similar plasma profiles and pharmacokinetics.
A single-blind, multicentre, comparative clinical trial was performed in 59 hayfever sufferers to compare the efficacy of mequitazine 5 mg bd and terfenadine 60 mg bd over a period of 14 days. Clinical assessments of nasal and ocular symptoms were made on admission to the trial and after seven and 14 days treatment by both physicians and patients. Critical flicker fusion threshold was measured at each assessment. A global assessment of efficacy was determined by both the doctor and patient at the end of treatment. Patients also completed a daily diary card. Thirty patients on mequitazine and 22 on terfenadine completed the trial. There were seven dropouts (five on terfenadine and two on mequitazine). Both treatments were equally effective in reducing the severity of symptoms over the 14 days of treatment. The overall assessment at the end of treatment showed no important significant differences between the two drugs. According to the physicians, 60 per cent of the mequitazine-treated patients and 63 per cent of the terfenadine-treated patients had an excellent or good response. Patients assessed their response as excellent or good in 56 and 62 per cent of cases respectively. Neither drug significantly impaired performance.
In an open, randomized, parallel group study lasting 8 weeks, nine males and nine females with mild congestive cardiac failure were initially treated daily with 20 mg frusemide/2.5 mg amiloride or 0.5 mg bumetanide/573 mg potassium chloride. In two patients receiving the frusemide combination and in one receiving the bumetanide combination, the daily dose was doubled after 2 weeks' treatment because of inadequate control of symptoms. Mild congestive cardiac failure symptoms (raised jugular venous pressure, oedema and dyspnoea at rest and on effort) were controlled in 9/10 patients receiving frusemide/amiloride but two patients receiving bumetanide/potassium chloride still had mild oedema after 8 weeks. Both treatments were well tolerated overall and there were no clinically significant changes in plasma electrolytes, although one patient treated with frusemide/amiloride was withdrawn due to adverse events.
A two-centre, double-blind, placebo controlled, randomized 3-way crossover study was undertaken to assess the efficacy, tolerability and safety of celiprolol in mild to moderate essential hypertension. A 4-week single-blind placebo run-in/screening period, during which no antihypertensive medication was given, was followed by 3 consecutive 4-week treatment periods with placebo or celiprolol (200 mg or 400 mg daily). At the end of the 4-week placebo run-in/screening period, 26 hospital out-patients with a seated mean blood pressure (systolic/diastolic) of 161.4/101.7 mmHg and a mean pulse rate of 75 beats/min entered the double-blind crossover phase of the study. Results showed that there was no significant difference in seated mean systolic or diastolic blood pressure between 200 mg celiprolol daily (149.2/92.3 mmHg) and 400 mg celiprolol daily (149.1/92.5 mmHg). However, mean seated systolic and diastolic blood pressures were significantly (p less than 0.05) lower on celiprolol than on placebo (157.1/98.2 mmHg). Neither dose of celiprolol had a significant effect on seated pulse rate. No patient was withdrawn due to an adverse event and no laboratory assessment outside the normal range was reported to be of any clinical significance. It is concluded that oral celiprolol, 200 mg or 400 mg daily, is effective and well tolerated for controlling mild to moderate essential hypertension. Since both doses had very similar effects on blood pressure there is no advantage in this group of patients for the 400 mg daily dose of celiprolol.
Eighty one patients with uncomplicated hypertension who required additional antihypertensive medication (diastolic Phase V [dBP] greater than or equal to 95 mm Hg) after 4 weeks treatment with hydrochlorothiazide (HCTZ) 25 mg o.m. were randomized to receive felodipine 5 mg b.i.d. (n = 40) or propranolol (n = 41) 80 mg b.i.d. in addition to HCTZ 25 mg o.m. If the dBP measured about 12 h post-dose was not less than or equal to 90 mm Hg after 4 weeks, the dose of felodipine or propranolol was doubled. The double blind trial period was 8 weeks for all patients. Over the 8 week period, felodipine reduced the seated dBP from 100 to 83 mm Hg and propranolol from 101 to 86 mm Hg. The attained seated dBPs were significantly different in the two groups. About one third of patients in each group received the high dose of second-line therapy. After 8 weeks 91% of patients receiving HCTZ+felodipine and 84% receiving HCTZ+propranolol had a dBP less than or equal to 90 mm Hg. Both regimens were well-tolerated with an equal incidence but different pattern of adverse events (felodipine: flushing, headache and peripheral oedema; propranolol: dyspepsia, fatigue and vasospasm). In this 8-week study, felodipine and propranolol were safe and effective second-line antihypertensive drugs when added to hydrochlorothiazide. At the doses selected, felodipine was at least as effective as propranolol.
This study was performed to evaluate the hypothesis that adrenal aldosterone output is modulated by daily potassium intake in man. Eight normotensive subjects, aged 24-38 yr, were fed 3 separate 150 mEq sodium-containing diets. Potassium content ranged from 300 mEq daily during the first week, to 80 mEq daily and 10 mEq daily for the subsequent 2 wk. On days 4 and 5 of each diet each subject took oral dexamethasone 0.5 mg B.I.D. to prevent endogenous ACTH secretion. On day 6 an infusion of angiotension II (AII) was administered in doses of 0.1, 0.3, 1.0, 3.0 and 10.0 ng/kg/min, each lasting 30 min. Blood pressure, pulse, and plasma aldosterone and potassium were measured throughout the infusions. All at infusion rates of 3 and 10 ng/kg/min, produced significant increases in plasma aldosterone values during liberal potassium intake but not when potassium intake was 10 mEq/day. We conclude that dietary potassium in man modulates All-mediated aldosterone secretion.
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