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Furosemide increases sodium (Na+) and potassium (K+) excretion but if dietary salt is provided, a compensatory reduction in Na+ and K+ excretion follows which restores neutral balances within 18 to 24 hours. This compensation is not interrupted by blockade of the renin-angiotensin-aldosterone system (RAA) alone with captopril. Since plasma norepinephrine concentration increases after furosemide and alpha 1 adrenoreceptors can mediate enhanced Na+ reabsorption, we administered prazosin (2 mg 6 hr-1) to six normal volunteers consuming a daily intake of 270 mmol of Na+ and 75 mmol of K+, and added captopril (25 mg 6 hr-1) for an additional day to block the RAA system concurrently. Furosemide (40 mg day-1) was given for the last four days. Prazosin given alone before the diuretic reduced (P less than 0.05) BP and plasma angiotensin II (AII) concentration and increased body weight and heart rate. However, when given with furosemide, neither prazosin nor prazosin with captopril modified the short-term natriuretic or kaliuretic responses to furosemide, or the ensuing compensatory reductions in Na+ and K+ excretion. Accordingly, cumulative balances for Na+ and K+ remained neutral over four days of diuretic administration. Neither drug altered the renal responsiveness to the diuretic which was assessed from the relationship between renal Na+ and K+ excretion and diuretic elimination. Although the BP was maintained when furosemide was given alone, when given with prazosin and captopril, the mean BP fell by 13 +/- 5 mm Hg (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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1. PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2. The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300 mg) were administered to each group (n = 24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30 min and 2, 5 and 24 h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30 min and 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. 3. PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4. These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention.

Many containers for intravenous solutions are made with plasticized polyvinyl chloride, the common form of which is di-2-ethylhexylphthalate (DEHP). Extraction of DEHP into blood and plasma stored in such plastic containers can occur, and harmful effects of DEHP in the human body consequently have been suggested. Reports on toxicity of DEHP in animals during pregnancy and the developmental period are critically reviewed.

We tested an inexpensive controlled-release nicotinic acid product (Bronson Pharmaceuticals, LaCanada, CA) and compared it with the standard, more expensive, controlled release product, Nicobid (Rorer Pharmaceuticals), by measuring the 24 hour urinary recovery of nicotinic and nicotinuric acids from ten subjects following 500 mg oral ingestion of each product. Nicotinuric acid is the major detoxification product of nicotinic acid and may serve as a simple quantitative index of hepatic biotransformation of nicotinic acid. Although both products demonstrated controlled release profiles, the rate of appearance of nicotinic and nicotinuric acid in the urine as well as the rate of in vitro drug dissolution of the Bronson product were more rapid compared with Nicobid. Moreover, the total amounts of nicotinic acid and nicotinuric acid recovered in the urine after 24 hours were greater for the Bronson product (P less than .05). Since sustained presentation of nicotinic acid to the liver may correlate with clinical antihyperlipidemic effects, our results suggest that the Bronson product may prove to be a clinically useful preparation.

Nicotinic acid (niacin) is a water-soluble vitamin widely used for the treatment of lipid disorders. In pharmacologic doses (1 g or more/day), alone or in combination with other lipid-lowering drugs, nicotinic acid lowers very low-density (VLDL) and low-density lipoprotein (LDL) levels, while concurrently increasing high-density lipoprotein (HDL) levels. It may reduce long-term mortality in patients with known coronary artery disease and may slow or reverse the progression of atherosclerosis. A major consideration against using nicotinic acid is the occurrence of frequent, bothersome, adverse reactions such as cutaneous flushing, skin rash, and gastric upset. Careful dosing titration may, however, minimize these effects. The beneficial effects, taken together with the low cost of nicotinic acid therapy and the relative freedom from serious side effects, have made nicotinic acid the agent of choice for the treatment of many patients with hyperlipidemia.