Food and drug regulation after 75 years.
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Advertising↗
Biomedical subjects
A H Hayes
Publications and source records attributed to A H Hayes.
Therapeutic implications of drug interactions with acetaminophen and aspirin.
Only drug-drug interactions that are believed clinically important and that are primarily pharmacokinetic in nature are discussed in this article. Drugs reported to interact with aspirin are oral anticoagulants, methotrexate, probenecid, and sulfinpyrazone; those that are believed to interact with acetaminophen are propantheline bromide, narcotics, and metoclopramide hydrochloride, as well as food (carbohydrates). Ethyl alcohol, ammonium chloride, antacids, oral antidiabetic agents, corticosteroids, and heparin sodium probably interact with aspirin. Fenoprofen calcium, gold sodium thiomalate, indomethacin, naproxen, penicillin, phenylbutazone, phenytoin sodium, and spironolactone may also cause such interactions. Ethyl alcohol, beta-adrenergic blockers, oral anticoagulants, chlorpromazine hydrochloride, and miscellaneous mutual toxicities may cause interactions with acetaminophen. The concomitant use of drugs that are believed to interact importantly with either aspirin or acetaminophen should be avoided when designing a treatment regimen. The remaining agents discussed here (of doubtful importance in man) demand careful monitoring in difficult clinical situations and must be submitted to further controlled studies.
Acetaminophen↗
Acute renal failure, hemolytic anemia and skin rash associated with captopril therapy.
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Acute Kidney Injury↗
How the FDA looks ahead while celebrating its 75th anniversary.
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Organizational Objectives↗
Effect of dose and uremia on plasma and urine profiles of propranolol metabolites.
The relationship between plasma levels of 4 propranolol metabolites--naphthoxylactic acid (NLA), 4-hydroxypropranolol (4-OH), naphthoxyacetic acid (NAA), and propranolol glycol (PG)--and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4-OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cli) from 425 to 200 1/hr. Half-life rose from 3 to 5 hr. Urinary recovery of 4-OH fell as Cli rose. Urinary recovery of propranolol conjugates, NLA, and N-desisopropylpropranolol (NDIPP) rose as Cli fell. Our results suggest that naphthalene ring oxidation of propranolol represents a high-affinity low-capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long-term propranolol therapy. Mean plasma NLA was 4.372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml.
Absorption↗
Effect of probenecid on the kinetics of epsilon-aminocaproic acid.
Healthy male subjects received, 1 wk apart, single oral doses of epsilon-aminocaproic acid (EACA) 100 mg/kg alone, EACA within probenecid (0.5 gm), or EACA 2 hr after 2.0 gm probenecid. Probenecid (2.0 gm) reduced the 8-hr urinary clearance and recovery of EACA by 50% without affecting plasma kinetics. Recovery of EACA in urine rose to 78% of the dose 48 hr after EACA. Plasma clearance of EACA did not differ from control EACA urinary clearance when 0.5 gm probenecid was given with EACA. In both cases all the EACA dose was recovered in urine within 8 hr.
Aminocaproates↗
The inhibition of rat hepatic microsomal propranolol metabolism by a covalently bound reactive metabolite.
Repetitive oral propranolol administration to rats (100 mg/kg/day for 5 days) resulted in an 80% inhibition of propranolol Type I spectral binding capacity. This paralleled a similar reduction in the microsomal metabolism of propranolol when incubated at low substrate concentrations (less than 2 microM). Propranolo was converted both in vitro and in vivo by a microsomal mixed function oxidase to a reactive intermediate metabolite capable of covalently binding with microsomal macromolecules. We propose that covalent binding of the intermediate to the catalytic site of a form(s) of cytochrome P-450 that metabolizes propranolol would account for the marked inhibition of propranolol metabolism observed following propranolol pretreatment.
Animals↗
Mechanism of action of castor oil: a biochemical link to the prostaglandins.
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Animals↗
The effect of hydralazine on arachidonic acid metabolism in isolated, washed human platelets.
The effects of hydralazine on arachidonic acid metabolism were studied in isolated washed human platelets. The washed platelets (10(9)/ml) were exposed to 14C-arachidonic acid and incubated for 15 minutes in a platelet aggregometer (37 degrees C). The media was then extracted and the reaction products separated by means of reversed phase high pressure liquid chromatography. In this system, hydralazine inhibited the production of TXB2 (the stable metabolite of TXA2) and enhanced the production of PGF2 alpha and PGE2 in a dose dependent fashion. Indomethacin, blocked the production of all prostaglandin compounds normally synthesized by platelets. These results suggest that hydralazine is a specific thromboxane synthetase inhibitor and that its vasodilatory effects might be related to its ability to block the production of an endogenous vasoconstrictor (i.e. TXA2).
Arachidonic Acids↗
Therapeutic rounds at the Milton S. Hershey Medical Center.
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Aged↗
Determination of propranolol and six metabolites in human urine by high-pressure liquid chromatography.
A method for the determination of propranolol and six of its metabolites, as well as their glucuronide and/or aryl sulfate conjugates in human urine is described. Propranolol and its basic and neutral metabolites are extracted into ether at pH 9.8, evaporated to dryness, reconstituted, separated on a reversed-phase, high-pressure liquid chromatographic system and quantitated using fluorescence detection. The aqueous urine aliquot is then made acidic and the acid metabolites extracted and measured using similar methods. The presence of 2% sodium metabisulfite in all urines collected is essential to ensure the stability of 4-hydroxy-propranolol during collection and storage. Preliminary data is presented from 24-h urine samples collected from three patients chronically receiving propranolol.
Chromatography, High Pressure Liquid↗
Effect of coadministration of procainamide and isoniazid on each other's acetylation pathway.
The effect of isoniazid (INH) and procainamide (PA) on each other's acetylation pathway was studied in 7 normal subjects (3 rapid acetylators, 3 slow acetylators, 1 of indeterminate phenotype). Oral PA (6 mg/kg) was administered every 4 h for a total of seven doses. Following the final dose subjects received a single 300-mg oral dose of INH. Analysis of the parent drugs and their acetylated metabolites in plasma and urine revealed no effect on the acetylation of either drug. In 2 subjects (1 rapid, 1 slow acetylator) increasing doses of PA were given and the effect on INH (300 mg) acetylation measured. High mean circulating levels of PA (7.1 microgram/ml) appeared to inhibit acetylation of INH in the rapid acetylator whereas a mean PA plasma level of 8.6 microgram/ml had no effect on INH acetylation in the slow acetylator. However, the results from this study suggest that alterations of INH acetylation by PA are unlikely to be of clinical significance.
Administration, Oral↗
Measurement of propranolol, 4-hydroxypropranolol and propranolol glycol in human plasma.
An HPLC method for the quantitative determination of propranolol, 4-hydroxypropranolol, and propranolol glycol in human plasma is described. The limits of sensitivity for the method were: 1 ng/ml propranolol; 5 ng/ml 4-hydroxypropranolol; and 1 ng/ml propranolol glycol. Data obtained from 6 healthy volunteers given a single 160 mg oral dose of propranolol revealed mean (+/- SEM) peak plasma levels of 31 +/- 10 ng/ml for 4-hydroxypropranolol and 9 +/- 2 ng/ml for propranolol glycol. These plasma levels were less than the peak concentrations recorded for propranolol (123 +/- 34 ng/ml. The rates of plasma decay of these two metabolites were greater than that observed for propranolol.
Chromatography, High Pressure Liquid↗
Plasma levels of free and acid-labile hydralazine: effects of multiple dosing and of procainamide.
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Acetylation↗
Propranolol rebound--a retrospective study.
To assess the effects of sudden withdrawal of propranolol on inpatients with coronary artery disease, 102 patients admitted for cardiac catheterization were evaluated. Criteria for inclusion in the study were angiographically documented coronary artery disease, propranolol therapy at a mean daily dose of at least 80 mg and abrupt discontinuation of propranolol therapy before catheterization. There were 55 patients (mean age 52.5) who discontinued propranolol therapy (mean daily dose 127 mg) and a control group of 47 patients (mean age 53) who continued to receive propranolol (mean daily dose 143 mg). The criteria for morbidity were death, myocardial infarction or change in pain pattern. In the withdrawal group there were no deaths, one myocardial infarction judged to be related to catheterization and only one instance of a change in pain pattern. Thus, propranolol rebound appears to occur infrequently among hospitalized patients with reduced activity.
Adult↗
The contribution of propranolol metabolites to the fluorometric assay of propranolol in human plasma.
1. Studies were undertaken to determine the fluorescent properties of several propranolol metabolites under the conditions of the fluorometric propranolol assay. Of the metabolites studied, propranolol glycol and N-desisopropylpropranolol had significant molar fluorescent coefficients relative to propranolol (72 and 79% respectively). N-desisopropylpropranolol was extracted with the same efficiency as propranolol (greater than 90%) wheras the glycol metabolite had only 34% extraction efficiency. Addition of each metabolite to samples of human plasma containing propranolol produced the predicted increase in fluorescent intensity. 2. Gas chromatographic analysis of plasma collected from 22 hypertensive patients chronically receiving oral propranolol revealed low concentrations of propranolol glycol and N-desisopropylpropranolol relative to propranolol. The results of these studies indicate that fluorescent metabolites of propranolol are not present in sufficient concentration to significantly interfere with the fluorometric assay of propranolol.
Chromatography, Gas↗
The effect of hydralazine and other drugs on the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase.
The objectives of this study were to investigate 1) the tissue distribution of procainamide acetylase activity in the rat and 2) the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase and 3) to determine the effect of drugs thought to be similarly acetylated on procainamide acetylation. The cytosol fraction (100,000 X g) of tissue homogenates served as the source of N-acetyltransferase. Of the tissues studied the liver possessed the greatest acetylase activity followed by the kidney, lung, intestine and spleen. The apparent procainamide Michalis constant (Km) for liver and kidney was 2.03 X 10(-4) and 2.09 X 10(-4) M in the presence of 4.2 X 10(-4) M acetyl CoA. The liver Km for procainamide with "infinite" acetylCoA concentration was 4.36 X 10(-3) M. The liver Km for acetyl CoA in the presence of "infinite" PA concentration was 2.44 X 10(-3) M. Hydralazine, para-aminobenzoic acid, isoniazid, and sulfapyridine competitively inhibited procainamide acetylation by liver and kidney N-acetyltransferase.
Acetylation↗
The quantitative disposition of procainamide and N-acetylprocainamide in the rat.
The objectives of this study were to investigate: 1) the rat acetylator phenotype, 2) the systemic availability of oral procainamide (PA), 3) the kinetic disposition of PA and its N-acetyl metabolite (NAPA) and 4) the relationship between PA dose and steady-state blood PA and NAPA levels. The rat acetylator phenotype seems to be monomorphic in type. The systemic availability of PA was estimated to be 78%. The half-life (T 1/2) of PA elimination was 55 minutes and that of NAPA was 51 minutes. PA clearance was 64 ml/kg/min and NAPA clearance 22.4 ml/kg/min. The apparent distribution volume for PA was 4.92 liters/kg and for NAPA 1.64 liters/kg. Acetylation accounted for 38% of PA disposition, urinary excretion 34% and other metabolism 28%. Urinary excretion of NAPA accounted for 72% of administered drug. Steady-state blood PA levels showed a linear increase with dose whereas NAPA did not. The latter observation suggests saturation of PA acetylation at higher PA doses.
Acetylation↗