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Biomedical subjects

R M Welch

Publications and source records attributed to R M Welch.

At least 55 records · Page 3Linked to original sources
PubMed1982

Plasma levels of a novel antidysrhythmic agent, meobentine sulfate, in humans as determined by radioimmunoassay.

A radioimmunoassay for the quantitation of meobentine sulfate, a novel antidysrhythmic and antifibrillatory agent in biological fluids, is described. Antisera were raised in rabbits in response to immunization with a conjugate of bovine serum albumin and a meobentine analog with a propionic acid sidechain ortho to the methoxyl group. These antisera have low affinities for N- and O-desmethylmeobentine metabolites, which show less than 5% cross-reaction in radioimmunoassay procedures employing either tritiated or radioiodinated radioligands. The radioimmunoassay using[125I]meobentine was capable of detecting less than 0.4 ng/ml (40-pg mass) of meobentine. This assay was used to demonstrate the absorption of meobentine in humans after oral administration and also permitted studies of meobentine sulfate disposition in human plasma following two (2.5 and 5 mg/kg) oral doses. Mean peak meobentine concentrations in plasma occurred 3 hr postdose in both cases and were 230 and 451 ng/ml following the 2.5- and 5-mg/kg doses, respectively. The approximate mean terminal half-life after all treatments was 12 hr.

Animals↗
PubMed1982

Codeine disposition in smokers and nonsmokers.

The bioavailability of codeine and extent of its transformation to morphine were stated in 12 smoking and 11 nonsmoking subjects after single doses 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12-hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half-life (t1/2), or areas under plasma concentration-time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 +/- 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 +/- 2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 +/- 4.9%) and in nonsmokers (50.2 +/- 2.1%) did not offer. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first-pass O-demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O-demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

Administration, Oral↗
PubMed1982

Availability to rats of zinc from soybean seeds as affected by maturity of seed, source of dietary protein, and soluble phytate.

Male rats were used to assess the availability of zinc in soybean seeds (Glycine max, var. 'Amsoy') as affected by maturity of seed, dietary protein source, and exogenous dietary sodium phytate. Seeds were harvested from either 84- (immature) or 120-day-old (mature) plants grown in 65Zn-labeled nutrient solutions that contained either 0.066 or 0.262 ppm zinc as zinc sulfate. Increased zinc supply to plants increased the zinc content of seeds; immature seeds had higher concentrations of zinc than mature seeds. Phytic acid concentration averaged about 0.6 and 1.7% dry weight in immature and mature seeds, respectively. Seeds of each type were incorporated into meals fed to zinc-depleted rats. In experiment 1, rats fed mature, high-phytate seeds absorbed about 60% of the 65Zn in the seeds, whereas rats fed immature, low-phytate seeds absorbed about 89% of the 65Zn (P less than 0.05). In experiment 2, the source of dietary protein (egg albumen or soy protein) did not markedly affect 65Zn absorption by rats fed mature soybean seeds. In experiment 3, dietary sodium phytate (1.76% of diet as phytic acid) depressed (P less than 0.05) 65Zn absorption by about 16 and 44% from mature soybean seeds and zinc sulfate, respectively. Zinc in soybean seeds apparently was as readily available to rats as that reported for other legume and cereal seeds. Moreover, the nutritional quality of soybean seeds with respect to zinc apparently can be increased by increasing zinc supplies to plants.

Animals↗
PubMed1982

Effect of phytic acid on the absorption, distribution, and endogenous excretion of zinc in rats.

Zinc metabolism in male rats was studied by combining nutritional balance methods with an analysis of 65Zn kinetics. The rats, two groups of 84 each, were fed zinc-adequate diets (33 ppm Zn) with either 0 (basal) or 2% phytic acid added as sodium phytate. A fourth-order exponential function described the time-course of 65Zn in plasma, and compartmental models were developed accordingly. Plasma zinc exchanged more rapidly with zinc in liver and kidneys than it did with zinc in testes, skeletal muscle, or bone. Total body zinc content (2.6 mg/100 g live body weight) measured chemically was about 9 times higher than estimates of exchangeable zinc in the body. Whole-body retention of 65Zn was higher and endogenous fecal zinc excretion was lower in rats fed phytate than in those fed the basal diet; these responses to phytate may reflect a homeostatic adjustment to decreased absorption of zinc. Respective values for apparent absorption and true absorption of zinc were 13 and 32% of zinc intake in rats fed phytate, and 19 and 46% of zinc intake in rats fed the basal diet. When whole grains or mature seeds constitute a major portion of the diet, the phytate: zinc molar ratio may approach that (60:1) used in our study. Whether or not phytic acid occurring naturally in foods affects zinc metabolism to the same extent as sodium phytate can not be determined from our study.

Absorption↗
PubMed1982

Some metabolic interrelationships between toxic levels of cadmium and nontoxic levels of selenium fed to rats.

Male rats were fed vitamin E-adequate, Torula yeast-based diets for 30 days to assess the influence of dietary selenium (0, 0.1, or 1.0 ppm) on the toxicity of dietary cadmium (0, 30, or 60 ppm). At all selenium levels, increased cadmium intake depressed feed consumption, reduced feed efficiency and lowered body weight gain. In liver, concentrations of cadmium and zinc increased, and iron concentration decreased with increased intake of cadmium. Dietary selenium did not affect concentrations of cadmium, zinc, iron or copper in liver. Blood hemoglobin level declined and relative heart weight (g/100 g body wt) increased with increased intake of cadmium. Increased selenium intake partially alleviated the cadmium-induced depression in blood hemoglobin levels in rats fed diets that contained 30 ppm cadmium, and partially ameliorated the cadmium-induced increase in heart size in rats fed either 30 or 60 ppm cadmium. Hepatic and renal glutathione peroxidase (GSH-Px) activity increased with increased selenium intake. Increased cadmium intake did not affect renal GSH-Px activity. Hepatic GSH-Px activity in rats fed diets that contained 0.1 ppm selenium decreased with increased cadmium intake; however, hepatic GSH-Px activity was not affected by dietary cadmium in rats fed diets that contained 1.0 ppm selenium. Interactions between nontoxic levels of dietary selenium and relatively high levels of dietary cadmium apparently resulted in an antagonism of selenium metabolism by cadmium in some systems, and partial amelioration of cadmium toxicity by selenium in other systems

Animals↗
PubMed1982

An evaluation of the effects of smoking on codeine pharmacokinetics and bioavailability in normal human volunteers.

Cigarette smoking has been shown to increase the clearance of several drugs, including pentazocine, theophylline, and phenacetin. This effect presumably is mediated through enzyme induction, resulting from inhaled polycyclic aromatic hydrocarbons. Because the O-demethylation pathway for codeine is similar to that of other drugs known to be influenced by cigarette smoking, a study was conducted to compare the pharmacokinetics and metabolism of codeine in smokers and nonsmokers. Twelve volunteers with no history of cigarette smoking and ten volunteers who smoke cigarettes were studied; an open, two-treatment, simultaneous parallel and crossover study design was used. Each volunteer received a single dose of codeine sulfate 60 mg po and codeine phosphate 60 mg im, in random treatment order, at one-week intervals. Serial blood samples were collected up to 12 hours after dosing, and plasma codeine and morphine concentrations were measured by radioimmunoassay. There was no significant difference between smokers and nonsmokers in either codeine or morphine areas under the plasma concentration-time curves (AUCs), with either route of administration. The relative codeine bioavailability in these groups was 54.8 +/- 4.9 percent and 50.2 +/- 2.1 percent (mean +/- SE), respectively. Smoking was associated with greater variability in plasma concentrations. Interestingly, greater morphine:codeine AUC ratios were observed in both groups after oral than after intramuscular administration. Cigarette smoking should have no clinically important influence on codeine absorption or disposition.

Adult↗
PubMed1981

Stereospecific radioimmunoassays for d-pseudoephedrine in human plasma and their application to bioequivalency studies.

Antiserum to d-pseudoephedrine was raised in New Zealand White rabbits in response to immunization with a conjugate of bovine serum albumin and d-pseudoephedrine-N-3-propionic acid. The hapten was prepared by reaction of methyl acrylate with d-pseudoephedrine, followed by ester hydrolysis. Sodium boro[3H]hydride reduction of dl-ephedrine gave [alpha-3H]-dl-ephedrine, and a Welsh rearrangement with acetic anhydride followed by deacetylation gave [alpha-3H]-dl-pseudoephedrine, which was used as a radioligand in radioimmunoassay procedures for direct plasma analyses. Three sensitive radioimmunoassay procedures were developed, two using [3H]pseudoephedrine as the radioligand and either adsorption on coated charcoal or polyethylene glycol precipitation for separation of antibody-bound from free radioligand. The third method used an [125I]tyrosine methyl ester analog of pseudoephedrine and charcoal separation, preceded by extraction and derivatization of pseudoephedrine with methyl acrylate. All three assays could detect less than or equal to 2.5 ng of pseudoephedrine/ml. The antiserum was stereospecific, showing low cross-reactivities with l-pseudoephedrine and d- and l-ephedrines. d-Norpseudoephedrine and some other related compounds also had low cross-reactivity in these radioimmunoassay procedures. Excellent agreement was found between pseudoephedrine concentrations in human plasma determined by radioimmunoassay and by a standard GLC method. The utility of radioimmunoassay was illustrated by application of one of these procedures to an assessment of the bioequivalence of immediate- and sustained-release pseudoephedrine formulations in normal volunteers. A sustained-release preparation containing 120 mg of pseudoephedrine hydrochloride given every 12 hr was shown by AUC comparisons to be bioequivalent to an immediate-release tablet (containing 60 mg of pseudoephedrine hydrochloride) given every 6 hr.

Adult↗
PubMed1981

Analgesic drugs in breast milk and plasma.

The disposition of salicylic acid, phenacetin, caffeine, and codeine, and two metabolites, acetaminophen and morphine, was studied in breast milk and plasma of two lactating mothers after single oral doses of a compound analgesic. Salicylic acid penetrated poorly into milk, with peak levels of only 1.12 to 1.60 micrograms/ml, whereas peak plasma levels were 33 to 43.4 micrograms/ml. The drug was also eliminated more slowly from milk than plasma. In contrast, caffeine and phenacetin kinetics in breast milk and plasma were similar, but milk levels were somewhat lower than plasma levels in both subjects. Metabolically produced acetaminophen levels in both fluids were much higher than those of the parent drug, phenacetin, in one subject, but early plasma and milk phenacetin levels exceeded those of acetaminophen in the other subject, thereafter dropping sharply to assume the pattern of the first subject. Elimination of the metabolite, acetaminophen, from milk was slower than from plasma (subject 1, half-life (t1/2) of drug in milk, 4.7 hr; t1/2 in plasma, 2.9 hr). In both subjects codeine concentrations in milk were 1.5 to 2.4 times as high as in plasma at the same times after drug. Metabolically produced morphine levels in milk from both mothers were low but exceeded those in plasma after 1 hr. Calculations based on average milk concentrations over the 12 hr after drug in subject 1 revealed milk excretion of 0.7% or less of the ingested dose of each drug. Similar calculations based on predicted steady-state milk drug concentrations in subject 2 indicated maximum milk excretion of 2.7% of the dose. In each case caffeine was excreted in the milk in the greatest amount.

Acetaminophen↗
PubMed1981

Excretion of drugs in human breast milk.

The present report briefly discusses some of the morphological, physiological, and compositional aspects of animal and human breast milk and how these characteristics might be important for the accumulation of drugs and foreign compounds. In addition, a study is described confirming the presence of caffeine, codeine, morphine, phenacetin, acetaminophen, and salicylic acid in the breast milk of a lactating mother following oral administration of a combination analgesic containing aspirin, phenacetin, caffeine, and codeine. Although the study is limited to one subject, it has provided critically needed data on the rates of appearance in, and elimination of these drugs from, breast milk. A similar amount of information is presented on phenacetin, also a component of the analgesic mixture, which has not been previously reported to enter human milk. The distribution of these drugs between the slightly more acidic breast milk and the relatively neutral plasma is consistent with their weakly basic, acidic, or relatively neutral properties. In general, the study shows that codeine and morphine milk concentrations are higher than, salicylic acid milk levels are much lower than, and phenacetin, caffeine, and acetaminophen milk concentrations are relatively similar to their respective plasma levels. It is projected, from estimated steady-state milk concentrations of the drugs and their metabolites studied, that very low percentages of the therapeutic dosages (less than 0.7%) would be excreted in mother's milk, too low an amount to be clinically significant to the infant.

Analgesics↗
PubMed1981

Radioimmunoassay and pharmacokinetic profile of bupropion in the dog.

A radioimmunoassay (RIA) procedure for the quantification of bupropion (dl-2-tert-butylamino-3'-chloropropiophenone) in biological fluids is described. Immunization of rabbits with conjugates of bovine serum albumin and p-succinoyl propylbupropion or p-carbomethoxybupropion resulted in the production of antisera which are capable of detecting less than 1 ng ml-1 (100 pg actual mass) of bupropion in the RIA, utilizing [6-3H] bupropion as radioligand. The antisera used in these studies have low cross-reaction (approximately 0.1% or less) with known side chain metabolites of bupropion, but exhibit significant cross-reaction with p-hydroxybupropion (30.3%). Excellent agreement was obtained between RIA and high-pressure liquid chromatography determinations of bupropion concentrations in human plasma samples, but plasma or serum from bupropion-treated dogs, rats and mice required extraction from basic medium to remove some interference before RIA. The assay was applied to a study of bupropion disposition in two beagles of each sex after i.v. and p.o. administrations of bupropion hydrochloride (100 mg). The pharmacokinetic profile in dogs was best described by an open two-compartment model after either route of drug administration. Peak plasma bupropion levels after oral dosing were highly variable, ranging from 12.9 to 63.5 ng ml-1 at 26 to 32 min after drug administration. The mean terminal phase half-life of bupropion was calculated to be 1.73 hr after either route and the absolute oral bioavailability of the drug varied from 2.0 to 6.5%.

Animals↗
PubMed1980

Quantitation of the anticonvulsant cinromide (3-bromo-N-ethylcinnamamide) and its major plasma metabolites by thin-layer chromatography.

A quantitative thin-layer chromatography (TLC) procedure is described for the analysis of cinromide (3-bromo-N-ethylcinnamamide) and its two major metabolites, 3-bromocinnamamide and 3-bromocinnamic acid in plasma of the dog. These compounds were recovered from acidified plasma by extraction into benzene with a recovery of 95 +/- 5%. All three compounds were quantitated directly on a TLC plate by ultraviolet absorbance densitometry at 270 nm. The linear dynamic range for the quantitation of the compounds on a TLC plate ranged between 10 and 1000 ng. The complete procedure is useful in the working range of 50 ng/ml to 100 microgram/ml of plasma with a coefficient of variability of about 10%. Specificity of the method for parent drug and each of its plasma metabolites was confirmed by high-performance liquid chromatography. The method was used to determine the pharmacokinetics of cinromide and its two major plasma metabolites in dogs following a single oral dose of the drug.

Animals↗
PubMed1980

Availability to rats of iron from spinach: Effects of oxalic acid.

The availability to rats of iron from two varieties of spinach was determined. Also, the absorption of Fe was compared between FeCl3 and Fe-oxalate and the effects of adding 0.75% oxalate to the diet were determined. Absorption of iron from both varieties of spinach was comparable to that from FeCl3 and the iron was equally available from Fe-oxalate and FeCl3. The addition of 0.75% oxalic acid to the diet did not depress iron absorption and, if anything, appeared to enhance iron utilization by rats.

Animals↗
PubMed1978

Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Acetaminophen↗