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Biomedical subjects

S M Pond

Publications and source records attributed to S M Pond.

At least 145 records · Page 8Linked to original sources
PubMed1981

Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects.

Plasma concentrations and urinary excretion of meperidine and its metabolite normeperidine were determined after intravenous and oral administration to 11 men; five men had hepatic cirrhosis and six were normal. Systemic clearance of meperidine was smaller and bioavailability and half-life greater in the cirrhotic patients than in the normal subjects. Plasma concentrations and 24-hr urinary excretion of normeperidine was lower and persistence of normeperidine in plasma longer in the patients with cirrhosis. The route of administration did not alter the fraction of normeperidine generated from meperidine. The results suggest that in patients requiring repeated meperidine dosage the drug should be taken parenterally rather than orally to allow maximal analgesia and minimal formation of normeperidine. Patients with cirrhosis may be relatively protected from normeperidine toxicity because of impaired formation, but the risk of cumulative toxicity may be greater than in normal subjects because of slower elimination of the metabolite and greater sensitivity to the effects of narcotics on the central nervous system.

Administration, Oral↗
PubMed1981

Effect of phenytoin on meperidine clearance and normeperidine formation.

The presystemic metabolism of meperidine to normeperidine was examined in four healthy men before, during, and 3 wk after phenytoin. The results from the two control periods were similar. Meperidine systemic clearance rose from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min during phenytoin dosing (P less than 0.01). Meperidine elimination half-life fell from 6.4 +/- 1.0 hr to 4.3 +/- 0.4 hr during phenytoin dosing (P less than 0.05). Bioavailability fell from 0.61 +/- 0.08 to 0.43 +/- 0.14 (P less than 0.07). Meperidine volume of distribution, renal clearance, and protein binding did not change. The normeperdine area under the blood concentration-time curve from 0 to 24 hr after intravenous meperidine rose from 385 +/- 105 ng/hr/ml-1 to 589 +/- 108 ng/hr/ml-1 during phenytoin dosing (P less than 0.01); after oral meperidine it rose from 592 +/- 50 ng/hr/ml-1 to 738 +/- 178 ng/hr/ml-1. Normeperidine renal clearance was approximately four times that of meperidine, but was not altered by phenytoin. Because analgesia relates to meperidine blood concentrations, patients on long-term phenytoin therapy may require more frequent parenteral doses and larger and more frequent oral doses than usual.

Adult↗
PubMed1981

An evaluation of the effects of lithium in the treatment of chronic alcoholism. I. Clinical results.

To evaluate the efficacy of lithium in chronic alcoholism, we enrolled 47 male alcoholics in a prospective double-blind two-period crossover study. Nineteen subjects completed the 6-mo study during which they received lithium and placebo each for a 3-mo period. Self-reported alcohol intake and social and psychological factors were monitored. Three subjects claimed that they did not drink during the study. Mean self-reported alcohol intake of the remaining 16 was less during lithium therapy but was also less during the first treatment period. Neither of these differences reached statistical significance. The nine depressed patients, diagnosed from their profiles of the Minnesota Multiphasic Personality Inventory did not consume significantly less alcohol and did not change scores for depression significantly during lithium therapy. We could not demonstrate the lithium therapy was of benefit in our group of alcoholic patients.

Adult↗
PubMed1981

An evaluation of the effects of lithium in the treatment of chronic alcoholism. II. Assessment of the two-period crossover design.

Analysis of self-reported alcohol intake by alcoholic subjects participating in a two-period crossover trial of lithium versus placebo failed to demonstrate a significant effect of lithium in reducing alcohol consumption. An appraisal of the adequacy of this study design to meet the original objective of the trial was undertaken. It was impossible under this study design to simultaneously and unequivocally estimate effects of treatment periods, drug carryover, sequence group and other period by treatment interactions in addiction to the lithium/placebo effects. Presence of one or more of these additional influences on the trial outcome not only complicated the interpretation of results but diminished the power of the trial design to test the major hypothesis of interest, that lithium could reduce alcohol intake. We conclude that the two-period crossover design has serious drawbacks in this clinical trial setting and that alternative strategies need to be considered for future trials.

Adult↗
PubMed1981

Phenytoin-induced methadone withdrawal.

Methadone-maintained volunteers experienced moderately severe opiate withdrawal symptoms within 3 or 4 days of beginning phenytoin in therapeutic doses. The area under the methadone plasma concentration-time curve decreased while the ratio of the pyrrolidine-to-metabolite excretion in urine to this area increased significantly. This suggests that phenytoin accelerates methadone metabolism. Methadone dosing adjustments should be anticipated when phenytoin is initiated or discontinued in methadone-maintained patients.

Adult↗
PubMed1980

Enhanced bioavailability of pethidine and pentazocine in patients with cirrhosis of the liver.

We studied the bioavailability and disposition kinetics of pethidine and pentazocine in patients with alcoholic cirrhosis and age-matched healthy subjects. In the presence of liver disease, the bioavailability of pethidine was 31% and pentazocine 233% greater than in normals. Systemic clearance was approximately half and terminal half-life double normal for both drugs, whereas volumes of distribution were unchanged. Because of greater bioavailability, oral doses of pethidine and pentazocine should be reduced substantially in patients with cirrhosis. When multiple oral or parenteral doses are required, dosing interval should be lengthened or repeated doses reduced below initial doses because of lower systemic clearance.

Administration, Oral↗
PubMed1979

Diazepam kinetics in acute alcohol withdrawal.

We performed a within-subject comparison of the kinetics of diazepam given to 7 alcoholic subjects during acute alcohol withdrawal and again after detoxification. The initial rapid exponential decline of plasma diazepam concentrations (t1/2 alpha) was more rapid during (0.21 +/- 0.03 hr) than after withdrawal (0.44 +/- 0.14 hr, p less than 0.05). Terminal t1/2, clearance, and volumes of distribution changed in individual patients, but mean values did not change. Protein binding was less in patients (93.4 +/- 2.4%) than in healthy controls (97.0 +/- 1.0, p less than 0.05). The effects of alcohol withdrawal on diazepam disposition do not explain the high doses of diazepam commonly required to treat the withdrawal.

Adult↗
PubMed1977

Mechanisms of inhibition of tolbutamide metabolism: phenylbutazone, oxyphenbutazone, sulfaphenazole.

Tolbutamide half-life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n = 2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within 1 to 2 hr of a single dose of sulfaphenazole and the tolbutamide half-life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing form of cytochrome P-450 with low activity for tolbutamide hydroxylation, whereas sulfaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.

Adult↗
PubMed1975

Effects of tricyclic antidepressants on drug metabolism.

The effects of chronic treatment with amitriptyline and nortriptyline on the elimination from plasma of warfarin, dicumarol, phenytoin, and tolbutamide were examined in man. No alteration of plasma half-life of warfarin, phenytoin, or tolbutamide was observed following dosage with the tricyclic antidepressants used. There was no consistent effect on the metabolism of dicumarol following treatment with amitriptyline or nortriptyline although the bioavailability of dicumarol appeared to be increased. In some subjects, this increased bioavailability was associated with significant prolongation of the plasma half-life of dicumarol due to its dose-dependent kinetics.

Adult↗
PubMed1975

The effects of allopurinol and clofibrate on the elimination of coumarin anticoagulants in man.

The effects of chronic treatment with allopurinol and clofibrate on the elimination from plasma of warfarin and dicoumarol were examined in man. In addition, the binding of warfarin to human serum proteins was measured with and without clofibrate and its metabolite chlorophenoxyisobutyric acid (CPIB), both present in therapeutic concentrations. Treatment with allopurinol and clofibrate did not alter the rate of elimination of warfarin from plasma. In addition, clofibrate and CPIB caused no significant displacement of warfarin from serum proteins. This evidence supports the conclusion that the clinically significant potentiation of warfarin activity by clofibrate in man is due to an interaction at the receptor site. In contrast, treatment with allopurinol resulted in significant prolongation of the plasma half-life of dicoumarol in one of three subjects. These data are consistent with inhibition of the metabolism of dicoumarol by allopurinol in some individuals.

Adult↗
PubMedDate not supplied

Failure of haemoperfusion and haemodialysis to prevent death in paraquat poisoning. A retrospective review of 42 patients.

In this review the efficacy of haemoperfusion in the treatment of paraquat poisoning is addressed. 42 reports containing sufficient information of paraquat-poisoned patients were evaluated. These reports, from 35 patients reported in the literature and 7 new cases, were chosen for the following reasons: the timed plasma paraquat concentrations were known, patient outcome was known, and details of haemoperfusion were available. In some cases, haemodialysis was also performed. The plasma paraquat concentrations and the specific times post-ingestion were plotted on a contour graph that predicts the probability of survival. Comparison of the predicted probability of survival versus the actual outcome showed that haemoperfusion, single or repeated, did not affect patient survival. None of the patients whose initial plasma concentrations were greater than 3 mg/L paraquat survived, regardless of the time after ingestion that the concentrations were measured, and despite haemoperfusion. Therefore, such patients might not be considered for haemoperfusion because of their uniformly bad prognosis, despite the procedure being used, and because of the morbidity, discomfort and cost associated with it. Clearly, the need for better techniques to remove paraquat and to prevent the consequences of the metabolic effects of the compound are required urgently before the treatment of the paraquat-poisoned patient will be successful.

Adolescent↗
PubMedDate not supplied

Urinary excretion of the N-acetyl cysteine conjugate of cis-1,3-dichloropropene by exposed individuals.

A gas chromatographic-mass spectrometric assay was developed to identify and measure the N-acetyl cysteine conjugate of cis-1,3-dichloropropene. The assay was used to show that individuals exposed to 1,3-dichloropropene vapor during field applications excrete this conjugate in their urine. The recoveries of the conjugate were correlated with the product of airborne concentrations and the duration of exposure (r = 0.83).

Absorption↗
PubMedDate not supplied

Determination of methadone and its primary metabolite in biologic fluids using gas chromatography with nitrogen-phosphorus detection.

A method is described for the determination of methadone and its primary metabolite, 1,5-dimethyl-3,3-diphenyl-2-ethylidinepyrrolidine, in biologic fluids using gas chromatography with nitrogen-phosphorus detection. A simple extraction scheme is employed that is convenient for processing the large numbers of samples generated in pharmacokinetic studies. The method is sensitive enough for accurate determination of concentrations less than 5 ng/mL of both methadone and its primary metabolite in 1 mL of biologic specimens.

Chromatography, Gas↗
PubMedDate not supplied

Toxicologic studies in a fatal overdose of 2,4-D, MCPP, and chlorpyrifos.

A death due to ingestion of 2,4-dichlorophenoxyacetic acid (2,4-D), 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP), and phosphorothioic acid O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl)ester (chlorpyrifos) is reported. The clinical course, dose ingested, and plasma levels of the chemicals were compatible with previous fatalities due to the chlorophenoxyacetic acids. Chlorpyrifos concentrations and tissue cholinesterase and in esterase inhibitions indicated the presence of the organophosphate and its biochemical effect, but few cholinergic signs were observed clinically. Lymphocytic neurotoxic esterase activity was decreased for a limited period of time after ingestion. Postmortem nervous tissue neurotoxic esterase was also decreased. This association has not been demonstrated before in man. HPLC and GC/NPD methods for measuring chlorophenoxy acetic acids and chlorpyrifos, respectively, are presented.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Illumination of therapeutics by toxicology: a personal view.

1. My specialties are therapeutics and toxicology. When we think in classical terms about drugs, therapeutics refers to curative healing, toxicology to the capacity to produce harm. However, they are not opposite disciplines, but rather reflect a continuum along the dose-response curve of a drug or toxin. Since antiquity, the study of toxicology has underpinned and illuminated therapeutics. Even the most potent toxins, such as botulinum and ricin, are used for therapeutic purposes. 2. In the case of one of my favourite research topics, the herbicide paraquat, I illustrate how investigating methods to treat patients poisoned by it has led to important advances in knowledge in medicine and therapeutics. Studying paraquat has launched my own research group on a path towards elucidating the mechanisms of the chronic neurological side effects of the antipsychotic drug, haloperidol, which is used widely to treat schizophrenia. In tracing these tortuous paths, the roles that serendipity and creativity play in research and their implications for education and funding policies are high-lighted.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Glucose transport and hypoxia-reoxygenation injury in the perfused rat liver.

During liver transplantation, oxidative stress occurs during hypoxia and reoxygenation of the donor organ. Chemical oxidative stress impairs cell membrane transport. Therefore, in this study the influence of hypoxia and reoxygenation on hepatocellular membrane transport was investigated. Specifically, glucose transport was studied in the perfused rat liver using the multiple indicator-dilution technique. First, it was observed that in normal rat livers, glucose transport was rapid but saturable (Km 48 +/- 10 mmol/L and Vmax 9.4 +/- 0.9 mumol/s per g of liver). To stimulate hypoxia and reoxygenation, livers were perfused for 30 min with nitrogen-saturated buffer and then with oxygen-saturated buffer for 20 min. The livers from fed rats were protected from hypoxia-reoxygenation injury whereas those from fasted rats were highly susceptible to injury as determined by lactate dehydrogenase release. After reoxygenation, the rate of glucose influx decreased significantly by approximately 50% in the fasted livers (P < 0.001) but was unaffected in the fed livers. This impairment of the hepatocellular transport of glucose, which could be secondary to oxidative injury to the hepatocyte membrane, has implications for the function of donor livers that have sustained hypoxia-reoxygenation ('preservation') injury during transplantation.

Animals↗