Metabolism of thioamide antithyroid drugs.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D S Sitar
Publications and source records attributed to D S Sitar.
A one-year, open, prospective study of sulfasalazine in the treatment of rheumatoid arthritis: adverse reactions and clinical response in relation to laboratory variables, drug and metabolite serum levels, and acetylator status.
Response to sulfasalazine was studied for 1 year in 45 patients with rheumatoid arthritis. Twenty-two patients achieved a satisfactory clinical response. Adverse reactions developed in 15. Hemoglobin rose, and platelet count, erythrocyte sedimentation rate, rheumatoid factor titer, immunoglobulins, and C3 component of complement fell in relation to degree of response. At 1 year, 18 patients elected to continue the treatment. No relationship between clinical response, adverse reactions, or laboratory changes and drug disposition was observed.
Acetylation↗
Does multiple-dose charcoal therapy enhance salicylate excretion?
Multiple-dose charcoal therapy has been shown to increase the excretion of some drugs. This study assesses the effects of this intervention on salicylate excretion in the postabsorptive phase. Ten human volunteers participated in this randomized, controlled, crossover, two-limbed protocol. On two occasions each volunteer ingested 2880 mg of aspirin. During the experimental limb, 25 g of activated charcoal was ingested at 4, 6, 8, and 10 hours after drug ingestion. Pharmacokinetic data were derived from serial serum salicylate concentrations, and urinary salicylate excretion was quantified. Treatment effects were 9% and 18%, respectively. Although both are significant, they are clinically modest, making multiple-dose charcoal therapy of questionable value for acute salicylate poisoning. Controlled data demonstrating the clinical efficacy of this therapy are required to validate it as an intervention for this condition.
Adult↗
Stereoselective inhibition of amantadine accumulation by quinine and quinidine in rat renal proximal tubules and cortical slices.
The renal organic cation transport system was examined. The accumulation of a nonchiral cation, amantadine, by rat renal proximal tubules and cortical slices was investigated, together with the effects of two diastereoisomers, quinine and quinidine. The proximal tubules actively concentrated amantadine with a tissue/medium ratio of 96.3 +/- 1.7 (mean +/- S.E.M., n = 18). Apparent Km was 85 +/- 2 microM and Vmax was 8.0 +/- 0.2 nmol/mg of tubular protein per min. Amantadine accumulation was inhibited competitively by quinine and quinidine with Ki values of 32 +/- 3 and 84 +/- 11 microM, respectively (n = 4). Amantadine was also concentrated by renal cortical slices with tissue/medium ratio of 3.3 +/- 0.3 (n = 4). Apparent Km and Vmax were 94.0 +/- 5.2 microM and 1.27 +/- 0.08 nmol/mg of tubular protein per min, respectively (n = 10). Quinine and quinidine again inhibited amantadine accumulation competitively by the slices, with Ki values of 368 +/- 28 and 780 +/- 84 microM, respectively (n = 4). A similar affinity (Km) for amantadine was observed in both preparations. However, the lower Vmax value in the slice system may be due to additional amantadine transport sites with lower capacity, lesser luminal accumulation and/or limited substrate(s) penetration in the cortical slices. In either preparation, quinine and quinidine functioned as competitive inhibitors and stereoselectivity was observed for the (-)-isomer, quinine, over the (+)-isomer, quinidine. Additional transport sites, reduced luminal substrate accumulation and/or diffusional restraints in the slices are also feasible mechanisms in explaining the differences in Ki values between the two preparations, and their relative contributions await further investigation.
Amantadine↗
Kinetic disposition of ethanol in the neonatal piglet and hemodynamic effects in the presence and absence of 4-methylpyrazole.
The hemodynamic effects of acute ethanol intoxication and the kinetic disposition of ethanol are reported for the first time in neonatal piglets under nitrous oxide anesthesia. Two hours after a single dose of ethanol (1.4 g/kg), blood pressure decreased from 76 +/- 4 to 71 +/- 4 mm Hg (p less than 0.05) and heart rate increased from 194 +/- 10 to 227 +/- 8 beats/min (p less than 0.05; means +/- SE). By 5 hr, blood pressure dropped to 67.5 +/- 4 mm Hg and heart rate increased to 239 +/- 8 beats/min. In piglets pretreated with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, there was a transient increase in blood pressure (p less than 0.05) and a decrease in heart rate (p less than 0.05) immediately after the end of the ethanol infusion. However, the hemodynamic alterations observed 2 hr after ethanol treatment alone were prevented with 4-methylpyrazole. These findings indicate that ethanol metabolites play a significant role in hemodynamic alterations observed after acute ethanol intoxication. The mean ethanol metabolic rate derived from plasma data was 94 +/- 9 mg/liter/hr. This corresponded to an apparent Km of 68 +/- 3 mg/liter and a Vm of 123 +/- 11 mg/liter/hr. The Vd was 0.966 +/- 0.031 liter/kg. The metabolic rate for ethanol, derived from plasma data, correlated with in vitro alcohol dehydrogenase activity at pH 7.4 and 25 and 37 degrees C. The optimum pH for hepatic alcohol dehydrogenase activity was 9.9.
Animals↗
Effect of acute experimental influenza A virus pneumonia on concentration of alpha 1-acid glycoprotein in mouse serum.
In mice, the mean serum concentration of the acute-phase reactant alpha 1-acid glycoprotein increased 34-48% over 14 days following experimental induction of pneumonitis by intranasal inoculation of influenza A virus. Inoculation of undiluted (hemagglutination titer 640) and 10(-1) dilution of virus was followed by development of maximum concentrations of alpha 1-acid glycoprotein in serum at seven days, of 334 micrograms/ml, compared to a concentration in control mice inoculated with irradiated inactivated virus of 225 micrograms/ml (P = 0.002). Infection with 10(-2) virus yielded a peak serum alpha 1-acid glycoprotein of 301 micrograms/ml at four days, 34% higher than in control mice at four days (P = 0.04). There were no differences in alpha 1-acid glycoprotein concentrations among virus-infected mice. Influenza A virus pneumonitis was confirmed histologically, by virus isolation, and by serologic testing, but no inoculum-dependent differences were observed. On day 7, there was a direct relationship demonstrated between the severity of pneumonitis evaluated histologically and the serum alpha 1-acid glycoprotein concentration (r = 0.50; P less than 0.02). Influenza A pneumonia in mice is associated with increased concentrations of alpha 1-acid glycoprotein in serum; the increase may be directly related to the severity of the pulmonary inflammation.
Acute Disease↗
Aging and alfentanil disposition in healthy volunteers and surgical patients.
We studied the pharmacokinetic disposition of alfentanil in 20 volunteers and in 15 surgical patients 20-72 years old. Pharmacokinetic disposition was first order and was well described by a two-compartment open model. Central-compartment volume of distribution was 0.131 +/- 0.087 L.kg-1 (mean +/- SD) in young healthy volunteers and decreased modestly with increasing age (r = -0.32, P less than 0.05). However, apparent volume of distribution at steady-state, 0.404 +/- 0.205 L.kg-1 for the whole study cohort, was not age-related. Plasma clearance of alfentanil in young healthy subjects, 9.3 +/- 6.3 ml.kg-1.min-1, also showed an inverse relationship with age (r = -0.54, P less than 0.001), and was not affected by surgical stress in subjects older than 60 years. Cigarette smoking and sex of the subjects did not contribute to interindividual differences in the kinetic disposition of this drug. Our finding that interindividual differences in disposition of alfentanil were the least in older subjects suggests that its pharmacological effects related to pharmacokinetic disposition should be most predictable in the elderly.
Adult↗
Human drug metabolism in vivo.
Explore the source record for details and available documents.
Biotransformation↗
Nadolol antihypertensive effect and disposition in young and elderly adults with mild to moderate essential hypertension.
Nadolol was effective and well tolerated as once-daily monotherapy for mild to moderate essential supine diastolic hypertension (SDBP) in 10 young (mean age, 39 years) and 12 elderly (mean age, 68 years) patients in a single-blind, placebo-baseline, escalating-dose study. Doses required to reduce SDBP to 90 mm Hg were not different in young (1.08 +/- 0.21 mg/kg/day) and elderly (0.82 +/- 0.14 mg/kg/day) patients (mean +/- SE). Trough plasma nadolol concentrations at steady state were similar and were linearly related to dose in both groups. More unchanged nadolol was recovered in 24-hour urine samples from young subjects (15.6% +/- 1.9%) than from elderly ones (10.7% +/- 1.1%) (p = 0.028). With increasing nadolol doses, plasma norepinephrine concentration increased and isoproterenol sensitivity decreased in both young and elderly subjects, and creatinine clearance and plasma active renin levels were unchanged; plasma inactive renin levels increased in the young, and aldosterone concentration declined in the elderly with the lowest nadolol dose.
Adult↗
Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals.
Overdose with modified-release pharmaceuticals is an increasing phenomenon. This study examines whole-bowel irrigation as a potential decontamination strategy after overdose with enteric-coated acetylsalicylic acid and compares it with administration of activated charcoal in sorbitol, which is currently the recommended intervention. A three-phase randomized crossover protocol was used in 10 adult volunteers. Each volunteer ingested nine 325 mg doses of enteric-coated acetylsalicylic acid on three occasions, with at least 1 week between each administration period. Serum samples were analyzed for salicylic acid concentration by HPLC. Both interventions decreased peak salicylic acid concentration, time-to-zero salicylic acid concentration, and AUC when compared with control (p less than 0.01). Whole-bowel irrigation was superior to activated charcoal in sorbitol by all three criteria (p less than 0.05). Adverse effects were qualitatively and quantitatively greater during activated charcoal in sorbitol, and the volunteers preferred whole-bowel irrigation over charcoal in sorbitol. Our data suggest that whole-bowel irrigation should be considered for overdose of other modified-release pharmaceuticals.
Adult↗
Changes in hepatic blood volume on galactose and indocyanine green uptake by cat liver.
The liver has important functions as a blood volume reserve and in uptake and metabolism of many substrates. This study examines whether changes in hepatic blood volume modify the uptakes of model substrates galactose and indocyanine green (ICG) in cats anesthetized with pentobarbital sodium. A hepatic venous long-circuit technique with an extracorporeal reservoir was used to control hepatic flow and venous pressure and to allow repeated sampling of arterial, portal, and hepatic venous blood without depletion of the cat's blood volume. Hepatic blood volume was measured by plethysmography. Galactose and ICG were infused intravenously at constant rates for 200 min in each of three series of experiments. The first series were time controls. In the second series, hepatic blood volume was increased by raising hepatic venous pressure. In the third series hepatic blood volume was decreased by hepatic nerve stimulation and infusions of norepinephrine and angiotensin. Hepatic congestion resulted in small increases in blood galactose levels, suggesting mild impairment of hepatic galactose metabolism. Decreases in liver blood volume did not modify hepatic galactose metabolism. Increases in hepatic blood volume facilitated while decreases inhibited ICG uptake, but the effects were small. Sinusoidal velocity and transit time have minor effects on uptake even for protein-bound substrates. In summary, large changes in hepatic blood volume had minor effects on galactose and ICG blood concentrations, suggesting that the metabolic functions of the liver are essentially independent of the blood reservoir function.
Animals↗
Cationic transport of amantadine by isolated renal proximal tubules.
Explore the source record for details and available documents.
Amantadine↗
Drug-associated hospital admissions in older medical patients.
A survey of drug-related admissions of patients aged 50 years and older was conducted at the Health Sciences Centre, Winnipeg to determine the interrelationship of risk factors, and isolate the effect of age. All nonelective medical admissions were prospectively assessed to determine the role of drug therapy as a contributory factor. Of the 863 eligible admissions, 162 exhibited at least one drug-related adverse patient event (DRAPE) at the time of hospitalization. This accounted for 19% of the admissions (23% of 718 admissions that involved prescription drugs). Although adverse drug reactions were responsible for many DRAPEs (48%), intentional noncompliance (27%), treatment failure (19%), alcohol (14%), and medication error (10%) were also frequent contributing causes. Drugs commonly implicated in DRAPEs were systemic steroids, digoxin, nonsteroidal anti-inflammatory agents, alpha-methyldopa, calcium channel blockers, beta-blockers, theophylline, furosemide, sympathomimetics, thiazides, and benzodiazepines. The risk of a DRAPE was related to the number of diseases prior to admission (r = 0.81; P less than .026) and the number of drugs used (r = 0.77; P less than .001). Age was not correlated with the risk of a DRAPE. Females had significantly more adverse drug reactions, although sex was not a predictor for overall DRAPE risk.
Aged↗
Rapid measurement of blood ethanol concentrations using the alcohol oxidase membrane technique.
The alcohol oxidase membrane technique is available for measurement of ethanol in commercial fluids. In this paper we examined its usefulness for cat and human blood in comparison with gas-liquid chromatography (GLC). The membrane method proved to be simple, reproducible, accurate, and inexpensive. Analysis took 1-2 min per sample and required only 25 microL of whole blood for measurement of concentrations between 0.05 and 1.0 mM (0.25-5 mg/dL) and 10 microL of whole blood for measurement of concentrations between 1.0 and 40 mM (5-190 mg/dL). Background concentrations were undetectable in cats after extraneous sources of alcohols were removed. The alcohol oxidase membrane technique is less specific than GLC, but it may be useful when ethanol is administered after background samples have shown an absence of other nonspecific reactants. Its high sensitivity is useful for kinetic studies where blood ethanol concentrations are below or close to those required for maximal hepatic ethanol metabolism.
Alcohol Oxidoreductases↗
Hepatic uptake of indocyanine green and perfusion rate in rats: effect of age and albumin concentration.
Liver blood flow and hepatic uptake of some indicator substances have been reported to fall with age in both rats and humans. We used an isolated liver system, which was perfused in one pass with hemoglobin free buffer, to investigate the effect of albumin concentration, buffer flow rate, and age upon hepatic clearance of the dye, indocyanine green. We measured the half-life of a bolus of indocyanine green given intravenously to male Sprague-Dawley rats aged 10 and 24 months and then examined its clearance in vitro using their isolated perfused livers. After perfusion, the livers were homogenized and separated into subcellular fractions. The mean liver weight declined significantly (young, 19.7 +/- 2.9 g vs. old, 13.9 +/- 2.6 g; p less than 0.02). In vivo the indocyanine green clearance was reduced in the aged rats (3.2 +/- 1.0 vs. 5.1 +/- 1.7 mL/min; p less than 0.05). In the isolated perfused liver system, extraction ratio showed an inverse curvilinear correlation with albumin concentration and buffer flow rate, but did not differ with age. Hepatic protein content and dye subcellular localization did not differ between the two groups. In conclusion, the fall in indocyanine green clearance in vivo is not paralleled by the ability of the organs to extract the dye in vitro, and likely reflects a decline in hepatic mass and blood flow.
Aging↗
Hepatic blood flow: estimation from clearances of very low dose infusions of ethanol in cats.
Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from systemic clearances of ethanol during very low dose (8 mumol.min-1.kg-1) infusions of ethanol in anesthetized cats. Systemic clearances were compared with directly measured hepatic blood flow using a hepatic venous long-circuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. In 18 cats, Vmax for ethanol was 93 +/- 7 mumol.min-1 per 100 g liver or 21 +/- 2 mumol.min-1.kg body weight-1 and Km was 144 +/- 19 microM in terms of logarithmic mean sinusoidal concentration. At the dose of 8 mumol.min-1.kg body weight-1 used for estimation of hepatic blood flow, extraction was 0.95 +/- 0.07 (mean +/- SD). Systemic clearance of ethanol overestimated directly measured hepatic blood flow by 15 +/- 16%. Hepatic blood flow changes expressed as percentages of the control level were accurately estimated from systemic ethanol clearance (100 +/- 10%). Since 73 +/- 12% of the infused ethanol was eliminated by the liver and 83 +/- 11% was eliminated by the splanchnic bed, an extrasplanchnic uptake of 17% accounted for the overestimation of hepatic blood flow. Estimation of hepatic blood flow from systemic clearances of ethanol during very low dose infusions may have advantages over other clearance methods. Its use in cats was illustrated in a separate series of experiments and it was shown that surgery significantly reduced hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Algorithms↗
Effect of morphine on breathing and behavior in fetal sheep.
To define the dose response of apnea and breathing to morphine we studied 12 fetuses at 116-141 days of gestation using our window technique. We instrumented the fetus to record electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (integral of EMGdi), heart rate, carotid blood pressure, and amniotic pressure. Saline and morphine in doses of 0.03, 0.1, 0.5, 1, and 3 mg/kg were injected in random order in the jugular vein of the fetus during low-voltage ECoG. Fetuses were videotaped for evaluation of fetal behavior. We found 1) that saline did not elicit a response; 2) apnea, associated with a change from low- to high-voltage ECoG, increased from 2.2 +/- 1.5 (SE) min in two fetuses at a dose of 0.03 mg to 20 +/- 6.3 min in seven fetuses at 3 mg/kg (P less than 0.005); 3) the length of the breathing responses, associated with a change from high- to low-voltage ECoG, were 15 +/- 1.8 and 135.9 +/- 18.1 min (P less than 0.0005); 4) integral of EMGdi X frequency, an index equivalent to minute ventilation, increased from 1,763 +/- 317 arbitrary units to 10,658 +/- 1,843 at 1.0 mg/kg and then decreased to 7,997 +/- 1,335 at 3.0 mg/kg. These changes were related to a steady increase in integral of EMGdi, whereas frequency decreased at 3 mg/kg. There was an increase in breathing response to morphine plasma concentrations or morphine doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Propylthiouracil disposition in older hypothyroid patients.
The pharmacokinetic disposition of propylthiouracil (PTU) after a single oral dose was studied in 6 severely hypothyroid patients. Severity of disease, as indicated by thyroid-stimulating hormone concentration, was inversely related to plasma clearance of PTU. There were trends to increased apparent volume of distribution and plasma half-life for PTU as a function of age. The large apparent volume of distribution for PTU in these patients compared to euthyroid and hyperthyroid subjects, after a single drug dose, suggests that hypothyroidism as well as chronic drug ingestion must be considered as possible factors mediating this change.
Aged↗