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Biomedical subjects

D S Sitar

Publications and source records attributed to D S Sitar.

At least 91 records · Page 5Linked to original sources
PubMed1988

Clinical pharmacokinetics of amantadine hydrochloride.

Amantadine is a drug with diverse uses ranging from prevention of influenza A illness to the treatment of patients with Parkinson's disease. It is available only in oral formulations from which it is well absorbed and widely distributed, little drug being present in the circulation. Apparent volume of distribution is inversely related to dose over the therapeutic range and accounts in part for a noteworthy logarithmic increase in plasma concentration as a function of dose. Elimination is primarily by renal clearance by both glomerular filtration and tubular secretion. Amantadine accumulates in patients with renal dysfunction. Hence, doses must be reduced in such patients to avoid toxicity. Interactions with other drugs appear uncommon. Relationships have been demonstrated between amantadine therapeutic effects and plasma concentrations in different study cohorts, but not in individual patients. Dose schedules have been suggested for individuals in whom amantadine kinetics are different from healthy subjects. However, these schedules are controversial in their choice of target concentrations and in being untested as to predictive value.

Administration, Inhalation↗
PubMed1987

Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose.

The efficacy of ipecac-induced emesis, large-bore orogastric lavage, and activated charcoal as gastrointestinal decontamination procedures after acute drug overdose is unknown. Using an ampicillin overdose model, these three procedures were compared with one another and to a control ingestion in ten human volunteers. Serial serum ampicillin levels were used to compute the areas under the concentration vs time curves (AUC) for each study. The reductions of ampicillin absorption compared to control were as follows: orogastric lavage 32% (NS), ipecac-induced emesis 38% (P less than .01), and activated charcoal 57% (P less than .01). This model examines each intervention in a mutually exclusive fashion. It supports activated charcoal administration as the primary gastrointestinal decontamination procedure after acute drug overdose.

Acute Disease↗
PubMed1987

Enprofylline disposition in the presence and absence of amoxycillin or erythromycin.

1 The kinetic disposition of a novel xanthine bronchodilator, enprofylline, was determined in young healthy male volunteers in the presence and absence of amoxycillin or erythromycin. These data were compared to those derived from a similar study of theophylline disposition in the presence and absence of erythromycin. 2 Erythromycin inhibited theophylline disposition only in those subjects in whom the control kinetic study was done after antibiotic ingestion, but the effect was modest. Erythromycin had no effect on enprofylline disposition. 3 Amoxycillin reduced the renal clearance of enprofylline, but the change was not statistically significant.

Adult↗
PubMed1987

Hepatic blood flow: accuracy of estimation from infusions of indocyanine green in anaesthetized cats.

Experiments were performed to determine the accuracy of the estimation of hepatic blood flow from infusions of indocyanine green (ICG) in anaesthetized cats. The estimated flows were compared to hepatic blood flows measured directly in a hepatic venous long-circuit preparation. This preparation allowed direct measurement and alteration of hepatic blood flows, and collection of arterial and mixed hepatic venous blood samples without depletion of blood volume in the animal. Mean hepatic plasma flows estimated during infusions of 3.22 and 6.44 nmol kg-1 min-1 were reliable indicators of true hepatic flow at three different flow levels, provided that a sufficiently long time (greater than 30 min) was allowed for distribution equilibrium and that data from several animals were pooled to reduce random variability. Variability arose through subtraction of plasma arterial and hepatic venous levels to obtain the arteriovenous difference. Estimations of hepatic plasma flow by intravenous infusions of ICG were more accurate and reliable than estimations from bolus injections of ICG, or intravenous infusions of galactose studied previously. The kinetics of hepatic uptake of ICG are complex. Extraction and clearance of ICG fell steadily with time during the infusions and constant plasma ICG levels were not attained during 150 min infusions. This is attributed to the effects of accumulation of ICG within the liver cells since hepatic uptake substantially exceeded biliary excretion rate. Total ICG concentrations in sinusoid and liver cells increased in parallel. The concentration in the liver cell was 88 (60-115) times the concentration in the sinusoid but we have no data on whether or not the free concentrations in plasma and cell were in equilibrium.

Anesthesia↗
PubMed1987

Effect of age and chronic obstructive pulmonary disease on the Breathalyzer estimation of blood alcohol level.

Twenty volunteers, 10 with chronic obstructive pulmonary disease (COPD) and 10 with no disease, ingested a vodka cocktail. Serial determinations of blood alcohol level (BAL) by gas-liquid chromatography and simultaneous Breathalyzer estimations of BAL were used to calculate blood:breath alcohol partition coefficients (PCs). Data from the present study were combined with data obtained in a previous study using identical methodology to examine the relationship between age and BAL estimation. It was found that the Breathalyzer significantly underestimated BAL as a function of age. It was hypothesized that the underestimation may be due to closing volume (CV) as the Breathalyzer samples end-expiratory breath.

Adult↗
PubMed1987

Cerebral blood flow in intoxicated newborn piglets.

Ethanol exposure in the neonatal period causes impaired brain growth and altered adult behaviour in rats. One possible mechanism may be altered cerebral perfusion caused by ethanol intoxication. We assessed the effects of ethanol on cerebral blood flow and its autoregulation in 2-day-old piglets. Piglets received ethanol (1.4 g/kg) or an equivalent volume of dextrose 5% in water over 30 min. One hour later, cerebral blood flow was measured using the microsphere technique at resting, elevated, and decreased mean arterial blood pressure. Ethanol-treated piglets had total cerebral blood flows of 88 +/- 14, 82 +/- 10, and 82 +/- 12 mL X 100 g-1 X min-1 (mean +/- SE) at mean arterial blood pressures of 12.4 +/- 1.1, 15.7 +/- 1.5, and 8.2 +/- 0.9 kPa. Corresponding values in control piglets were 82 +/- 14, 78 +/- 4, and 82 +/- 7 mL X 100 g-1 X min-1 at mean arterial blood pressures of 10.5 +/- 1.5, 14.0 +/- 1.2, and 7.7 +/- 1.1 kPa. At resting arterial blood pressures, regional blood flows to basal ganglia, cortex, brainstem, and cerebellum in ethanol-treated piglets were 123 +/- 21, 90 +/- 16, 94 +/- 17, and 77 +/- 12 mL X 100 g-1 X min-1, respectively. Corresponding regional blood flows for the control piglets were 118 +/- 16, 85 +/- 15, 76 +/- 16, and 76 +/- 16 mL X 100 g-1 X min-1. Blood flow to basal ganglia was greater than to other brain regions in both ethanol-treated and control piglets (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1987

Hepatic plasma flow: accuracy of estimation from bolus injections of indocyanine green.

Experiments were performed to determine the validity of the indocyanine green (ICG) clearance technique, with and without allowances for incomplete hepatic extraction, as an estimate of hepatic plasma flow. This technique was compared with that of directly measured hepatic blood flow using a hepatic venous long-circuit preparation in the anesthetized cat. This preparation 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. Measurements of ICG by spectrophotometry and high-pressure liquid chromatography (HPLC) were equally accurate, but the HPLC was 100 times more sensitive and allowed smaller sample volumes. It was determined that systemic clearance of ICG after a bolus dose (1.3 mumol/kg) was much smaller than hepatic blood flow. Allowance must be made for the incomplete extraction. When the clearance was multiplied by extraction, mean estimated hepatic plasma flow exceeded the measured flow values by 20-30%, and this difference was attributed to temporary extrahepatic distribution. In all experiments estimated hepatic plasma flows were highly variable, and reasons for this are discussed. In hepatectomized cats ICG was found to be distributed into extrahepatic tissues.

Animals↗
PubMed1987

Whole bowel irrigation as a decontamination procedure after acute drug overdose.

Whole bowel irrigation, routinely used before colonoscopy, is evaluated as a potential gastrointestinal decontamination procedure for acute drug overdose. Nine adult volunteers, who served as their own controls, each ingested 5.0 g of ampicillin trihydrate on two occasions, one week apart. Whole bowel irrigation with polyethylene glycol electrolyte lavage solution was performed one hour after one ingestion. Serial serum ampicillin levels, electrolytes, osmolalities, body weights, and hematocrits were obtained. The areas under the concentration vs time curves for ampicillin were computed for both groups, and their means were compared. Mean duration of the procedure was 234 minutes and mean volume of infused polyethylene glycol electrolyte lavage solution was 7.7 L. Whole bowel irrigation produced a 67% decrease in ampicillin absorption and there were no significant changes in body weight, hematocrit, serum electrolytes, or osmolality. We conclude that whole bowel irrigation is an effective and safe gastrointestinal decontamination procedure for acute drug ingestion.

Adult↗
PubMed1986

Kinetic disposition of morphine in young males after intravenous loading and maintenance infusions.

Loading and maintenance infusions of morphine sulfate were administered to 5 young male patients 23-34-yr-old prior to elective surgery. Apparent steady-state plasma concentrations were achieved 30 minutes after the start of the drug infusion. The volume of distribution at steady-state (2.43 +/- 0.48 L X kg-1), beta elimination rate constant (0.700 +/- 0.162/h) and plasma clearance (1.66 +/- 0.33 L X kg-1 X h-1) were similar to values previously determined in young healthy subjects receiving a single bolus infusion. These data confirm our findings concerning morphine disposition in healthy young subjects and demonstrate the feasibility of achieving predictable plasma concentrations of morphine for future assessment of pharmacodynamic/pharmacokinetic relationships for this drug.

Adult↗
PubMed1986

The effects of sulindac and its metabolites on acute stress-induced gastric ulcers in rats.

Rats were given a single intragastric administration of the prodrug sulindac (4.0 mg/kg) or its sulfide (1.0, 2.0, 4.0, or 8.0 mg/kg) or sulfone (1.0, 2.0, 4.0, or 8.0 mg/kg) metabolites and were then subjected to acute stress in the form of immobilization for 3 hr in a cold environment. Control rats received an equal volume of propylene glycol vehicle or nothing po. Other rats received 200 mg/kg acetylsalicylic acid (ASA) with or without stress, to compare the gastrointestinal effects of sulindac metabolites with those of a known non-steroidal anti-inflammatory agent. The sulfide metabolite exacerbated stress-induced gastric glandular ulcer incidence and severity in a dose-related manner relative to all groups except the ASA-stress group, which exhibited the greatest amount of gastric damage. The sulfone metabolite did not potentiate ulcer incidence or severity beyond control (stress only) levels at lower doses. However, at 4.0 and 8.0 mg/kg, the observed ulceration was greater than that seen in stressed but otherwise untreated animals. Sulindac, vehicle, and otherwise untreated rats exhibited a similar degree of stress-induced gastric damage. It appears that the prodrug does not significantly enhance stress-related gut disease, but that the active sulfide metabolite does. Although the clinical literature suggests that the sulfone metabolite is inactive, the present results suggest otherwise. While this metabolite did not, by itself, induce gastric damage at higher doses, sulfone did exacerbate stress ulcer formation. This is the only report of which we are aware, indicating a possible toxic effect of the sulfone metabolite.

Administration, Oral↗
PubMed1986

Salicylate metabolism: effects of age and sex in adults.

The plasma concentrations and urinary excretion rates of salicylic acid (SA) and some of its metabolites (salicyluric acid [SUA] and acyl and phenolic glucuronide conjugates) were measured after an oral dose of acetylsalicylic acid to 44 healthy subjects of both sexes 20 to 78 years old. There was no change in the SA absorption rate, and plasma clearance of SA was not affected by age or sex. The volume of distribution increased with age in men but not in women. Plasma concentrations of SUA rose with age as the renal clearance of this metabolite fell. The kinetic parameters Km and Vmax for the SA-to-SUA reaction did not change with age; Vmax was significantly higher in women than in men. Urinary recovery of SA and its metabolites essentially accounted for the administered dose, and was little influenced by age or sex. We conclude that these factors play a minor role in the disposition of salicylate.

Administration, Oral↗
PubMed1986

Effects of circulating catecholamines on hepatic blood volume in anesthetized cats.

Arterial and portal norepinephrine and epinephrine levels, and hepatic blood volumes were measured in cats anesthetized with pentobarbital sodium to determine the basal levels after surgery and adrenalectomy in comparison with levels during intravenous infusions of norepinephrine and epinephrine that produced hepatic venoconstriction. In addition, the hypothesis that norepinephrine released into portal blood during mesenteric nerve stimulation might produce hepatic venous responses was tested. No epinephrine was detected in any plasma samples except during intravenous epinephrine infusions. Surgery did not increase, and adrenalectomy did not decrease, the basal norepinephrine levels measured after anesthesia (0.8 +/- 0.1 ng/ml). These basal levels were below the minimal levels required to produce hepatic venous responses. Equal plasma levels of norepinephrine and epinephrine produced similar hepatic venous responses and maximal responses required increases in plasma levels of 100 times the basal levels. Stimulation of mesenteric nerves at 2 Hz produced no change in portal norepinephrine levels, whereas at 8 Hz it produced a doubling of these levels. No significant changes in hepatic volume occurred. It is concluded that although basal levels of circulating catecholamines may reflect overall sympathetic nervous activity, they are not high enough to produce hepatic venous responses. Sympathetic control of the hepatic venous bed is mediated through the hepatic innervation, and circulating catecholamines play at most a minor role.

Adrenalectomy↗
PubMed1986

Hydroxylation and glucuronidation of various xenobiotics by hepatic microsomes from the fetal lamb, pregnant ewe and human fetus.

The ability of microsomes isolated from liver of pregnant ewes and their fetuses at near term to catalyze the biotransformation of benzo[a]pyrene, hexobarbital, meperidine, methadone and morphine was investigated. Cytochromes P-450 and b5, NADPH and NADH cytochrome c reductase, methadone and meperidine N-demethylase and morphine glucuronyltransferase activities were detected in microsomes from both maternal and fetal livers. Fetal hepatic microsomes however, lacked the ability to catalyze the hydroxylation of hexobarbital and benzo[a]pyrene.

Animals↗
PubMed1986

The pulmonary disposition of theophylline and its influence on human alveolar macrophage bactericidal function.

We studied the pulmonary disposition of theophylline by performing bronchoalveolar lavage on 19 normal, nonsmoking volunteers who had taken theophylline orally for 14 days. In addition, we determined the influence of theophylline on human alveolar macrophage bacterial phagocytosis, intracellular killing, and hydrogen peroxide release. We found a 1:1 relationship between serum and bronchoalveolar lavage theophylline concentrations when lavage fluid concentrations were corrected for saline dilution. We found marked impairment of the bactericidal activity of alveolar macrophages from theophylline-treated subjects (intracellular killing efficiency of 24.7 +/- 1.5% compared with 60.2 +/- 0.9% by macrophages from control subjects; p less than 0.001). This defect in alveolar macrophage bactericidal activity was inversely correlated with the bronchoalveolar lavage theophylline concentrations, and was corrected after the alveolar macrophages were cultured under serum-free conditions for 48 h. Theophylline significantly impaired alveolar macrophage release of hydrogen peroxide. Hence, theophylline may compromise lung host defenses by suppressing alveolar macrophage bactericidal activity and oxidative metabolite release.

Adult↗
PubMed1985

Effects of age and disease on the pharmacokinetics and pharmacodynamics of sulindac.

The disposition and effect on hemostasis of a single 150 mg dose of sulindac was studied in young healthy subjects and in older patients with arthritis. Older patients were restudied after 2 weeks of sulindac, 150 mg b.i.d. The only difference in disposition of the first dose was a reduced plasma sulfone metabolite concentration in the elderly patients with arthritis. Chronic sulindac dosing resulted in accumulation of the drug and its sulfone and sulfide metabolites in plasma to a greater extent than previously reported for young subjects. No differences in renal clearance of sulindac and its sulfone metabolite related to age or chronic drug dosing were observed. No renal excretion of the active sulfide metabolite was detected. Bleeding time in the elderly patients was shorter than in the young healthy subjects before sulindac dosing, but was prolonged in the elderly patients after 2 weeks of dosing to values similar to control data from the young healthy subjects. This change correlated weakly with plasma sulfide metabolite concentrations. Differences in bleeding time were not reflected in changes in platelet aggregation induced by adenosine diphosphate either with respect to age or chronic drug dosing. Our data provide no justification for lowering the recommended dose of sulindac for patients older than 65 years of age.

Adult↗
PubMed1985

Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults.

Amantadine dose, plasma concentration, prophylactic and adverse effect relationships for prevention of influenza A virus infection in healthy young adult subjects were investigated in a double-blind, placebo-controlled study. Seventy-four subjects with hemagglutination inhibition antibody titers less than or equal to 16 against an attenuated influenza A virus AF9/Montreal/3/72 (H3N2) were randomly allocated to groups taking 0 (placebo), 25, 100, or 150 mg amantadine syrup prophylactically twice a day for 31 doses. Eighteen other subjects were randomly allocated to control groups for investigation of drug toxicity (150 mg) or concurrent other virus infection (placebo). Steady-state trough plasma concentrations were 110 +/- 39, 302 +/- 80, and 572 +/- 207 ng/ml (X +/- SD) for the three amantadine doses and increased out of proportion to dose. Prophylaxis groups were challenged intranasally with virus after the fifth dose at steady state; control subjects received saline solution. No subject became ill. Input virus was recovered 48 or 72 hr after challenge from nose or throat swabs of nine of 21 subjects taking placebo, one of 18 subjects taking 100 mg amantadine, three of 18 subjects taking 25 mg amantadine, and six of 17 subjects taking 150 mg amantadine. There were no differences in seroconversion rates or adverse symptoms. Our data do not support a change in the recommended amantadine prophylactic dose for influenza A virus infection in healthy young adults. We defined trough steady-state plasma concentrations associated with the recommended amantadine dose of 100 mg twice a day that should be mimicked in devising dose schedules for populations with differing amantadine kinetics.

Adolescent↗