PubMed Health⌕ Search

Biomedical subjects

G R Wilkinson

Publications and source records attributed to G R Wilkinson.

At least 127 records · Page 7Linked to original sources
PubMed1984

Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients.

Plasma urine, and cerebrospinal fluid etoposide concentrations have been measured in 12 adult patients after administration of high-dose (400 to 800 mg/sq m) etoposide in order to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27 to 114 micrograms/ml) and total areas under the concentration-time curve (9,200 to 48,000 micrograms/ml X min). The etoposide mean (+/- S.D.) terminal half-life of 8.05 +/- 4.3 hr and plasma clearance of 28.0 +/- 9.7 ml/min/sq m, however, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 +/- 4.3 ml/min/sq m, representing from 35 to 40% of the total clearance of this drug from plasma. Cerebrospinal fluid etoposide concentrations ranged from 0.1 to 1.4 micrograms/ml, as measured in 6 patients at 1 to 8 hr after high-dose etoposide therapy, and were 1.8 +/- 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hr posttherapy contained etoposide at 1.8 micrograms/ml. Our data, combined with data published previously, indicate that the pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the cerebrospinal fluid.

Etoposide↗
PubMed1983

Amiodarone dosing: a proposal based on its pharmacokinetics.

The available data concerning amiodarone dosing may be summarized as follows: (1) there is an empirically demonstrated improvement in lag before onset of antiarrhythmic effect if amiodarone is given initially in large "loading" doses. (2) A regimen such as that described in this article may allow more predictable and safe therapy and should be evaluated in patients, in order to develop uniform dosing guidelines. (3) Amiodarone clearance appears to decrease with time, and for this reason guidance of long-term therapy by plasma concentration determinations could potentially improve safety and efficacy. However, a close correlation between drug levels and drug toxicity and efficacy is lacking. (4) Finally, plasma concentrations, although potentially useful for monitoring long-term therapy, are likely to be unhelpful or misleading during the 4- to 6-week loading period at the beginning of treatment.

Amiodarone↗
PubMed1983

Drug distribution and renal excretion in the elderly.

Drug responsiveness in the elderly often differs from that in younger individuals. A causative factor is often thought to be age-related changes in the quantitative fashion in which the body handles the drug. It is speculated that changes in body size, composition, and tissue perfusion lead to differences in drug distribution. The limited supportive evidence for this is reviewed, along with the practical consequences in drug therapy. More definitive data is presented on the age-related impairment of renal function and its effects on the urinary elimination of drugs and metabolites. Methods are presented to permit rationale dosage regimen modifications for elderly patients with reduced renal function.

Aged↗
PubMed1983

Effect of thyrotoxicosis on liver blood flow and propranolol disposition after long-term dosing.

The effects of thyrotoxicosis on Liver blood flow and propranolol disposition were followed in five patients while thyrotoxic and when euthyroid. Propranolol was taken orally to achieve steady state and then radiolabeled drug was given simultaneously by intravenous injection. Thyrotoxicosis was associated with doubling of both oral and systemic clearances of unbound propranolol, which resulted in an approximately 50% reduction in blood concentrations after oral doses. These changes were attributable to increases in hepatic blood flow and drug-metabolizing activity of the liver. The propranolol elimination t 1/2 was not affected by thyrotoxicosis since the enhanced clearance was offset by a change in volume of distribution. These findings may explain the reduction of plasma propranolol concentration and many of the therapeutic failures reported in the treatment of thyrotoxicosis. The dose required to achieve therapeutic blood concentrations of propranolol in thyrotoxic patients is variable and will usually be substantially larger than that required for euthyroid patients.

Administration, Oral↗
PubMed1983

The oral yeast flora of 10-year-old schoolchildren.

The yeast flora of the hard palate mucosa and pooled saliva of 122 schoolchildren (average age 9 years 10 months, 63 males, 59 females) has been studied in detail. Of the population sampled, 71.3% carried oral yeasts. The carriage was approximately 3 times greater in females than in males. The yeast isolates were Candida albicans 71% Saccharomyces spp. 19.7% and Candida tropicalis 8.6%. No isolates of Torulopsis spp. or Rhodotorula spp. were recovered. 71.5% of the Candida albicans isolates were serotype A and 26.3% were serotype B.

Candida albicans↗
PubMed1983

Induction of propranolol metabolism by rifampicin.

The effect of rifampicin on the blood concentration-time curve of propranolol at steady-state following oral administration of 120 mg every 8 h was investigated in six normal, young, male subjects. After an initial 2 week dosing period, all individuals additionally received 600 mg rifampicin daily for 3 weeks followed by a 4 week period during which again only the propranolol was given. In four of the subjects the effects of 900 and 1200 mg rifampicin daily was also studied. Changes in disposition were assessed by estimation of propranolol's oral clearance and elimination half-life during the dosage interval. Rifampicin (600 mg/day) caused a large increase in propranolol's oral clearance (35.7 +/- 16.3 vs 96.1 +/- 26.9 ml min-1 kg-1, mean +/- s.d.), but neither the elimination half-life nor extent of plasma binding were affected. Increasing the daily dosage to 900 and 1200 mg did not cause any additional changes in oral clearance. Four weeks after discontinuing rifampicin, propranolol's oral clearance had essentially returned to its pre-induction level. The oral clearance of propranolol was significantly smaller (89.5 +/- 14.4%) during the dosage interval immediately after administration of the last rifampicin dose than the value measured 24 h later. The findings are consistent with rifampicin causing induction of the drug metabolizing enzymes responsible for propranolol's biotransformation. The marked reduction in the steady-state propranolol blood concentration that results from chronic rifampicin administration would be expected to result in a significant change in clinical effectiveness of the beta-adrenoceptor blocker when the two drugs are used concurrently.

Adult↗
PubMed1982

Aging and benzodiazepine binding in the rat cerebral cortex.

The specific binding of 3H-diazepam in the cerebral cortex was investigated in membrane preparations from 6 and 30 month old Fisher-344 rats. No age-related differences in the association, equilibrium, or dissociation, binding characteristics were observed. The increased sensitivity of the elderly to the central sedative effects of the benzodiazepines does not, therefore, appear to involve changes in binding to the receptor site located in the cortex.

Aging↗
PubMed1982

Furosemide disposition in cirrhosis.

Furosemide disposition after rapid intravenous injection (80 mg) was studied in 10 normal healthy subjects and eight patients with cirrhosis and ascites. In the cirrhotic patients the elimination half-life was modestly longer (81.0 +/- 8.0 min and 60.2 +/- 5.8 min). This prolongation was not associated with a difference in systemic clearance (156 +/- 7 ml/min in normal and 142 +/- 16 ml/min in cirrhotic subjects), rather it was a reflection of alterations in furosemide distribution. The steady-state volume of distribution was increased from 8.5 +/- 0.4 l in the healthy subjects to 12.1 +/- 1.3 l in the cirrhotic subjects; estimation in terms of unbound drug indicated an approximately 50% smaller value in cirrhosis. These observations were quantitatively consistent with the increased percentage of furosemide in plasma in the unbound form in the patients (10.2 +/- 1.0%) compared to in the normal subjects (4.0 +/- 0.1%). The 24-hr percentage urinary recovery of unchanged drug (58.8 +/- 2.8% and 53.1 6.5%) and the glucuronide metabolite (17.8 +/- 1.5 and 21.3 +/- 3.4) were on the same order in the normal and cirrhotic groups. The lack of major effects of cirrhosis on furosemide disposition suggests that changes in furosemide diuretic efficacy in such patients is a result of altered dynamic factors rather than altered disposition.

Adult↗
PubMed1982

Increased toxicity and reduced clearance of lidocaine by cimetidine.

Cimetidine reduced liver blood flow and the systemic clearance of drugs, such as propranolol, that are highly extracted by the liver. In a randomized placebo-controlled study, we examined the influence of cimetidine, 300 mg four times daily for 1 d, on the disposition of lidocaine, 1 mg/kg body weight by a 10-minute intravenous infusion. Cimetidine reduced the systemic clearance of lidocaine from 766 +/- 50 mL/min to 576 +/- 47 mL/min (p less than 0.05); the apparent volume of distribution at steady-state and the degree of plasma protein binding of lidocaine also were decreased. Five of the six subjects noted lidocaine toxicity during the cimetidine infusion in contrast to one subject on the placebo day. The peak lidocaine concentration (mean +/- SE) was 50% +/- 10% higher when subjects received cimetidine. This study provides additional evidence that the effect of cimetidine on the elimination of other drugs has multiple factors, and shows a previously unrecognized mechanism, involving altered initial drug distribution, whereby the interaction of cimetidine with other drugs may cause toxicity.

Adult↗
PubMed1981

Reduction of liver blood flow and propranolol metabolism by cimetidine.

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing live blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P less than 0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow.

Administration, Oral↗
PubMed1981

Meperidine disposition in man: influence of urinary pH and route of administration.

The effects of route of administration and altered urinary pH on the disposition of meperidine and its metabolite normeperidine were investigated in six normal, nonsmoking young men from 23 to 31 yr old. Meperidine (21.75 mg) was injected intravenously simultaneous with the same dose of deuterated (2H5) drug given orally in solution or by injection into the deltoid muscle. After intravenous administration with no control of urinary pH, meperidine blood levels declined triexponentially over 24 hr with a terminal half-life (t1/2) of 4.9 to 9.4 hr and a clearance of 472 to 686 ml/min. The 48-hr urinary recoveries of meperidine and normeperidine were about 7% and 12%. Urinary acidification with ammonium chloride reduced these amounts to less than 1% and about 7%, whereas urinary alkalinization increased them to about 20% and 24%. These pronounced changes had negligible effects on the blood concentration/time profiles. Plasma levels were proportional to the blood concentrations with a ratio of about unity for meperidine and a value 25% greater for normeperidine. Absorption after intramuscular injection was complete and followed a first-order process with t1/2 ranging from 7 to 13 min. Accordingly, maximum blood levels were achieved within 5 to 15 min and the concentration was essentially the same as after intravenous dosing. In contrast, oral bioavailability was incomplete, ranging from 47% to 73%, and at a much slower rate, with peak concentrations being observed after about 1 hr. Absorption was biphasic and was preceded by a 5- to 10-min lag period. Normeperidine blood concentration after intravenous dosing reached a maximum within 2 to 4 hr and remained at this value through 12 hr before modestly declining by 24 hr. After oral dosing the peak level was achieved more rapidly and sharply. Thus, presystemic elimination occurs after oral dosing within meperidine consistent in value with the measured blood clearance which, therefore, probably reflects only hepatic metabolism.

Administration, Oral↗
PubMed1981

Disposition of furosemide in functionally hepatectomized dogs.

To assess the role of the liver in the elimination of furosemide, the disposition kinetics of the diuretic after intravenous administration were studied in dogs with total devascularization of the liver and sham-operated animals. Functional hepatectomy caused no significant changes in either the renal or the nonrenal clearances of furosemide; renal = 124.2 +/- 27.1 (mean +/- SE) and 106.6 +/- 17.5 ml/min and nonrenal = 148.2 +/- 11.4 and 112.6 +/- 21.0 ml/min in sham-operated and hepatectomized dogs, respectively. Devascularization of the liver had no effect on the plasma binding of furosemide which was 90.0% in the sham-operated and 88.2% in the hepatectomized animals. The steady-state volume of distribution of furosemide was relatively small, 0.70 +/- 0.09 liters/kg in control dogs and hepatectomy resulted in a reduction in this volume (0.58 +/- 0.09 liters/kg). This indicates that the liver is a significant organ for distribution of furosemide in the dog. Urinary recoveries of parent drug (43.2% of the dose in sham-operated dogs ad 49.1% in hepatectomized animals) and of its glucuronide (4.3% in sham-operated and 5.5% in hepatectomized dogs) were not influenced by hepatic devascularization. These findings demonstrate that, although nonrenal clearance accounts for about 50% of the elimination of furosemide, the liver does not play a significant role in this process in the dog.

Animals↗
PubMed1981

Normal metabolism of morphine in cirrhosis.

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Adult↗
PubMed1980

The determination of meperidine, noremeperidine and deuterated analogs in blood and plasma by gas chromatography mass spectrometry selected ion monitoring.

A gas chromatographic mass spectrometric assay using selected ion monitoring for meperidine and normeperidine in blood and plasma is described. Both unlabeled and [3H]-phenyl ring labeled drugs may be determined simultaneously using [2H10] analogs as internal standards. Calibration curves are linear over the range 5--100 ng ml-1, the results reproducible (coefficient of variation < 5%), the sensitivity limit is about 5 ng using a 1 ml sample and no interference is present in blank blood or plasma, or by isotope inpurity. The method is shown to be applicable to measuring the concentration of meperidine and its metabolite, normeperidine, in blood, following simultaneous administration by the intravenous and oral routes of 25 mg each of unlabeled and [2H5] labeled drug, respectively.

Gas Chromatography-Mass Spectrometry↗
PubMed1980

Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans.

Dichloroacetate decreases plasma glucose, lactate, and alanine concentrations in normal and diabetic subjects, and lowers lactate concentrations and increases survival in animals with experimentally induced lactic acidosis. The relationship between these effects and plasma dichloroacetate concentrations have not been previously studied in man. Dichloroacetate (1-50 mg/kg) was infused over 30 min to 16 healthy subjects and plasma drug concentrations were followed by gas chromatography over the next 8 h. Peak plasma concentrations were linearly related to the dose (r = 0.98, p < 0.001) up to 30 mg/kg, above which 4 of 7 subjects had disproportionately high plasma drug concentrations. Nonlinear disposition was also indicated by the convex decreasing plasma elimination curves; levels declining less rapidly initially than later. At plasma concentrations below 10 micrograms/ml, elimination was monoexponential with a half-life of 32 +/- 11 min (mean +/- SD). Plasma drug clearance also decreased with doses greater than 20 mg/kg. Within 2 h of administration of the maximally effective dichloroacetate dose of 35 mg/kg, plasma lactate concentrations fell 75% below baseline and alanine fell 50% below baseline, while blood glucose was unaffected.

Acetates↗
PubMed1980

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patient's procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

Acecainide↗