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P R Gwilt

Publications and source records attributed to P R Gwilt.

At least 19 recordsLinked to original sources
PubMed1999

The pharmacokinetics and pharmaco-dynamics of Procysteine in amyotrophic lateral sclerosis.

In 13 subjects with ALS, we studied the safety and pharmacokinetic properties of Procysteine, a cysteine prodrug that increases levels of intracellular glutathione. We found that oral administration of Procysteine was safe. Procysteine enters CSF after both IV and oral dosing and accumulates to significant levels in CSF. We also observed that CSF levels of glutathione fall dramatically with aging.

Administration, Oral↗
PubMed1998

Colorimetric determination of hydroxyurea in human serum using high-performance liquid chromatography.

A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.

Chromatography, High Pressure Liquid↗
PubMed1998

Assay for etoposide in human serum using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

An HPLC assay for etoposide in human serum was developed. Serum, spiked with podophyllotoxin (internal standard), was treated with sodium dodecyl sulphate prior to solid phase extraction. Analysis was performed on a 300x3.9 mm Bondclone 10 C18 column coupled with a fluorometric detector (lambda(ex) 230 nm, lambda(em) 330 nm). The retention times for etoposide and podophyllotoxin were 14 and 28 min respectively. The range of assay was 0.5 to 20 microg/ml with a detection limit of 0.2 microg/ml. This assay is suitable for use in clinical studies with etoposide.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine.

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2-hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis-Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.

Adult↗
PubMed1998

Pharmacokinetics and pharmacodynamics of hydroxyurea.

Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection. Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms. Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics. Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination. The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Population pharmacokinetics of hydroxyurea in cancer patients.

The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (Vmax), 0.097 mmol h-1 l-1; Michaelis constant for HU elimination (KM), 0.323 mmol/l; renal clearance (ClR), 90.8 ml/min; volume of distribution (Vd), 0.186 x (body weight) + 25.4 l; absorption rate constant (Ka), 2.92 h-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration.

Administration, Oral↗
PubMed1994

The effect of garlic extract on human metabolism of acetaminophen.

Several studies suggest that the constituents of garlic may inhibit experimentally induced carcinogenesis. To evaluate the chemopreventive properties of garlic in humans, the effects of chronic administration of an aged garlic extract on the disposition of acetaminophen and metabolites were studied. This commonly used drug was chosen because it forms a reactive electrophilic metabolite after oxidative metabolism. Sixteen subjects ingested daily doses of garlic extract (approximately equivalent to six to seven cloves of garlic) for 3 months. Before the course of garlic, at the end of each month and 1 month after termination of garlic administration, a 1-g oral dose of acetaminophen was given to each subject. Plasma and urine were measured for acetaminophen and the glucuronide, sulfate, cysteinyl, mercapturate, and methylthio metabolites. It was found that garlic treatment had no discernible effect on oxidative metabolism but was associated with a slight increase in sulfate conjugation of drug. These findings suggest that garlic extract has limited potential as a chemopreventive agent.

Acetaminophen↗
PubMed1993

Clofibrate enhances the DNA damaging action and cytotoxicity of nitrosoureas.

The ability of N-ethyl-N-nitrosourea (ENU) to produce single strand breaks (SSB) and N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to produce SSB and DNA-DNA interstrand cross-links was measured in L1210 cells that had been pretreated with clofibrate (CLO). When ENU was used the SSB frequency rose from 12.4 +/- 1.6/10(6) bases in control cells to 17.3 +/- 1.5/10(6) bases in CLO-treated cells and from 2.8 +/- 0.1/10(6) bases in control cells to 5.5 +/- 0.4/10(6) in CLO-treated cells when BCNU was the damaging agent. Similarly the cross-linking frequency rose from 3.5 +/- 0.1/10(6) bases in control cells to 12.1 +/- 0.5/10(6) bases in CLO-treated cells when BCNU was the cross-linking agent. CLO treatment increased the production of superoxide anion four-fold over the controls and it increased the cytotoxicity of BCNU. Forty-two percent of the control+BCNU cells survived after 24 h whereas only 24% of the CLO+BCNU cells survived. The stimulation of the diffuse condition known as oxidative stress increased the interaction of nitrosoureas with DNA and resulted in increased biological responses, e.g. cytotoxicity.

Animals↗
PubMed1993

A phase I trial of high-dose continuous-infusion hydroxyurea.

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated doses (MTD) of intravenous hydroxyurea given as a 24- or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m2 following a bolus of 1,690 mg/m2, and the mean (+/- SD) plasma steady-state concentration was 1.93 +/- 0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m2 following a bolus of 2,197 mg/m2 and the mean steady-state level was 1.43 +/- 0.31 mM. The dose-limiting toxicity on both schedules was marrow suppression manifesting as neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.

Adult↗
PubMed1991

The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans.

The article reviews the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs in humans. For most drugs which cross the gastrointestinal wall by passive diffusion, oral absorption is unlikely to be affected by diabetes, although a delay in the absorption of tolazamide and a decrease in the extent of absorption of ampicillin have been reported. Subcutaneous absorption of insulin is more rapid in diabetic patients, whereas the intramuscular absorption of several drugs is slower. The binding of a number of drugs in the blood is reduced in diabetes, which may be due to glycosylation of plasma proteins or displacement by plasma free fatty acids, the level of which is increased in diabetic patients. Plasma concentrations of albumin and alpha 1-acid glycoprotein do not appear to be changed by the disease. The distribution of drugs with little or no binding in the blood is generally not altered, although the volume of distribution of phenazone (antipyrine) is reduced by 20% in insulin-dependent diabetes mellitus (IDDM). In contrast to animal studies, the metabolic clearance of most drugs in humans appears to be unaffected or slightly reduced by the disease. The presence of fatty liver in non-insulin-dependent diabetes mellitus (NIDDM) may contribute to a reduced hepatic clearance, whereas decreased binding in the blood may cause an increase in clearance. The effect of diabetes on hepatic blood flow in humans appears to be unknown. Diabetes affects kidney function in a significant number of diabetic patients. During the first 10 years after the onset of the disease, glomerular filtration is elevated in these patients. Thus, the renal clearance of a number of antibiotics has been shown to be increased in diabetic children. As the disease progresses, renal function is impaired and glomerular function declines from the initial elevated state. In diabetic adults the renal clearance of drugs either is comparable with that found in nondiabetic individuals or is reduced. A limited number of studies have been conducted comparing the dose-response of cardiovascular drugs in diabetic patients with that in nondiabetic controls. Decreased, increased and unchanged responses have been reported. It is apparent that in some cases an altered response may be observed for a drug when administered to a diabetic patient compared with a similar nondiabetic individual. At the present time, it is not possible to ascertain whether these studies reflect true pharmacodynamic changes or merely alterations in pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus↗
PubMed1989

Time to steady state following a change in dosing rate.

Drugs administered at fixed intervals or by continuous infusion will accumulate in the body until steady state is achieved. The time to a given percentage of the eventual steady-state concentration has previously been considered to be dependent only on the elimination half-life. This is incorrect. Although the rate of drug accumulation in the body is dependent only on the elimination half-life, the time to a given percentage of steady state is dependent on both the elimination half-life of the drug and the initial concentration. This paper presents the mathematical proof of this concept, computer simulations demonstrating the use of these equations, and nomograms for use in clinical practice. The use of this method allows serum drug concentrations to be evaluated earlier than previously predicted after changes in the dosing rate.

Adult↗
PubMed1987

Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure.

Furosemide, a potent loop diuretic, is commonly used in the treatment of congestive heart failure (CHF). Unpredictability in the diuretic effect following oral doses has been attributed to variable and incomplete absorption and to variability in the pharmacodynamic response to furosemide. The present study is undertaken to investigate the absorption kinetics and pharmacodynamics of furosemide in patients with CHF during chronic medication. Ten patients with congestive heart failure were maintained on 40 to 160 mg furosemide for a month. The final dose at the end of this period was administered on an empty stomach. Plasma and urine were collected and assayed for furosemide, potassium, chloride, sodium and creatinine. Urine flow was also measured as a function of time. Plasma furosemide concentration-time data were fit to a two-compartment model with either two consecutive, discontinuous first order absorption rate constants or with a single monoexponential input; the former absorption model describing the data better than the latter. Average values of the half-life (205 +/- 28 min) and renal clearance (0.8 +/- 0.09 ml/min/kg) were similar to those reported by previous investigators. Drug excretion-response curves were lower and shifted to the right compared to data reported for normal subjects. Furthermore, a clockwise hysteresis was evident indicating acute within-dose tolerance.

Aged↗
PubMed1986

Protein binding and pharmacokinetics of lincomycin following intravenous administration of high doses.

High-dose infusions of lincomycin 600, 1,200, and 2,400 mg were administered to 14 healthy, adult men. Using model-independent pharmacokinetics, it was found that the half-life, mean residence time, and steady-state volume of distribution of total drug increased with dose, whereas the same parameters remained unchanged for the unbound lincomycin. Although the mean clearance value for total drug increased, this change fell short of being significant at the 5% level and was associated with a decrease in unbound clearance following administration of the 2,400 mg dose. Protein binding studies using ultrafiltration gave direct evidence of saturable serum protein binding and indicated that binding involved at least two distinct classes of binding sites.

Absorption↗
PubMed1986

Absorption and disposition of aluminum in the rat.

The kinetics of aluminum were determined in the rat. Intravenous bolus and oral doses of 8.1-mg/kg of aluminum as the chloride salt were administered to six rats. Serial blood samples and total urine and feces were collected and assayed for aluminum by atomic absorption spectrophotometry. The fraction absorbed orally (mean +/- SEM) was 0.27 +/- 0.03; the half-life was 5.29 +/- 0.47 h; the steady-state volume of distribution was 38.4 +/- 6.4 mL/kg, and the clearance was 8.87 +/- 1.76 mL X h-1 X kg-1. It was found that aluminum did not significantly penetrate the cellular components of blood. Plasma protein binding was determined to be approximately 98%. Sixty percent of the intravenous dose was excreted in the urine and the remaining 40% was excreted in the feces.

Administration, Oral↗
PubMed1985

Pharmacokinetics of methyprylon following a single oral dose.

Single oral doses of 300 mg of methyprylon were administered to 10 healthy volunteers. Plasma concentrations of methyprylon and its dehydro metabolite were measured using a recently developed HPLC assay. Plasma concentration-time data were fitted to a two-compartment model with either first-order absorption, zero-order absorption, or two consecutive, discontinuous, first-order absorption rate constants. Based on the criteria of visual inspection, the correlation coefficient, standard deviations of the parameter estimates, and the residual sum of squares, it was concluded that the zero-order absorption model fit the data best. Mean (+/- SD) values for the half-life (9.2 +/- 2.2 h), apparent clearance, (11.91 +/- 4.42 mL/h/kg) and apparent steady-state volume of distribution, (0.97 +/- 0.33 L/kg) were found.

Administration, Oral↗