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Biomedical subjects

W J Tilstone

Publications and source records attributed to W J Tilstone.

At least 19 recordsLinked to original sources
PubMed1983

Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine.

Chronic administration of cimetidine was found to produce a fall in steady-state plasma concentrations of chlorpromazine and of indomethacin in patients. In each case there was some evidence of inhibition of metabolism, suggesting that the mechanism must therefore be decreased absorption sufficient to over-ride the metabolic change. This was confirmed by measurement of excretion of metabolites in the indomethacin study. The fall in indomethacin plasma concentrations was not associated with a change in the clinical effectiveness of the anti-inflammatory therapy.

Absorption↗
PubMed1980

Will hemoperfusion be useful for cancer chemotherapeutic drug removal?

One of the major problems in clinical cancer chemotherapy is the inability to safely administer full therapeutic doses of specific drugs in the face of dysfunction of an organ system controlling that drug's metabolism and excretion. Should efficient drug removal from blood be possible following full therapeutic doses and after tumor exposure, then theoretically, even in the presence of organ dysfunction, anticancer drug toxicity may be reduced or avoided. Preliminary experiments in our laboratory have shown that adriamycin may be efficiently removed by activated charcoal from aqueous and protein solutions and blood in vivo, and that daunorubicin is removed in vitro to the same extent. However, although methotrexate is removed efficiently in vitro and extracted 50% in vivo by charcoal hemoperfusion, its overall pharmacokinetics do not appear to be altered in comparison with the alteration in pharmacokinetics of adriamycin achieved with charcoal hemoperfusion. Computer modeling has suggested that efficient adriamycin removal is achievable, and that clinical studies are warranted. For methotrexate removal, however, previous clinical studies and our own data suggest that charcoal hemoperfusion has little utility unless a highly specific sorbent for methotrexate removal can be developed.

Adsorption↗
PubMed1979

Acetylation of phenelzine.

Microsome-free preparations of rodent and human liver were shown to contain N-acetyl transferase from experiments using procainamide as substrate. These preparations then acetylated phenelzine from the quantitative transfer of radiolabeled acetate. This in vitro demonstration of phenelzine acetylation in rodent and human liver was corroborated by the finding of a negative correlation between excretion of phenelzine in urine and sulphadimidine acetylation in 27 patients.

Acetyl Coenzyme A↗
PubMed1979

Clinical pharmacokinetics of procainamide infusions in relation to acetylator phenotype.

The pharmacokinetics of procainamide was determined in 21 lidocaine-resistant patients who received the drug according to a pharmacokinetically designed double-infusion technique. Thirteen patients were phenotyped as slow acetylators, seven as fast, and one as intermediate. The total body clearances (ClT) of PA in slow and fast acetylators were 22.6 and 34.8 liters/hr, respectively. The fraction of PA cleared by the formation of NAPA in the corresponding acetylator group was 0.2 and 0.4. Renal impairment affected the pharmacokinetics of PA more profoundly as the ClT's of PA in patients with and without renal impairment were 17.9 and 31.2 liters/hr, respectively. None of the calculated volumes of distribution was affected by acetylator phenotype or renal impairment. These data identify the contribution of at least two of the major factors accounting for variability in PA disposition in patients undergoing therapy.

Acetylation↗
PubMed1978

The pharmacokinetics of slow-release procainamide.

Procainamide was given to 20 patients with normal renal function as an i.v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6 +/- 27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0 +/- 0.8 h, compared to a mean of 3.4 +/- 0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75 +/- 0.9 h in fast acetylators, and 4.4 +/- 2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose.

Biological Availability↗
PubMed1978

Furosemide kinetics in renal failure.

Furosemide kinetics were studied in normal volunteers and patients with renal failure. Comparison of results from intravenous bolus and intravenous infusion in normal subjects showed no significant model dependency of estimations of furosemide clearance, although the average clearance by fitting to a one-compartment model was 16% higher than that obtained by fitting to a two-compartment model. Normal subjects had a total body clearance of furosemide of 1.53 +/- 0.11 (SE) ml/min/kg, a volume of the central compartment of 2.61 +/- 0.37 L, a volume of the peripheral compartment of 2.48 +/- 0.24 L, and a half-life of 0.8 +/- 0.06 hr and they absorbed 68.9% +/- 7.1% of a solution of furosemide given by mouth. The corresponding values in patients with renal failure were 0.27 +/- 0.03 ml/min/kg, 8.02 +/- 0.96 L, 14.1 +/- 3.57 L, 14.2 +/- 2.30 hr, and 43.4% +/- 8.0%, all differing significantly different from the normal. The bioavailability of 500-mg tablets of furosemide in the renal failure patients was 43.4% +/- 7.4%, equivalent to the absorption of the dose given to the same patients in the form of a solution.

Administration, Oral↗
PubMed1978

Interaction of ethanol with amylobarbitone, phenobarbitone and methaqualone.

The presence and mechanism of synergism of action between ethanol and amylobarbitone, phenobarbitone or methaqualone was determined by application of simple pharmacokinetic models to log dose-response curves and plasma concentration-time curves for the hypnotics alone or when ethanol was given concurrently. For all three hypnotics, ethanol was found to increase the duration of hypnosis, but the mechanism of action was different for each. A sub-hypnotic dose of ethanol increased the volume of distribution of amylobarbitone and the consequent reduction in fractional elimination prolonged the half-life of the hypnotic. The distribution and elimination of methaqualone were not affected by ethanol, but there was a sensitisation of the target organ, shown by a reduced minimum effective dose. The minimum effective dose of phenobarbitone was also reduced by ethanol, but in addition, the rate of elimination of phenobarbitone was increased after the period of hypnosis.

Amobarbital↗
PubMed1978

Capacity-limited elimination of procainamide in man.

Procainamide (PA) pharmacokinetics were studied at steady state in 19 patients. The PA was given as 1.0 or 1.5 g eight hourly (L and H dose groups) and acetylator phenotype determined from sulphadimidine acetylation was classified as Slow or Fast (S or F). Thus, four groups were categorized, HF, LF, HS and LS with 7, 5, 3, and 4 patients in each respective group. Overall the mean steady state plasma concentration of PA (Cpss) expressed as a fraction of dose did not depend on dose or on acetylator status, but the HS group had significantly higher Cpss per gram dose (6.3 mug/ml) than LS (2.7 mug/ml) or the HF (2.3 mug/ml) groups. Clearance of PA be acetylation (C1A) was 23.8% of the total in fast acetylators and 16.5% in slow acetylators. C1A was not dose-dependent in the HF or LF groups (mean 177.9 ml/min and 168.4 ml/min) but was dose-dependent in the HS group (mean 74.6 ml/min) which differed significantly from the LS group (mean 113.4 ml/min).

Acetylation↗
PubMed1977

Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin.

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.

Adult↗