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Biomedical subjects

W G Crouthamel

Publications and source records attributed to W G Crouthamel.

At least 19 recordsLinked to original sources
PubMed1987

Plasma protein binding of ceftriaxone.

1. The plasma protein binding characteristics of ceftriaxone, a new cephalosporin antibiotic, were determined in human, baboon, rabbit, dog and rat plasma. 2. The protein binding of ceftriaxone was similar and concentration-dependent in human, baboon, rabbit and rat plasma, being highly bound (90-95%) at low concentrations (less than 100 micrograms/ml) but considerably less bound (approx. 60%) at high concentrations (greater than 400 micrograms/ml). Binding in dog plasma was also concentration-dependent but much lower (approx. 25%) at lower concentrations (30 micrograms/ml) and virtually unbound (2%) at high concentrations (1 mg/ml) over a similar concentration range. 3. Binding of ceftriaxone to human plasma involved two sites: a high affinity-low capacity (saturable) site and a low affinity-high capacity site. Binding to dog plasma apparently was at a single, high affinity-low capacity site. 4. The pharmacokinetics of ceftriaxone in an animal species with binding characteristics similar to man (baboon), appear to be non-linear when based on total drug concentration and linear when based on the free drug concentration. In the dog, pharmacokinetic parameters did not change appreciably if calculated from total or free drug concentrations, due to the low protein binding.

Animals↗
PubMed1983

Quinidine saliva concentrations: absence of correlation with serum concentrations at steady state.

Serum and saliva quinidine concentrations were measured in eight subjects with cardiac arrhythmias on various dosage regimens. There was good correlation between serum and saliva quinidine concentration after a single dose, but there was no such relationship after repeated dosing. Comparison of the area under a hysteresis loop, obtained by plotting the saliva/serum quinidine concentration ratio as a function of serum quinidine concentration over a dosing interval, indicated an exponential increase with increasing mean serum quinidine concentration. Salivary quinidine concentration predictions based on the Henderson-Hasselbalch equation did not correlate with the serum quinidine concentration under the steady-state conditions. These data suggest that quinidine concentration in saliva is not a direct reflection of its serum concentration in cardiac patients on maintenance (steady-state) therapy and hence not useful for therapeutic drug monitoring.

Administration, Oral↗
PubMed1980

Relation of ventricular premature beat suppression to serum quinidine concentraton determined by a new and specific assay.

Fourteen patients who were receiving quinidine in doses of 800 to 1800 mg. per day for ventricular arrhythmias underwent Holter monitoring during a steady state dosing interval at a mean of four days after the initiation of quinidine therapy. Serum quinidine concentration, determined by a specific high performance liquid chromatography method, was measured hourly during the dosing interval. Ventricular premature beat (VPB) frequency during quinidine therapy was compared to the baseline VPB frequency. A reduction in VPB frequency of at least 90% was required to substantiate the presence of a therapeutic response to quinidine. In 12 of the 14 patients a therapeutic response to quinidine was present at serum levels ranging from 0.72 to 5.92 micrograms/ml. There was no group correlation between serum quinidine concentration and VPB frequency, but there was a tendency in individual patients for VPB frequency to decrease as serum quinidine level increased. Quinidine toxicity was not observed in these 14 patients. Because of the wide variation in response to quinidine, a serum quinidine concentration that is within the therapeutic range is not necessarily the optimal serum quinidine concentration for an individual patient. The clinician may therefore consider increasing the dose if there is no evidence of quinidine toxicity and the ventricular rhythm disturbance is not adequately controlled.

Aged↗
PubMed1979

Specific high-performance liquid chromatographic assay for nitroglycerin in dosage forms.

A specific assay for nitroglycerin dosage forms using high-performance liquid chromatography was developed. Sublingual nitroglycerin tablets are dissolved in 25 ml of water and injected directly into the chromatograph. Chromatographic conditions are: mobile phase, 60% methanol in water; flow rate, 2 ml/min; column, microparticulate reversed phase; and detection, 200 nm. The glyceryl mononitrate and dinitrate degradation products of nitroglycerin are separated from nitroglycerin and can be identified by altering the mobile phase composition of methanol.

Chromatography, High Pressure Liquid↗
PubMed1979

Dihydroquinidine contamination of quinidine raw materials and dosage forms: rapid estimation by high-performance liquid chromatography.

Dihydroquinidine is a commonly encountered contaminant in quinidine raw materials. The USP allows 0-20% dihydroquinidine in quinidine products, but the assays used to quantitate dihydroquinidine have been lengthy or have required sophisticated equipment. The present method separates dihydroquinidine from quinidine and provides rapid, precise quantitation of both dihydroquinidine and quinidine. The clinical importance of dihydroquinidine contamination of quinidine dosage forms remains unanswered.

Chromatography, High Pressure Liquid↗
PubMed1979

Quinidine therapy in hospitalized patients with ventricular arrhythmias.

Quinidine serum levels and pharmacokinetic data were assessed during steady state therapy with oral quinidine sulfate in 19 hospitalized patients who were being treated for ventricular arrhythmias. A new high performance liquid chromatography assay was employed. Four patients were studied both after the first dose of quinidine and at steady state, and the initial dose pharmacokinetic values were found not to be predictive of steady state. The mean half-life of quinidine was 4.5 hours, but there was wide individual variation. The elimination rate constant for quinidine was significantly lower in patients with echocardiographic evidence of left ventricular dilatation than in patients with normal echocardiographic left ventricular size. The average urinary excretion of quinidine was only 11.3%. The pharmacokinetic data in seven chronic alcoholic patients without clinical or laboratory evidence of hepatic insufficiency did not differ from the data obtained in nonalcoholic patients. However, with severely impaired liver function, there may be marked prolongation of quinidine half-life predisposing to quinidine toxicity. The possible clinical implications of these findings are discussed.

Aged↗
PubMed1978

Lidocaine and its active metabolites.

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.

Chromatography, High Pressure Liquid↗
PubMed1978

Mechanism of fluorometric analysis of tetracycline involving metal complexation.

Tetracycline complexation with calcium and organic ligands was studied using fluorescence, circular dichroism, and solvent extraction methods. The results were used to interpret the mechanism of the commonly used fluorometric methods for the analysis of tetracycline in biological fluids. Tetracycline formed ternary calcium complexes with barbital sodium and L-tryptophan in alkaline solutions. The circular dichroism studies indicate that the calcium ion in these complexes is bound to the C-4 dimethylamino and the C-12a hydroxyl groups of tetracycline. These ternary complexes are strongly fluorescent and can be extracted easily into 1-butanol or ethyl acetate. Based on the characteristics of the ternary complexes and of the tetracycline degradation products, it is concluded that only the active form of tetracycline can be complexed and extracted for fluorescence analysis.

Barbital↗
PubMed1977

Specific serum quinidine assay by high-performance liquid chromatography.

The cardioactive drug quinidine has a narrow therapeutic index; consequently, determination of serum quinidine concentrations can be important. We describe a relatively rapid and specific assay for quinidine in serum by high-performance liquid chromatography. It is suitable for use in patient monitoring or pharmacodynamic studies. Alkalinized serum is extracted with benzene, which is evaporated under nitrogen and reconstituted with methanol; an aliquot is chromatographed. Quinidine is separated from its metabolites and dihydroquinidine (a contaminant in quinidine raw materials). The retention time for quinidine is 4 min 10 s, for dihydroquinidine it is 5.5 min. Results for patients' sera by this assay method and the double-extraction method of Cramer and Isaksson [Scand. J. Clin. Lab. Invest. 15, 553 (1963] correlate well (r = .975).

Chromatography, High Pressure Liquid↗
PubMed1976

Halofenate and clofibrate: mechanism of hypotriglyceridemic action in the rat.

Rats fed a fat-free diet containing no drug, 0.02% or 0.10% halofenate, or 0.25% clofibrate for 14 days were injected intravenously with equivalent amounts of either [2-3H]glycerol or [1(3)-3H]glycerol. Blood samples were collected at times up to 150 min after injection and serum triglycerides were isolated and assayed for radioactivity. Kinetic analysis of the serum appearance and clearance curves of 3H-labeled triglyceride permits estimation of serum total 3H-labeled triglyceride formation and triglyceride fractional turnover rates. The total amounts of 3H-labeled triglyceride formed from [2-3H] or from [1(3)-3H] glycerol in control-fed animals were very similar. Over 95% of the serum 3H-labeled triglyceride formed from either substrate circulated in a rapidly turning-over triglyceride pool (t1/2 = 8 min). Treatment with 0.10% halofenate or 0.25% clofibrate decreased labeling of serum triglycerides by 75-80% without increasing serum 3H-labeled triglyceride fractional turnover rates. Furthermore, both drugs decreased incorporation in vivo of 14C from [U-14C]glycerol into hepatic but not intestinal triglycerides without significantly decreasing incorporation of 14C into total phospholipids of either tissue. From these observations we suggest that, in the intact normal rat, sustained reduction of serum triglyceride levels produced by treatment with halofenate or clofibrate is due to inhibition of hepatic triglyceride formation.

Animals↗
PubMed1975

Drug absorption VII: influence of mesenteric blood flow on intestinal drug absorption in dogs.

Intestinal absorption of sulfaethidole and haloperidol was determined using an in situ canine intestinal preparation. Intestinal absorption of sulfaethidole was determined at three or four mesenteric blood flow rates in each dog, ranging from unaltered flow (100%) to no flow (0%). A relatively small change in absorption rate occurred when the splanchnic blood flow rate was decreased about 35%. Further reductions in mesenteric blood flow resulted in progressive impairment of sulfaethidole absorption. The simultaneous measurement of sulfaethidole intestinal disappearance and appearance in blood indicates that sulfaethidole disappearance is equivalent to absorption. Haloperidol absorption also decreased with decreased intestinal perfusion but differed from sulfaethidole in that membrane storage of haloperidol appeared to take place during its absorption.

Animals↗
PubMed1975

Intestinal pH as a factor in selection of animal models for bioavailability testing.

Previous in situ studies showed that intestinal drug absorption is strongly influenced by intestinal pH. Three animal species considered for bioavailability testing were studied in situ to determine intestinal pH. Results from the rat and dog correlated well with results in humans, while results from the rabbit did not. The rabbit appears to be a poor candidate for attempted animal-human bioavailability correlations.

Animals↗
PubMed1975

The effect of congestive heart failure on quinidine pharmacokinetics.

Quinidine is an effective antiarrhythmic agent whose therapeutic effects and toxicity have been related to its serum concentrations. Many patients with cardiac arrhythmias also suffer from congestive heart failure. It is well documented that congestive heart failure can reduce blood perfusion to many regions of the body, and could conceivably alter drug pharmacokinetics. A pharmacokinetic evaluation of two sets of quinidine data in congestive heart failure patients indicates that congestive heart failure reduced the rate of absorption and volume of distribution following oral or intramuscular administration of quinidine. Furthermore, the amount of quinidine absorbed following oral administration is reduced, but congestive heart failure does not appear to alter the elimination rate of quinidine. The interpretation of the data presented herein strongly suggests that the site of administration, extent of distribution, and rate of absorption must be considered when determining dosage regimens in congestive heart failure patients since normal dosages in these patients result in abnormally high serum quinidine concentrations.

Administration, Oral↗
PubMed1975

Clofibrate pharmacokinetics: effect of elevation of plasma-free fatty acids.

The pharmacokinetics of rho-chlorophenoxyisobutyrate (CPIB), the active metabolite of clofibrate were determined following intravenous administration in the rat. Serum CPIB concentrations were measured using an new TLC-GLC method. The results agree favourably with pharmacokinetics in human subjects after oral administration of clofibrate. Both clofibrate and free fatty acids (FFA) are extensively bound to circulating plasma proteins. When plasma FFA were elevated to about 2,000 muEq/1, the CPIB elimination half-life decreased form 19.3 h in controls to 7.3 h. Thus, elevation of FFA appears to significantly alter the pharmacokinetics of a highly bound drug.

Animals↗