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Biomedical subjects

W R Ravis

Publications and source records attributed to W R Ravis.

At least 19 recordsLinked to original sources
PubMed1994

The pharmacokinetics and pharmacodynamics of procainamide in horses after intravenous administration.

Six horses were administered either 15 or 20 mg/kg body weight (b.w.) procainamide (PA) as an intravenous (i.v.) dose over 10 min. The plasma concentrations of PA and N-acetylprocainamide (NAPA) as well as the pharmacodynamic effect (prolongation of the QT interval) were monitored. The PA plasma concentrations could be described by a one-compartment model with a t1/2 of 3.49 +/- 0.61 h. The total body clearance of PA was 0.395 +/- 0.090 l/hr/kg and the volume of distribution was 1.93 +/- 0.27 l/kg. As observed after PA administration, NAPA (an active metabolite) had a t1/2 longer than PA of 6.31 +/- 1.49 h. Peak NAPA concentrations (1.91 +/- 0.51 micrograms/ml) occurred at 5.2 h after the PA i.v. dose. The ratio of area under the curves for NAPA to PA was 0.46 +/- 0.15 which is similar to that expected in humans classified as slow acetylators. Percentage change in the QT interval was examined with respect to PA and PA + NAPA plasma concentrations. For PA, % delta QT = 41.2 log (PA) - 13.26 and correlations (r) ranged from 0.77 to 0.91 among the horses. In the case of PA+ NAPA, % delta QT = 57.3 log (PA + NAPA) - 31.83 and ranged from 0.77 to 0.90. No evidence of toxicity was noted with respect to changes in the PR interval.

Acecainide↗
PubMed1994

Influence of cholestyramine resin administration on single dose sulindac pharmacokinetics.

Cholestyramine, a nonabsorbable anion exchange resin, has been reported to bind concomitantly administered drugs and decrease their bioavailability. The objective of the study was to determine cholestyramine effect on the plasma concentrations of sulindac and its sulfide metabolite following concurrent and staggered (sulindac 3 hours before cholestyramine) dosing. Six healthy volunteers participated in an open-label, 3-way crossover study. Subjects received 400 mg sulindac orally followed by serial blood sampling for sulindac and sulindac sulfide plasma concentrations over a 24-hour period. During the concurrent phase, 4 g of cholestyramine was coadministered resulting in a decrease (p < 0.05) in the area under the curve (AUC) for sulindac compared to sulindac alone (7.11 +/- 3.25 micrograms-h/ml vs 31.65 +/- 7.94 micrograms-h/ml respectively). Also, the sulindac sulfide AUC decreased (p < 0.05) to 7.26 +/- 4.37 micrograms-h/ml coadministration of both drugs compared to 44.69 +/- 11.81 micrograms-h/ml when sulindac is given alone. When the same doses of each drug were given 3 hours apart, the AUC for sulindac (17.88 +/- 3.69 micrograms-h/ml) and its sulfide metabolite (20.12 +/- 7.46 micrograms-h/ml) were still significantly decreased (p < 0.05) when compared to sulindac given alone (31.65 +/- 7.94 micrograms-h/ml for sulindac and 44.69 +/- 11.81 micrograms-h/ml for sulindac sulfide). Based on the lower AUCs for sulindac and sulindac sulfide, separating sulindac and cholestyramine by 3-hour intervals did not prevent the interaction. It is likely that the enterohepatic recycling features of sulindac may not prevent the interaction with cholestyramine even when the 2 drugs are staggered.

Adult↗
PubMed1992

Pharmacokinetics and intramuscular bioavailability of amikacin in chickens following single and multiple dosing.

The pharmacokinetics of amikacin were studied in healthy mature female chickens (n = 6). Single doses of amikacin were injected as an i.v. bolus (10 mg/kg) and i.m. (20 mg/kg) into the same birds with a 30-day rest period between treatments. Amikacin was determined by the fluorescence polarization immunoassay method. The i.v. pharmacokinetics could be described by a two-compartment model with a t1/2 alpha of 0.150 +/- 0.064 h and a t1/2 beta of 1.44 +/- 0.34 h. The total body clearance was 0.109 +/- 0.017 1/h/kg and the volume of distribution at steady-state was 0.193 +/- 0.060 l/kg. Following a single i.m. injection, the peak plasma concentration (Cmax) was 50.79 +/- 4.05 micrograms/ml and occurred at 0.50 +/- 0.26 h. The i.m. extent of absorption was 91.2 +/- 17.6%. Simultaneous modeling of i.v. and i.m. results provided estimates of an absorption half-life of 0.480 +/- 0.158 h. The i.m. pharmacokinetics after repeated administration were studied following the tenth dose (20 mg/kg, every 8 h). The Cssmax was 38.58 +/- 6.96 micrograms/ml and occurred at 0.79 +/- 0.37 h, and the biological half-life of amikacin was 1.86 +/- 0.47 h. The multiple dosing yielded peak concentrations of 39 micrograms/ml and trough concentrations of 3.26 micrograms/ml. Based on these data, the recommended amikacin dosage in chickens is 20 mg/kg body weight every 8 h.

Absorption↗
PubMed1992

Effect of a perfluorochemical emulsion on the rat hepatic mixed function oxidase system.

The perfluorochemical components of synthetic oxygen transporting emulsions may persist in hepatic tissue. After a single 30% blood exchange with the perfluorochemical emulsion, Fluosol-DA 20%, the effects on the microsomal metabolism of 7-methoxycoumarin and 7-ethoxycoumarin were studied over a 9-week period. Fluosol-DA treated animals were compared with controls (sham) and hetastarch-treated controls. Changes in dealkylase activities were compared with induction by phenobarbitone and 3-methylcholanthrene. The liver to body weight ratio increased by 49% in Fluosol-DA-treated rats over the controls at 1 week and the microsomal protein was increased in the Fluosol-DA-treated rats after 4 and 9 weeks. Fluosol-DA treatment induced 7-methoxycoumarin demethylase with peak differences occurring at 1 week and a Vmax 75% greater than controls. Fluosol-DA was a more potent inducer of demethylase than phenobarbitone. In addition, 7-ethoxycoumarin de-ethylase was induced by Fluosol-DA with a peak induction at 4 weeks. The Vmax at 4 weeks in Fluosol-DA-treated rats was 122% greater than control. In this case, Fluosol-DA produced less induction in de-ethylase than 3-methylcholanthrene. These studies show that Fluosol-DA induces more than one form of cytochrome P450 and the effects resemble those of phenobarbitone more than those of 3-methylcholanthrene. Hetastarch, a plasma expander, did not affect liver weights, microsomal protein content, or the cytochrome P450 system.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1992

Pharmacokinetics of phenobarbital in horses after single and repeated oral administration of the drug.

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 +/- 4.7 and 11.2 +/- 2.3 hours, volume of distribution = 0.960 +/- 0.060 and 0.914 +/- 0.119 L/kg, and clearance = 28.2 +/- 5.1 and 57.3 +/- 9.6 ml/h/kg, respectively. Results indicated that significant (P less than 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for gamma-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1992

Effects of lactated Ringer solution and prednisolone sodium succinate on dogs with induced hemorrhagic shock.

Hemorrhagic shock was induced in nonsplenectomized dogs by removing 41% of their blood volume over a 15-minute period. Hemodynamic and metabolic variables were determined prior to and for 3 hours after completion of hemorrhage. One group of 5 dogs was not treated. After the 30-minute sample was collected, a second group of 5 dogs was given lactated Ringer solution (LRS) at 88 ml/kg of body weight, IV. A third group of 5 dogs was given LRS (88 ml/kg, IV) and prednisolone sodium succinate (11 mg/kg, IV) 30 minutes after hemorrhage. The IV administration of LRS was completed within 15 minutes. The glucocorticoid was administered as an IV bolus after 500 ml of LRS had been given. The large volume and administration of LRS significantly (P = 0.05) improved many of the hemodynamic and metabolic effects of acute hemorrhage and hemorrhagic shock. At one time or another during the 2.5-hour observation period after the initiation of treatment, mean arterial pressure, cardiac index, systemic vascular resistance, heart rate, respiratory rate, lactate, glucose, and arterial and venous blood gas values were significantly (P = 0.05) improved, compared with baseline values. The addition of prednisolone sodium succinate to the treatment regimen improved the effectiveness of LRS alone only in some dogs at random sampling times. Significant trends were not observed except, possibly, the improvement of venous pH and A-V pH and PCO2 differences.

Acute Disease↗
PubMed1991

Determination of neomycin in plasma and urine by high-performance liquid chromatography. Application to a preliminary pharmacokinetic study.

A reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the determination of neomycin in plasma and urine. The plasma was deproteinated with trichloroacetic acid and centrifuged. The supernatant was mixed with ion-pair concentrate and centrifuged again. The resultant supernatant was analyzed by HPLC. Urine was centrifuged to remove debris, if any, mixed with ion-pair concentrate and analyzed directly by HPLC. The HPLC conditions consisted of an ion-pairing mobile phase, a reversed-phase column, post-column derivatization with o-phthalaldehyde (OPA) reagent and fluorescence detection. The overall average recovery of neomycin was 97 and 113% from plasma spiked at 0.25-1.0 micrograms/ml, using standard curves prepared in plasma extract and in water, respectively, and 94% for urine spiked at 1-10 micrograms/ml using a standard curve prepared in water. The method was used to detect neomycin in plasma and urine obtained from animals injected intramuscularly with neomycin. Various pharmacokinetic parameters of neomycin were also determined from its profile of plasma concentration versus time.

Animals↗
PubMed1991

Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin.

This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when exposed to different beta-lactams, beta-lactamase inhibitors, and heparin. The aminoglycosides (5, 10, 20, and 50 micrograms/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 micrograms/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin, oxacillin, and sulbactam (20 and 120 micrograms/ml) for 48 h at 37 degrees C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial diffusion bioassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood containing either heparin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P less than 0.003) and gentamicin (P less than 0.0002) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation was measured by FPI. A significant difference in the degree of inactivation was noted between isepamicin and gentamicin (P less than 0.003 at 8 h and P less than 0.006 at 48 h) but not between isepamicin and amikacin (P greater than 0.7 at 8 h and P greater than 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the presence of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivation by beta-lactam compounds and beta-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPI.

Amikacin↗
PubMed1991

Perfluorochemical erythrocyte substitutes: disposition and effects on drug distribution and elimination.

As a result of their ability to transport oxygen, PFC emulsions are being investigated for possible use in a wide variety of conditions. The recent FDA approval of F-DA to diminish myocardial ischemia during angioplasty is the first marketing approval for such a product in the world. The many potential uses of such products may result in their common application in the future, especially as new and better products are developed. The elimination, distribution, and tissue retention of PFC emulsions as well as the physiological changes that occur upon their administration have been the subject of many investigations. The results indicate that these agents may influence the pharmacokinetic properties of other drugs by a wide variety of mechanisms. Several studies have shown significant, but not necessarily consistent, changes in drug elimination and distribution following PFC emulsion infusion. Changes appear dependent on the drug examined, emulsion utilized, degree of blood exchange, species utilized, and the controls chosen for comparison. Often, the changes are time dependent indicating the importance of conducting long-term studies. While PFC emulsions do not appear to alter renal elimination of drugs, several studies have demonstrated that these agents have the potential to induce drug metabolism from several days to possibly months after exposure. Observed changes in drug volumes of distribution, which are often time dependent, may be due to changes in normal drug transport throughout the circulation and/or changes in membrane permeability and cell transport mechanisms. Changes in drug transport may result from depletion of plasma proteins or increases in alpha 1-acid glycoprotein levels due to trauma or PFC emulsion effects. The binding of drugs by PFC emulsion droplets varies greatly and PFC emulsion components displace some plasma protein bound drugs. The wide variability in the results and conclusions of the pharmacokinetic studies conducted to date emphasize the importance of utilizing adequate controls to identify which alterations are PFC emulsion specific.

Animals↗
PubMed1991

Physiological effects of a perfluorochemical blood substitute in beagle dogs.

Perfluorochemical (PFC) emulsions have been examined for use as erythrocyte substitutes in the treatment of various disease states. The physiological changes induced by PFC infusion would be an important determinant of successful clinical therapy. Previous studies have reported PFC induced changes in the disposition of drugs. This report describes some physiological (hematology, cardiovascular, liver enzyme) changes resulting from a 30% blood exchange with a PFC emulsion in Beagle dogs. A 30% blood exchange with hydroxyethylstarch (HES) also was evaluated and compared to the PFC emulsion exchange. The blood pressure was markedly reduced shortly after PFC infusion while HES infusion produced only minor changes. Changes in the heart rate following blood replacement were similar for PFC and HES treated dogs. Hematology profiles also were similar for the PFC and HES treatment groups. The liver enzyme levels in PFC treated dogs showed marked elevations beginning shortly after PFC infusion and remained elevated for months after the initial PFC blood replacement. In contrast, HES treated dogs exhibited no observable changes in liver enzyme levels over the time course of the study.

Animals↗
PubMed1991

Perfluorochemical emulsion effect on human albumin binding of valproic acid.

At 37 degrees C, valproic acid was weakly bound by a PFCE through an interaction with the emulsifiers that was independent of both buffer and PFCE concentration. The binding by PFCE was dependent on valproic acid concentration in 0.1 M buffer, but not in 0.2 M buffer. The addition of PFCE to 4% HSA increased the percent free valproic acid due to both HSA dilution and displacement of HSA bound drug. This displacement was apparently due to an interaction with the PFC liquids and/or intact PFCE droplets, and with the oleic acid component of the PFCE.

Binding Sites↗
PubMed1991

Effects of treatment with aspirin or aspirin/dipyridamole combination in heartworm-negative, heartworm-infected, and embolized heartworm-infected dogs.

To determine the drug dose required to inhibit platelet reactivity by at least 50%, 2 drug regimens were evaluated in heartworm-negative, heartworm-infected, and heartworm-infected dogs embolized with dead heartworms. Aspirin, or a combination of aspirin and dipyridamole, were administered to 2 groups of Beagles (n = 5 each) for 5 to 9 days; a third group of 5 Beagles served as nontreated controls. For heartworm-negative dogs, mean (+/- SD) aspirin dosage that inhibited collagen-induced platelet reactivity by at least 50% was 6 (+/- 2) mg/kg of body weight given once daily. The aspirin/diphridamole combination dosage was 1 mg of each drug/kg given every 12 hours. All dogs (n = 15) were implanted with 7 adult heartworms each and remedicated (or not treated) beginning at 21 days after heartworm implantation. In heartworm-infected dogs, mean aspirin dosage required to inhibit collagen-induced platelet reactivity greater than or equal to 50% was 10 (+/- 6) mg/kg. Mean dosage of aspirin/dipyridamole combination was 1.6 +/- (0.5) mg of each drug/kg given every 12 hours. When platelet reactivity in response to collagen was determined to be inhibited by at least 50% in all medicated dogs, each dog (n = 15) was embolized with 7 dead adult heartworms to mimic heartworm adulticidal treatment. Platelet reactivity was monitored for 21 days after treatment, and drug dose was adjusted to maintain platelet inhibition by at least 50%. In embolized dogs, mean aspirin dosage was 17 (+/- 14) mg/kg given once daily. Mean dosage of the aspirin/dipyridamole combination was 2.8 (+/- 1.3) mg of each drug/kg given every 12 hours. All dogs (n = 15) were euthanatized 21 days after heartworm embolization. Each lung lobe was evaluated for severity of lesions and presence of organized or fibrinous thrombi. Lesion severity in the aspirin- and aspirin/dipyridamole-treated dogs was not significantly different from that in control dogs.

Adenosine Diphosphate↗
PubMed1991

Effects of treatment with ticlopidine in heartworm-negative, heartworm-infected, and embolized heartworm-infected dogs.

Ticlopidine hydrochloride was evaluated for its effectiveness in inhibiting platelet aggregation and serotonin release in 5 laboratory Beagles before and after heartworm implantation with 7 adult Dirofilaria immitis, and after embolization with 7 dead heartworms to mimic what happens after heartworm adulticide treatment. Five other laboratory Beagles, similarly implanted and embolized with heartworms, were used as nonmedicated controls. During the heartworm-negative stage, the dosage of ticlopidine that inhibited adenosine diphosphate (ADP)-induced platelet aggregation in 5 dogs by at least 50% after 5 days of treatment was 62 mg/kg of body weight once a day. In the same dogs implanted with 7 adult heartworms 21 days previously, mean (+/- SD) ticlopidine dosage required to obtain similar results was 71 (+/- 13) mg/kg given once daily. During the 21 days after dead heartworms were implanted in heartworm-infected dogs, mean ticlopidine dosage was 108 (+/- 35) mg/kg (range, 62 to 150 mg/kg). Ticlopidine treatment was associated with increased platelet numbers in all 5 dogs during the heartworm-negative stage and in 4 of 5 dogs during the heartworm implantation and heartworm embolization stages. Mean platelet volume tended to decrease as platelet numbers increased. At necropsy, gross and histologic pulmonary lesions were less severe in ticlopidine-treated dogs than in nonmedicated control dogs.

Adenosine Diphosphate↗
PubMed1991

Effect of a perfluorochemical erythrocyte substitute on the in vitro metabolism of lidocaine using rat liver slices.

Perfluorochemical (PFC) emulsions have recently been investigated for use in the treatment of various clinical conditions requiring red blood cell replacement. The physiological changes which develop following PFC infusion may directly, or indirectly alter the disposition of concomitantly administered agents. This study examined the in vitro metabolism of lidocaine (LC) following pretreatment of rats with a PFC emulsion. Studies were conducted from 2 days to 6 months after initial blood replacement. The control treatment included rats that received a blood exchange with their own blood (SHAM). Analysis of LC and its metabolites was performed using solid phase extraction (SPE) and a modified high performance liquid chromatography (HPLC) method. The predominate metabolite observed in the liver slice preparation was monoethylglycinexylidide (MEGX). No glycinexylidide (GX) was noted in any of the treatments. The results indicate an increase in the in vitro rate of metabolism of LC in rats pretreated with the PFC emulsion. These effects appeared to be time-dependent with maximal increase in metabolism at approximately 5 weeks after the blood exchange and persisting for up to 6 months. These changes in the disappearance of LC in liver slice preparations may reflect PFC-induced enzyme induction and/or altered tissue uptake of LC.

Animals↗
PubMed1991

Ototoxic potential of gentamicin in ponies.

Ototoxicosis was evaluated in 6 healthy ponies given 5 mg of gentamicin/kg of body weight, q 8 h, IM. Ponies 1, 2, and 3 were dosed for 7 days and ponies 4, 5, and 6 were dosed for 14 days. Serum peak and trough concentrations of gentamicin were measured by radioimmunoassay at regular intervals. Brain stem auditory-evoked responses were recorded every 5 days up to 60 days after the first dose to monitor auditory function. Although serum gentamicin concentrations were within or above the accepted clinical therapeutic range, loss of auditory function was not observed at the frequency range (1 to 4 kHz) tested. Serum chemical values remained within the accepted clinical range and no evidence of nephrotoxicosis was observed. Seemingly, gentamicin given IM to healthy ponies was safe and had minimal risk of side effects.

Animals↗
PubMed1990

Liquid chromatographic measurement of hydrophobicity constants for N-arylsulfonylglycine aldose reductase inhibitors.

The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k' data is used to estimate the capacity factor in 100% water (log k'w) for each compound. The log k'w values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953. The same procedure is then used to estimate the log k'w values for a large group of ARIs and their log P values, calculated from the established relationship between log k'w and log P from the reference compounds. An initial analysis of the aldose reductase inhibitory activity of these compounds as a function of hydrophobicity alone fails to reveal a clear relationship, demonstrating the need for a multivariant approach for quantitative structure-activity analysis in this series of compounds.

Aldehyde Reductase↗
PubMed1990

Liquid chromatographic properties and aqueous solution stability of N-hydroxy-3,4-methylenedioxyamphetamine.

The reversed-phase liquid chromatographic properties of N-hydroxy-3,4-methylenedioxyamphetamine (NOHMDA) were determined on a C8 stationary phase specifically prepared for the separation of basic compounds. NOHMDA and several N-alkyl MDA derivatives displayed excellent peak shape on this stationary phase without the need for competing bases such as triethylamine. The k' values for NOHMDA varied with mobile phase pH in the range of 2.5 to 6.0, but the retention of the primary amine, MDA, and N-alkyl MDAs remained relatively constant over this range. The pKa value for NOHMDA was determined by titration to be 6.22 compared to a pKa of 10.04 for MDA. Thus, the variation of k' with mobile phase pH for NOHMDA may be a result of appreciable changes in degree of protonation. The stability of NOHMDA was found to decrease with an increase in aqueous solution pH. At pH 7.0 the degradation half-life was determined to be 49.8 h, which decreased to 2.57 h at pH 10.0. Above pH 10.0 the decomposition to the corresponding oxime was too fast for a reliable half-life determination.

3,4-Methylenedioxyamphetamine↗