Biomedical subjects

W R Ravis

Publications and source records attributed to W R Ravis.

At least 55 records · Page 3Linked to original sources

PubMed1989

Pharmacokinetics of phenobarbital in dogs given multiple doses.

Studies were conducted to examine the temporal changes in phenobarbital pharmacokinetics during chronic dosing in dogs. Ten dogs were allotted into 2 groups, administered a single oral dose, rested for 35 days, and then given the drug for 90 consecutive days. After single administration of 5.5 mg/kg of body weight or 15 mg/kg, the total body clearance (Clt/F) was 5.58 +/- 1.89 ml/h/kg and 7.28 +/- 1.07 ml/h/kg, respectively. The half-lives (t1/2) for the 2 groups were 88.7 +/- 19.6 hours for the 5.5-mg/kg dose and 99.6 +/- 22.6 hours for the 15-mg/kg dose. Significant differences in Clt/F or t1/2 were not observed between the 2 groups. Multiple-dosing regimens (5.5 mg/kg/day or 11 mg/kg/day) were initiated in the same dogs for 90 days. The Clt/F was significantly (P less than 0.05) greater on days 30, 60, and 90 than the single dose for both groups. After the last dose on day 90, several blood samples were obtained to determine phenobarbital t1/2. On day 90, the t1/2 was significantly (P less than 0.05) shorter and the Clt/F was significantly greater than single-dose values. The Clt/F and t1/2 were 10.2 +/- 1.7 ml/h/kg and 47.3 +/- 10.7 hours for the group given the low dose and 15.6 +/- 2.5 ml/h/kg and 31.1 +/- 4.4 hours for the group given the high dose, respectively. Both Clt/F and t1/2 were significantly (P less than 0.05) different between the 2 groups on day 90.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1988

Liquid chromatographic determination of serum levels of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide, a new benzamide anticonvulsant.

A method for the high-performance liquid chromatographic (HPLC) determination of serum concentrations of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide and its N-acetylated metabolite is described. The compounds are isolated from a 50-microL sample of serum using solid phase extraction. The compounds and internal standard are eluted from the extraction column with acetonitrile. Quantitation is performed via UV detection at 275 nm following isocratic reversed-phase (C18) separation using a ternary solvent system. The assay procedure is useful for the determination of concentrations of parent compound from 0.63 to 87.9 micrograms/mL from 50 microL of serum.

Acetylation↗

PubMed1988

Buffer and pH effects on propranolol binding by human albumin and alpha 1-acid glycoprotein.

Propranolol binding to isolated human alpha-1-acid glycoprotein (AGP) and human albumin (HSA) was studied by equilibrium dialysis at 37 degrees C. With AGP (0.067%) and HSA (4%), total propranolol concentration was varied from 0.7 to 93,000 ng mL-1. Over this concentration range the percentage drug bound to HSA declined from 49 to 39% while that to AGP declined from 68 to 4%. Two classes of sites were identified on AGP with n1k1 = 8.50 X 10(4) M-1 and n2k2 = 3.12 X 10(4) M-1. With a pH 7.4 phosphate buffer, propranolol binding to AGP was greatest when the protein was initially dissolved in pH 7.4 water compared with pH 7.2 water or the phosphate buffer. Thus, the method of AGP solution preparation affected propranolol binding by this protein. For both AGP and HSA, greater drug binding was noted with phosphate buffers in comparison with a physiological buffer. With phosphate buffers, decreasing pH from 7.4 to 7.0 decreased propranolol binding by AGP, while decreasing pH from 7.7 to 7.4 had little effect. With HSA, the percent propranolol bound consistently decreased on lowering pH from 7.7 to 7.0.

Buffers↗

PubMed1988

Calcium antagonism in isolated rat uterus by methylmethacrylate.

Methylmethacrylate (MMA) was evaluated for the ability to block actions of calcium in the isolated rat uterine preparation. MMA blocked receptor-mediated contraction and the phasic and tonic portions of the KCl induced contraction of the uterus. The effects of MMA could be antagonized by increasing the concentration of calcium. In the Ca++-free, K-depolarized preparation, MMA produced dose related depression of contraction.

Animals↗

PubMed1987

Liquid chromatographic determination of sulindac and metabolites in serum.

An improved liquid chromatographic procedure is described for the quantitative determination of sulindac, sulindac sulfone, and sulindac sulfide from serum. The procedure makes use of acetonitrile extraction of the compounds of interest from acidified serum samples. Under these conditions extraction efficiencies in the 85 percent range are obtained for each of the compounds. The liquid chromatographic separation of the compounds of interest and the internal standard (indomethacin) is accomplished in an isocratic elution procedure using a nitrile (CN) stationary phase. The HPLC separation procedure is completed in less than 10 minutes, giving excellent resolution and peak shape.

Biotransformation↗

PubMed1987

A pharmacokinetic study of phenobarbital in mature horses after oral dosing.

The pharmacokinetics of phenobarbital were determined in six mature horses after a single oral dose. Horses were administered a 5.5 mg/kg of body weight oral dose of phenobarbital tablets. Based on the combined evaluation of i.v. and oral results, phenobarbital displayed two-compartment pharmacokinetics in the horse with a terminal half-life of 19.0 +/- 4.4 (mean +/- SD) h. This half-life is considerably shorter than those reported for dogs and humans. The steady-state volume of distribution (Vdss/F) and the total body clearance (Clt/F) of phenobarbital were 0.753 +/- 0.115 l/kg and 27.9 +/- 9.2 ml/h/kg, respectively. The average extent of oral absorption was 101% with a range of 76 to 124% among the six horses. Examination of the absorption kinetics demonstrated a biphasic absorption process in four horses with a rapid absorption followed by a slower absorption phase. The mean residence time (MRT) was 36.9 +/- 4.1 h and the mean residence time for oral absorption (MRTabs) was 11.3 h. Based on the results of the present study, an oral dosing regimen of 11 mg/kg of body weight every 24 h can be recommended.

Absorption↗

PubMed1987

Pharmacokinetics of single doses of phenobarbital given intravenously and orally to dogs.

Pharmacokinetics of phenobarbital was studied in 10 healthy dogs after single IV or oral administration. Phenobarbital sodium was administered IV to 5 dogs in group A (5.5 mg/kg of body weight) and 5 dogs in group B (15 mg/kg). Serial venous blood samples (n = 21) were collected from each dog before (base line) and after the administration of phenobarbital sodium for pharmacokinetic evaluation. After a 30-day resting period, 3 dogs in group A and 3 in group B were randomly selected and used for an IV crossover treatment. The IV treatment mean half-life of phenobarbital sodium was 92.6 +/- 23.7 and 72.3 +/- 15.5 hours, whereas mean total clearance was 5.60 +/- 2.31 and 6.66 +/- 0.78 ml/hr/kg for doses of 5 and 15 mg/kg, respectively. The mean residence time was 124 +/- 34 hours and 106 +/- 23 hours for the 5.5 and 15 mg/kg, IV doses, respectively. Significant differences (P greater than 0.05) were not observed in pharmacokinetic parameters between the 2-dose study. After a 35-day resting period, dogs in groups A and B were treated as described for the single IV treatment, except that they were given a phenobarbital tablet orally. Serial venous blood samples (n = 24) were collected before (base line) and after the administration of phenobarbital. Mean bioavailability was 88.1 +/- 12.4% and 96.8 +/- 9.0%, half life of absorption was 0.263 +/- 0.185 and 0.353 +/- 0.443 hour, and lag time was 0.611 +/- 0.683 and 0.741 +/- 0.554 hour for groups A and B, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1987

Pharmacokinetics of phenobarbital in the horse.

Pharmacokinetics of phenobarbital was examined in 6 mature horses after 12 mg of phenobarbital/kg of body weight was infused over 20 minutes. Biexponential decrease in serum phenobarbital concentrations was observed with a distribution-phase half-life of 0.101 +/- 0.086 hour (mean +/- SD) and a terminal-phase elimination half-life of 18.3 +/- 3.65 hours. The volume of distribution at steady state was 0.803 +/- 0.070 L/kg. Total body clearance of phenobarbital was 30.8 +/- 6.2 ml/h/kg. The high clearance in the horse seems to explain the markedly shorter half-life of phenobarbital in this species. Seemingly, 6.65 mg of phenobarbital/kg as a 20-minute infusion given every 12 hours would provide approximate peaks of 29 micrograms/ml and troughs of 15 micrograms/ml. A loading dose of 12 mg of phenobarbital/kg would be appropriate for this regimen.

Animals↗

PubMed1987

Pharmacokinetics and interactions of digoxin with phenobarbital in dogs.

In one experiment, 5 dogs were administered digoxin (0.022 mg/kg of body weight, IV), were rested for 2 weeks, were then given phenobarbital (13.2 mg/kg orally) for 14 days, and then were given digoxin again (0.022 mg/kg, IV). Comparing prephenobarbital (control) digoxin half-lives of 42.4 +/- 8.8 hours and postphenobarbital digoxin half-lives of 18.0 +/- 2.2 hours, the half-life was significantly (P less than 0.05) decreased after phenobarbital administration. Clearance was increased by 84%, and the volume of distribution given was decreased by 34%. In a second experiment, 5 dogs were given digoxin (0.022 mg/kg, orally) daily for 11 days, and the digoxin kinetics were evaluated after the last dosing. The dogs were then rested and given phenobarbital (13.2 mg/kg, orally) once daily for 14 days and digoxin (0.022 mg/kg) once daily for 11 days, and the pharmacokinetics of digoxin was determined on the last day of dosing. Significant differences in steady-state serum concentrations and the pharmacokinetics of digoxin were not found between the control and phenobarbital phases of the experiment. Mean (+/- SD) half-lives of digoxin were 29.0 +/- 7.2 hours before phenobarbital treatment (control) and were 34.8 +/- 7.2 hours after phenobarbital treatment. In comparing results of the single-dose experiment vs the oral multiple-dose experiment, dogs had shorter half-lives for digoxin after multiple dosing. Therefore, if phenobarbital and digoxin are to be chronically coadministered orally, an adjustment in the digoxin dose is not necessary.

Animals↗

PubMed1987

Pharmacokinetics of oxytetracycline hydrochloride in rabbits.

Pharmacokinetics of oxytetracycline HCl (OTC) was studied in rabbits. After 10 mg of OTC/kg of body weight was administered IV, the distribution half-life was 0.06 hour, terminal half-life was 1.32 hours, volume of distribution area was 0.861 L/kg, and total body clearance was 0.434 L/kg/h. After 10 mg of OTC/kg was given IM, the absorption half-life was 2.09 hours, extent of absorption was 71.4%, and total body clearance of the absorbed fraction was 0.576 L/kg/h. Based on these kinetic data, a dosage of 15 mg of OTC/kg, every 8 hours was developed. This dose given IM for 7 consecutive days resulted in observed steady-state maximum and minimum concentrations (mean +/- SD) of 4.7 +/- 0.3 micrograms/ml and 3.2 +/- 0.6 micrograms/ml, respectively. Twice this dose (30 mg of OTC/kg, every 8 hours) given IM caused anorexia and diarrhea.

Animals↗

PubMed1987

Accuracy of three methods for predicting concentrations of free phenytoin.

Predictions of free (unbound) serum phenytoin concentration by three methods were compared with results obtained by the Abbott TDx Free Phenytoin ultrafiltration and fluorescence-polarization immunoassay technique. Data were obtained for hospitalized adults who had been receiving phenytoin for at least five days and were free of renal or hepatic disease. Total phenytoin concentration was determined, and free phenytoin concentration was measured in ultrafiltrate at 25 degrees C. For each patient, measured concentrations of total phenytoin and albumin were used to predict free phenytoin concentrations by the Gugler method, the Sheiner-Tozer nomogram, and the Sheiner-Tozer equation. Mean measured percentages of free phenytoin were 17.79%, 12.13%, and 8.73%, respectively, for patients with albumin concentrations of less than 2 g/dL (n = 5), 2-3 g/dL (n = 18), and greater than 3 g/dL (n = 26). There was a strong correlation between actual and predicted free phenytoin concentrations for each of the methods, but all methods were found to lack precision. All methods also exhibited bias, as demonstrated by overprediction of the free concentration; however, none of the methods exhibited bias when the difference between the in vitro temperature of 25 degrees C and the in vivo temperature of 37 degrees C was considered. Because of their poor precision, the three methods evaluated in this study are not recommended for predicting free phenytoin concentration.

Adult↗

PubMed1987

Pharmacokinetics and tissue residues of gentamicin in lactating cows after multiple intramuscular doses are administered.

Gentamicin was administered IM to 6 healthy, mature, lactating cows at a dosage of 3.5 or 5 mg/kg of body weight every 8 hours for 10 consecutive days (total, 30 doses). Endometrial biopsies were done at 72, 136 or 144, and 216 hours after the first dose was administered. On the 10th day, just before the last dose of gentamicin was administered, blood samples (designated 10th-day base-line samples) were obtained, and serial blood samples were obtained for 144 hours after the last injection was given. The cows were catheterized on the 10th day, and urine was obtained for 10 to 18 consecutive hours. Milk samples were also obtained. The cows were slaughtered at different times after the last dose was given, and samples were taken from 22 tissues and organs. Serum, milk, urine, and tissue gentamicin concentrations were determined by radioimmunoassay. Serum gentamicin concentrations were best fitted to a 2-compartment open model. The mean half-lives for absorption, distribution, and elimination were 0.16 +/- 0.14, 2.59 +/- 0.53, and 44.91 +/- 9.38 hours, respectively. Total body clearance and renal clearance were 1.65 +/- 0.69 and 1.32 +/- 0.25 ml/min/kg, respectively. The percentage of the dose excreted unchanged in the urine at 8 hours after the last dose was given was 98 +/- 15. As expected, of the tissues examined, the gentamicin concentrations in the kidney cortex and medulla were 1,500 times greater than those in serum. Renal function remained within the baseline range during the 10 days of gentamicin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Cyclosporine pharmacokinetics in normal and pancreatectomized dogs.

Oral and i.v. cyclosporine (Cs) pharmacokinetics determined from radioimmunoassay (RIA) data were compared in normal and pancreatectomized dogs. An altered pharmacokinetics of Cs was observed in the pancreatectomized dogs that include: a 170% larger central compartment volume; a 34% greater total-body clearance; and lower steady-state average serum concentrations relative to the normals. Even though there were marked intersubject variations, both groups displayed a triexponential decline in Cs serum concentrations and disposition kinetics. Following 7 daily oral doses of commercial cyclosporine (CsA) (20 mg/kg) the Cs serum trough concentrations of the pancreatectomized dogs were consistently below 100 ng/ml, while those of the normal dogs were above 400 ng/ml. No alteration of CsA oral absorption was noted following pancreatectomy. This study suggests that frequent serum Cs concentration monitoring, with appropriate dosage adjustments, even in normals, is necessary to assure adequate drug levels. More significantly, the CsA dosage for pancreatectomized dogs should be several times greater to maintain serum concentrations comparable to normal dogs.

Animals↗

PubMed1986

Concentrations of gentamicin in serum, milk, urine, endometrium, and skeletal muscle of cows after repeated intrauterine injections.

Healthy mature cows (n = 6) were injected intrauterinally (IU) with gentamicin (50 ml of a 5% injectable solution) daily for 3 consecutive days. Venous blood and milk samples were collected at postinjection (initial) hours (PIH) 1, 3, 6, 9, 12, 24, 28, 31, 34, 37, 48, 51, 54, 57, 60, and 71, and endometrial biopsies were performed at PIH 6, 25, 48, 73, 95, and 119. Skeletal muscle biopsy samples were taken at PIH 25 and 73, and urine was collected every 1 or 2 hours during 12 consecutive hours after the first IU injection. Serum, milk, urine, and tissue concentrations of gentamicin were measured by radioimmunoassay. The highest mean serum concentration of gentamicin occurred during the 3 hours after each injection (2.49 +/- 1.46, 6.60 +/- 5.47, and 4.98 +/- 2.70 micrograms/ml). The mean peak concentration of gentamicin in milk occurred 3 to 6 hours after each injection. Mean peak urine concentration of gentamicin (256.8 +/- 127.9 micrograms/ml) was measured at PIH 6. The mean percentage of the first dose of gentamicin excreted in the urine within 12 hours was 14.78 +/- 3.56. The highest concentration of gentamicin in endometrial tissue (639.16 +/- 307.22 micrograms/g) was measured at PIH 6, decreasing to 9.64 +/- 3.55 micrograms/g before the next IU dose. Gentamicin was still detectable in endometrial tissue (0.86 +/- 0.43 microgram/g) 71 hours after the 3rd (last) IU injection.

Animals↗

PubMed1986

Inhibition of isoproterenol positive atrial chronotropic effect by methylmethacrylate polymer and monomer.

Atria from rats exposed in vivo to methylmethacrylate polymer or monomer were superfused and chronotropic responses to isoproterenol determined. Control and polymer-exposed atria superfused with oxygen-saturated buffer yielded dose-response curves which were essentially identical with regard to maximal increase and potency of isoproterenol. Control atria superfused with buffer containing 70% of possible oxygen saturation showed a 10-fold decrease in isoproterenol potency and a maximal effect approximately 75-80% that of fully oxygenated atria. Atria exposed to methylmethacrylate polymer and superfused with 70% oxygen saturated buffer showed a 100-fold decrease in isoproterenol potency and a maximal effect approximately 25% that of fully oxygenated control atria. Exposure of rats to methylmethacrylate monomer in vivo resulted in complete abolition of the chronotropic response to isoproterenol in atria superfused with 70% oxygen saturated media.

Animals↗

PubMed1986

Pharmacokinetics of single doses of gentamicin given by intravenous and intramuscular routes to lactating cows.

Healthy mature lactating cows (n = 6) were given gentamicin (5 mg/kg of body weight) by IV route and another dose 19 days later by IM route. Serum gentamicin concentrations were determined over a period of 48 hours after each drug dosing, using radioimmunoassay. With the aid of a nonlinear least-square regression analysis program, the combined data of the IV and IM treatments were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the sum of squares by F test and the SD of the estimated values. The distribution phase half-life was 0.25 +/- 0.12 hour, and postdistribution half-life was 1.83 +/- 0.18 hours. The volume of the central compartment was 0.10 +/- 0.02 L/kg, volume of distribution at steady state was 0.16 +/- 0.03 L/kg, and the total body clearance was 1.32 +/- 0.17 ml/min/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.63 +/- 0.28 hour. The extent of IM absorption was 92% +/- 15%. The percentage of the IM dose eliminated in the urine during the first 8 hours was 83 +/- 8. Gentamicin was detected in milk for 48 hours. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 3.5 mg/kg of body weight every 8 hours would provide average steady-state serum drug concentrations of 5.08 micrograms/ml, with minimum and maximum steady-state concentrations of 1.03 and 12.05 micrograms/ml, respectively, whereas an IM injection of a 5 mg/kg dosage every 8 hours would provide average steady-state serum concentrations of 7.26 micrograms/ml, with minimum and maximum steady-state serum concentrations of 1.47 and 17.21 micrograms/ml, respectively.

Animals↗

PubMed1986

Accuracy of five methods for predicting phenobarbital concentrations in pediatric patients.

Four published methods of predicting steady-state phenobarbital concentrations were evaluated and compared with a new method. In phase 1, steady-state serum phenobarbital concentrations were obtained from 36 complaint patients who were 6 months to 15 years old. Patients were stratified into five groups according to weight. Each patient's steady-state serum phenobarbital concentration was then predicted using clearance (CL) values from four published methods (methods 1-4), and these serum-concentration values were compared with actual steady-state concentrations. In phase 2, 17 new patients were selected. The mean CL values determined for each weight group of phase 1 patients were incorporated into another method (method 5) and used to calculate steady-state phenobarbital concentrations for phase 2 patients. In both study phases, predicted concentrations were compared with both the actual concentration in each patient and a naive predictor. In phase 1, method 1 was the least biased; methods 2-4 were significantly biased and were not significantly better than the naive predictor. In phase 2, methods 1-4 were more biased and less precise than method 5. In both study phases, methods 2-4 consistently under-predicted phenobarbital concentrations. The prediction method based on clearance data obtained in a group of pediatric patients at our institution (method 5) appears to be more useful for predicting serum phenobarbital concentrations than four other prediction methods based on published clearance values.

Adolescent↗

PubMed1986

Pharmacokinetics of cefotaxime in the domestic cat.

Cefotaxime was administered as single IV or IM dose for the purpose of examining its pharmacokinetics in healthy cats. The mean predicted plasma concentration of cefotaxime in 6 cats at 0 time after a single IV dosage of 10 mg/kg of body weight was 88.9 micrograms/ml. The mean plasma concentrations decreased to 10.8 micrograms/ml at 2 hours, 3.7 micrograms/ml at 3 hours, and 0.5 microgram/ml at 6 hours. The half-life was 0.98 +/- 0.25 hour (mean +/- SD), and the total body clearance was determined to be 2.76 +/- 1.25 ml/min/kg. After a single IM injection of 10 mg/kg of body weight, the mean maximum observed plasma concentration was 36.2 micrograms/ml at 0.75 hour. The mean absorption half-life was 0.24 hour. In 2 animals, the bioavailability of an IM injection was 98.2% and 93.0%.

Animals↗