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Biomedical subjects

G J Yakatan

Publications and source records attributed to G J Yakatan.

At least 19 recordsLinked to original sources
PubMed2004

Influence of concomitant quinidine administration on dextromethorphan disposition in rats.

High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague-Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI-LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED(50) of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.

Animals↗
PubMed2001

Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial.

BACKGROUND: Recurrent herpes simplex labialis (HSL) occurs in 20% to 40% of the US population. Although the disease is self-limiting in persons with a healthy immune response, patients seek treatment because of the discomfort and visibility of a recurrent lesion. OBJECTIVE: Our purpose was to determine whether docosanol 10% cream (docosanol) is efficacious compared with placebo for the topical treatment of episodes of acute HSL. METHODS: Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of HSL, were randomized to receive either docosanol or polyethylene glycol placebo and initiated therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times daily until healing occurred (ie, the crust fell off spontaneously or there was no longer evidence of an active lesion) with twice-daily visits. RESULTS: The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than observed in the 367 placebo-treated patients (P =.008; 95% confidence interval [CI]: 2, 22). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P =.002; 95% CI: 3, 16.5); (2) complete healing of classic lesions (P =.023; 95% CI: 1, 24.5); and (3) cessation of the ulcer or soft crust stage of classic lesions (P <.001; 95% CI: 8, 25). Aborted episodes were experienced by 40% of the docosanol recipients versus 34% of placebo recipients (P =.109; 95% CI for odds ratio: 0.95, 1.73). Adverse experiences with docosanol were mild and similar to those with placebo. CONCLUSION: Docosanol applied 5 times daily is safe and effective in the treatment of recurrent HSL. Differences in healing time compared favorably with those reported for the only treatment of HSL that has been approved by the Food and Drug Administration.

Acute Disease↗
PubMed1984

Dose-dependent pharmacokinetics and hepatobiliary transport of bromophenol blue in the beagle.

The pharmacokinetic profile of bromophenol blue (I) in the plasma, urine, and bile of beagle dogs was determined after intravenous administration of 5-, 20-, and 30-mg/kg doses. In addition, two competitors, probenecid and phenylbutazone, were interacted with I in vivo and with I and rat liver cytoplasmic protein fractions Y and Z in vitro as a means of elucidating the mechanism of intrahepatic transport of I. Compound I was determined spectrophotometrically at 587 nm. In plasma, I displayed apparent first-order dose-dependent kinetics. The percentage of I bound to plasma proteins was approximately 92.5% over the dose range studied. Consecutive injections of equal doses of I produced statistically different terminal half-lives (p less than 0.05), suggesting the possibility of a saturable uptake process. In the presence of each competitor, the disposition of I was altered significantly (p less than 0.05): phenylbutazone displaced I from plasma protein, while probenecid decreased the binding of I to liver proteins in the Z-fraction. The Z-fraction bound a larger amount of I than the Y-fraction, suggesting a larger binding capacity. Under no circumstances was the binding of I to the Y-fraction altered. Cumulative biliary excretion data showed that the elimination of I in bile accounted for 92-99% of the dose delivered. The biliary excretion sigma- plots displayed no dose dependency, suggesting that the dose-dependent plasma half-life is due to a dose-dependent liver uptake (as opposed to elimination) process.

Animals↗
PubMed1984

Effect of nonuniform bile flow rate on the rate of biliary excretion of bromophenol blue in the beagle.

Following the intravenous administration of bromophenol blue to beagle dogs, graphs of the biliary excretion rate versus time displayed drastic fluctuations which render them of little value for standard pharmacokinetic modeling purposes. It was shown that these fluctuations in excretion rate are highly correlated with corresponding fluctuations in the bile flow rate. An expression was derived which accounts for the primary effect of nonuniform bile flow rate on the biliary excretion rate. This treatment would enable the use of such biliary excretion rate data for pharmacokinetic modeling. Secondary effects of nonuniform bile flow on the biliary excretion rate are also discussed. It is suggested that the modeling of other flow rate-dependent elimination processes could benefit from such a treatment.

Animals↗
PubMed1983

Dose-dependent pharmacokinetics and biliary excretion of bromophenol blue in the rat.

Concentrations of bromophenol blue (I) in plasma, urine, and bile were determined spectrophotometrically after intravenous bolus injections and infusions in rats. The plasma concentrations were found to decrease monoexponentially after all doses except the highest, where the decrease was biexponential. Although the disposition kinetics of I were apparently first-order at all doses, the half-life increased with increasing dose. The area under the plasma concentration-time curve (AUC0-infinity) increased disproportionately with increasing dose. The binding of I to rat plasma proteins, as determined by equilibrium dialysis, showed that the fraction bound (96%) remained constant in the concentration range of 10-300 micrograms/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose administered 20 min later when plasma concentrations from the first dose were minimal. The apparent first-order elimination rate constant for the plasma concentration decline following the second dose was significantly less than after the first dose, indicating that the residual dye in the liver altered the elimination of I after the second dose. The fraction of the dose in the liver decreased with increasing dose, indicating a saturable uptake process. The biliary excretion profile reflected the uptake saturation that occurred in the liver and demonstrated that the biliary excretion of I depended on the amount present in the liver. When liver damage was induced by exposure to carbon tetrachloride, dye concentrations in the plasma, liver, and kidney increased markedly.

Animals↗
PubMed1982

The effect of probenecid on nafcillin disposition.

Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup-plate technique with M. luteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration-time curve (AUC) two-fold and decreased the total body clearance significantly with decreases in both renal and non-renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non-renal clearances of nafcillin.

Adult↗
PubMed1982

Disposition and absolute bioavailability of furosemide in healthy males.

Furosemide (40 mg) was administered to 18 healthy adult males as an intravenous dose, an oral solution, and in tablet form. The pharmacokinetics of intravenous furosemide were studied, determining a total body clearance rate of 117.6 +/- 41.3 ml/min and a harmonic mean half-life of 78 min. The mean absolute bioavailability determined by ratio of areas under the plasma-time curves was 64 and 71% for the solution and tablet, respectively. The mean absolute bioavailability determined by the ratio of urinary cumulative excretion data was 61 and 66% for the solution and tablet, respectively. The absolute bioavailability of furosemide determined with plasma and urine data were not significantly different. Thus, urine data alone may be used to establish bioavailability of furosemide. Inspection of plasma-time curves revealed secondary maxima in several subjects, suggesting enterohepatic cycling.

Administration, Oral↗
PubMed1982

Clodronate kinetics and bioavailability.

Carbon 13-labeled clodronate disodium was given to healthy adult men by intravenous infusion and orally in a crossover design. Serum and urine levels were determined as a function of time by isotope-ratio mass spectrometry. Clodronate disodium (Cl2/MDP) is primarily excreted unchanged by the kidney; more than 80% of the intravenous dose was recovered within 48 hr. The serum concentrations-time curve over the first 8 hr after intravenous dosing appears biexponential with the disposition phase having a harmonic mean half-life (t 1/2) of 2 hr. The mean serum clearance was found to be 1.4 ml min-1 kg-1 and the apparent volume of distribution was approximately 25% of body weight. Simulations and computer fitting of the cumulative urinary excretion and urinary excretion rates based on the biexponential serum decay curve demonstrated the presence of a slow disposition component with a t 1/2 of 12.8 hr. Thus, the disposition kinetics of Cl2MDP appear to be triexponentials, although the slowest component is not of major significance after a single dose and could not be verified because of a lack of serum data after 8 hr. Cl2MDP is poorly absorbed with an absolute bioavailability of only 1% to 2%.

Administration, Oral↗
PubMed1982

Pharmacokinetics of gold sodium thiomalate.

Two normal males participated in a study designed to examine the disposition of gold given intravenously and intramuscularly as gold sodium thiomalate. Blood samples were collected for 30 days, urine and feces for ten. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 12.5 days. Absolute bioavailability of IM gold sodium thiomalate appears to be variable with one subject having complete absorption and the other absorbing 64% of the administered IM dose. The major route of elimination of an IV dose of gold sodium thiomalate is urinary excretion, with a mean of 35% of the dose found in the urine in ten days. Fecal elimination accounts for an additional 9.4% of the IV dose excreted in ten days, probably as a result of biliary secretion.

Adult↗
PubMed1981

High-performance liquid chromatographic analysis of triamterene and p-hydroxytriamterene in plasma.

A rapid and sensitive high-performance liquid chromatographic assay was developed for triamterene and 6-p-hydroxytriamterene in plasma. Plasma (0.5 ml), after addition of the internal standard, was extracted with 10 ml of ether-isopropanol (95:5). After thorough mixing and separation of phases, the organic layer was evaporated to dryness under nitrogen. The residue was reconstituted with 500 microliters of mobile phase [acetonitrile-water-acetic acid (60:39.5:0.5)], and 100 microliters was injected into the chromatograph. Chromatographic separation was carried out on a C18 muBondapak column at a flow rate of 1 ml/min. Detection of compounds in the column eluent was by UV absorption at 365 nm. The retention times for 6-p-hydroxytriamterene, triamterene, and the internal standard were 7.5, 9.0, and 12.0 min, respectively. The lower limit of detection for each compound was 20 ng/ml. Recoveries of triamterene and 6-p-hydroxytriamterene were 91--99 and 828--95%, respectively, over a 40--240-ng/ml range.

Chromatography, High Pressure Liquid↗
PubMed1980

Pharmacokinetics, bioavailability, and dosage regimens of digoxin in dogs.

Digoxin, 30 micrograms/kg, was given by IV injection and orally, in the forms of pediatric elixir and tablet, on three separate occasions to six healthy dogs. Multiple serum samples were collected at timed intervals and assayed by radioimmunoassay. Data were analyzed, using nonlinear least squares regression analysis. The mean serum digoxin-time relationship was triexponential. Rapid and slow distributive phases with half lives of 9 minutes and 4.7 hours were followed by a biological disposition phase with a half life of 30.1 hours. Mean volume of distribution by extrapolation was 15.6 L/kg. When calculated by the area method, mean volume of distribution was 12.4 L/kg. Digoxin elixir was rapidly absorbed, with a mean bioavailability estimate of 71.4 +/- 8.2% SD. Digoxin tablets were less rapidly and less completely absorbed, with a mean bioavailability estimate of 58.0 +/- 11.6%. Data collected in this series of experiments and data from the literature were applied to standard pharmacokinetic equations to formulate loading and maintenance doses of digoxin for the IV injection, the elixir, and the tablet. Mean loading doses were, in micrograms/kg/24 hours: 27, 38, and 45 for the IV injection, elixir, and tablet, respectively. Corresponding mean maintenance doses were 13, 18, and 23.

Administration, Oral↗
PubMed1980

Digoxin pharmacokinetics, bioavailability, efficacy, and dosage regimens in the horse.

The pharmacokinetics of IV administered digoxin and the bioavailability of intragastrically administered powdered digoxin tables suspended in water were investigated in 6 clinically normal adult horses by 125I radioimmunoassay. The effect of 3 to 5 sequential IV doses of 5 micrograms of digoxin/kg of body weight at 2-hour intervals on a left ventricular index of contractility (Vmax) was assessed in 5 clinically normal horses. Standard pharmacokinetic equations and mean pharmacokinetic variables were used to derive parenteral and oral (loading and maintenance) doses for digoxin in horses. The calculated dosage regimens were administered and resulting plasma digoxin concentrations were monitored in 5 horses and 1 pony. Digoxin disposition after IV injection was triexponential. A rapid distributive phase with a half life (t 1/2 of 15 minutes was followed by a slow distributive phase with a t 1/2 of 4.1 hours. The biological disposition t 1/2 was 23.1 hours. The volume of distribution by extrapolation was 6.79 L/kg of body weight and 4.89 L/kg by the area method. The average bioavailability estimate for intragastrically administered digoxin was 19.2%. The Vmax increased significantly (P < 0.01) after IV digoxin administration. Greatest changes in Vmax were recorded after the first 2 injections (5 micrograms of digoxin/kg) corresponding to plasma digoxin concentrations of 0.83 and 1.68 ng/ml. Doses of digoxin were calculated as follows: IV loading 14, IV maintenance 7, oral loading 70, and oral maintenance 35 micrograms/kg/24 hours. When these doses were given to a group of horses, plasma digoxin concentrations measured 12 and 24 hours after administrated were mostly in the proposed therapeutic, nontoxic range of 0.5 to 2.0 ng/ml.

Administration, Oral↗
PubMed1979

Single-dose fasting bioequivalence assessment of erythromycin stearate tablets in man.

The bioequivalence of film-coated erythromycin stearate tablets produced by five different manufacturers was evaluated in a balanced incomplete block design involving the five formulations given to 30 fasted subjects over a 3-week study period. Serum levels of erythromycin activity were determined microbiologically. Statistical analysis of variance was performed on the observed bioavailability parameters: maximum serum concentration (Cmax), time to maximum serum concentration (Tmax), and area under the serum concentration-time curve (AUC). There was no statistical difference between formulations for the Tmax parameter. Formulation differences were found, however, based on the analysis of variance of the Cmax and AUC parameters. Two products, although not significantly different from one another, showed significantly greater Cmax and AUC values than the other three products.

Adult↗
PubMed1979

Plasma and tissue levels of furosemide in dogs and monkeys following single and multiple oral doses.

35S-Furosemide was administered to beagle dogs and rhesus monkeys as an oral solution on a single and a 20 repeated 5 mg/kg/day dosing regimen. In both species, furosemide is rapidly but incompletely absorbed with peak plasma levels being achieved within one hour after dosing. The plasma level versus time profiles do not appear to be significantly altered as a result of the repetitive dosing regimen employed, although the profiles themselves are quite different for the two species studied. Following single oral doses, the observed peak plasma levels achieved in dogs are approximately eight-fold higher than in monkeys. In dogs, oral administration of furosemide results in a biexponential disposition curve while in monkeys the profile appears monoexponential. The major disposition phase in dogs has a half-life or approximately 30 minutes and is followed by a slow elimination phase with a half-life of approximately 7 hours. Only a small percentage of the absorbed dose is affected by the slow disposition phase and consequently accumulation of furosemide on the once-daily dosing regimen is slight. In the monkey studies, the rapid disposition phase was not observed and the slow disposition phase had a half-life of approximately 11 hours. On the repetitive dosing regimen, the monkey appeared to accumulate furosemide to a slightly greater extnet than the dog and showed a lesser degree of fluctuation within a dosing interval. In both species, liver and kidney radioactivity levels were not detectable three days after a single dose although low levels of furosemide and/or metabolites were observed for six days following the last dose of the multiple dosing regimen. At the dosage level and regimen employed, no unusual or "typical" lesions associated with furosemide were found in the dog and monkey tissues examined histopathologically.

Administration, Oral↗
PubMed1978

Pharmacokinetic considerations in exchange transfusion in neonates.

Neonates undergoing blood exchange often receive concomitant therapy. Questions may be raised whether dosage regimen alterations are necessary to replace drug lost as a result of the exchange procedure. Our study reports the changes in plasma concentration of kanamycin during an exchange transfusion and a pharmacokinetic analysis of the effect of the exchange on drug elimination. The relationships of the volumes of distribution, elimination rate constant, and time after dosing on the fraction of the dose eliminated in the blood exchange are developed on the basis of a one-compartment body model. Computer simulations using the equations developed were used to estimate the fraction of a dose that might be removed as a result of an exchange transfusion. As the disposition rate constant or the apparent volume of distribution increase, i.e., the clearance of the drug increases, the fraction of the dose removed by the exchange process decreases. Thus, significant amounts of drug removal may occur in an exchange transfusion for drugs with low clearance when the exchange is initiated early in the drug dosing interval. In our study, only 3% of the kanamycin dose was removed as a result of the exchange process, and dosing adjustment would not be required. This was in part due to initiation of the exchange late in the dosing interval, although the maximum calculated percentage of the dose which could have been removed under the exchange conditions employed was only 10%.

Exchange Transfusion, Whole Blood↗