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Biomedical subjects

J J Vallner

Publications and source records attributed to J J Vallner.

At least 19 recordsLinked to original sources
PubMed1994

Evaluation of the performance of controlled release dosage forms of ticlopidine using in vitro intestinal permeability and computer simulations.

Prototype controlled release formulations of ticlopidine hydrochloride were developed, but when administered to humans, these formulations significantly reduced the bioavailability of intact drug in plasma. In order to examine the intestinal permeability characteristics and gastrointestinal metabolism of 14C-ticlopidine, we employed an in vitro diffusion cell system to directly measure the permeation of ticlopidine across various segments of monkey and rabbit intestine. High pressure liquid chromatography was used to determine the amount of intact ticlopidine on both the mucosal and serosal sides of the intestinal tissue. Simulations based upon the known pharmacokinetics of ticlopidine were conducted using STELLA, a modeling program, to provide insight as to the nature of the decreased bioavailability of these ticlopidine CR dosage forms. These simulations indicate that the absorption of intact ticlopidine is a non-linear phenomena, with inordinately large increases in absorbed intact drug with increases in dose. Conversely, decreases in drug available for immediate absorption, as with the controlled release dosage forms, lead to non-linear decreases in bioavailability. Such a finding is very consistent with the extensive first-pass metabolism suggested from the tissue permeability studies.

Animals↗
PubMed1985

Intraoperative serum and tissue activity of cefazolin and cefoxitin.

We determined the intraoperative serum and wound-muscle concentrations of cefazolin and cefoxitin in 40 patients who were undergoing cholecystectomies. The study employed an open-label design in which all of the patients randomly received cefazolin sodium (20 mg/kg) or cefoxitin sodium (30 mg/kg) intravenously while the patient was in the ward ("on call") or with the induction of anesthesia. Multiple blood and wound-muscle samples were collected intraoperatively and assayed for their cephalosporin concentrations. Considerable differences in intraoperative serum and tissue concentrations between antibiotics were apparent; there were usually higher levels of cefazolin. In all of the patients who received cefazolin sodium, the antimicrobial was detectable in wound tissue at wound closure, while it was detectable in 86% and 38% of patients who received cefoxitin sodium with anesthesia and on call, respectively. Because cefoxitin has a much shorter elimination half-life than cefazolin it seems prudent to administer the agent as close to the start of the operation as possible, and readminister the agent every two to three hours until the wound is closed. For cefazolin, on-call administration appears to be acceptable, with readministration not required for at least four hours.

Abdominal Muscles↗
PubMed1985

Age-related changes in the pharmacodynamics of verapamil.

Age-related differences in the pharmacodynamics of numerous drugs are well documented. In this study, changes in the pharmacodynamics of verapamil were examined in anesthetized and unanesthetized puppies (6 weeks old) and adult dogs. Unanesthetized puppies and adult dogs were given verapamil (0.5 mg/kg intravenously and 2.5 mg/kg orally), and anesthetized dogs received only intravenous infusions. Plasma samples and ECG tracings were taken over a 4- to 7-hour period. Plasma verapamil was determined by high-pressure liquid chromatography with spectrofluorometric detection. Puppies exhibited a shorter t1/2 than adults after intravenous administration (62.3 +/- 10.8 minutes compared to 87.3 +/- 7.8 minutes). Puppies had a greater area under concentration (AUC) after oral dosing than adults, indicating a greater amount of the dose reaching the systemic circulation. The PR interval was significantly prolonged in adults but not in puppies, even though the blood levels in the puppies were greater than those in the adults. Therefore, even though there is little variation in the pharmacokinetic parameters between adult dogs and puppies, there is a marked reduction in the sensitivity of the puppies to the ECG effects of verapamil.

Administration, Oral↗
PubMed1985

Prazosin alters free and total plasma digoxin levels in dogs.

Digoxin has been associated with a variety of drug interactions. Studies in our laboratory indicate that single doses of prazosin may alter plasma steady-state digoxin levels. Adult mongrel dogs were given digoxin tablets orally (0.008 mg/kg, twice daily) until steady-state levels of digoxin were reached. Dogs were then tested in a cross-over study with prazosin and saline. Plasma samples were assayed for both free and total plasma digoxin via radioimmunoassay. Free drug was separated from protein bound drug utilizing a micropartition system. Plasma binding of digoxin as well as nonspecific tissue binding was reduced by prazosin and resulted in an increased fraction of free digoxin in plasma. The increase in free digoxin leads to an increase in the pool of digoxin available for pharmacologic activity. Acute experiments demonstrated such an increased pharmacologic effect of digoxin in the presence of prazosin. Prazosin pretreatment prior to a continuous digoxin infusion significantly increased the positive inotropic effect of digoxin compared to dogs receiving only digoxin.

Animals↗
PubMed1985

Cephalosporins for surgical prophylaxis: computer projections of intraoperative availability.

Cephalosporin antibiotics are the most frequently used agents for surgical prophylaxis. Within this class are considerable pharmacokinetic variations that could have significant implications. We used a computer simulation of cephalosporin serum levels to describe concentrations achieved and maintained intraoperatively when the agents are given intravenously "on call" to the operating room or with induction of anesthesia. Intraoperative serum concentrations fall below 1 microgram/ml if an operation lasts longer than 2.3, 2.7, 3.8, or 4.0 hours when cephalothin, cephapirin, cefamandole, or cefoxitin, respectively, is given in usual doses upon induction of anesthesia. When the same agents are given intravenously on call to the operating room, intraoperative serum concentrations fall below 1 microgram/ml for operations lasting longer than 1.1, 1.5, 2.6, or 2.8 hours, respectively. If cephalothin, cephapirin, cefamandole, or cefoxitin is used, it should be given at induction of anesthesia to provide maximal intraoperative serum concentrations. The longer half-life of cefazolin, ceforanide, cefonicid, and cefuroxime is a potential advantage because serum concentrations of these agents are well above 1 microgram/ml for as long as eight to 22 hours even after on-call administration.

Anesthesia, General↗
PubMed1985

Intraoperative ceforanide pharmacokinetics and protein binding.

The pharmacokinetics and protein binding of ceforanide were studied in 15 patients undergoing cholecystectomies. Each patient received ceforanide (20 mg/kg) intravenously on arrival in the operating room, after which serial blood samples were collected during the elimination phase for determination of total and free ceforanide concentrations in the serum. A high-pressure liquid chromatography assay was used, with a centrifugal filtration system for free-drug determinations. Serum concentration data for each individual were subjected to linear regression to determine the elimination rate constants (total and free drug), volumes of distribution, and systemic clearances. The mean elimination rate constants were 0.41 and 0.50 h-1 for total and free ceforanide, respectively. The mean percentage of ceforanide bound to serum protein was 87.9%. The relationship of the free ceforanide concentration to the total concentration appeared to be linear. The data were fit to double-reciprocal and half-reciprocal relationships with good agreement, showing one binding site and an association constant range of 1.6 X 10(7) to 1.9 X 10(7) at these in vivo concentrations. The mean volume of distribution and mean systemic clearance of total drug were 100 ml/kg and 45.9 ml/min per 1.73 m2, respectively. Ceforanide consistently produced higher intraoperative total drug concentrations compared with those of cefazolin and cefoxitin from similar studies.

Adolescent↗
PubMed1982

Effect of albumin conformation on binding of phenylbutazone and oxyphenbutazone to human serum albumin.

The binding of phenylbutazone (I) and oxyphenbutazone (II) to human serum albumin over pH 6.9-9.3 was studied by difference spectrophotometry and equilibrium dialysis. At each pH tested, there was higher binding affinity of I to human serum albumin than II. Equilibrium dialysis showed that over the pH 7-8.2 range both agents had a single high-affinity site and several sites of lower affinity, with the highest binding constant and number of binding sites at pH 7.4 for both I and II. Both techniques showed that the affinity of both drugs to albumin was higher for the neutral form than for the basic form and this transition occurred in both cases around the neutral region (7-7.4). Both the ionized and unionized forms of I and II participated in the binding. In the neutral region, magnesium ion increased the affinity of both drugs to albumin while chloride ion decreased it slightly.

Chemical Phenomena↗
PubMed1982

Bioavailability of regular and controlled-release chlorpheniramine products.

The bioavailability of chlorpheniramine regular-release versus controlled-release products was compared using 15 human subjects. The dosage forms evaluated were an 8-mg barrier coated-bead capsule, an 8-mg repeat action tablet, two 4-mg tablets, and 4- and 8-mg syrups. Single doses of each product were administered orally in a 5-way crossover study, plasma samples were collected at specific time intervals, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The average plasma elimination half-life of chlorpheniramine was calculated to be approximately 18.3 hr. The controlled-release products gave a higher Cmax than the 4-mg syrup, but less than two 4-mg tablets. The controlled-release products also extended the time necessary to attain peak drug levels compared to the 4- and 8-mg syrups. The area under the curve (AUC) data for the controlled-release products was not equivalent to equal amounts of the regular-release products. The study indicated that while the controlled-release chlorpheniramine products were successful in prolonging the time course of absorption, this was at the expense of incomplete bioavailability of the drug.

Adolescent↗
PubMed1981

Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects.

In a relatively small pilot study, the half-life of elimination of hydromorphone in six subjects was 2.64 +/- 0.88 hours and the drug had a high volume of distribution, 1.22 l./kg. In addition, the drug was rapidly but incompletely absorbed after oral administration. An equation to predict the plasma concentration of hydromorphone on oral administration was developed from the data of these six subjects.

Administration, Oral↗
PubMed1981

Circular dichroic examination of the interaction of some planar acidic drugs with tryptophan-modified human serum albumin.

The single tryptophan region in human serum albumin was investigated for its involvement in binding planar hydrophobic and acidic drug molecules. The lone tryptophan was alkylated with a selective and specific agent, 2-hydroxy-5 nitrobenzyl bromide. The subsequent interaction of four drug molecules with tryptophan modified, and normal albumin was examined by circular dichroism (CD). In all cases the CD signal of tryptophan modified albumin was perturbed at low drug concentrations. The predominantly alpha-helical structure of the albumin remained intact. It is suggested that the primary binding site of these four acidic planar drugs does involve the tryptophan region.

Acids↗
PubMed1981

Clearance of serum cortisol in suckled and nonsuckled postpartum beef cows.

Clearance of cortisol from the sera of suckled (S) and nonsuckled (NS) beef cows was studied on days 14 +/- 1 and 28 +/- 1 (mean +/- SE) postpartum (periods 1 and 2, respectively). Eight multiparous Angus cows (325 kg to 445 kg) were assigned at calving to S (n = 4) and NS (n = 4) treatments. Basal cortisol concentrations tended to be higher (p less than .10) in S (19.0 +/- 1.3 ng/Ml) than in NS (12.9 +/- .9 ng/ml) cows across both periods. After administration of 20 mg of cortisol, serum cortisol concentrations increased (p less than .01) similarly in S and NS cows to 122.1 +/- 6.4 and 165.6 +/- 11.5 ng/Ml at 2 min postinjection at periods 1 and 2, respectively. Clearance of cortisol from the body was evaluated by biological half-life (t 1/2), volume of distribution (Vd) and total body clearance (TBC) of cortisol. Serum cortisol had a similar t 1/2 in S (32.5 +/- 2.3 min) and NS (29.2 +/- 3.2 min) cows and did not not differ between sampling periods. Vd did not differ (p greater than .3) between S (248 +/- 29 liters) and NS (199 +/- 14 liters) cows across both periods, but was greater (p less than .05) at period 1 than at period 2 for both S and NS cows. Total body clearance was similar in S (5.2 +/- .4 liters/min) and NS (5.0 +/- .6 liters/min) cows and was similar at both sampling periods. On the basis of these results, we conclude that clearance of cortisol from the serum was not affected by lactational status or by postpartum interval, but that the volume of distribution of cortisol in the body decreased during the postpartum period studied.

Animals↗
PubMed1980

Plasma levels of clobazam after 10-, 20-, and 40-mg tablet doses in healthy subjects.

It is evident that substantial intersubject and intrasubject varition in the bioavailability of clobazam exists following ingestion of 10, 20 and 40 mg doses in these 12 volunteers. Peak concentrations and area under the plasma level-time curve were directly proportional to the dose of clobazam and the mean plasma half-life of clobazam was about 18 hours regardless of dose administered. The t1/2 value was less than that previously reported, as the current results allow differentiation of parent drug from metabolites. This 18 hr t1/2 compares favorably with the half-life of other benzodiazepines.

Adolescent↗
PubMed1979

Interaction of the antimalarial alpha-dibutylaminomethyl-2,6-bis(trifluoromethylphenyl)-4-pyridinemethanol with human serum albumin.

Binding of the antimalarial alpha-dibutylaminomethyl-2,6-bis(trifluoromethylphenyl)-4-pyridinemethanol with human serum albumin was studied using difference spectroscopy, fluorescence quenching, and equilibrium dialysis. Results indicated that the number of high affinity binding sites of the drug on protein is 0.45, with the total number of binding sites being 3.3--4.0. The binding constants were in the range of 0.57--4.00 x 10(6) M-1. The drug was bound more strongly to a nonionic detergent than to either a cationic or anionic detergent. Interpretation of these data and fluorescence quenching results indicated that the drug is possibly bound to a hydrophobic site on human serum albumin.

Antimalarials↗
PubMed1979

Dynamic dialysis in drug-erythrocyte interactions.

Application of dynamic dialysis to drug binding to erythrocytes was found to be more complex than previously described. Drug molecules located intracellularly in erythrocytes must diffuse through erythrocytes membranes before diffusing through the dialysis membrane to the external sink in dynamic dialysis. One must consider drug within the dialysis sack and within the erythrocyte and their corresponding volumes. When binding occurs in these internal compartments, different equations result for computing Dt, the total drug within the dialysis bag. With these equations and theoretically generated data, the results of "double dialysis" on the data produced in dynamic dialysis studies of drug-erythrocyte interactions were examined. The intracellular binding of drug by the erythrocyte to a single class of preexisting noninteracting sites could be misinterpreted as cooperative binding, or binding to at least two classes of sites, when the data of dynamic dialysis are treated in the Scatchard format.

Dialysis↗