Biomedical subjects

M Bialer

Publications and source records attributed to M Bialer.

121 records · Page 7Linked to original sources

PubMedDate not supplied

Pharmacokinetic analysis of sustained-release dosage forms of theophylline in humans: comparison of single and multiple dose studies.

A pharmacokinetic analysis of two sustained-release dosage forms of theophylline (Theo-Dur and Theotrim) was carried out following single and multiple dose administrations of the two formulations in five healthy subjects. Despite the prolonged absorption after administration of the two sustained-release formulations, theoretical predictions of theophylline steady-state levels following multiple dosages based upon data obtained from the single dose study, correlated with the data of the multiple dose study. This study shows that the recommended dose and dosage regimen of new sustained-release formulations of theophylline can be based upon single dose studies. In the population studied, repetitive doses of 450 mg b.i.d. of Theo-Dur and Theotrim maintain steady-state concentrations of theophylline within the drug's therapeutic window.

Absorption↗

PubMedDate not supplied

The logical structure and validity of experimental designs in pharmacokinetics and clinical pharmacology.

Much of the literature on research design in clinical pharmacology and pharmacokinetics emphasizes statistical concerns, thus suggesting that a primary ingredient of a valid research design is an appropriate plan for statistical analysis of data. However, statistical validity is only one of several ways to evaluate an experimental study. The present paper reviews the underlying logic and sources of invalidity of experimental drug research suggesting influences and factors which may deceive or lure an experimenter into erroneous conclusions.

Models, Biological↗

PubMedDate not supplied

Pharmacokinetic interaction between diltiazem and amiodarone in the dog.

The pharmacokinetic interaction between diltiazem and amiodarone was investigated in dogs. In the presence of amiodarone, diltiazem's AUC values were significantly increased and its total body clearance and volume of distribution at steady-state significantly decreased. This study indicates that cardiac patients on combined diltiazem-amiodarone therapy may indeed be in a high risk situation in regards to the unexpectedly high blood levels of diltiazem induced: with the ultimate introduction of such side-effects as (1) the lowering of blood pressure, (2) A/V block, and (3) sinus node depression. Such cases would require immediate dosage adjustment. Assuming that the data obtained in this study can be extrapolated to humans, a patient's physiological parameters should be monitored at periodic intervals and, more importantly, the patient should report the first sign of any untoward effect.

Amiodarone↗

PubMedDate not supplied

In vitro protein binding interaction studies involving cefixime.

Cefixime is a new oral cephalosporin currently undergoing clinical trials. Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man. Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations. In contrast, both salicylic acid and probenecid resulted in concentration-dependent increases in the free fraction of cefixime (up to 2.5-fold). These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.

Animals↗

PubMedDate not supplied

Metabolism of cannabidiol by the rat.

Metabolites of CBD excreted into the bile and perfusion fluid were examined in a rat liver perfusion preparation. Metabolites were extracted with ethyl acetate and identified by GC/MS as TMS derivatives. Four mono- and five di-hydroxy metabolites were identified with major sites of metabolic attack being at C-7 and C-4". A hydroxy-ketone was detected but not fully identified. All biliary metabolites were conjugated with glucuronic acid. Urinary metabolites were studied in rats with samples taken at times to 25 h after drug administration. Unmetabolized CBD and 13 metabolites were identified by GC/MS. Major metabolites were acids with beta-oxidation being a prominent pathway. The 6- and 7-hydroxy derivatives of 4",5"-bis,nor-CBD-3"-oic acid were the most abundant compounds but substantial concentrations of the di-acids, CBD-5",7-dioic acid and 4",5"-bis,nor-CBD-3",7-dioic acid were present. Concentrations of the more highly oxidized metabolites increased with time.

Animals↗

PubMedDate not supplied

Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation.

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.

Adult↗

PubMedDate not supplied

Single-needle insertion technique for thoracocentesis for bilateral pleural effusions.

A 28-week fetus with hydrops and bilateral pleural effusions underwent drainage of both pleural spaces via a single-needle supradiaphragmatic insertion technique. The traditional approach was not feasible due to a persistently unfavorable fetal position. The dependent pleural effusion was drained by a needle which coursed through the nondependent pleural effusion. The needle traversed the midline pleura through an avascular plane. Thereafter the needle was withdrawn into nondependent pleural effusion which was drained. Both lungs expanded with favorable neonatal outcome.

Adult↗

PubMedDate not supplied

The disposition of valpromide in rats and the isolated perfused rat liver.

The pharmacokinetics and metabolism of valpromide (VPD) were investigated in intact rats and in the isolated perfused rat liver (IPL). The rats and the IPLs were divided into three groups. One was a control (untreated) group. The second consisted of intact rats and IPLs obtained from rats pretreated with phenobarbital. A third group of rats received VPD by oral administration. VPD was partially hydrolyzed to valproic acid (VPA) by the IPL following iv administration to intact rats. The fraction of the total body clearance of VPD which furnished VPA as a metabolite (fm) in the rats was 63%. The rate and extent of this conversion were greater in the phenobarbital-pretreated rats and in the IPLs than in the control group. Our studies showed that phenobarbital can induce the hydrolytic biotransformation of VPD to VPA. This is in addition to its known effect on oxidative metabolic pathways. In rats, as in humans and dogs, VPD is biotransformed to VPA in the liver. The complete oral bioavailability of VPD and the fact that the AUC of VPA obtained after oral administration of VPD was not higher than that obtained after the iv injection of VPD indicates that the gastrointestinal tract is not one of the metabolic sites of VPD to VPA conversion.

Administration, Oral↗

PubMedDate not supplied

Identification of urinary metabolites of cannabidiol in the dog.

Three dogs were treated with cannabidiol (CBD) and urine samples were collected periodically to 30 hr. Metabolites were extracted with ethyl acetate before and after hydrolysis with beta-glucuronidase, and examined by GC/MS,. Thirty-seven metabolites were identified and another nine partially characterized. Twenty-one of the identified metabolites have not been reported before for this drug. The major oxidative metabolic routes were 6-hydroxylation, both alpha and beta, and beta-oxidation. At 10 hr the major metabolites of this type were 6-hydroxy-4'',5''-bis,nor-CBD-3''-oic acid and 6-oxo-4'',5''-bis,nor-CBD-3''-oic acid, whereas at 22 hr, further beta-oxidation had occurred to give 6-hydroxy-2'',3'',4'',5''-tetrakis,nor-CBD-1"pr-oic acid as the major metabolite. Other metabolic routes were carboxylic acid formation at C-7 accompanied by hydroxylation in the side chain, and dihydroxylation of the C-8,9 double bond. Three compounds, 4''-hydroxy-CBD, 5''hydroxy-CBD, and 6-oxo-CBD were found at early times as glucose conjugates in concentrations that exceeded those of the other metabolites. The unconjugated forms of these metabolites were not found and none of the identified oxidized metabolites were found as glucosides. Only 4'',6-dihydroxy-CBD was found conjugated with glucuronic acid.

Aluminum↗

PubMedDate not supplied

Serum protein binding of a new oral cephalosporin, CL 284,635, in various species.

CL 284,635 is a new third generation oral cephalosporin. Its serum protein binding was investigated in the human, monkey, dog, rat, and rabbit. This study was performed by using an equilibrium dialysis and ultrafiltration method, using radiolabeled and cold CL 284,635. In humans, CL 284,635 was found to have a mean free fraction [fu = concentration of unbound (free) drug divided by total concentration of unbound plus bound to serum proteins] of 31.3 +/- 3.3% with no serum concentration dependency in a range of 0.5 to 26 micrograms/ml. The drug was mainly bound to albumin. In rabbits and monkeys the protein binding profile of CL 284,635 was found to be 36.1 +/- 2.3% and 33.9 +/- 1.5% with no serum concentration dependency. In rats and dogs a non-concentration-dependent fu was observed at serum concentrations ranging from 0.5 to 30 micrograms/ml. A gradual increase in fu values was observed at higher serum concentrations of CL 284,635. Overall, the protein binding profile of CL 284,635 was found to be different in the five investigated species. The protein binding of CL 284,635 in monkeys and rabbits was most similar to that in humans. These species differences in protein binding may have an impact on the disposition of the drug in different species.

Animals↗

PubMedDate not supplied

Pharmacokinetics of T-2 toxin and its metabolite HT-2 toxin, after intravenous administration in dogs.

The pharmacokinetics of T-2 toxin and HT-2 toxin were investigated comparatively in five dogs, after iv administration of the toxins (0.4 mg/kg). T-2 toxin was very rapidly and almost completely biotransformed to HT-2 toxin (fm = 83.6 +/- 3.9%). The following mean pharmacokinetic parameters were determined in this study for T-2 toxin and HT-2 toxin, respectively: half-life 5.3 +/- 2.1 and 19.6 +/- 4.7 min, clearance 0.107 +/- 0.056 and 0.167 +/- 0.074 liters/min/kg, and volume of distribution 0.86 +/- 0.63 and 4.47 +/- 1.38 liters/kg. The high clearance values suggest that the metabolism of T-2 toxin and HT-2 toxin is carried out in blood and/or through diffusion by nonspecific carboxyesterases. The results of this study suggest the possibility of a sustenance of T-2 toxin metabolism by its binding to blood cells.

Animals↗

PubMedDate not supplied

Pharmacokinetics of cannabidiol in dogs.

Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that CBD has a high protective index, comparable to that of phenobarbital and phenytoin. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of two iv doses (45 and 90 mg) and one oral dose (180 mg) to dogs. After iv administration, CBD was rapidly distributed, followed by a prolonged elimination. It has a terminal half-life of 9 hr. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 liters/hr (after the 45-mg dose) and 16 liters/hr (after the 90-mg dose). This clearance value, after its normalization to blood clearance using mathematical equations, approaches the value of the hepatic blood flow; the extraction ratio in the liver is 0.74. CBD was observed to have a large volume of distribution, approximately 100 liters. In the dose range of 45 to 90 mg, the increase in the AUC was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CBD in this dose range was not dose dependent. In three of the six dogs studied, CBD could not be detected in the plasma after oral administration. In the other three, the oral bioavailability ranged from 13 to 19%. The results of this study show that CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a first pass effect.

Animals↗

PubMedDate not supplied

Pharmacokinetics of the dimethylheptyl homolog of cannabidiol in dogs.

Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that a dimethylheptyl homolog (DMH) of CBD is more active as an anticonvulsant than is the naturally occurring CBD. In considering DMH as a potential antiepileptic agent, its pharmacokinetics was studied in dogs (N = 8) after both iv (20 mg) and oral (80 mg) administration. After iv administration, DMH was rapidly distributed. DMH has a mean terminal half-life of 2 hr, its plasma levels decline in a biphasic fashion, and its total body clearance is 8.3 liters/hr. This clearance value, after being normalized to blood clearance by the use of mathematical equations, was less than one half of the value of the hepatic blood flow and its extraction ratio (E) by the liver is 0.39, DMH was observed to have a mean volume of distribution of 10 liters (or 0.5 liters/kg). In four of the eight dogs studied, DMH could not be detected in the plasma after oral administration. In the other four, the oral bioavailability was 3, 21, 39, and 43%, respectively. After oral administration, DMH has a low and variable bioavailability, due to a liver first-pass effect and incomplete absorption from the gastrointestinal tract. In comparison with CBD, DMH has a shorter half-life and lower clearance and volume of distribution values, and its liver extraction ratio is about one half that of CBD.

Animals↗