bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple dose comparison of a whole 240 mg verapamil sustained‐release tablet with two half tablets
Authors: Moreland T. A. , McMurdo M. E. T. , McEwen J. 
Published: October 2006

AbstractTwelve healthy male volunteers were studied in a balanced crossover comparison of an intact 240 mg verapamil sustained‐release tablet (Securon SR, Isoptin Forte Retard) given once daily for 7 days, and the same dose given as two half tablets. One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment. The mean Cmax after dosing with whole tablets, 143 (95 per cent confidence limits 91·6–223) ngml−1 was lower than after dosing with half tablets, 160 (107–241) ngml−1, but this was not significant (p=0·49). The mean steady‐state Cmin values after whole and half tablets were also similar: 22·2 (12·6–39·4) ngml−1 and 22·0 (16·2–29·9) ngml−1, respectively (p=0·96). The mean (± S.D.) tmax, AUC0–24 and t1/2 were not significantly different: whole tablet 3·5 ± 1·2h, 1733 ± 1125 ng.h ml−1 and 10·5 ± 3·4h, respectively, and half tablets 3·6 ± 1·0h, 1780 ± 1057 ng.h ml−1 and 9·6 ± 2·3h, respectively. The findings for plasma norverapamil were generally similar to those for the parent drug. This investigation indicates that the formulation is sufficiently robust to retain its sustained‐release properties when the tablet is halved.
Absorption kinetics of topical clindamycin preparations
Authors: Eller Mark G. , Smith Randal L. B. , Phillips J. Paul 
Published: October 2006

AbstractSystemic clindamycin absorption was examined in 12 male Caucasians without acne who recieved 1 ml of Cleocin‐T® and 1 ml of 1 per cent clindamycin HCl in Vehicle‐N® (Neutrogena) applied topically the face every 12 h for 4 days according to a crossover design. In a separate phase clindamycin phosphate was administered by an IV infusion of 300 mg over 10 min. Systemic absorption was much higher with clindamycin in Vehicle‐N than with Cleocin‐T. Absolute bioavailability calculated from cumulative urinary excretion and serum AUCs were in good agreement and averaged 1·7 per cent and 7·5 per cent for Cleocin‐T and clindamycin in Vehicle‐N, respectively. Peak serum concentrations ranged from less than 0·5 ng ml−1 to 6 ng ml−1 for Cleocin‐T and from 4–20 ng ml−1 for clindamycin in Vehicle‐N. Absorption profiles indicated zero order absorption with Cleocin‐T. No appreciable systemic accumulation from the repeated topical applications was noted. Systemic exposure to clindamycin from these formulations is minimal.
Investigation of mezlocillin disposition with a porcine model
Authors: Dipiro Dr Joseph T. , Davis John B. , Boudinot F. Douglas , Cheung Richard P. F. , Sisley John F. 
Published: October 2006

AbstractThe suitability of the pig as an animal model for mezlocillin disposition was assessed. Serum, urine, and bile were collected after the administration of 50, 100 and 200 mg kg−1 mezlocillin to pigs and drug pharmacokinetics were characterized. Mezlocillin concentrations in biological fluids were determined by HPLC and free mezlocillin was determined by ultrafiltration. The pharmacokinetics of mezlocillin appeared to be independent of dose over the dosage range studied. Total clearance, renal clearance, and biliary clearance were 0·18 (0·05) 1 h−1 kg−1, 0·13 (0·03) 1 h−1 kg−1, and 0·07 (0·02) 1 h−1 kg−1, respectively. The steady‐state volume of distribution was 0·29 (0·08) 1 kg−1. The pharmacokinetic parameters determined in the porcine model are similar to those reported for health human volunteers. Therefore, this model appears suitable for the study of mezlocillin disposition, and may be applied to the study of other agents that are appreciably biliary excreted.
Interspecies pharmacokinetic scaling of metazosin, a novel alpha‐adrenergic antagonist
Authors: Lapka Roman , Rejholec Václav , Sechser Tomás , Peterková Marcela , Šmíd Milan 
Published: October 2006

AbstractBased on pharmacokinetic data from mice, rats, and rabbits the prediction of pharmacokinetics of intravenous metazosin in man has been performed. The correlations were based upon allometric scaling of plasma clearance and the volume of distribution at steady‐state. A one‐compartment body model approximating clinical pharmacokinetics fits well the elimination phase of subsequently measured metazosin concentrations in volunteers. Fitting human pharmacokinetic data to allometric equations enabled us to superimpose pharmacokinetic curves from different species.
Simulation of the hepatic metabolism of stilbene and its tricyclic derivatives by fenton and ruff reagents: Models for cytochrome P‐450 activation of chemical carcinogens
Authors: Zbaida Shumel , Kariv Rami 
Published: October 2006

AbstractReactions of trans‐stilbene, cis‐stilbene, 5H‐dibenzo [a, d] cyclo‐heptene 5‐one and 5H‐dibenz [b, f] azepine (iminostilbene) with Fenton reagent [Fe (II)/H2O2] clearly simulate their hepatic metabolism. Epoxidation on the corresponding ethylenic linkage was found to be a common pathway of these compounds. Epoxides of trans‐stilbene, cis‐stilbene, and 5H‐dibenzo[a, d]cycloheptene 5‐one were further oxidized to dihydrodiols, α‐hydroxyketones, diketones, and finally cleavage of the ethylenic bonds to the formation of the corresponding aldehydes. However, the unstable epoxide of iminostilbene gave 9‐acridinecarbaldehyde that is further oxidized to 9‐acridone.Reaction of both trans‐ and cis‐stilbene with Ruff reagent [Fe III/H2O2] gave the same oxidative products to that obtained from Fenton reagent. The radical scavenger 2,6 bis (1,1‐dimethylethyl)‐4‐methyl phenol (BHT) decreases the total yield conversion and increases the formation ratio of both cis‐epoxide and d, l‐hydrobenzoin from cis‐stilbene.
A computer simulation of the food effect: Transient changes in hepatic blood flow and michaelis‐menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol
Authors: Semple H. A. , Tam Y. K. , Coutts R. T. 
Published: October 2006

AbstractA physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis‐Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal.The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.
Bioequivalence of two pharmaceutical forms of diltiazem
Authors: Rubio Modesto , Masana Mónica I. , Garcilazo Enrique , de Los Santos Antonio R. , di Girolamo Guillermo 
Published: October 2006

AbstractDiltiazem, a calcium‐channel blocking agent, has been shown to be a potent coronary vasodilator used in the treatment of ischaemic heart disease. The present study was conducted to compare the bioavailability of regular 60 mg tablets administered every 6 h with sustained release capsules of 120 mg administered every 12 h. High‐performance liquid chromatographic analysis was carried out for determination of diltiazem and one of its metabolites desacetildiltiazem in six male patients. The relative bioavailability of this sustained‐release pharmaceutical form did not show any significant difference with that of tablets.
The disposition of cytosine arabinoside and its metabolite after single doses to rabbits
Authors: Zimmerman Cheryl L. 
Published: October 2006

AbstractCytosine arabinoside (ara‐C) is rapidly deaminated vivo to ara‐U by cytidine‐deoxycytidine deaminase. The purpose of this study was to determine the contribution of the deamination pathway to the overall clearance of ara‐C after a single dose to rabbits, as well as to determine the pharmacokinetics of ara‐U itself. Male rabbits were cannulated in the marginal ear vein and received a single IV bolus dose (50 mg kg −1) of either ara‐C (n=10) or ara‐U (n=10). Blood samples were collected for up to 24 h. One week later, the rabbits received the opposite treatment. Plasma samples were analyzed by reversed‐phase HPLC. The plasma clearance of ara‐C (8·16 ± 2·43 ml min−1 kg−1) was significantly higher than the clearance of ara‐U (5·66 ± 2·59 ml min−1 kg−1). The volume of distribution of ara‐C was 0·64 ± 0·161 kg−1 (mean ± SD) and was significantly smaller (p <0.05) than that of ara‐U (1·22 ± 0·701 kg−1). As a result, the elimination rate constant of ara‐C was significantly larger than that of ara‐U (0·602 ± 0·097 h−1 vs 0·258 ± 0·051 h−1). In the rabbits that received both treatments (n=7), the fraction of the ara‐C dose metabolized to ara‐U (fm) was 0·53 ± 0·20. Qualitatively, the pharmacokinetics of ara‐C and ara‐U resemble those in humans. This study provides the basis for further work into the modulation of ara‐C disposition either by ara‐U or other agents.
Influence of lovastatin on the pharmacokinetics, toxicity and immunologic response of cyclosporine in the obese zucker rat
Authors: Berens Kurt L. , Vadiei Kiumars , Brunner Lane J. , Wasan Kishor M. , Luke David R. 
Published: October 2006

AbstractThe combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug‐free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre‐treated with either oral lovastatin 2.5 mg kg−1 day−1 or propylene glycol vehicle for 1 week. Although no differences in renal function were observed in rat groups administered cyclosporine or lovastatin alone, there was a significant reduction in baseline creatinine clearance following combination therapy compared to placebo controls (70 ± 18 vs 121 ± 16 per cent of baseline; p<0·05). No differences in trough cyclosporine concentrations were observed between groups. Similarly, mean areas under the whole blood concentration‐time profiles were not significantly different with or without concomitant lovastatin (61823 ± 27295 vs 41470 ± 10312 ng h ml−1;p=0·13). No differences in systemic clearance or volume of distribution of parent cyclosporine were observed with combination therapy. Furthermore, lipid levels and T‐lymphocyte activity were unchanged with the addition of lovastatin. Per cent increases in creatine kinase were significantly correlated with percentage drop in baseline renal function, suggesting the development of rhabdomyolysis. The present data support the interaction between cyclosporine and lovastatin observed clinically, resulting in acute renal dysfunction. Caution should be exercised in their combined use.
Oxcarbazepine disposition: Preliminary observations in patients
Authors: Kumps A. , Wurth C. 
Published: October 2006

AbstractWe describe a preliminary retrospective study based on the concentration of two hydroxylated metabolites of oxcarbazepine (OCZ), a new anticonvulsant substance, measured in the plasma of 15 patients with epilepsy. Their ages ranged from 8 to 68 years. 6 of them also received phenobarbital and/or phenytoin as co‐medication. The concentration of 10‐hydroxy‐10,11‐dihydrocarbamazepine (HCBZ) or of trans‐10,11‐dihydroxy‐10,11‐dihydrocarbamazepine (DHCBZ), the metabolites measured, are significantly correlated with the dose of OCZ (p < 0·05 and p < 0·01, respectively). DHCBZ concentrations, standardized to a constant OCZ dose or to a constant HCBZ concentration, are significantly higher during co‐medication (p < 0·01 and p < 0·05, respectively); HCBZ levels are unaffected. These results confirm that enzyme‐inducing drugs, although accelerating the oxidation HCBZ, do not induce its formation. Since HCBZ is the active metabolite, such drug interaction seems unlikely to alter OCZ pharmacological activity.
Elevation of carbamazepine plasma levels by diltiazem in rabbits: A potentially important drug interaction
Authors: Al‐Humayyd Mohammad Saad 
Published: October 2006

AbstractThe effect of diltiazem on the plasma level of carbamazepine (CBZ) was investigated in rabbits. The animals were given either CBZ alone or in combination with diltiazem and plasma samples were collected at different time intervals. The concentration of CBZ was detected using an HPLC method. Diltiazem significantly increased the area under the curve (AUC), the maximum plasma concentration (Cmax), and the elimination half‐life (t1/2) of CBZ (p < 0·05). These results suggest that a potentially harmful drug‐ drug interaction may occur if CBZ and diltiazem are administered concurrently.
Pharmacokinetics of morphine and its surrogates XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog
Authors: Langguth Peter , Khan Patricia J. , Garrett Edward R. 
Published: October 2006

AbstractThere were no dramatic modifications of the pharmacokinetics in the dog of i.v. bolus doses of 0·5, 2·7 and 5 mg kg−1 morphine by coadministering i.v. 5 mg kg−1 naltrexone as bolus injections over 15–20s and 12·3 mg kg−1 by continuous infusion. Morphine's terminal half‐life, clearances, apparent volumes of distribution (except for that of the central compartment), percentages of drug and conjugated metabolite excreted in urine and bile did not differ significantly by paired t‐test (probability (p) > 0·5 for rejection of the null hypothesis of no difference) when naltrexone was coadministered. There were no statistically significant (by t‐test) modifications of the plasma pharmacokinetics in the dog of i.v. bolus doses of 5 mg kg−1 naltrexone with and without morphine coadministration except for the coefficient of the second (or terminal) exponential of the sum that fitted the plasma concentration‐time data of naltrexone. Although morphine coadministration did not significantly affect the terminal half‐life of naltrexone, its clearances or apparent volumes of distribution by t‐test of the differences between averages (with each dog equally weighted), drug coadministration did significantly (by t‐test) affect the fraction of naltrexone dose secreted into bile as conjugate (fB), the fraction of the dose excreted as conjugate in urine, and the fraction excreted elsewhere (fB). Although naltrexone reversed the central action of morphine in affecting monitored pupil diameters, it did not antagonize the peripheral effects of morphine in perturbing renal and biliary flow rates. This led to a larger fraction of the naltrxone does being metabolized to conjugate on morphine coadministration. Since less naltrexone conjugate was renally and biliary excreted initially, due to morphine inhibition of the initial renal and biliary processes, naltrexone conjugate plasma concentrations were higher when morphine was coadministered.
Modfit: A pharmacokinetics computer program
Authors: Allen Graham D. 
Published: October 2006

AbstractThis paper presents a computer program, MODFIT, written in FORTRAN, primarily for use on the Digital Equipment Company VAX series computers for the mathematical analysis of concentration‐time data. Drug data generated from biological fluids and tissues may be fitted by a variety of different models. For many models, parameter starting estimates are program generated prior to automatic nonlinear regression analysis using a modified Davidon‐Fletcher‐Powell algorithm. The output of results is extensive and plotting facilities are available. Explicit and differential equation models may be fitted to single dose data and simulations using all models (single or repeat dose) may be employed to generate drug concentration‐time data with plotting output. The package has been tested on numerous data with no problems regarding local function minima. Some comparisons with existing programs have been made and MODFIT compares well with respect to robustness, efficiency, and ease of use.
Assay of glyceryl trinitrate, isosorbide dinitrate, and their metabolites in plasma by large‐bore capillary column gas‐liquid chromatography
Authors: Booth Brian P. , Bennett Brian M. , Brien James F. , Elliott Douglas A. , Marks Gerald S. , McCans John L. , Nakatsu Kanji 
Published: October 2006

AbstractTwo large‐bore capillary columns, one with dimethyl polysiloxane (HP‐1®) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB‐17), were used to develop gas‐liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide‐2‐mononitrate (2‐ISMN), and isosorbide‐5‐mononitrate (5‐ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl‐1,2‐dinitrate (1,2‐GDN). and glyceryl‐1,3‐dinitrate (1,3‐GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0·75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl‐methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large‐bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary‐column assays. The chromatographic resolution of analytes and column efficiency of the large‐bore capillary columns were comparable to the results previously found using capillary‐column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP‐1® column is appropriate for the analysis of GTN and metabolites, and the DB‐17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large‐bore capillary columns provides rapid and reliable GLC assays for organic nitrates.
Placental transfer and tissue distribution of vitamin e in pregnant rabbits
Authors: Bortolotti A. , Traina G. L. , Barzago M. M. , Celardo A. , Bonati M. 
Published: October 2006

Abstractα‐Tocopherol (vitamin E) is widely prescribed in neonatal intensive care units, in large doses and by different schedules, for the prevention of retrolental fibroplasia, intraventricular haemorrhage, bronchopulmonary dysplasia, and haemolytic anaemia. Since the efficacy of the drug in premature newborns seems related to early administration, the physicochemical characteristics of the drug itself and available formulations limit the major therapeutic aim of promptly raising levels of vitamin E in premature babies during the early hours of life. It has thus been suggested that vitamin E be given to the mother before delivery to produce higher drug concentrations in the newborn.To see whether this would work, the tissue distribution and transplacental transfer of vitamin E were studied in six pregnant rabbits at steady‐state after an i.v. bolus + infusion to give a mean venous blood concentration of about 325 μmol l−1 of a‐tocopherol acetate, corresponding to about 30 μmol l−1 of α‐tocopherol. Endogenous levels were measured in six control pregnant rabbits.In treated animals α‐tocopherol was increased in liver, spleen, placenta, lung, mammary gland, blood, and bile but not in brain, heart, fat, muscle or adrenals probably because distribution into these tissues is very slow. Vitamin E levels in the placenta of treated mothers were 15 times those of control rabbits, but the vitamin was not detectable in amniotic fluid and only very low levels were found in fetal blood.These findings do not indicate any advantage of giving mothers a‐tocopherol acetate before delivery.
Pharmacokinetics of midaglizole, a new hypoglycaemic agent, in healthy subjects
Authors: Nomura Hisashi , Yamada Fusako , Hakusui Hideo 
Published: October 2006

AbstractThe objective of this study was to evaluate the pharmacokinetics of midaglizole, a new orally effective hypoglycaemic agent, in healthy male subjects. In Study I, volunteers were given single oral doses of 150, 200, 300, and 500 mg of midaglizole 20 min before breakfast. In Study II, 200 mg of midaglizole was given 30 min after breakfast. In Study III, multiple oral administration study was carried out at a dose of 200 mg t.i.d. 20 min before meals for 7 days.The disposition of midaglizole was adequately described by a one‐compartment open model with first order absorption. It was essentially dose‐independent up to 500 mg given orally. The pharmacokinetic parameters calculated by employing this model indicated that the disposition of this drug was characterized by good absorption from the intestine, a wide distribution in the body, and a rapid excretion via the kidneys. The absorption rate of midaglizole from the intestine was definitely slowed by the presence of food, probably due to a decrease in the rate of gastric emptying. No clinical significant accumulation of midaglizole in the body was observed during or after multiple doses.A linear correlation was found between the area under the curve of plasma concentration of midaglizole versus time and the area calculated from the curve of change in blood glucose level versus time after oral administration of midaglizole.
Moment method for the estimation of mass transfer coefficients for physiological pharmacokinetic models
Authors: Gallo James M. , Lam Fred C. , Perrier Donald G. 
Published: October 2006

AbstractIn vitro and in vivo techniques have been utilized to estimate mass transfer coefficients for physiological pharmacokinetic models. No single method has been adopted for estimating this parameter, in part, due to the different model structures with which this parameter may be associated. A specific method has been derived to calculate mass transfer coefficients for non‐eliminating membrane‐limited tissue compartments. The present method is based on observed concentration–time data, and requires the calculation of the areas under the zero and first moment curves for plasma, and the first moment curve for the tissue. A Monte Carlo simulation technique was used to determine the percentage biases of the method based on a published model for streptozoticin and adriamycin. For the latter model, the method was compared to a non‐linear regression parameter estimation technique.