bluuebunny/crossref_metadata_2025_split huggingface dataset:
Removal of sulfonamides by hemofiltration
Authors: Yu Shue‐Sheng , Waters Donald H. , Shen Shueh‐Hui , Lempert Kenneth D. , Gwilt Peter R. 
Published: October 2006

AbstractHemofiltration is a relatively new technique for removing toxic substances from the body. Unlike hemodialysis or hemoperfusion, the driving force behind hemofiltration is ultrafiltration. There have been several studies examining the clearance of drugs by hemofiltration but to date no study has investigated in a systematic way the effects of protein binding, perfusate flow, transmembrane pressure, and the duration of treatment on drug clearance by hemofiltration. The influence of these factors on the hemofiltration clearance of three sulfonamides with differing degrees of protein binding was investigated. It was found that hemofiltration drug clearance decreased with the duration of hemofiltration and protein binding but increased with perfusate flow and transmembrane pressure.
Sustained release properties of the once daily theophylline capsule BY912 as compared with Theo–24® capsules
Authors: Jonkman J. H. G. , Steinijans V. W. , Beier W. , Van Der Boon W. J. V. , Crasmeijer G. 
Published: October 2006

AbstractIn a multiple dose cross‐over experiment in 12 healthy male adults the bioavailability and sustained release characteristics of new once daily BY912 400 mg theophylline capsules (= B, Byk Gulden Research Laboratories, FRG) were studied using Theo‐24® capsules (= T, Searle & Co., USA) as reference.Both products were given once daily for a period of 7 days as an 800 mg theophylline dose at 8 am, half an hour after a standardized breakfast.Theophylline concentrations in plasma were measured on days 1, 6, and 7 using highperformance liquid chromatography.Significantly better sustained release characteristics, resulting in longer plateau time (t75%, 11·6 vs 9·2 h on day 6 and 13·1 vs 8·8 h on day 7) and smaller per cent peak‐trough fluctuation in the steady state (per cent PTF, 80 vs 103 per cent on day 6 and 66 vs 100 per cent on day 7), were found for B in comparison with T.The extent of absorption on both days, however, was smaller for B compared with T (relative bioavailability 84 per cent and 81 per cent, respectively).In conclusion, the absorption of theophylline from B resulted in a more extended shape of the plateau phase, indicating better sustained release characteristics. The extent of absorption, however, over the dosing intervals was more complete with T.
Relative bioavailability of almitrine bismesylate in humans
Authors: Stavchansky S. , Doluisio J. T. , MacLeod C. M. , Sebree T. B. , Heilman R. , Bachand R. T. , Szalkowski M. B. , Geary R. S. 
Published: October 2006

AbstractBioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0·5 per cent (w/v) oral reference solution of almitrine bismesylate in d,1 malic acid. The U.S. manufactured formulations were 85·88 and 87·85 per cent of the calculated mean area under the individual concentration‐time curve for almitrine bismesylate reference solution compared to 88·40 and 88·86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176·3 ng ml−1 and 180·1 ng ml−1 compared to 196·3 and 200·1 ng ml−1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3·22, 3·33, 3·06, and 3·26h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222·8 ng ml−1 and a mean time to peak plasma concentration of 2·68 h. Analysis of variance and multiple range comparisons (p < 0·05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.
One year administration of almitrine bismesylate (vectarion) to chronic obstructive pulmonary disease patients: Pharmacokinetic analysis
Authors: Stavchansky S. , Doluisio J. T. , MacLeod C. M. , Szalkowski M. B. , Bachand R. T. , Heilman R. , Sebree T. B. , Geary R. S. 
Published: October 2006

AbstractA double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen‐phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p < 0·01) between test day 14 and test day 360 (243 ± 213 per cent and 199 ± 170 per cent for predose and 3 h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half‐life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500ng ml−1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700ng ml−1. Mean accumulation was estimated to be 4·21 ± 1·98 at one year.
The logical structure and validity of experimental designs in pharmacokinetics and clinical pharmacology
Authors: Mason Emanuel J. , Bialer Meir 
Published: October 2006

AbstractMuch 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.
Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril·HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration
Authors: Kaiser Günther , Ackermann Roland , Brechbühler Sylvia , Dieterle Walter 
Published: October 2006

AbstractThe pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril·Ȟl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once‐daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril·Ȟl was rapidly absorbed (tmax □ 0·5 h) and rapidly eliminated from plasma (t1/2 □ 0·6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax □ 1·5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t1/2 □ 2·7 h), whereas the terminal phase (t1/2 = 22·3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24‐h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1·20 for AUC and 1·24 for urinary excretion. The effective half‐life for accumulation was estimated at about 10–11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.
Biomimetic models for monooxygenases
Authors: Zbaida Shmuel , Kariv Rami 
Published: October 2006

AbstractThe microsomal mixed function oxidase system contains the cytochrome P‐450 oxidative drug metabolizing family of enzymes. The catalytic cycle of cytochrome P‐450 is believed to involve the formation of an active iron‐oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co‐reactants in most oxidative reactions of microsomal cytochrome P‐450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P‐450 in hydroxylation, exposidation, sulfoxidation, and N‐demethylation of various drugs. The existance of an iron‐oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p‐450.Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed.The present paper reviews the various biomimetic models of the heme cytochrome P‐450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and industrial applications.
Pharmacokinetics and dose linearity testing of methylprednisolone phosphate
Authors: Möllmann Helmut , Rohdewald Peter , Barth Jürgen , Verho Matthi , Derendorf Hartmut 
Published: October 2006

AbstractThe pharmacokinetics of methylprednisolone and methylprednisolone phosphate were investigated after intravenous administration of methylprednisolone phosphate to six healthy subjects at seven different doses between 16 and 1000 mg. Plasma, urine, and saliva were analyzed for methylprednisolone and methylprednisolone phosphate. Furthermore, endogenous hydrocortisone was measured in plasma. No non‐linearity in the total body clearance of methylprednisolone phosphate or methylprednisolone could be detected. The average elimination half‐life for the prodrug was 3·7 min indicating rapid hydrolysis. After 15 min more than 90 per cent of the phosphate has been hydrolyzed. No prodrug could be detected in saliva; very little of the ester (average 0·9 per cent of the dose) was excreted unchanged into the urine. Methylprednisolone is formed rapidly. The total body clearance was 21 1h−1, the terminal half‐life 2·8 h. In the post‐distribution phase methylprednisolone levels in saliva went parallel to plasma levels. The mean saliva/plasma ratio was 0·22. An average of 5·2 per cent of the dose was eliminated into the urine in the form of methylprednisolone. Hydrocortisone suppression was dosedependent. For doses above 125 mg hydrocortisone levels were significantly lowered after 24 h. For doses above 500 mg the suppression was still significant after 48 h. The results indicate a rapid and predictable in vivo conversion of methylprednisolone phosphate to its active form methylprednisolone.
Absorption kinetics of cyclosporine in healthy volunteers
Authors: Gupta Suneel K. , Benet Leslie Z. 
Published: October 2006

AbstractThe absorption kinetics of cyclosporine were studied in eight healthy volunteers following oral and intravenous administration. Bioavailability of cyclosporine was observed to be 20±8 ± 5·5 per cent. Absorption of cyclosporine was found to be better described by first order processes rather than by a zero order process as previously reported.
A single and multiple dose pharmacokinetic and metabolism study of meclofenamate sodium
Authors: Koup J. R. , Tucker E. , Thomas D. J. , Kinkel A. W. , Sedman A. J. , Dyer R. , Sharoky M. 
Published: October 2006

AbstractA single and multiple oral dose administration study of meclofenamate sodium (Meclomen®) was conducted in ten healthy male volunteers. An initial 300 mg oral dose on day I was followed by a 100 mg every 8 h dosage regimen on study days 4 through 18. Intensive plasma and urine sample collection was carried out over the first three study days, and for 120 h following administration of the final dose on day 18. Plasma and urine specimens were analyzed by a specific HPLC assay for unconjugated meclofenamic acid and metabolites I and II of meclofenamic acid before and after sample incubation with β‐glucuronidase.Meclofenamic acid was rapidly absorbed following oral dose administration. Concentrations of meclofenamic acid existed primarily as unconjugated drug in plasma, with only a small amount present in the conjugated form. Meclofenamic acid was rapidly eliminated, with an elimination half‐life of approximately 1.3 h. This resulted in no detectable accumulation upon multiple dose administration. Metabolite I, which is one‐fifth as active as meclofenamic acid in in vitro inhibition of cyclooxygenase, was present in unconjugated form at steady state in concentrations approximately 50 per cent of those of meclofenamic acid, as unconjugated drug. The majority of metabolite I in plasma existed as glucuronide conjugate. Metabolite II, which is inactive, was present in very significant concentrations in unconjugated form. Plasma protein binding determinations conducted on meclofenamic acid and metabolite I indicated that the free fraction of metabolite I was 8·7 to 10·9 times higher than that of meclofenamic acid. When the lower activity and lower steady state concentrations, but higher free fraction, are considered, it would appear that metabolite I may contribute significantly to the in vivo inhibition of cyclooxygenase activity seen after administration of meclofenamic acid.
Effect of dietary fat content on the bioavailability of a sustained release quinidine gluconate tablet
Authors: Martinez M. N. , Pelsor F. R. , Shah V. P. , Skelly J. P. , Honigberg I. L. , Hemingway S. M. , Gallo J. M. , Kotzan J. A. , Zaman R. , Brown W. J. , Cliett S. 
Published: October 2006

AbstractQuinidine gluconate 324 mg sustained release tablets (Quinaglute) was administered as a single dose to 15 healthy male subjects following an overnight fast, immediately following a high fat (HF) breakfast or immediately following a low fat (LF) breakfast. Serum samples were obtained over a 48 h period and analyzed for quinidine content using a high performance liquid chromatographic assay. Under the conditions of the study, both the rate and extent of quinidine bioavailability was significantly affected by food. The extent of bioavailability was statistically significantly greater (p<0·05) following both the HF and LF meals as compared to that in the fasted state. Rate of bioavailability was significantly enhanced following the LF meal as compared to that of the other two treatment groups. Although peak concentrations were greater and time to peak concentrations somewhat later following the HF meal versus those under fasting conditions, these differences were not statistically significant. In addition, the characteristics of the serum concentration‐time profile (as defined by the number, magnitude, and time of occurrence of the multiple absorption maxima) was unique for each of the three treatment groups. Possible mechanisms underlying these results are explored.
Absolute bioavailability of terbutaline from a CR‐granulate in asthmatic children
Authors: Fuglsang Gunver , Hertz Birgitte , Holm Eva Bettina , Borgström Lars 
Published: October 2006

AbstractThe study aimed at finding the absolute bioavailability of terbutaline of a newly developed CR‐granulate. Eight asthmatic children, aged 8–13 years, were given 3 mg of terbutaline as the CR‐granulate, concomitant with the intravenous administration of 0·100 mg of deuterium‐labelled terbutaline. The labelling of the intravenous dose made possible a separation, in the analytical step, of terbutaline originating from the intravenous and oral administration. Maximal plasma concentration, 8·7 (range: 4·9–15·2) nmoll−1, was reached after 4·7 (2·2–6·0) h. Absolute bioavailability was 10·8 (7·63–16·4) per cent. The parameter values were similar to those found after administration of terbutaline CR‐tablets to adults. The CR‐formulation is easily swallowed and can be dosed twice daily. Thus it should be a good alternative to elixir or plain tablets, dosed three times a day.
Dose dependent pharmacokinetics of N‐ACETYLCYSTEINE AFTER ORAL DOSING TO MAN
Authors: Borgström Lars , Kågedal Bertil 
Published: October 2006

AbstractThe pharmacokinetics after oral administration of 200, 600 or 1200 mg of N‐acetylcysteine (NAC) were studied in 10 healthy subjects. Normalized maximal plasma concentration was significantly higher after a 600 mg dose than after a 200 mg dose. Bioavailability of NAC significantly increased with increasing dose. Time for maximal plasma concentration also increased with increasing dose. The observations can be explained by a capacity‐limited presystemic elimination of NAC. In an extension of the study, 600 mg of NAC was given twice a day for 5 days and the plasma concentrations were followed after the morning dose on day 6. No differences in the pharmacokinetic parameters were observed in comparison with the single 600 mg dose. This indicates that the beneficial clinical effects observed after repeated dosing can not be ascribed to an accumulation of NAC in plasma.
Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs
Authors: Murata Kazuo , Noda Kazuo , Kohno Keiichi , Samejima Masayoshi 
Published: October 2006

AbstractPharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N‐(N‐acetyl‐L‐methionyl)0,0‐bis(ethoxycarbonyl) dopamine(1). Plasma concentrations of DA, DA‐SO4. and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first‐pass metabolism for the formation of DA‐SO4 and DOPAC, Though plasma concentration of DA was quite different from that of DA‐SO4 or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA‐SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N‐(N‐acetyl‐L‐methionyl)dopamine(2), DA‐SO4, and DOPAC after oral administration of 1 were simultaneously analysed using the compartment model including the first‐pass metabolism and two‐fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of 2(K4) is larger than that of DA‐SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially played an important role to the reduction of first‐pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of reduction of first‐pass metabolism of DA.
Effect of nifedipine on antipyrine and theophylline disposition
Authors: Adebayo G. I. , Mabadeje A. F. B. 
Published: October 2006

AbstractOn the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half‐life of 10·04 ± 1·43 h (mean ± SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10·64 ± 2·15 h; nor was that of 10·02 ± 1·49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min−1) of 44·40 ± 10·58 was not significantly different from that of 45·66 ± 9·34 and 46·87 ± 9·63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0·601 ± 0·074. 0·591 ± 0·078 and 0·602 ± 0·051 1 kg−1, respectively.A week pretreatment with nifedipine did not significantly alter either of theophylline half‐life (7·32 ± 0·81 h (control) to 7·50 ± 0·80 h) or clearance (42·10 ± 5·84 ml min−1 (control) to 43·77 ± 4·00 ml min−1) in six volunteers. However the change in volume of distribution: 0·451 ± 0·053 1kg−1 (control) to 0·483 ± 0·0621 kg−1 was significant (p < 0·025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post‐dosing (p < 0·05).It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed‐function oxygenase enzymes, but might displace theophylline from plasma protein.
Bioavailability of a new sustained‐release theophylline capsule in fasted and non‐fasted healthy subjects: Single and multiple dosing studies
Authors: West Raelene J. , Boehm Garth , Dwyer Mark , Williams Desmond B. , Sansom Lloyd N. , Penna Antonio C. 
Published: October 2006

AbstractEighteen healthy, non‐smoking, adult volunteers participated in single and multiple dose three‐way crossover studies to evaluate a sustained‐release, pellet‐filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained‐release capsule was investigated by administering 300 mg single doses of Austyn, with a high‐fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin(R) elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p > 0·05) between the three regimens with respect to AUC0−∞ values (mghl−1), (mean ± SD); Elixophyllin® fasting = 97·1 ± 33·7, Austy with food = 90·9 ± 31·3. Austyn fasting = 91·2 ± 33·8. Similarly, multiple dosing with rapid‐release Nuelin(r) tablets, Austyn capsules, and sustained‐release Theo‐Dur(r) tablets demonstrated that there were no significant differences between regimens with respect to AUC0‐24h, AUC0‐12h, and AUC12‐24h values calculated from the steady‐state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady‐state over the total blood sampling period was significantly less for treatment with the sustained‐release capsule, Austyn, compared with the sustained‐release tablet, Theo‐Dur(r) (Austyn = 36·7 ± 13·7 per cent, Theo‐Dur® = 53·1 ± 14·1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high‐fat meal and with no eyidence of dose dumping.