摘要:

AbstractA single‐blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen‐phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R= 0·96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200mg dose, The same trend was observed for the mean maximum almitrine plasma concentration,Cmax, which ranged from 38·9 ± 11·8 to 286·2 ± 99·1 ngml−1for the 25 and 200mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2·4 ± 0·5h to 2·8 ± 0·8h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268·2 ± 132·8 to 436·4 ± 191·4 ml min−1for doses

ISSN:0142-2782    

DOI:10.1002/bdd.2510100302

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

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−1and 180·1 ng ml−1compared to 196·3 and 200·1 ng ml−1for 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−1and 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 Eur

ISSN:0142-2782    

DOI:10.1002/bdd.2510100303

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

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 ± 1·9

ISSN:0142-2782    

DOI:10.1002/bdd.2510100304

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractComparative invivostudies of aqueous solution, multiple w/o/w, and w/o emulsions showed that formulating 5‐fluorouracil in emulsion systems significantly sustained the release of the drug from intramuscular injection sites in the rat.Intramuscular injection of the drug in both w/o and w/o/w emulsion systems produced sustained blood concentrations with a later blood level peak than observed following intramuscular injection of aqueous solutions of the drug. The multiple w/o/w emulsion exhibited a more rapid release of drug from the injection site than the w/o emulsion because of partitioning of the drug to the external aqueous phase during secondary emulsification.The fate of the oil phase following intramuscular injection of a water/hexadecane/water multiple emulsion spiked with 1‐14C‐hexadecane has been studied in rats as a function of stabilizer concentrations. Increasing the lipophilic surfactant (Span 80) concentration facilitated the clearance of the oily vehicle from the injection site, by mechanisms which remain to be eluci

ISSN:0142-2782    

DOI:10.1002/bdd.2510100305

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe bioavailability of rectally administered sodium ibuprofen solution and aluminum ibuprofen suspension was determined in eight normal subjects relative to the same treatments administered orally. The results indicate that the suspension was less bioavailable than the solution irrespective of the route of administration. Although not bioequivalent, rectally administered ibuprofen solution compared favourably with orally administered ibuprofen solution. The mean AUC andCmaxfrom rectal administration were 87 per cent and 62 per cent of the corresponding values achieved after oral administration. Mean residence times and peak times were 1–3 h longer with the rectal solution, indicating a slower rate of absorption. Absorption after rectal administration was zero order in some subjects while absorption after oral administration was first order. This may be due to the large differences in surface area between absorption sites. Since sodium ibuprofen solution is absorbed when given rectally, this route of administration could be used in patients unable to take oral ibuprofe

ISSN:0142-2782    

DOI:10.1002/bdd.2510100306

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractAbsorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats insitu, is shown to be a specialized transport mechanism obeying Michaelis‐Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis‐Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yieldedVmandKmvalues of 12·0mgh−1and 8·0mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady‐state are needed. On the other hand, more than 8‐h sustainedrelease preparations of baclofen should, probably,

ISSN:0142-2782    

DOI:10.1002/bdd.2510100307

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg−1of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg−1of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two‐fold greater and the corresponding elimination half‐life (t1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of14C‐salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the largerVdobserved in this group of rats. After the administration of 173 mg kg−1of SA, no differences in CL,Vd,kjort1/2were noted between the analbuminemic and control rats. Dose‐dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA pr

ISSN:0142-2782    

DOI:10.1002/bdd.2510100308

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

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 meanCmaxafter dosing with whole tablets, 143 (95 per cent confidence limits 91·6–223) ngml−1was lower than after dosing with half tablets, 160 (107–241) ngml−1, but this was not significant (p=0·49). The mean steady‐stateCminvalues after whole and half tablets were also similar: 22·2 (12·6–39·4) ngml−1and 22·0 (16·2–29·9) ngml−1, respectively (p=0·96). The mean (± S.D.)tmax, AUC0–24andt1/2were not significantly different: whole tablet 3·5 ± 1·2h, 1733 ± 1125 ng.h ml−1and 10·5 ± 3·4h, respectively, and half tablets 3·6 ± 1·0h, 1780 ± 1057 ng.h ml−1and 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 susta

ISSN:0142-2782    

DOI:10.1002/bdd.2510100309

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractFour 50 mg and three 100 mg marketed nitrofurantoin tablets were studied in 14 healthy male subjects. Urine was collected 1, 2, 3, 4, 6, 8, 12, and 23 h after each dose, and nitrofurantoin was assayed by HPLC. Thein vitrodissolution of the tablets was determined using USP Apparatus 1 and 2, with 0·1 N hydrochloric acid and pH 7·2 buffer as the dissolution fluids. One of the 50 mg tablets was more rapidly and completely absorbed than the other six products. The incidence of side‐effects for this product was as low or lower than the other products. It was determined that the use of the USP Apparatus 1, at 100 rev min−1, with sampling of the pH 7·2 fluid at 30 min, provided for the best overall relationship between the urinary excretion andin vitrodisso

ISSN:0142-2782    

DOI:10.1002/bdd.2510100310

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100301

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY