摘要:

Cynomolgus monkeys were treated for 28 days with fluticasone propionate aqueous nasal spray (FPANS) 8 × 0.1 ml/day, which contained 0.02% benzalkonium chloride (BKC). Rats were treated for 1 hour/day for 28 days with a beclomethasone dipropionate aqueous nasal spray (BDPANS) essentially similar to the commercial preparation (Allen and Hanburys Ltd, Middlesex, England), which contained 0.01% BKC. Control animals received 5% glucose (monkeys) or air (rats). Sections of nasal mucosa were examined at 4 different levels by light microscopy. Counts of ciliated cells were made and scanning and transmission electron microscopy was performed on target sites that had been directly exposed to treatment (inferior turbinate of monkeys and intermediate turbinate of rats). No reduction in the number of ciliated cells or microscopical changes were seen in the nasal epithelium of the animals, and in particular there was no damage to the ultrastructure of the ciliated cells, the cilia themselves or their basal bodies that was related to treatment. The findings were compared with the results of previousin vitroandin vivostudies. Although ciliostasis has been reported with BKC inin vitromodels, where mucus is relatively depleted, such results should be interpreted with caution since BKC repeatedly applied to the nasal respiratory epitheliumin vivohas not caused damage to the ciliated epithelial cells. The animals received greater exposure to BKC-containing corticosteroids than patients who are treated with the aqueous nasal sprays for allergic rhinitis. The lack of any morphological damage supports previous findings that no damage to ciliated cells occurs in patients treated with FPANS or BDPANS.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

High doses of zidovudine, fluorouracil and calcium folinate have been simultaneously administered as a weekly 24-hour infusion in a chemotherapeutic protocol for cancer patients with solid tumours. The established therapeutic regimen, fluorouracil and calcium folinate, acts by inhibiting thymidylate synthase in tumour tissues. The theoretical basis for incorporation of zidovudine into this chemotherapeutic regimen is to interfere with the thymidine salvage pathway leading to more effective depletion of thymidine nucleotide levels and enhanced cytotoxicity to rapidly proliferating cells. Patient plasma sampling was performed prior to termination of the 24-hour infusion to assess steady-state levels and during a 4-hour postinfusion period to observe the decay kinetics. Samples were assayed for zidovudine by high-performance liquid chromatography. Pharmacokinetic profiles were evaluated for 11 patients administered doses at escalating levels in the range of 7 to 15 g/m2of zidovudine (6 patients received 3 dose levels, 1 patient received 2 levels, and 4 patients received only 1 level). The data was analysed using NONMEM, a computer program for population pharmacokinetic analysis. A 2-compartment pharmacokinetic model with parallel first-order and Michaelis-Menten elimination was used as the structural model, and a constant variance model was used to model intraindividual error. First-order clearance was modelled as being proportional to a covariate (serum creatinine clearance). Population estimates for volumes of the central and peripheral compartments were 24.3 and 62.5L, respectively. Estimates of first-order clearance and intercompartmental clearance in L/h were (0.436 x serum creatinine clearance) [in ml/min] and 50.2, respectively. The Michaelis-Menten constants, Vmaxand Km, were 22.0 mg/L/h and 9.28 mg/L, respectively, where Vmaxis the maximum velocity of the capacity-limited process and Kmis the concentration at half the maximum velocity. The 2-compartment parallel elimination model described provided a good fit for the nonlinear kinetics observed for zidovudine at high doses. NONMEM was found to be useful for pharmacokinetic analysis of a small population with dense sampling.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The pharmacokinetic properties of chloroquine are still under debate. To establish the pharmacokinetics of a single dose of chloroquine and its metabolites, 19 healthy volunteers, including one Black and one albino subject, received a single dose of chloroquine 600mg. In addition, one participant also received an oral dose of de-ethylchloroquine 150mg. Blood and saliva samples were obtained up to 77 days after drug administration. High-performance liquid chromatography was used to measure the concentrations of chloroquine, de-ethylchloroquine andbis-de-ethylchloroquine. The mean volume of distribution (Vd), elimination half-life (t½) and clearance (CL) of chloroquine were 411 L/kg, 432 hours and 0.77 L/h/kg, respectively. For de-ethylchloroquine these values were 161 L/kg, 649 hours and 0.18 L/h/kg. The results of the Black and albino subject were similar. When 150mg of this compound was administered, the Vd of deethylchloroquine was 122 L/kg, t½was 529 hours and CL was 0.16 L/h/kg.Bis-de-ethylchloroquine was detectable in 6 volunteers. No evidence for a bimodal distribution of chloroquine elimination was found in this study. Concentrations of chloroquine in saliva in the terminal elimination phase were 3-fold higher than in plasma.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The effects of a new generation ruthenium(III) complex, Na[trans-RuCl4(DMSO)Im], were compared with the effects of cisplatin in a model of the solid metastasising tumour MCa mammary carcinoma of CBA mice. By examining a number of intraperitoneal and intravenous administration schedules in mice either with spontaneous lung metastases or after artificial induction of tumour colonies, Na[trans-RuCl4(DMSO)Im] was found to behave differently from cisplatin. Unlike cisplatin, which is equally active on primary tumour growth and lung colonies, Na[trans-RuCl4(DMSO)Im] was markedly effective only on spontaneous metastases. The selectivity of Na[trans-RuCl4(DMSO)Im] on lung metastases was also marked on advanced metastases and accounted for a significant prolongation of host survival time, particularly in the experiments in which drug treatment was associated with surgical removal of a primary tumour. In combination with surgery, Na[trans-RuCl4(DMSO)Im] prevented metastasis formation and inhibited the growth of those already formed. This effect, although dependent on the dose used, was not associated with any residual effect on primary tumour cells after treatment discontinuation, whereas it tended to reduce the metastatic ability of the same tumour. This observation stresses the particular propensity of Na[trans-RuCl4(DMSO)Im] to binding metastatic cells rather than other tumour cell clones. On pBR 322 plasmid, Na[trans-RuCl4(DMSO)Im] was as effective as cisplatin in causing termination sites for replication, although it was only weakly active in generating interstrand crosslinking on calf thymus DNA. These data support the view that Na[trans-RuCl4(DMSO)Im] is the first compound capable of selective activity on metastatic tumours, and is therefore capable of showing a significant advantage for the postsurgical prognosis when associated with surgical ablation of primary tumours.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Twenty healthy male volunteers completed an open, partially randomised, crossover study to assess a possible pharmacokinetic interaction between nisoldipine and quinidine. Volunteers received either 1 nisoldipine coat-core 20mg tablet once daily, or 2 quinidine gluconate 324mg tablets twice daily, according to a randomised 2-period crossover design. Between the 2 treatment periods there was a washout phase of 7 days. After a further washout phase of 7 days, all volunteers received nisoldipine coat-core 20mg (1 tablet) and quinidine gluconate 648mg (2 tablets) concomitantly, as well as a second quinidine gluconate 648mg (2 tablets) dose 12 hours later. The results of this study indicate that the concomitant administration of nisoldipine and quinidine has no effect on the bioavailability of quinidine. However, it cannot be ruled out that the concomitant administration of these 2 drugs has an attenuating effect on the bioavailability of nisoldipine, although the clinical significance of a possible attenuation may be small in view of the very high intrasubject variation of this parameter. Concomitant administration of nisoldipine and quinidine was well tolerated.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The pharmacokinetics of total plasma platinum (TP), ultrafilterable plasma platinum (UF) and urinary excretion were studied in 15 patients receiving 2 consecutive 6-hour intravenous infusions of cisplatin (80 to 100 mg/m2) at a dose interval of 3 weeks. After first drug exposure, TP was slowly eliminated from plasma [terminal half-life (t½&ggr;) of 11.6 ± 2.5 days]. On second drug exposure, the mean plasma clearance and volume of distribution at steady-state decreased significantly (p<0.001) from 0.15 to 0.11 L/h/m2and from 49.5 to 42.1 L/m2, respectively, but no significant change was observed in the t½&ggr;(11.6 to 12.6 days) or in the mean residence time (14.6 to 16.3 days). A significant linear correlation was found between observed and predicted plasma levels of TP during the second course. The mean peak UF levels, the area under the concentrationvstime curve from zero to infinity (AUC0-∞) and urinary excretion (0 to 24 hours) were not significantly different between the 2 courses. The extent of reduction in plasma clearance of TP over 3 drug infusions in 3 evaluated patients correlated with the development of ototoxicity.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

242 patients over 16 years of age with community-acquired lower respiratory tract infection (LRTI) were randomised to receive either roxithromycin 150mg twice daily or amoxicillin 500mg/clavulanic acid 125mg three times daily for 7 days, with a further 7 days if insufficient response was seen. Patients in each group were found to be well matched for age and gender. Intention-to-treat analysis showed that clinical response at 7 days was 69% for roxithromycin and 56% for amoxicillin/clavulanic acid (p = 0.05) and at study end was 91% for both treatment groups. There were fewer second treatment courses in the roxithromycin group (26vs38%, p = 0.04) and a shorter mean treatment duration (8.29 daysvs9.34 days, p>0.05). 12 patients (9.8%) on roxithromycin and 19 (17.1%) on amoxicillin/clavulanic acid had adverse effects possibly or probably related to the antibiotic (p>0.05). A prospective economic analysis showed that the benefit (difference between the 2 treatment costs) per clinical success was $A17.04 in favour of roxithromycin. Roxithromycin appears to be a more appropriate choice than amoxicillin/clavulanic acid for the treatment of LRTI in the community given the more appropriatein vitrospectrum, the efficacy against all common pathogens, greater cost-effectiveness, the more convenient dosage regimen, and because it is better tolerated.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS