Dose proportionality of stavudine in hiv seropositive asymptomatic subjects: Application to bioequivalence assessment of various capsule formulations

The dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single-dose, randomized four-way crossover study in 16 asymptomatic HIV-infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration-time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean C_max and AUC_0-∞ values were in the range of 110.36–889.34 ng mL^?1 and 246.46–1945.97 h ng mL^?1 respectively. The mean C_max and AUC_0-∞ of stavudine increased in a dose-proportional manner. Irrespective of the dose, mean C_max values were observed at a median t_max of 0.75 h or less. Mean t_1/2 values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment, C_max and AUC_0-∞ values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase-3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose-normalized C_max values with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose-normalized AUC_0-∞ values for the 5, 20, and 40 mg capsules relative to the 10 mg phase-3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.     

Gastric pH Influences the Appearance of Double Peaks in the Plasma Concentration-Time Profiles of Cimetidine After Oral Administration in Dogs

The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted state, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, absorption of cimetidine after a single dose in the fasted state was studied as a function of gastric pH in male beagle dogs to determine whether gastric pH plays a role in the double peak phenomenon and/or can account for the decrease in bioavailability when antacids are coadministered. The extent of absorption of cimetidine was not influenced significantly by gastric pH, indicating that elevation of gastric pH is not the cause of decreases in the bioavailability of cimietidine when it is administered with antacids. Distinct double peaks or plateaux were noted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irregular absorption behavior was observed in 2 of 6 profiles in the pH range of 3 to 5, while single peaks were observed in all 10 profiles when the gastric pH was maintained at pH 5. It was concluded that gastric pH is a major factor in the generation of cimetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kinetic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH 5, however, absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from variations in gastric emptying as a function of pH and/or carryover effects of gastric pH into the upper intestine.     

Speech identification and cortical potentials in individuals with auditory neuropathy

Background  

Present study investigated the relationship between speech identification scores in quiet and parameters of cortical potentials (latency of P1, N1, and P2; and amplitude of N1/P2) in individuals with auditory neuropathy.     

Actinomyces in cervical smears of women using the intrauterine device in Singapore

OBJECTIVES: Reproductive tract actinomyces have been associated with the use of intrauterine contraceptive device (IUCD). Thus, there is a need to evaluate the prevalence of colonization with Actinomyces israelii in a cohort of Singaporean women using an IUCD. Second, the occurrence of actinomycosis in colonized women and the clinical need to remove the IUCD and/or possibly the need to treat asymptomatic carriers with antibiotics were evaluated. METHODS: The study population consisted of 1,108 IUCD users attending the Fertility Control Clinic, National University Hospital, Singapore. RESULTS: In our study, the prevalence of actinomyces-positive cervical smears among IUCD users was 13.7%; the incidence of actinomyces-positive smears was similar with Copper T (34.2%), Multiload (32.9%) and Nova T (32.9%) IUCDs. We found no association with the duration of use of IUCD and actinomyces infection. In our study, 150 out of 152 (98.7%) IUCD users with actinomyces-positive smears were asymptomatic, and only 2 out of 152 (1.3%) who had actinomyces-positive cervical smears developed pelvic inflammatory disease at 6 months. CONCLUSIONS: Our study suggests that removal of the IUCD in asymptomatic women with actinomyces-positive cervical smear is not necessary. Moreover, we suggest that asymptomatic carriers of actinomyces do not require preemptive antibiotic treatment.     

Some observations on skin smear examination

40 slit and scrape smears in a planned study and 35 routine smears picked up from the laboratory were examined. An end-to-end examination of the smears detected additional positives and gave a higher bacterial index than what was reported in the routine. Acid-fast bacilli were found to be distributed in only 1 to 3 per cent of the fields in the smears. The bacilli were found mostly in the centre and in narrow bands between centre and periphery of the smears. Some of the high BI smears were found to contain areas completely free from bacilli.     

Evidence for a Hazardous Interaction between Ethanol and the Insecticide Endosulf an in Rats

Abstract: Protein supplemented diet was protective against the deleterious action of endosulfan on body growth and liver. Hepatomegaly and a reduction of body weight produced concurrently by endosulfan and ethanol were greater in male rats, suggesting that males are more susceptible than female rats to the metabolic stress caused by their interaction. Chronic endosulfan exposure resulted in a prolongation of ethanol sleeping time in female and not in male rats. This finding suggests failure of female rats to metabolize ethanol readily on account of their greater susceptibility than male rats to the hepatotoxic action of endosulfan.     

A study of 5-aminolevulinic acid and its methyl ester used in in vitro and in vivo systems of human bladder cancer

The use of 5-aminolevulinic acid and its esters to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation for the purpose of cancer detection. Photodynamic diagnosis of cancer using 5-aminolevulinic acid (ALA) and its ester derivatives is being actively investigated. In this study, we compared ALA with ALA methyl ester (AME) derivative in terms of PpIX fluorescence intensity in in vitro and in vivo systems of bladder carcinoma. For the in vivo system consisting of RT112 xenografts, the modes of drug administration compared were intravenous administration and topical application. The Karl Storz fluorescence endoscopy system was used to obtain macroscopic fluorescence images. The macroscopic images were further analysed for fluorescence intensity distribution. For the intravenous administration, over all time points studied (1, 3, 6 h), AME-PpIX fluorescence was lower than ALA-PpIX fluorescence and was cleared at a faster rate than the ALA-PpIX when administered intravenously. Topical application with two different polymers, Gantrez and Polyvinyl pyrrolidone (PVP) which are fast releasing polymers was found to be comparable in inducing PpIX fluorescence. Topical AME-PpIX fluorescence was found to be comparable with ALA-PpIX fluorescence. The results of this study suggest that the AME can also be used as a good diagnostic agent.