Characterization of AUCs from Sparsely Sampled Populations in Toxicology Studies

Purpose. The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. Methods. Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13–16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed critical time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each critical point. The data were subsequently modeled using PCNONLIN, and the parameters (k_a, k_e, and V_d) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally, Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. Results. The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was ~10%, with a precision (%CV) of ~15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. Conclusions. Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.     

Functional voice disorders and their occurrence in 100 patients of hoarseness as seen on fibreoptic laryngoscopy

During a six month period, one hundred patients presenting with the primary complaint of hoarseness, in the out- patients department of otolaryngology at Safdarjung Hospital New Delhi were taken up fot the study Fach patient after being subjected to a detailed history- taking and examination, including a Fibreoptic Laryngoscopy was then put into one of ten categories on the basis of the ultimate diagnosis Functional voice disorders, forming the largest category with 51%, included lesions such as vocal nodules and polyps, which are secondary to vocal abuse A detailed study of the various types of functional voice disorders along with factors such as male female ratio and associated contributory factors was done the efficacy of the Fibreoptic laryngoscope as a diagnostic tool was also assessed     

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted.     

Variability in tablet fragment weights when splitting unscored cyclobenzaprine 10 mg tablets.

OBJECTIVE: To determine the weight variation and calculated dosing variability of tablet fragments upon splitting unscored cyclobenzaprine hydrochloride 10 mg tablets using two common tablet splitting devices. DESIGN: Comparative pharmaceutics study. SETTING: Pharmacy school laboratory. PARTICIPANTS: Not applicable. INTERVENTIONS: Unscored cyclobenzaprine hydrochloride 10 mg tablets from one generic manufacturer were split with a tablet splitter or a kitchen knife by a licensed pharmacist and two doctor of pharmacy students (n = 15 tablets for each method per participant). MAIN OUTCOME MEASURES: Fragment weights (FWs) were compared with the theoretical weights (TWs), which were calculated as one half of the mean weight of the tablets used in each part of the experiment; means, relative standard deviations (RSDs), and percentages of TW were also calculated. RESULTS: The mean weight before splitting the 45 tablets with the tablet splitter was 136.6 +/- 2.1 mg (TW = 68.3 mg). The mean FW after splitting was 67.9 +/- 7.9 mg. The RSD of 11.6% corresponded to a range of 69.4% to 130.2% of the TW and an estimated drug content of the split fragments between 3.47 mg and 6.51 mg. The mean weight before splitting the 45 tablets cut with a kitchen knife was 136.6 +/- 2.0 mg (TW = 68.3 mg). The mean FW was 68.0 +/- 15.7 mg with a RSD of 23.2%, corresponding to a range of 49.9% to 149.5% of the TW and an estimated drug content of the split fragments between 2.49 mg and 7.48 CONCLUSION: Tablet fragments obtained after splitting this generic cyclobenzaprine 10 mg product varied considerably in weight and estimated drug content. Accordingly, splitting cyclobenzaprine 10 mg tablets to achieve 5 mg doses could result in unpredictable dosing and therapeutic response.     

Menstrual hygiene management and its determinants among adolescent girls in low-income urban areas of Delhi,India: a community-based study

ObjectivesMenstrual hygiene management (MHM) in developing countries is linked to human rights, social justice, and the education and empowerment of young girls. The objective of this study was to assess menstrual hygiene practices and their determinants among adolescent girls, including school dropouts, and the effects of pad distribution programs in urban resettlement areas of Delhi, India.Methods A cross-sectional study was conducted from March 2019 to February 2020 in urban resettlement colonies and 2 villages of Delhi among 1,130 adolescent girls aged 10 to 19 years, who were interviewed face to face.Results In total, 954 participants (84.4%) used only disposable sanitary pads, 150 (13.3%) used both sanitary pads and cloths, and 26 (2.3%) used only cloths (n=1,130). Most school-going girls utilized the scheme for pad distribution, but only two-thirds of the girls who were out of school utilized the scheme. In the adjusted analysis, girls with lower educational status, those who had dropped out of school, and those from the Muslim religious community were more likely to use cloths for MHM.Conclusion More than 4 out of 5 adolescent girls in Delhi in low-income neighborhoods preferred sanitary pads for MHM. The government free pad scheme reached near-universal utilization among school-going girls (97%), but the subsidized pad scheme for girls who did not attend school was insufficiently utilized (75%).     

Effect of cord factor, a toxic glycolipid from Mycobacterium tuberculosis, on mouse liver drug metabolizing enzymes

Cord factor (a mycobacterial toxin) treatment of mice for 72 hr resulted in decreased activities of hepatic drug metabolizing enzymes. The toxin treated animals exhibited reduced levels of liver cytochrome P-450 and cytochrome b5, accompanied by significant lowering of NADPH-cytochrome c reductase and NADH-cytochrome b5 reductase activities. The hepatic activities of aminopyrine N-demethylase and aniline hydroxylase were diminished, while liver cytosolic glutathione S-transferase activity was inhibited in mice receiving the toxin. Earlier studies from this laboratory (J. K. Batra, Ph.D. Thesis, Delhi University, India, 1982) on the effects of experimental tuberculosis on hepatic drug metabolism revealed changes similar to the presently reported influence of cord factor on mouse liver microsomal monooxygenases. Thus, the action of cord factor (on hepatic drug metabolism) largely mimics the effects of tuberculosis infection.