Assessment of oral bioavailability and preclinical pharmacokinetics of DRF-6196, a novel oxazolidinone analogue, in comparison to linezolid.

The aim of this study was to determine the bioavailability of a novel oxazolidinone, DRF-6196, in mice and rats following intravenous (i.v) and oral dosing and to compare the pharmacokinetics with those obtained following linezolid dosing. Blood samples were drawn at predetermined intervals up to 24 h post-dose after either DRF-6196 or linezolid administration. The concentrations of DRF-6196 and linezolid in various plasma samples were determined by a HPLC method. Following oral administration maximum concentrations of DRF-6196 were achieved within 0.5 h irrespective of the species. While the doses increased in the ratio of 1 : 3 : 10, mean Cmax and AUC(0-infinity) values in mice for DRF-6196 increased in the ratio of 1 : 3.87 : 8.53 and 1 : 2.51 : 9.24, respectively. Both the Cmax and AUC(0-infinity) values increased almost proportional to the dose administered in mice. Following i.v administration, the concentration of DRF-6196 declined in a bi-exponential fashion with terminal elimination half-life of 1.5 h irrespective of the species. The systemic clearance and volume of distribution of DRF-6196 in mice were 1.14 L/h/kg and 0.66 L/kg, respectively after i.v administration, while the respective values in rats were 0.61 L/h/kg and 0.41L/kg, respectively. Elimination half-life ranged between 0.8-1.5 h. Absolute oral bioavailability of DRF-6196 was found to be 80-96% across the test dose range. Although plasma levels of DRF-6196 were lesser compared to linezolid in the initial hours, it may not have any consequences on the clinical effectiveness of the molecule.     

Tuberculosis of paranasal sinuses

Nasal tuberculosis is very rare but much rarer is tuberculosis of paranasal sinuses. It involves especially the maxillary sinus and is usually unilateral. We report an unusual case of tuberculosis of frontal and maxillary sinus in a 68 years old male, who presented with a swelling above left medial canthus, with no other eye or nasal complaints. Clinical and radiological findings on our initial evaluation suggested that the patient had left frontal mucocoele with bilateral maxillary haziness. Diagnosis was established on FNAC report and subsequent Ziehl — Neelsen staining of nasal swabs and tuberculin skin test. Later chest x-ray examination was suggestive of pulmonary tuberculosis, which was the primary cause. Patient responded well to antituberculosis drug therapy.     

Effectiveness of generic fixed-dose combinations of highly active antiretroviral therapy for treatment of HIV infection in India

OBJECTIVE: To assess clinical and immunologic effectiveness and acute toxicity to nevirapine (NVP)-based fixed-dose combinations (FDCs) in antiretroviral-naive HIV-1-infected patients in India. DESIGN: Observational study of patients initiated on NVP-based combination therapy delivered as FDCs. METHODS: Antiretroviral-naive HIV-1-infected patients initiated on FDCs (zidovudine/lamivudine [3TC]/NVP or stavudine/3TC/NVP) were assessed clinically and with CD4 counts periodically. Adverse events to NVP were assessed clinically and by laboratory markers. Frequency and risk factors for development of adverse events and clinical outcomes were determined. RESULTS: Of the 1291 patients started on therapy, 1253 completed a minimum of 3 months of follow-up. Rash and hepatitis were documented in 6.6% (95% confidence interval [CI]: 5.5-8.3) and 3.2% (95% CI: 2.3-4.8) of patients initiating therapy, respectively. There was significant improvement in CD4 counts over 2 years. Fourty-eight patients died, and 186 clinical events were documented in these patients. Tuberculosis was the most common cause of morbidity and mortality. Self-reported adherence was high. CONCLUSION: Fixed-dose formulations of NVP-based combination therapy are safe and produced durable clinical and immunologic benefit.     

Time course of the elevation of nerve growth factor (NGF) content in the hippocampus and septum following lesions of the septohippocampal pathway in rats

Axotomy of cholinergic neurons in the medial septum-diagonal band and degeneration of their terminals in the hippocampus resulting from fornix-fimbria lesions induce elevation of NGF content in these two brain regions. Postlesion levels of cholinergic neuron-specific ChAT activity in the septum suggest that endogenously produced NGF may, at least partly, promote survival of axotomized cholinergic neurons or induce ChAT activity in undamaged cells or both. These findings thus support the proposed trophic role for NGF in central cholinergic neurons.     

Difficult Airway Society Guidelines for the management of tracheal extubation

Tracheal extubation is a high-risk phase of anaesthesia. The majority of problems that occur during extubation and emergence are of a minor nature, but a small and significant number may result in injury or death. The need for a strategy incorporating extubation is mentioned in several international airway management guidelines, but the subject is not discussed in detail, and the emphasis has been on extubation of the patient with a difficult airway. The Difficult Airway Society has developed guidelines for the safe management of tracheal extubation in adult peri-operative practice. The guidelines discuss the problems arising during extubation and recovery and promote a strategic, stepwise approach to extubation. They emphasise the importance of planning and preparation, and include practical techniques for use in clinical practice and recommendations for post-extubation care.     

Recovery of enzyme markers for cholinergic terminals in septo-temporal regions of the hippocampus following selective fimbrial lesions in adult rats

The activities of choline actyltransferase and acetylcholinesterase were determined in five consecutive septo-temporal regions of the ipsilateral and contralateral hippocampus from unlesioned controls and lesioned animals at various times following lateral, medial or complete unilateral transection of the fimbrial bundle in rats. In control animals distribution of cholinergic enzymes suggests a relatively heavier innervation of the ventral hippocampus. In lesioned animals depletion of enzyme activities in septo-temporal regions of the ipsilateral hippocampus was consonant with the known topography of cholinergic innervation of the hippocampus via the dorsal and ventral pathways. After 4 and 8 week post-lesion survival, a substantial recovery of both enzyme activities was evident following either of the lesion paradigms employed. However, the extent and the pattern of enzyme restitution depended on the type of fimbrial transection and the hippocampal region under consideration. Significant enzyme alterations were also observed in the contralateral hippocampus following all three lesion types. We interpret the lesion-induced temporal consequences in cholinergic enzymes to indicate initial degeneration and subsequent regeneration of cholinergic terminals in the hippocampus. The present findings also suggest that homologous fimbrial fibres spared by the partial lesions are responsible for the ensuing recovery. Thus, partial lesions of well-defined efferents constitute a suitable experimental paradigm to demonstrate homotypic reconstruction in the adult mammalian central nervous system.