Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome

Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used.     

Primary spinal epidural non-Hodgkin's lymphoma. The contribution of nuclear magnetic resonance imaging, therapeutic approach and review of the literature.

Primary spinal epidural lymphoma (Stage I) is diagnosed predominantly late after a long prodromal phase of local back pain resulting in spinal cord compression. The use of CT and NMR images in the early stage of investigation and their analysis may help to diagnose these cases prior to the appearance of neurologic deficit. We report on 2 patients who presented with prolonged localized back pain with sudden symptoms of spinal cord compression. CAT scan and NMR imaging demonstrated the characteristic appearance of lymphoma. Decompressive laminectomy supported the diagnosis. Radiotherapy treatment to the region of the non-Hodgkin's lymphoma resulted in complete resolution. Thereafter, systemic chemotherapy with CHOP achieved a good response.     

Glutathione effects on vitamin D metabolism in control and streptozotocin diabetic rat

The circulating concentration of 1,25-dihydroxycholecalciferol [1,25-(OH)₂D₃] is a physiologic index of enzymatic activity of the renal 1-hydroxylase of 25-hydroxychole-calciferol (25-OH-D₃). Hydroxylation of 25-OH-D₃ and circulating 1,25-(OH)₂D₃ are decreased in the streptozotocin diabetic rat. We previously found that activity of another redox enzyme system, cytosolic superoxide dismutase, also decreased in streptozotocin diabetes, can be restored by treatment with glutathione. In the present experiment we tested the effect of glutathione treatment on vitamin D metabolism in control and diabetic rats. Enteral glutathione increased circulating 1,25-(OH)₂D₃ and decreased 25-OH-D₃ in both control and diabetic animals. These results suggest that exogenous glutathione increases 25-OH-D₃ 1-hydroxylation both under basal conditions in the normal animal and in diabetes-induced depression.     

Spatial Learning Deficits in Mice with a Targeted Glucocorticoid Receptor Gene Disruption

Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor-mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor.     

Occurrence of multiple antibiotic resistance and R plasmids in Enterobacteriaceae isolated from children in the Sudan

The prevalence of resistance to six commonly-used antimicrobial agents in faecal coliforms from children in Khartoum, Sudan was studied. A relatively high prevalence of resistance was found, ranging from 96% of children with isolates resistant to ampicillin to 70% of children with isolates resistant to chloramphenicol. Seventy-seven percent of children had isolates with high-level resistance to trimethoprim (MIC greater than 1000 micrograms/ml). Twenty-nine different resistance patterns were found. Thirty-nine percent of the children had isolates resistant to all six antibiotics studied, and 80% of children had isolates resistant to at least four. Transfer of resistance to each of the antimicrobials, in varying combinations, was demonstrated, but did not occur for all resistance patterns. Plasmid analysis showed plasmids ranging from 160 MDa to 2.8 MDa and isolates contained from one to five plasmids of different sizes. There were no consistent relationships between resistance pattern and plasmid profile, but multiple resistance transfer was mediated commonly by plasmids with a molecular weight of 62 MDa. The high prevalence of potentially transferable antibiotic resistance in gut commensals of children in the Sudan may be of importance in the management of enteric and other infections requiring antimicrobial treatment.