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.     

N-methyl-N-nitrosourea-induced transformation of rat urothelial cells in vitro is not mediated by activation of ras oncogenes

Adult rat urothelial cells were transformed in vitro following treatment with a single dose of N-methyl-N-nitrosourea (MNU) or MNU treatment followed by promotion with sodium saccharin. This in vitro transformation process involves multiple steps: slow-growing 'pre-neoplastic' epithelial foci are induced 70-100 days after MNU treatment and from such foci rapidly proliferating immortal cell lines were established, some of which became tumorigenic after a further latent period. A series of epithelial cell lines and a single fibroblast cell line established in this way were analysed for the presence of transforming genes by DNA transfection into NIH3T3 cells. None of the epithelial cell lines induced foci in a focus formation assay. The single non-epithelial line induced foci and was found to contain an activated c-Ki-ras gene with a G----A transition in codon 12. To assay for the possible presence of transforming genes which were not active in a focus formation assay, two of the epithelial lines were analysed further by co-transfection with a dominant selectable marker, followed by selection and inoculation into nude mice. No tumours were induced within the latent period for tumour production by control cells transfected with NIH3T3 cell DNA (40-60 days). These results suggest that there is cell type specificity for oncogene activation during in vitro rat bladder transformation initiated by a single carcinogen and that ras gene activation is not a necessary step in urothelial transformation in vitro.     

Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis.

BACKGROUND--It has been hypothesised that cryptogenic fibrosing alveolitis has an immunological pathogenesis mediated by T lymphocytes. It is, however, recognised that patients may show dysregulation of the humoral immune system and that the presence of large numbers of B lymphocytes in open lung biopsies may be associated with a poor prognosis. Evidence of a role for the humoral immune system in the pathogenesis of cryptogenic fibrosing alveolitis has been suggested, but attempts to demonstrate circulating immunoglobulin to antigen within the lung have been inconclusive. METHODS--Plasma samples from 22 patients with cryptogenic fibrosing alveolitis, 22 patients with sarcoidosis, and 17 healthy controls were screened by SDS-PAGE and Western blotting for the presence of autoantibodies to lung proteins derived from cryptogenic fibrosing alveolitis, sarcoid and control lung tissue, as well as four normal non-pulmonary tissues. Possible site(s) of target protein(s) within the lung tissue were identified by immunohistochemical examination using IgG purified from the plasma of six patients and two controls. RESULTS--Eighteen of the plasma samples from patients with cryptogenic fibrosing alveolitis had reactive IgG to lung protein(s) in the 70-90 kDa molecular weight range compared with five of 18 plasma samples from patients with sarcoidosis and one of 17 controls. Plasma from patients with cryptogenic fibrosing alveolitis recognised antigen(s) of the same molecular weight in control and sarcoid lung tissue, but not non-pulmonary tissues, with a similar frequency. Immunohistochemical staining of cryptogenic fibrosing alveolitis biopsy material using IgG purified from plasma samples from patients with cryptogenic fibrosing alveolitis, but not control samples, revealed fine linear positivity in the lung parenchyma in a pattern suggestive of reaction with alveolar lining cells. The pattern was cytoplasmic/membranous and not nuclear. CONCLUSIONS--Patients with cryptogenic fibrosing alveolitis have a high frequency of plasma IgG autoantibodies to protein(s) within lung tissue associated with alveolar lining cells. This is believed to be the site where immunological injury occurs in cryptogenic fibrosing alveolitis, but the significance of these antibodies to the aetiology and pathogenesis is as yet unclear.     

Cerebral infarction associated with protein C deficiency following allogeneic bone marrow transplantation.

Hypercoagulable states associated with deficiencies in circulating anticoagulant protein C occur after chemotherapy for a variety of malignant diseases. Protein C deficiency also occurs following bone marrow transplantation (BMT) and may be responsible for a variety of transplantation-associated complications. We report the case of a child who suffered a stroke associated with low protein C antigen and activity occurring 11 months after allogeneic BMT. Protein C levels recovered spontaneously by 18 months after BMT. We speculate that the protein C deficiency and and resultant hypercoagulable state led to the stroke, and the deficiency of this anticoagulant was a sequela of the transplant.     

Implementation of a successful endovascular surgical program in a non-teaching tertiary-care centre in Ontario.

Endovascular surgical techniques have become an accepted standard of care for high-risk patients with abdominal aortic aneurysms and for certain patients with thoracic aortic pathology and peripheral arterial aneurysms. In Canada, endovascular surgery has been concentrated in tertiary-care academic teaching institutions. As the technology evolves and as expertise advances, the applicability of endovascular techniques will expand. With time, and as the demand for endovascular techniques rises, this expertise will increasingly need to be delivered by dedicated vascular surgical services in nonteaching institutions. The dissemination of endovascular surgical capabilities represent a unique challenge. We report the successful implementation of an endovascular surgical program in a tertiary-care nonteaching institution using a carefully planned preceptorship model. We review our initial 49 cases and discuss 6 factors important to the successful establishment of an endovascular surgical service: education, teamwork, strict selection of patients, use of a single stent-graft manufacturer, industry support and endovascular preceptorship. Our experience may be used as a model by other institutions in Canada.