Compound A (3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid), a hydrophilic zwitter-ion, is a potent and selective alphavbeta3 integrin antagonist currently under clinical development for the treatment of osteoporosis. The mechanism of renal excretion of compound A was investigated using a combination of in vivo and in vitro approaches. In rats, renal excretion of compound A involved tubular secretion; ratios between renal clearance, corrected for unbound fraction in plasma (CLr,u) and glomerular filtration rate (GFR) were greater than unity (2-5). The tubular secretion of compound A was saturable at high plasma levels (> 26 microM), and was inhibited significantly, although modestly (about twofold) by relatively high plasma concentrations of the organic anion PAH (160 microM) and the cation cimetidine (about 400 microM), but not by the P-gp inhibitor quinidine (about 50 microM). However, compound A (about 100 microM) had a minimal effect on CLr/GFRs for cimetidine and PAH. In rhesus monkeys, renal elimination of compound A also involved tubular secretion, with a CLr,u/GFR ratio of about 30. The renal secretion of compound A was not affected by either cimetidine (about 120 microM) or PAH (about 80 microM). Similarly, compound A (about 40 microM) had a minimal effect on the renal tubular secretion of both cimetidine and PAH. At the doses studied, neither rat nor monkey plasma protein binding of compound A, cimetidine or PAH was affected in the presence of each other. In vitro transport studies showed that compound A was not a substrate for P-gp in the Caco-2, human MDR1 and mouse mdr1a transfected LLC-PK1 cell lines. In an uptake study using rOAT1 and rOAT3 transfected HEK cell lines, compound A was shown to be a substrate for rat OAT3 (Km= 15 microM), but not rat OAT1. The results suggest that the tubular secretion of compound A is not mediated by P-gp, but rather is mediated, at least in part, via the organic anion transporter OAT3, the renal transporter shown to be capable of transporting both the organic anion PAH and the organic cation cimetidine. Although there is a possibility for pharmacokinetic interactions between compound A and substrates or inhibitors of OAT3, at the renal excretion level, the magnitude of interaction would likely be modest in humans at clinically relevant doses.

Animals↗

PubMedDate not supplied

Bronchial tuberculosis. Cytologic diagnosis of fiberoptic bronchoscopic brushings.

OBJECTIVE: To determine the cytomorphologic features of bronchial tuberculosis on fiberoptic bronchoscopic brushings and its diagnostic value. STUDY DESIGN: Seven hundred forty-six bronchoscopic examinations were retrospectively studied. The patients' macroscopic findings made by fiberoptic bronchoscopic examination, as well as brush cytologic and biopsy findings, were reviewed. RESULTS: Of 746 bronchoscopic brushing specimens, 23 were diagnosed as endobronchial tuberculosis by cytomorphology; that accounted for about 3.1% of cases. The same or a similar diagnosis was made for both specimen types in 16 of the specimen pairs. Acid-fast stain showed that only one brushing was positive (4.3%); all the biopsy specimens were negative. Epithelioid cell granulomas and/or caseous necrosis were found in 23 cases of brush smears, while tuberculous granulomas accounted for 16 bronchial biopsies. Seven were nonspecific chronic bronchitis or normal bronchial mucosa. CONCLUSION: The cytomorphologic alterations of tuberculosis are suitable for diagnosing bronchial tuberculosis on fiberoptic bronchoscopic brushings. Its sensitivity for defining bronchial tuberculosis is not lower than that of bronchial histologic biopsies or bacteriologic examination.

Adolescent↗

PubMedDate not supplied

Cure of pulmonary Rhizomucor pusillus infection in a patient with hairy-cell leukemia: role of liposomal amphotericin B and GM-CSF.

We describe a case of successfully treated multifocal pulmonary Rhizomucor pusillus, a condition which has previously been universally fatal. A 77 year-old man had a background of chronic neutropenia due to hairy-cell leukemia, splenectomy, corticosteroid therapy and an obstructing left ureteric transitional-cell carcinoma. He was successfully treated with 3 months of high-dose liposomal amphotericin B and 7 months of granulocyte-macrophage colony-stimulating factor. Treatment was complicated by mild reversible deterioration of renal function. There was a near complete radiological response to the therapy at 6 months and the patient remains well 20 months following diagnosis of R. pusillus and 13 months following cessation of treatment.

Aged↗

PubMedDate not supplied

Preliminary characterization and natural history of hantaviruses in rodents in northern Greece.

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Animals↗