Tenofovir-induced osteomalacia.

We present an HIV-infected woman in whom antiretroviral treatment with tenofovir disoproxil fumarate (TDF) induced severe skeletal pain, synovial effusions and multiple fractures secondary to a Fanconi syndrome with hypophosphatemia and osteomalacia. TDF interferes with the replication of mitochondrial DNA in the proximal tubules of the kidney, which can explain the delayed onset of this form of renal phosphate loss. Nephrotoxicity had been precipitated by cotreatment with lopinavir/r, an HIV protease inhibitor which increases tenofovir serum levels and inhibits the tubular multidrug resistance protein 4, which is responsible for the efflux of tenofovir from tubular cells.Awareness is needed to link the typically prolonged onset of clinical symptoms with TDF exposure and then establish the correct diagnosis.

Measurements of blood pressure and electrocardiogram in conscious freely moving guineapigs: a model for screening QT interval prolongation effects.

The pro-arrhythmic risk inherent to a new drug must be assessed at an early preclinical stage. Telemetry system implantation is a method widely used in vivo in various species. The present study was designed to assess whether conscious freely moving guineapigs can be used to predict QT prolongation in vivo. The guineapig has three advantages over the dog and the primate. First, it has specific ion channels similar to man; second, a smaller amount of test article is required for the investigation and third, its housing is less expensive. Under sterile conditions and isoflurane anaesthesia, telemetry transmitters were implanted intraperitoneally in male Dunkin Hartley guineapigs. Blood pressure, heart rate and electrocardiographic intervals were measured from two days up to eight months. Chronic implantation of the telemetry device did not lead to anatomic or macroscopic alterations in the abdominal cavity and no inflammation of the peritoneum or infection was observed. Four reference compounds were used: three positive (sotalol, terfenadine and dofetilide) and one negative reference (enalapril). Single oral administration of all three positive references dose-dependently induced bradycardia and QT corrected (QTc) prolongation. In contrast, neither enalapril nor its vehicle prolonged the QTc. These results demonstrate that the guineapig is both a suitable model and a good alternative to dogs or primates to assess the potential of compounds for QT interval prolongation in the early stages of drug development.

The diagnostic yield of vitrectomy specimen analysis in chronic idiopathic endogenous uveitis.

PURPOSE: The low diagnostic yield of vitrectomy specimen analysis in chronic idiopathic uveitis (CIU) has been related to the complex nature of the underlying disease and to methodologic and tissue immanent factors in older studies. In an attempt to evaluate the impact of recently acquired analytic methods, the authors assessed the current diagnostic yield in CIU. METHODS: Retrospective analysis of consecutive vitrectomy specimens from patients with chronic endogenous uveitis (n = 56) in whom extensive systemic workup had not revealed a specific diagnosis (idiopathic) and medical treatment had not resulted in a satisfying clinical situation. Patients with acute postoperative endophthalmitis served a basis for methodologic comparison (Group 2; n = 21). RESULTS: In CIU, a specific diagnosis provided in 17.9% and a specific diagnosis excluded in 21.4%. In 60.7% the laboratory investigations were inconclusive. In postoperative endophthalmitis, microbiological culture established the infectious agent in 47.6%. In six of eight randomly selected cases, eubacterial PCR identified bacterial DNA confirming the culture results in three, remaining negative in two with a positive culture and being positive in three no growth specimens. A double negative result never occurred, suggesting a very high detection rate, when both tests were applied. CONCLUSIONS: The diagnostic yield of vitrectomy specimen analysis has not been improved by currently routinely applied methods in recent years in contrast to the significantly improved sensitivity of combined standardized culture and PCR analysis in endophthalmitis. Consequently, the low diagnostic yield in CIU has to be attributed to insufficient understanding of the underlying pathophysiologic mechanisms.

Pharmacologic evaluation of the discriminative stimulus of metachlorophenylpiperazine.

A pharmacologic analysis of the discriminative stimulus of metachlorophenylpiperazine (mCPP) is reported. mCPP and m-trifluoromethylphenylpiperazine generalised, whereas 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 6-chloro-2-(1-piperazinyl)-pyrazine, and mesulergine partially generalised to the mCPP discriminative cue. However, although mianserin, methiothepin, ritanserin, mesulergine and N-(1-methyl-5'-indolyl)-N'-(3-pyridyl)urea hydrochloride (SB 200646) all antagonised the effect of 5-hydroxytryptamine (5-HT) on IP3 formation in the rat choroid plexus, they failed to antagonise the mCPP response in the drug discrimination studies. The 5-HT3 receptor antagonist MDL 72222 neither generalised nor antagonised the mCPP cue. These data suggest that neither the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5, 5-HT6, nor 5-HT7 receptors are involved. The response does appear to be mediated by a postsynaptic 5-HT receptor, however, because fenfluramine generalised to the cue. Haloperidol generalises, and amphetamine partially antagonises the mCPP discriminative cue and low doses of apomorphine partially generalises to the mCPP cue, which suggests that a decrease in dopamine neurotransmission may also be involved.

Effects of P. aeruginosa-derived bacterial products on tracheal ciliary function: role of O2 radicals.

The purpose of this investigation was to evaluate the effects of bacterial products derived from Pseudomonas aeruginosa on the function of airway cilia and to assess the role of phagocytes and oxygen radicals in the observed responses. Ciliary beat frequency (CBF) was measured in a perfusion chamber with a microscopic technique using tracheal epithelial cells obtained from normal sheep by brush biopsy (70% epithelial cells, 18% macrophages, 11% neutrophils). Baseline CBF ranged between 678 and 1,126 min-1. After 20 min of perfusion with the cell free supernatant of P. aeruginosa culture (mucoid strain), a concentration-dependent depression of CBF was observed with a 58% inhibition at a 1:1 dilution (P less than 0.05). The P. aeruginosa-derived products pyocyanin and 1-hydroxyphenazine also decreased CBF in a dose-related fashion. The cilion-inhibitory effects of the supernatant and bacterial products were markedly attenuated after centrifugation of the brush preparation (80% epithelial cells, 16.5% macrophages, 3.5% neutrophils). Glucose/glucose oxidase also caused a rapid, concentration-dependent cilioinhibition or ciliostasis. Catalase blocked or attenuated the ciliary effects of the supernatant, bacterial products and glucose/glucose oxidase. Thus bacterial products released from P. aeruginosa impaired ciliary activity by a pathway which involved neutrophils and was mediated by toxic oxygen radicals.