Urinary NO3 excretion and renal failure in indinavir-treated patients

Eira, Margareth; Araújo, Magali; Seguro, Antônio Carlos

doi:10.1590/s0100-879x2006000800009

Cited by 10 publications

(3 citation statements)

References 18 publications

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“…HIV patients treated with Indinavir presented lower urinary excretion of the NO metabolite NO 3 [82]. Wang et al demonstrated that Indinavir, at a clinical plasma concentration, can cause endothelial dysfunction through eNOS (endothelial nitric oxide synthase) down-regulation in porcine pulmonary artery rings and HPAECs (human pulmonary arterial endothelial cells), and that endothelium-dependent relaxation of the vessel rings was also reduced following Indinavir treatment [83].…”

Section: Discussionmentioning

confidence: 99%

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

et al. 2011

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Background and MotivationThe Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Methods and ResultsLigand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity.

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Section: Discussionmentioning

confidence: 99%

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

et al. 2011

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“…In previous studies conducted by our group in patients and in animal models, we found that indinavir also decreases NO production. 28,29…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone reverses tenofovir-induced nephrotoxicity

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Andrade

Pereira

et al. 2008

Kidney International

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Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi's-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.

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“…Treatment with indinavir has been found to be frequently associated with renal abnormalities and causes renal failure. 43 Lipodystrophy and other fat distribution disorders have been reported in patients receiving PI therapy for HIV infection. 44 PIs are reported to cause hepatotoxicity at any time from the start of medication.…”

Section: Viral Protease Inhibitors and Toxicity Of Antiprotease Drugsmentioning

confidence: 99%