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Biomedical subjects

Gilbert Deray

Publications and source records attributed to Gilbert Deray.

At least 55 records · Page 3Linked to original sources
PubMed2005

Renal tubular transporters and antiviral drugs: an update.

Systemic disposition of antiviral drugs partly depends on renal handling of these compounds. There are some known, functionally characterized anionic and cationic transporters with varying substrate specificities for those drugs: human organic anion transporter (OAT) family (hOAT1-3) and human organic cation transporter (OCT) family (hOCT1-3), which mediate the intracellular flux, and adenosine 5'-triphosphate (ATP) binding cassette transporter family (P-glycoprotein, MRP2-5), which mediate the cellular efflux of antiviral drugs. The peptide transporter (PEPT1-2) mediate bi-directional facilitated diffusion of valacyclovir. All these transporters are expressed in the kidney. Organic anion and cation transporters primarily localize to the basolateral membrane of renal epithelial cells while ATP-binding cassette transporters primarily localize to the apical membrane. These transporters work in concert to mediate renal intracellular concentration of occurring antiviral drugs. Along with drug-metabolizing enzymes, these transporters are important determinants of drug effectiveness and toxicity. This review examines the role that these transporters play in renal disposition of antiviral drugs.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Renal disease in cardiovascular disorders: an underrecognized problem.

Chronic renal disease is generally appreciated as a major and rapidly growing health problem. In the United States alone, as many as 19.5 million people may have markers of early renal disease, and more than 660,000 people are expected to require renal replacement therapy by the year 2010. By contrast, the presence and pathological role of renal disease in patients with cardiovascular disease are somewhat underrecognized. Evidence now shows that even minor impairments in renal function, as indicated by measures including glomerular filtration rate and microalbuminuria, are common in cardiovascular disease states and predictive of cardiovascular events. Indeed, microalbuminuria may be a marker of systemic vascular disease rather than kidney dysfunction alone. In patients with hypertension, diabetes, metabolic syndrome, acute coronary syndromes, and stroke, markers of renal disease have proved to be at least as predictive of morbidity and mortality as conventional risk factors. Yet, chart reviews in a variety of clinical settings reflect poor recognition and management of renal disease in at-risk patients. Models for renal protection are based on the control of risk factors, particularly blood pressure, that are associated with renal and cardiovascular outcomes. Screening protocols for markers of renal disease should recognize the potential inaccuracy of serum creatinine concentrations and the preferability of glomerular filtration rate estimates that take age and gender into account. Pilot programs for screening high-risk populations have shown efficacy in detecting renal disease.

Biomarkers↗
PubMed2005

Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) was developed for the treatment of human immunodeficiency virus (HIV) infection. However, controlled data are sparse on the long-term renal tolerability of TDF at the currently approved daily dose of 300 mg in treatment-naive HIV-infected patients. METHODS: Over 144 weeks, this 600 patient, multicentre randomized, placebo-controlled, double-blind trial compared stavudine (301 patients) and TDF (299 patients), both administered in combination with lamivudine and efavirenz, in antiretroviral-naive patients. TDF or placebo and stavudine or placebo were administered in an open-label fashion. All medications were taken orally. At screening, all patients had serum creatinines <1.5 mg/dl, calculated creatinine clearances > or =60 ml/min and a serum phosphorus > or =2.2 mg/dl. RESULTS: The incidences of grades 1 (> or =0.5 mg/dl increase from baseline), 2 (2.1-3.0 mg/dl) and 3 (3.1-6.0 mg/dl) serum creatinine elevations at week 144 were 4, <1 and 0%, respectively, in the TDF group and 2, 0 and <1% in the stavudine control group (P = NS). There were no grade 4 (>6 mg/dl) serum creatinine elevations. At week 144, there was no change from baseline in the mean (0.83 mg/dl) serum creatinine in the TDF group compared with a 0.1 mg/dl decrease from baseline (0.83 mg/dl) in the stavudine control group. The incidences of grades 1 (2.0-2.2 mg/dl), 2 (1.5-1.9 mg/dl) and 3 (1.0-1.4 mg/dl) hypophosphataemia at week 144 were 4, 3 and <1%, respectively, in the TDF group and 4, 2 and <1% in the control group (P = NS). No patient experienced grade 4 (<1.0 mg/dl) hypophosphataemia. At week 144, the decrease (Delta) of mean serum phosphorus levels from baseline in both groups was similar (Delta 0.2 from 3.6 mg/dl for the TDF group, and 0.1 from 3.5 mg/dl for the stavudine control group). No patient developed Fanconi's syndrome or proximal renal tubular dysfunction during the study. CONCLUSION: Through 144 weeks, TDF and stavudine, each administered in combination with efavirenz and lamivudine, had similar renal safety profiles in treatment-naive HIV-infected patients with normal renal function at baseline.

Adenine↗
PubMed2005

Treatment of pain in patients with renal insufficiency: the World Health Organization three-step ladder adapted.

The World Health Organization established official recommendations for managing pain in cancer patients. Since then, this stepladder approach has been widely adopted as a conceptual framework to treat all types of pain. However, those guidelines have not been critically evaluated for use in patients with renal insufficiency. In these patients, the questions of drug dosage adjustment and renal toxicity must be considered. This article reviews the pharmacokinetics of major analgesic drugs and data on their use and/or behavior in renal failure and considers their potential nephrotoxicity. Finally, according to available data in the international literature on pharmacokinetics, recommendations for dosage adjustment in patients with renal failure, and their potential nephrotoxicity, the World Health Organization three-step ladder for the treatment of pain was modified and adapted for patients with impaired renal function. Perspective This well-known treatment strategy now adapted for use in patients with renal insufficiency should secure and rationalize pain treatment in those patients.

Analgesics↗
PubMed2005

Antiviral drug-induced nephrotoxicity.

Drug-induced kidney injury is a major side effect in clinical practice, frequently leading to acute renal failure (ARF). It accounts for more than 2% to 15% of cases of ARF in patients admitted to the hospital or in the intensive care unit, respectively. The exact frequency of nephrotoxicity induced by antiviral drugs is difficult to determine. Antiviral drugs cause renal failure through a variety of mechanisms. Direct renal tubular toxicity has been described with a number of new medications with unique effects on epithelial cells of the kidney. These include cidofovir, adefovir dipivoxil, and tenofovir, as well as acyclovir. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including acyclovir and the protease inhibitor indinavir. Renal injury associated with antiviral drugs involves diverse processes having effects on the renal transporters, as well as on tubule cells. In this article, we review the pathogenesis of antiviral drug-induced kidney injury, common nephrotoxic renal syndromes, and strategies for preventing kidney injury.

Acidosis, Renal Tubular↗
PubMed2005

Chronic calcifying pancreatitis and systemic lupus erythematous.

Gastrointestinal manifestations are common in systemic lupus erythematous (SLE), occurring in 35% to 40% of patients at some stage of their illness. SLE is an uncommon etiology of pancreatic disease. Only 3 cases of chronic pancreatitis associated with SLE have been reported in adults. We report the case of a 59-year-old white woman with a history of mechanic aortic valve replacement and SLE presented to the emergency unit for acute pancreatitis with no other identifiable etiology.

Acute Disease↗
PubMed2005

A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination.

Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing.

Animals↗
PubMed2005

Drug-induced diabetes mellitus.

AIMS: To review the medications that influence glucose metabolism with a focus on hypertensive, transplant and HIV-infected patient populations. METHODS: Literature obtained from a MEDLINE search from 1970 to present, including studies published in the English language. The search strategy linked drugs, hyperglycaemia and diabetes mellitus, HIV, transplantation, hypertension and psychiatric patients. RESULTS: Many common therapeutic agents influence glucose metabolism. Multiple mechanisms of action on glucose metabolism exist through pancreatic, hepatic and peripheral effects. The prevalence of hyperglycaemia was higher with the use of thiazide diuretic, beta-blocker, calcineurin, protease inhibitors and atypical antipsychotic drugs. CONCLUSIONS: Patients treated with those drugs appear to be at increased risk for developing diabetes. It is prudent to monitor plasma glucose values when it is not possible to avoid prescription of medication with known effects on carbohydrate metabolism.

Anti-HIV Agents↗
PubMed2005

Pharmacokinetic considerations in the treatment of tuberculosis in patients with renal failure.

Tuberculosis is re-emerging in patients with altered immune status, such as those with chronic renal failure. Clinicians should thus be aware of the pharmacokinetics and dosage adjustment of antitubercular drugs in patients with renal insufficiency. Among patients with renal insufficiency, those who are dialysed should be treated with special care. Indeed, dosage should always be closely adjusted in these patients and potential removal by dialysis must be taken into account. However reliable the dosage adjustment recommendations are for these drugs in patients with renal failure, further pharmacokinetic investigations need to be performed, especially in dialysis patients in whom the influence of haemodialysis and continuous ambulatory peritoneal dialysis on drug pharmacokinetics needs to be detailed. In the meantime, it could be generally advised to administer all antitubercular drugs after the haemodialysis session, even though some drugs are known to be non-dialysable.

Antitubercular Agents↗
PubMed2004

Renal safety of tenofovir in HIV treatment-experienced patients.

The safety of tenovir disoproxil fumarate (TDF) was assessed in two double-blind, placebo-controlled studies. Furthermore, we retrospectively collected 19 cases of TDF-associated tubular dysfunction. The incidence of renal events was similar among the active TDF groups and the placebo group in the two double-blind, placebo-controlled studies. Proximal tubulopathy was diagnosed 6.89 +/- 5.51 months after TDF therapy started. All abnormalities normalized within 4.7 +/- 2.94 weeks after drug discontinuation.

Adenine↗
PubMed2004

Incidence of renal insufficiency in cancer patients and evaluation of information available on the use of anticancer drugs in renally impaired patients.

BACKGROUND: Chronic renal failure is a common pathology. The high frequency of this disease in the general US population has been assessed in the NHANES III study. However, the frequency of chronic renal insufficiency among cancer patients remains unclear. MATERIAL/METHODS: 316 cancer patients were in a one-month study, included regardless of their pathology, treatment (antineoplastic drugs used or programmed to be used, pretreated, or no treatment), or any other criteria. RESULTS: Among the patients, 287 (90.8%) had normal serum creatinine levels (<110 micromol/l), i.e. a frequency of 9.2% for renal insufficiency in our population. However, when renal function was estimated by calculating creatinine clearance using the Cockcroft and Gault formula, 33% of the patients had an estimated GFR of less than 80 ml/min. Among these, 28% had a creatinine clearance ranging form 80 to 50 ml/min and 5% had a creatinine clearance of less than 50 ml/min. Renal insufficiency is frequent in cancer patients since almost one third of the patients present renal insufficiency. Furthermore, among patients with normal serum creatinine levels, one patient out of five has asymptomatic renal insufficiency. CONCLUSIONS: Therefore, it is of major importance that renal function be assessed by calculation of creatinine clearance using the Cockcroft and Gault formula in every patient, even when serum creatinine is within the normal range.

Aged↗