cerivastatin and Kidney-Diseases

Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease.. Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys.. In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries.. In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Animals; Blotting, Western; Collagen Type I; Collagen Type III; Drug Therapy, Combination; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Losartan; Male; Nephrectomy; NF-kappa B; Pyridines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Chemical and Drug Induced Liver Injury; Drug Approval; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Lipoproteins, LDL; Pyridines; Pyrimidines; Risk Assessment; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome

Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports.. We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis.. The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Topics: Consumer Product Safety; Drug Evaluation; Drug Prescriptions; Fluorobenzenes; Humans; Kidney Diseases; Morbidity; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Renal Insufficiency; Retrospective Studies; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

Topics: beta 2-Microglobulin; Biomarkers; Drug Therapy, Combination; Gemfibrozil; Humans; Hyperlipidemias; Kidney Diseases; Kidney Tubules; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Pyridines; Rhabdomyolysis; Trypsin Inhibitor, Kunitz Soybean