Application of Direct Renin Inhibition to Chronic Kidney Disease

Chronic kidney disease has serious implications with a high risk for progressive loss of renal function, increased cardiovascular events as well as a substantial financial burden. The renin-angiotensin-aldosterone system (RAAS) is activated in chronic kidney disease, especially in diabetes and hypertension, which are the leading causes of chronic kidney disease. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease the rate of progression of diabetic and non-diabetic nephropathy and are recommended therapy for chronic kidney disease. Key clinical trials supporting the use of ACE inhibitors and ARBs in chronic kidney disease are discussed. Recent developments in our understanding of RAAS biology and the use of direct renin inhibition are reviewed in the context of their potential impact on the prevention and management of chronic kidney disease. Despite the clinical success of ACE inhibitors and ARBs the rates of mortality and progression to renal failure remain high in these patient populations. ACE inhibitor or ARB monotherapy, in doses commonly used in clinical practice does not result in complete suppression of the RAAS. Aliskiren, a direct renin inhibitor, offers a novel approach to inhibit the RAAS in chronic kidney disease. High dose ARB therapy or combination therapies with ACE inhibitors and ARBs have shown beneficial effects on surrogate markers of chronic kidney disease. Early data based on urinary protein excretion rates as a surrogate marker for renal function suggest a possibly novel role for aliskiren alone or in combination with ARBs in chronic kidney disease

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Protective effects of dextromethorphan and tizanidine on ouabain-induced arrhythmias

The effects of the opioid agonist dextromethorphan and the alpha(2)-adrenoceptor agonist tizanidine on ouabain-induced cardiac arrhythmias were investigated in rats. Ouabain (10 mg/kg i.v.) elicited ventricular arrhythmias in all of the control rats. Administration of dextromethorphan (25 mg/kg i.v.) and tizanidine (0.1 mg/kg i.v.) 30 min before ouabain treatment significantly reduced the incidence of arrhythmias. We suggest that dextromethorphan and tizanidine showed these effects by decreasing excitatory amino acid (EAA) activity. It can be speculated that opioids and other EAA antagonists may have antiarrhythmic actions through both their central and peripheral effects as well. (C) 2002 Prous Science. All rights reserved

Optimizing the absorption of valspodar, a P-glycoprotein modulator .1. Selecting an oral formulation and exploring its clinical pharmacokinetics/dynamics

Valspodar is a cyclosporine D analog used as a chemotherapy adjunct for modifying multidrug resistance. Two studies were sequentially performed to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four-way crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 600 mg orally as a conventional oral solution, a microemulsion oral solution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rates of absorption compared with the conventional oral solution. The microemulsion dosage forms were bioequivalent with absolute bioavailability nearly double that of the conventional oral solution. Based on these results, the microemulsion capsule was further investigated in a four-way randomized crossover study with 24 volunteers who received single fasting administrations of 200, 400, and 600 mg and a 400-mg administration after a fat-rich meal. Dose proportionality in area under the curve (AUC) was demonstrated over this dose range. Administration after a fat-rich meal caused a slight time lag until absorption began, a delay in time to reach the peak concentration, and a moderate increase of 24 % in A UC. Serial determinations of total bilirubin were explored as a potential pharmacodynamic marker for P-glycoprotein inhibition. A similar magnitude of reversible hyperbilirubinemia was seen at all dose levels suggesting that P-glycoprotein inhibition in the biliary canaliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an improved and less variable oral delivery form providing dose-proportional drug exposure over a clinically relevant dose range