Aliskiren, the future of renin-angiotensin system blockade?

The suppression of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been proven in many studies to treat hypertension and reduce cardiovascular events; however, reducing angiotensin I receptor stimulation results in the loss of the negative-feedback signal, leading to increased plasma renin activity. Numerous direct renin inhibitors were synthesized, but abandoned owing to low potency, poor bioavailability and short half-life. Aliskiren, a direct renin inhibitor of a novel structural class, inhibits the activity of the renin produced and, thus, its capacity to form angiotensin I, as measured by plasma renin activity. Aliskiren has been recently shown to be efficacious in hypertensive patients at once-daily oral dosing with favorable pharmacokinetics and the potential to improve end-organ protection.

Efficacy and safety of extended-release fluvastatin in Turkish patients with hypercholesterolaemia: TULIPS (Turkish Lipid Study).

OBJECTIVE: The efficacy and safety of extended-release fluvastatin (fluvastatin XL), 80 mg once daily, was assessed in Turkish patients with primary hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C) 3.37-5.70 mmol/l and triglyceride (TG) < 4.52 mmol/l). RESEARCH DESIGN: In this open-label, prospective, multi-centre study, 154 patients were given fluvastatin XL 80 mg once daily and lipid levels were assessed after 2 and 12 weeks. RESULTS: Fluvastatin XL 80 mg once daily significantly reduced LDL-C levels by 38.8 and 38.1% at weeks 2 (n = 140) and 12 (n = 116), respectively (p < 0.001 vs. baseline). Treatment with fluvastatin XL for 2 and 12 weeks significantly reduced total cholesterol levels by 30.2 and 27.4%, respectively (p < 0.001 vs. baseline) and reduced TG levels by 14.9 and 7.5%, respectively (p < 0.001 vs. baseline). Following stratification by risk factors for coronary heart disease (CHD) according to the National Cholesterol Education Program Adult Treatment Panel III guidelines, 87.3% of patients with > or = 2 risk factors, and 67.4% of patients with existing CHD or CHD risk equivalents achieved target LDL-C levels (< 3.37 mmol/l and < 2.59 mmol/l, respectively) with fluvastatin XL. Fluvastatin XL reduced high-density lipoprotein cholesterol by 8.9 and 4.7% at weeks 2 and 12 weeks, respectively. fluvastatin XL 80 mg once daily was generally well-tolerated. CONCLUSIONS: This open-label study indicates fluvastatin XL 80 mg once daily is an effective and well-tolerated lipid-lowering therapy for the reduction of CHD risk in Turkish patients.

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.

Protective role of immobilization on ouabain-induced arrhythmias.

The effects of the opioid-type stressor, immobilization, on severity of ouabain-induced cardiac arrhythmias and the possible involvement of serum catecholamines were investigated in rats. Immobilization significantly reduced the number of ventricular premature beats and the incidence of ventricular tachycardia episodes. The arterial serum catecholamine levels (A, NA and DA), measured immediately after the stressor application, were increased significantly and were in negative correlation with the arrhythmia parameters. Both changes were reversed by naloxone (5 mg/kg) treatment after application of immobilization. The effects observed in this study may be attributed to the actions of endogenous opioid peptides released during stress.

Optimizing the absorption of valspodar, a P-glycoprotein modulator, Part I: 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 AUC. 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.

Effects of opioid-type stressors on serum digoxin-like immunoreactivity in rats.

The effects of opioid-type stressors (immobilization, electric footshock and forced swimming) on serum digoxin-like immunoreactivity (SDLI) were investigated in rats. All of the stressors significantly elevated the SDLI. Naloxone treatment after application of stressors prevented the elevation of SDLI, whereas naloxone treatment alone did not cause any significant changes. The observed increase in SDLI in this study may be attributed to the actions of endogenous opioid peptides released during stress.

Morphine and naloxone act similarly on glutamate-caused guinea pig ileum contraction.

Both morphine (M) and naloxone (NL) have been reported to have NMDA receptor blocking effects, regarded as the reason of opiate physical dependence development. On the other hand, glutamate (GLU) has been known to induce the contraction of isolated guinea pig ileum via acetylcholine release. Therefore, different concentrations of M or NL were investigated on the 1 mM GLU-induced contraction of isolated guinea pig ileum fixed at a resting tension of 1 g in isolated organ bath. The mean value (359.3 +/- 20 mg) of the GLU-elicited contraction force was significantly reduced (318.4 +/- 19.4) by 25 nM M concentration in the medium. Consequently, 500 and 750 nM M caused further decreases in a rather dose-dependent manner (270.8 +/- 17.4 and 167.8 +/- 16.5 mg, respectively). One micromolar M contraction nearly abolished (8.0 +/- 8.2 mg) the GLU-induced contraction. A similar effect was obtained with the naloxone concentrations of 10, 20, 40, and 50 microM. In addition, NL has been shown to elicit the contraction of the isolated M-dependent guinea pig ileum. In the present study, 20- and 30-microM NL concentrations in the bathing medium caused the contraction of the ileum made M-dependent by preincubation with M (333.0 +/- 32.4 and 309.5 +/- 17.7 mg, respectively). These contraction forces were significantly reduced when the NL concentration was increased to 40 microM. And, 50 microM NL concentration not only failed to induce contraction but caused a relaxation (-10.6 +/- 2.3) as well. The results were considered supporting evidence for the fact that both M and NL are NMDA receptor blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tizanidine on morphine physical dependence: attenuation and intensification.

It has previously been shown that subchronic and acute administration of L-asparaginase and glutaminase inhibitors D-Aspartic acid (D-ASP) and prolyl-leucyl-glycinamide (PLG) intensifies and attenuates morphine (M) physical dependence, respectively, by the inhibition of ASP and glutamic acid (GLU) production, and subsequently their normal releases. Tizanidine (TIZ) has long been known to be an alpha 2-adrenoceptor agonist and inhibitor of ASP and GLU release. Therefore, in this study TIZ has been administered subchronically during the development of M physical dependence to rats in which M-containing pellets had been implanted or acutely 30 min before naloxone (NL)-induced abstinence syndrome. The subchronic administration of TIZ intensified NL-precipitated abstinence syndrome whereas its acute administration attenuated it, as did D-ASP and PLG. On the other hand, TIZ added into the medium prevented the in vitro M-dependent-made guinea pig ileum from contracting following NL application. Furthermore, TIZ stopped the already started contraction by NL of the M-dependent ileum, which completely relaxed later. These effects of TIZ on M-dependent ileum were antagonized by the alpha 2-adrenoceptor antagonist yohimbine. The intensification by subchronic TIZ administration of abstinence syndrome was attributed to the lesser release of ASP and GLU, which resulted in the larger blockade of M of ASPergic/GLUergic receptors due to the lesser release of their endogenous agonist ASP and GLU and consequently the higher upregulation of the receptors. The attenuation by acute TIZ administration of NL-precipitated abstinence syndrome was explained with lesser release of ASP and GLU and concomitantly the lesser stimulation of the receptors.(ABSTRACT TRUNCATED AT 250 WORDS)