Effect of Lercanidipine on the Pharmacokinetics-Pharmacodynamics of Carvedilol Enantiomers in Patients With Chronic Kidney Disease.

This study evaluates the carvedilol-lercanidipine drug interaction, and the influence of chronic kidney disease (CKD) on both drugs. Patients with high blood pressure (8 with normal renal function [control] and 8 with CKD with estimated glomerular filtration rate categories of G3b to G5 [12-38 mL/min/1.73 m2 ]) were included and prescribed 3 different treatment regimens, a single oral dose of racemic carvedilol 25 mg (CAR), a single oral dose of racemic lercanidipine 20 mg (LER), and single oral doses of CAR plus LER. Blood samples were collected and variations in heart rate were assessed (using isometric exercise with handgrip) for up to 32 hours. Lercanidipine pharmacokinetics were not enantioselective, and were not affected by carvedilol and CKD. Carvedilol pharmacokinetics (data presented as median) were enantioselective with higher plasma exposure of (R)-(+)-carvedilol in both control (103.5 vs 46.0 ng ∙ h/mL) and CKD (190.6 vs 98.9 ng ∙ h/mL) groups. Lercanidipine increased the area under the plasma concentration-time curve of only (R)-(+)-carvedilol in the CKD group (190.6 vs 242.2 ng ∙ h/mL) but not in the control group (103.5 vs 98.7 ng ∙ h/mL). CKD increased plasma exposure (46.0 vs 98.9 ng ∙ h/mL) and effect-compartment exposure (5.5 vs 20.9 ng ∙ h/mL) to (S)-(-)-carvedilol, resulting in higher ß-adrenergic inhibition (10.0 vs 6.1 bpm). Therefore, carvedilol dose titration in CKD patients with estimated glomerular filtration rate categories of G3b to G5 should be initiated, with no more than half the dose used for patients with normal renal function.

PCL/PHBV microparticles as innovative carriers for oral controlled release of manidipine dihydrochloride.

Microparticles of poly(ε-caprolactone) (PCL) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) containing manidipine dihydrochloride (MAN) were successfully prepared by the simple emulsion/solvent evaporation method. All formulations showed loading efficiency rates greater than 80% and average particle size less than 8 µm. Formulations had spherical shape with smooth and porous surface for PCL and PHBV, respectively. According to Fourier-transform infrared spectroscopy, initial components were not chemically modified during microencapsulation. X-ray diffraction patterns and differential scanning calorimetry demonstrated that this process led to drug amorphization. In vitro dissolution studies showed that all microparticles prolonged MAN release, mainly which one obtained using PCL that contained 5% of drug loaded (PCL-M5). Animal studies demonstrated that formulation PCL-M5 was able to keep the variation of mean arterial pressure after phenylephrine administration up to 24 hours. These data confirmed the sustained antihypertensive effect of the investigated microparticles. Results provided an experimental basis for using formulation PCL-M5 as a feasible carrier for oral controlled release of MAN intended for treating high blood pressure.

The role of PAF/PAFR signaling in zymosan-induced articular inflammatory hyperalgesia.

Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR(-/-)). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 µg/joint), time- and PAFR-dependent articular hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB(4) as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory hyperalgesia.

The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis.

Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster.

Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive patients with type 2 diabetes and microalbuminuria.

INTRODUCTION: Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria. METHODS: Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56). RESULTS: Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group. CONCLUSIONS: A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

Role of PAF receptors during intestinal ischemia and reperfusion injury. A comparative study between PAF receptor-deficient mice and PAF receptor antagonist treatment.

1 The reperfusion of ischemic tissues may be associated with local and systemic inflammation that prevents the full benefit of blood flow restoration. The present study aimed to confirm a role for platelet-activating factor receptor(s) (PAFR) during ischemia and reperfusion injury by using genetically modified mice deficient in the PAFR (PAFR(-/-) mice) and to evaluate comparatively the effectiveness of pharmacological treatment using the PAFR antagonist UK-74,505 (modipafant). 2 The reperfusion of the ischemic superior mesenteric artery (SMA) induced marked local (intestine) and remote (lungs) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx and intestinal hemorrhage and in the production of TNF-alpha. There was also a systemic inflammatory response, as shown by the increase in serum TNF-alpha concentrations and marked reperfusion-associated lethality. 3 After reperfusion of the ischemic SMA, PAFR(-/-) mice had little tissue or systemic inflammation and lethality was delayed, but not prevented, in these mice. Interestingly, the reperfusion-associated increases in tissue concentrations of IL-10 were significantly greater in PAFR(-/-) than wild-type mice. 4 Pretreatment with PAFR antagonist UK-74,505 (1 mg kg(-1)) markedly prevented tissue injury, as assessed by the increase in vascular permeability, neutrophil accumulation, hemorrhage and TNF-alpha concentrations in the intestine and lungs. In contrast, UK-74,505 failed to affect reperfusion-associated lethality and increases in serum TNF-alpha when used at 1 mg kg(-1). 5 Reperfusion-associated lethality and increase in serum TNF-alpha were only affected when a supra-maximal dose of the antagonist was used (10 mg kg(-1)). At this dose, UK-74,505 also induced a marked enhancement of reperfusion-associated increases in tissue concentrations of IL-10. However, at the same dose, UK-74,505 failed to prevent reperfusion-associated lethality in PAFR(-/-) mice any further. 6 The present studies using genetically modified animals and a receptor antagonist firmly establish a role of PAFR activation for the local, remote and systemic inflammatory injury and lethality which follows reperfusion of the ischemic SMA in mice. Moreover, it is suggested that high doses of PAFR antagonists need to be used if the real efficacy of these compounds is to be tested clinically.

[Isradipine: a Brazilian multicenter study for the evaluation of the efficacy and safety in the treatment of mild and moderate arterial hypertension]. / Isradipina: estudo multicêntrico brasileiro de avaliação de eficácia e tolerabilidade no tratamento da hipertensão arterial leve e moderada.

PURPOSE: To evaluate the efficacy and tolerability of isradipine, a new dihydropyridine calcium antagonist, in the treatment of mild-to-moderate hypertension. PATIENTS AND METHODS: One hundred and eighty outpatients with different races, who had supine and orthostatic diastolic blood pressure (DBP) > or = 95 mmHg and < or = 115 mmHg, with a mean age of 52.03 +/- 11.47 years, 70 men, 110 women; underwent the study. After a two-week wash-out period patients received isradipine 2.5 mg b.i.d. for 90 days. Follow-up visits were performed at the 30th, 60th and 90th days of treatment. RESULTS: At the end of treatment (90 days), a statistically significant decrease (p < 0.05) in SBP and DBP in supine position was observed. A mean SBP was reduced from 159.28 +/- 16.99 to 142.51 +/- 15.12, and mean DBP declined from 101.49 +/- 6.82 to 86.63 +/- 7.40. Heart rate, weight, electrocardiograms and laboratory tests did not shows significant changes during treatment when compared to baseline evaluation. The most frequent related side effects (headache and dizziness with nausea) were transient, and at the end of the study 96.7% of the patients did not have any complaint. However, two patients were withdrawn from the trial because of important headache. CONCLUSION: Isradipine 2.5 mg by oral route, b.i.d. has shown to be effective and well tolerated in the treatment of mild-to-moderate hypertension in patients of both sexes and several ages and races.

Isradipine in the treatment of hypertensive crisis in ambulatory patients.

In order to investigate the efficacy of isradipine in the treatment of hypertensive crisis, we treated three groups of patients who had diastolic blood pressure (DBP) greater than 120 mm Hg, and who were without signs of acute target-organ damage. Isradipine was given sublingually in doses of 1.25 mg (group 1; n = 10), 2.5 mg (group 2; n = 10), and 5 mg (group 3; n = 7). Mean arterial pressure (MAP) was reduced in all patients [from 153.4 +/- 4.3 to 124.0 +/- 2.3 mm Hg at 60 min, and to 118.0 +/- 2.1 mm Hg at 2 h after administration (p less than 0.001)]. The heart rate (HR) did not change significantly (from 82.4 +/- 3.7 to 84.0 +/- 6 beats/min; NS). No significant differences were noted in the overall responses of the three groups; however, blood pressure reduction was more rapid in the group receiving 5 mg compared with the other two dosages. These results show that isradipine given sublingually is effective in reducing the elevated blood pressure of a hypertensive crisis and is not accompanied by limiting side effects. Isradipine's onset of action is early (approximately 30 min after dosing) and reaches its maximum blood pressure response within 2 h of administration. No dose-dependent reductions in blood pressure were observed with the dosage range employed in this study.

Effects of long-term administration of isradipine on renal hemodynamics and sodium metabolism.

The objective of this double-blind, placebo-controlled study was to evaluate the effects of isradipine on renal hemodynamics and function. Ten patients with mild-to-moderate hypertension were given isradipine at 2.5 mg twice daily for 3 months after 4 weeks of placebo washout. Renal studies were performed 2 h after the morning administration of treatment. The results of these evaluations indicate that isradipine as monotherapy significantly reduced the mean arterial pressure, while the effective renal plasma flow was increased (+16%) and glomerular filtration rate remained virtually unchanged (-8.7 ml/min). The filtration fraction and renal vascular resistance decreased significantly. There was a significant decrease in the absolute rate of proximal sodium reabsorption, and a significant increase in the distal reabsorption. Clearance of sodium remained unchanged. In conclusion, monotherapy with low-dose isradipine was not only effective in controlling blood pressure, but also decreased the renal vascular resistance while avoiding glomerular hyperfiltration, and exerted a protective effect on renal hemodynamics. Natriuresis also remained stable despite the blood pressure reduction.