Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.
ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.
BackgroundThe pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes.HypothesisToxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors.Methodology/Principal FindingsThe recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The “short” ACE inhibitor enalaprilat (tripeptide analog) and “long” inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors.Conclusions/SignificanceThe estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.
Background. Secondary hyperparathyroidism (sHPT) is one of the serious complications in chronic kidney disease and is associated with progressive bone disease and vascular calcification. The objective of the study was to determine the impact of Mimpara (Cinacalcet HCl) on mineral disorder, bone turnover and bone mineral density (BMD) versus parathyroidectomy (PTx) in haemodialysis patients' refractory to alfacalcidol. Materials and methods. 62 haemodialysis patients with sHPT were enrolled in this 6 months prospective study. All of them had surgical indications for PTx. Surgical indications was established according to clinical or biological assessment. 40 patients underwent Mimpara treatment. Dose of Mimpara was titrated every 4 weeks. Sequential doses included 30-180 (mean 59.1 ± 34.2) mg/day. 22 patients underwent PTx. The sur gical technique was depended on quantity of hyperplastic parathyroid glands. Results. In 6 months mean iPTH, Ca, Са×Р, CTx and OC levels significantly decreased by 55.7%, 13.8%, 34.3%, 21.4 and 1.4% in the Mimpara group vs. 90.7%, 14%, 55.5%, 58.7% and 26.9% in the PTx group. Median serum iPTH level decreased by 30% after initiation of Mimpara in 94.3% patients, from them by 50% in 74.3%. Achieved the KDOQI treatment targets for PTH in 28.6% patients.In 6 months after PTx median serum iPTH level was <100 pg/ml in 50% patients, achieved the KDOQI treat ment targets in 27.3%, >300 pg/ml in 18.2%. Median serum 25(ОН)D after PTx significantly increase by 127.3% vs 6.72% in the Mimpara group. In 6 months active restoration of BMD was found in the PTx patients, and patients treated with Cinacalcet showed stabilization of BMD. Mimpara therapy led to a reduction in glandular volume during the course of the study: in both glands with a baseline volume <500 mm 3 and with a baseline volume ≥500 mm 3 . Conclusions. PTx and Cinacalcet therapy improves phosphorus calcium homeostasis, bone turnover, but bone resorption and formation markers decreased better in the PTx group compared to Cinacalcet group. The effectiveness and safety of Mimpara for secondary hyperparathyroidism were evaluated in dialysis patients' refractory to alfacalcidol, which reduced the need for parathyroidectomy in patient without severe osteodystrophy.
The effect of nitroNycerin and chloropromazine (plegomazin) on norepinephrine-induced contraction of rat aorta rings is studied in experiments on the intact and deendothelized aorta, and the combined myolytic effect of the two preparations is assessed. A possible cross-tolerance between nitroglycerin and chloropromazine is studied in experiments simulating the development of vascular tolerance of nitroglycerin.
Key Words: calcium ions; calmodulin; vasodilation; tolerance qf nitrates; cross-toleranceCalmodulin and calcium ions (Ca :+) play an important role in initiating the contraction of vascular smooth muscle cells. The cascade process of vasoconstriction comprises the foUowing stages: 1) an increase of the intracellular concentration of free CaZ+; 2) binding of 4 Ca z § ions by calmodulin; 3) activation of kinase of light myosin chains by the Ca2 § complex; 4) myosin phosphorylation and stimulation of its ATPaseactivity; 5) contraction of actin-myosin •aments in smooth muscle cells [11], Two main pathways of pharmacological regulation of the activity of Ca 2+-calmodulin leading to myocyte relaxation and vasodilation are distinguished. The ftrst of them is based on a change in the intracellular concentration of Ca 2 § Such a mechanism of myorelaxation is realized by Ca 2+ channel blockers (nifedipine and verapamil) and organic nitrates, specifically, nitroglycerin (NG). After penetrating into the smooth muscle cell, NG undergoes enzymatic biotransformation, forming nitric oxide (NO). Interaction of NO with the heme group of the soluble fraction of guanylate cyclase leads to activation of the enzyme [3] and accumulation of cGMP, this being followed by a decrease in the intracellular calcium content [4] due to the blocking of Ca :+ entry into the cell [1,2,10] and activation of the mechanisms of its "entrapment" [8]. The second pathway is via direct inhibition of calmodulin. Such a mechanism underlies the vasorelaxing effect of phenothiazine derivatives (chlorpromazine -CP -and triphthazine), which, in therapeutic concentrations, selectively suppress calmodulin activity [6,13]. However, the existence of other possible mechanisms of NG-and CP-induced myorelaxation, as well as the presence of common components in the effect of preparations from both groups on smooth muscle tone, cannot be ruled out. Specifically, the role of endothelium in vasodilation induced by phenothiazine derivatives is not clear. In the literature available to us we have found no data characterizing the interaction between nitrates and calmodulin antagonists. On the other hand, a study of the combined application of NG and CP, which nave different mecha-0007-4888/94/0009-0972512.50 9Plenum Publishing Corporation
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