硝苯地平缓释片联合缬沙坦治疗原发性高血压疗效和安全性的Meta分析

目的：系统评价硝苯地平缓释片联合缬沙坦治疗原发性高血压的疗效和安全性。方法：计算机检索PubMed、CochraneLi-brary、CBM、CNKI、V1P等数据库,按照纳入和排除标准纳入依硝苯地平缓释片联合缬沙坦治疗原发性高血压的随机对照试验（RCT）,并补充检索纳入研究的参考文献;按Cochrane系统评价方法由两名评价员独立评价纳入文献质量、提取资料并交叉核对无误后,采用RevMan5．1软件进行统计学分析。结果：共纳入4个RCT,包括共450例患者,其研究质量均为C级。Meta分析结果显示：硝苯地平缓释片联合缬沙坦治疗原发性高血压的显效率[RR=1．29,95％CI（1．08～1．55）,P〈O．011、总有效率[RR=I．19,95％CI（1．10～1．29）,P〈0．01]和无效率[RR=0．38,95％CI（0．24～0．62）,P〈0．01]与单用硝苯地平缓释片比较,两组差异有统计学意义,两组有效率差异无统计学意义[RR=I．02,95％CI（0．97～1．32）,P〉0．01]。结论：现有证据表明：硝苯地平缓释片联合缬沙坦治疗原发性高血压在显效率,总有效率和无效率方面优于硝苯地平缓释片单用,不良反应与苯地平缓释片单用无明显差异,但远期疗效尚不清楚,尚需更多高质量的随机双盲对照试验证实。     

Chronopharmacokinetics and Cardiovascular Effects of Nifedipine

Orcadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher C_max (peak concentration) and shorter t_max (time-to-peak concentration) after morning than evening application, and bioavailibility in the evening was reduced by about 40%. Orcadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.     

The cytosolic calcium concentration is affected by S-nitrosocysteine in human lymphomonocytes

The homeostasis of cytosolic calcium [Ca2+](c) in mammalian cells is a complex phenomenon, requiring the contribution of many cellular and extracellular systems. Nitric oxide (NO) acts on [Ca2+](c), although the mechanism of this action is unknown. We study the release and the uptake of Ca2+ in the endoplasmic reticulum and its capacitative entry in human lymphomonocytes in the presence of the NO donor S-nitrosocysteine (CysNO) at low (16 microM) and at high (160 microM) concentrations by measuring the [Ca2+](c) by the Fura 2-AM method. Thapsigargin (TG), which inhibits sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and nifedipine (NIF), which blocks the Ca2+ release from intracellular stores, are used to clarify the effects of NO on calcium movements. In the absence of extracellular Ca2+, CysNO decreases basal [Ca2+](c), whereas TG increases it as the result of SERCA inhibition. This effect of TG diminishes in the presence of the NO donor. In the presence of extracellular Ca2+(capacitative entry conditions), CysNO does not influence Ca2+ entry but reduces the toxic effects of TG connected to the increase of [Ca2+](c) in these conditions. The effect of NIF is, up to a certain extent, similar to that of CysNO, although the mechanisms of action of the two agents do not seem related. We conclude that CysNO participates in [Ca2+](c) homeostasis by stimulating the movement of the ion from the cytosol to other compartments.     

Effect of nifedipine on core cooling in rats during tail cold water immersion

Male rats (450 g, n=11/group) were heated at an ambient temperature of 42°C until a rectal temperature of 42.8°C was attained. Rats, then received either saline (30°C)+tail ice water immersion (F+I) or saline (30°C)+tail ice water immersion+Nifedipine, a peripheral vasodilator, (F+I+N) to determine cooling rate effectiveness and survivability. The time to reach a rectal temperature of 42.8°C averaged 172 min in both groups resulting in similar heating rates (0.029°C/min). The cooling rates in group F+I and F+I+N were not significantly different from each other. We conclude that since Nifedipine did not improve cooling rates when combined with fluid+tail ice water immersion, its use as a cooling adjunct does not seem warranted.     

Efficacy of combined medication of nifedipine and magnesium sulfate on gestational hypertension and the effect on PAPP-A,VEGF, NO,Hcy and vWF

ObjectiveTo investigate the effects of combined medication of nifedipine and magnesium sulfate on the blood pressure, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor (VEGF), nitric oxide (NO), homocysteine (Hcy) and von Willebrand factor (vWF) in gestational hypertension patients.MethodsA total of 220 gestational hypertension patients were enrolled as the subjects, and divided into two groups randomly, i.e. the observation group and the control group. In observation group, patients took combined medication of nifedipine and magnesium sulfate, while those in the control group only took magnesium sulfate for treatment. Clinical efficacy, and the changes in blood pressure, PAPP-A, VEGF, NO, Hcy and vWF before and after treatment were compared between two groups.ResultsIn the observation group and the control group, total effectiveness rates were 92.7% and 70.9%, respectively (p < 0.05). After treatment, we found significant decreases in PAPP-A, VEGF, NO, Hcy and vWF in patients of two groups, with more significant decreases in the observation group (p < 0.05). Incidence rates of the adverse reactions in two groups were 5.5% and 6.4%, respectively, without any statistically significant differences (p > 0.05). In the observation group, patients had fewer complications (p < 0.05).ConclusionCombined medication of magnesium sulfate and nifedipine can decrease the levels of PAPP-A, VEGF, NO, Hcy and vWF in serum as well as the blood pressure of patients with gestational hypertension, with a reduction in incidence rate of complications and improvement in efficacy.     

Sensitive high-performance liquid chromatographic determination of nifedipine in dog plasma using an automated sample preparation system with laboratory robot

Nifedipine, a calcium-channel blocking drug was analysed in dog plasma after oral dosing with two different formulations. Sample preparation was automated with a laboratory robot. Quantitative determination of the drug was performed on a reversed-phase HPLC system with electrochemical detection (ED) using an internal standard. Validation of the analytical method showed that the system is well suited for pharmacokinetic studies on dogs. The assay was linear in the range 1–50 ng/ml. Inter-day and intra-day variability were between 6.43–18.15% C.V. and 1.57–5.53% C.V., respectively.     

Voltage-dependent calcium current in dissociated smooth muscle cells of the buccal mass of Aplysia

Summary Isolated smooth muscle cells of the buccal mass of Aplysia contracted in response to depolarization elicited by a patch electrode in whole-cell configuration. With cesium-containing pipet solution and tetraethylammonium and 4-aminopyridine in the external solution depolarization elicited inward current. The voltage-dependent inward current was blocked completely by lanthanum (10 mmol·1^-1), inhibited 80–90% by nifedipine (1 mol·l^-1), and was dependent upon extracellular calcium. These results showed that the voltage-dependent inward current was due to activation of voltage-dependent calcium channels (VDCaCH). Minimal depolarization to begin activating VDCaCH was-60 to-30 mV. Inward current peaked within 8 ms and then decreased rapidly to a lower level of relatively non-inactivating current. The initial peak current could be mostly inactivated by a depolarization to-20 mV for 500 ms. Nifedipine reduced both the peak current and the relatively non-inactivating current. Nifedipine inhibited high potassium-elicited contractions of both intact and dissociated muscle. These results suggested that VDCaCH mediates calcium influx which triggers contraction in molluscan smooth muscle fibers.Abbreviations ACh acetylcholine - ATP adenosine triphosphate - EGTA ethyleneglycol-bis(-aminoethyl ether) N,N,N,N-tetraacetic acid - GTP guanosine triphosphate - HEPES N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid - MCG metacerebral giant cell - RNI relatively non-inactivating - SCP small cardioactive peptide - TEA-4AP-IO external solution containing Instant Ocean, tetraethylammonium chloride, and 4-aminopyridine (described in Methods) - TEA tetraethylammonium chloride - VDCaCH voltagedependent calcium channel - 4-AP 4-aminopyridine - 5-HT 5-hydroxytryptamine or serotonin     

Conformation of nifedipine in hydrated 1,2-di-myristoyl-sn-glycero-3-phosphorylcholine bilayer molecular dynamics simulation

The conformation of nifedipine, a cardiac and smooth muscle calcium ion channel antagonist is studied in a hydrated bilayer of forty nine 1,2-di-myristoyl-sn-glycero-3-phosphorylcho-line (DMPC) molecules using molecular dynamics (MD) simulation technique. The simulation was carried out in conditions of constant number, volume and temperature (NVT) at 310 K, which is above the liquid crystalline (Lα) transition temperature of DMPC. The periodic boundary conditions were applied in three-dimensions. Thus the model represented an infinite bilayer. The important geometric parameters characteristic to DMPC and nifedipine molecules were calculated and compared with other theoretical and experimental results pertaining to nifedipine and other related dihydrophyridine (DHP) analogues. Our results suggest that conformational parameters required for antagonist activity are fairly conserved during the interaction of nifedipine with DMPC bilary and bilayer stabilizes the drug conformation in the bioactive form.     

Calcium oscillations in human mesenteric vascular smooth muscle

Phenylephrine (PE)-induced oscillatory fluctuations in intracellular Ca²⁺ concentration ([Ca²⁺]_i) of vascular smooth muscle have been observed in many blood vessels isolated from a wide variety of mammals. Paradoxically, until recently similar observations in humans have proven elusive. In this study, we report for the first time observations of adrenergically-stimulated [Ca²⁺]_i oscillations in human mesenteric artery smooth muscle. In arterial segments preloaded with Fluo-4 AM and mounted on a myograph on the stage of a confocal microscope, we observed PE-induced oscillations in [Ca²⁺]_i, which initiated and maintained vasoconstriction. These oscillations present some variability, possibly due to compromised health of the tissue. This view is corroborated by our ultrastructural analysis of the cells, in which we found only (5 ± 2)% plasma membrane-sarcoplasmic reticulum apposition, markedly less than measured in healthy tissue from laboratory animals. We also partially characterized the oscillations by using the inhibitory drugs 2-aminoethoxydiphenyl borate (2-APB), cyclopiazonic acid (CPA) and nifedipine. After PE contraction, all drugs provoked relaxation of the vessel segments, sometimes only partial, and reduced or inhibited oscillations, except CPA, which rarely caused relaxation. These preliminary results point to a potential involvement of the sarcoplasmic reticulum Ca²⁺ and inositol 1,4,5-trisphosphate receptor (IP3R) in the maintenance of the Ca²⁺ oscillations observed in human blood vessels.     

Sensitive high-performance liquid chromatographic determination of nifedipine in cat plasma following improved sample treatment

A simple, easy and accurate reversed-phase high-performance liquid chromatographic method is described for the determination of nifedipine in cat plasma. The procedure involves extraction of nifedipine from plasma using a Sep-Pak C₁₈ cartridge and ultraviolet detection at 350 nm. The present method provides the required reproducibility and sensitivity for the determination of low concentrations of nifedipine without interference from plasma components or photodegradation products. The method was validated over the range 1–50 ng/ml nifedipine. Accuracy and precision were, respectively, 97% or more and 5% or less over the concentration range examined. The minimum quantifiable concentration of nifedipine was found to be 1 ng/ml.