Pharmacokinetics of nifedipine sustained-release tablets in healthy Chinese volunteers

Aim To establish a LC-MS method for determining the concentration of nifedipine in human plasma and to evaluate the pharmacokinetic characteristics of nifedipine sustained-release tablets. Methods A XB-C18 （5 μm, 4.6 mm ×150 mm） column and a mobile phase of methanol： 0.01 mol·L^-1ammonium acetate （60：40, V/V） were used to separate nifedipine, the detections was accuracy under atmosperic pressure electronic spray ionization （AP-ESI） mode and ion mass spectrum （m/z） of 314.9 [M＋H]^＋ for nifedipine, and 320.8 [M＋H]^＋ for lorazepam （Internal Standard, IS）. Results The linear range of nifedipine was 0.3 - 80 ng·mL^-1 （ r = 0.9997）, and the limit of quantitation （LOQ） was 0.3 ng·mL^-1. The nifedipine pharmacokinetic parameters after a single dose of 20 mg nifedipine sustained-release tablets test （T） or reference （R） were as the followings, t1/2 （6.73 ± 2.00） h and （7.04 ± 2.18） h, Tmax （4.28 ± 0.70） h and （4.48 ± 0.70） h, Cmax（39.66 ± 10.58） ng·mL^-1 and （40.19 ± 10.97） ng·mL^-1, AUC0-36 （391.63 ± 108.55） ng·mL^-1·h and （387.57 ± 121.51） ng·mL^-1·h, and AUC0-∞ （408.28 ± 121.16） ng·mL^-1·h and （406.15 ± 133.13） ng·mL^-1·h. The relative bioavailability of nifedipine sustained-release tablets （test） was （103.02 ± 13.93） %. Conclusion LC-MS method for the determination of concentrations of nifedipine in human plasma was sensitive and accurate, and could be used in nifedipine bioavailability and pharmacokinetic studies.

Nifedipine对烟草花粉萌发、花粉管生长及生殖核分裂的影响

用细胞学和统计学方法研究了Ｃａ２＋ 通道专一性阻滞剂ｎｉｆｅｄｉｐｉｎｅ（Ｎｉｆ）对烟草（Ｎｉｃｏｔｉａｎａ ｔａｂａｃｕｍＬ．）离体花粉萌发、花粉管生长及生殖核分裂的影响。１０－ ４ ｍ ｏｌ／ＬＮｉｆ可抑制花粉萌发。Ｎｉｆ对花粉管生长的影响与其浓度和处理持续时间有关，１０－ ４ ｍ ｏｌ／Ｌ Ｎｉｆ始终抑制花粉管生长；而１０－ ７～１０－ ５ ｍ ｏｌ／ＬＮｉｆ在较短时间内起不同程度的促进作用，之后逐渐过渡为抑制花粉管生长。较高浓度处理可使花粉管形态趋向异常，细胞质流动趋于停滞。Ｎｉｆ抑制生殖核的有丝分裂，相对推迟分裂高峰。Ｎｉｆ使花粉管中的金霉素（ＣＴＣ）荧光趋于减弱，表明Ｎｉｆ通过抑制Ｃａ２＋ 通道活性产生生理效应。

Nifedipine对缺血突触体游离钙和氨基酸释放的影响

目的：通过Nifedipine对缺血突触体内游离钙浓度及氨基酸释放量的影响，初步探讨其脑缺血保护作用与兴奋性氨基酸（EAA）和抑制性氨基酸（IAA）释放关系。方法：营养液中去除糖和氧建立大鼠脑突触体缺血模型，检测静息及高钾去极化状态下缺血突触体游离钙浓度及EAA和IAA释放量的变化，并检测Nifedipine对此变化的影响。结果：大鼠突触体缺血状态致游离钙浓度、门冬氨酸和甘氨酸、牛磺酸、γ-氨基丁酸释放量明显增加，而谷氨酸亦有增加趋势。缺血 + 50 mmol/L 高钾刺激后，游离钙浓度及上述EAA及IAA释放量均进一步增加。10-4 mol/L Nifedipine可明显降低两种状态下缺血突触体内游离钙浓度，同时亦显著阻遏静息状态缺血突触体IAA的释放及去极化状态EAA和IAA的释放。结论：Nifedipine的抗脑缺血致脑损伤作用主要与其对抗缺血引起的突触体内游离钙浓度升高有关，其抑制EAA和IAA释放与脑缺血保护作用的关系有待进一步研究。

Bay K8644及nifedipine对大鼠下丘脑神经元L-型Ca^(2+)通道特性的影响

采用神经元急性分离和膜片箝技术以及细胞贴附式方式记录通道活动 ,探讨DHP类Ca2 +通道激动剂BayK8644及拮抗剂nifedipine对下丘脑神经元L 型Ca2 +通道的影响。结果显示 ,在BayK8644作用下 ,通道开放形式发生变化 ,明显可见多级开放 ;通道平均开放时间、平均开放概率显著增加 ,但单通道电导无明显变化。nifedipine的作用与BayK8644相反。结果提示 ,BayK8644对下丘脑神经元L 型Ca2 +通道有明显激动作用 ,nifedip

Influence of Preparation Factors on the Sustained Release of Nifedipine from Eudragit RL/RS Microspheres

Sustained release Eudragit RL/RS microspheres encapsulating nifedipine were prepared using the acetone/liquid paraffin emulsion solvent evaporation method. The influence of different preparation factors on release of the drug in vitro was investigated. The release rate of nifedipine from the microspheres increased with increasing Eudragit RL/RS ratio and stirring rate during the preparation, and with decreasing the polymer concentration of internal phase and microsphere size. It was found that a linear relationship existed between the microsphere size and the time of 50% drug release. The drug release rate increased with increasing nifedipine content from 4.2 to 16.7% and was more rapid than the dissolution rate of pure nifedipine particles. However, the release rate of the microspheres with 26.6% drug content decreased significantly and was slower than the dissolution rate of pure drug particles. This was attributed mainly to the nifedipine dispersion state in the microspheres as confirmed by the differential thermal analysis and X ray diffraction study, which showed that nifedipine was present in an amorphous or molecular state in the microspheres with 4.2, 9.4 and 16.7% drug, whereas partly in the crystalline state in the microspheres with 26.6% drug. The amounts released for less than 70% nifedipine can be fitted to Higuchi square root of time model, independent of polymer ratio, drug content and microsphere size.

DHEA和nifedipine对大鼠低氧性肺动脉高压的治疗作用比较

目的 对慢性缺氧3周大鼠静脉注射钾通道开放剂脱氢表雄甾酮(DHEA)和钙通道阻断剂nifedipine,以对照研究它们对大鼠慢性低氧性肺动脉高压的治疗作用。方法 60只大鼠随机分为2组,每组30只,均给予缺氧3周。Ⅰ组再分为3个小组(A1,A2,A3),分别按100mg/kg,150mg/kg和200mg/kg给予DHEA,Ⅱ组再分为3个小组(B1,B2,B3),按100mg,/kg,150mg/kg和200mg,/kg给予nifedipine。大鼠3周低氧后,行右心插管于给药前后分别测定2组大鼠的肺动脉平均压(mPAP)、体动脉平均压(mSAP)。结果 2组大鼠在缺氧3周后肺劝脉压均明显增高,Ⅰ组静脉给予DHEA可见A1,A2,A3组大鼠mPAP明显降低,呈剂量依赖性变化,但平均体动脉压变化不明显;Ⅱ组给予nifedipine后,可见B1,B2,B3组大鼠伴随mSAP明显降低,大鼠mPAP呈剂量依赖性降低。结论 钾通道活性的改变在HPH发病机制中起着十分重要的作用,钾通道开放剂DHEA可有效治疗HPH,且DHEA对体循环的影响相对较小。

Development and characterization of ethylcellulose based microsphere for sustained release of nifedipine

This article introduced the work of ethylcellulose based polymeric microsphere loaded with nifedipine for reduction in frequency of administration with low solubility in aqueous medium and high rate of absorption in the stomach. The non-aqueous polymeric suspension was put dropwise into an aqueous medium containing polyvinyl alcohol as a surfactant for the synthesis of microsphere by solvent evaporation. The microspheres were characterized by different techniques, namely, XRD, SEM, and NMR. The formation of microspheres was confirmed by SEM. XRD analysis revealed the semi-crystallinity nature of microspheres. The NMR study indicated the presence of hetero-aromatic nucleus in the microsphere.

Aggressive treatment of acute anal fissure with 0.5% nifedipine ointment prevents its evolution to chronicity

AIM： To investigate the efficacy of topical application of 0.5% nifedipine ointment in healing acute anal tissue and preventing its progress to chronicity. METHODS： Thirty-one patients （10 males, 21 females） with acute anal fissure from September 1999 to January 2005 were treated topically with 0.5% nifedipine ointment （t.i.d.） for 8 wk. The patients were encouraged to follow a high-fiber diet and assessed at 2, 4 and 8 wk post-treatment. The healing of fissure and any side effects were recorded. The patients were subsequently followed up in the outpatient clinic for one year and contacted by phone every three months thereafter, while they were encouraged to come back if symptoms recurred. RESULTS： Twenty-seven of the 31 patients completed the 8-wk treatment course, of them 23 （85.2%） achieved a complete remission indicated by resolution of symptoms and healing of fissure. Of the remaining four unhealed patients （14.8%）, 2 opted to undergo lateral sphincterotomy and the other 2 to continue therapy for four additional weeks, resulting in healing of fissure. All the 25 patients with complete remission had a mean follow-up of 22.9 ± 14 （range 6-52） too. Recurrence of symptoms occurred in four of these 25 patients （16%） who were successfully treated with an additional 4-wk course of 0.5% nifedipine ointment. Two of the 27 （7.4%） patients who completed the 8-wk treatment presented with moderate headache as a side effect of nifedipine. CONCLUSION： Topical 0.5% nifedipine ointment, used as an agent in chemical sphincterotomy, appears to offer a significant healing rate for acute anal fissure and might prevent its evolution to chronicity.

Dissolution improvement by solid dispersions composed of nifedipine, Eudragit?E and silica from rice husk

Nifedipine is a practically water-insoluble drug used therapeutically as a calcium-channel blocker for systemic and coronary vasodilation.Poorly soluble drugs that undergo dissolution rate-limited gastrointestinal absorption generally show increased bioavailability when dissolution is improved by formulation techniques[1].In solid dispersion system,a drug may exist as an amorphous form in polymeric carriers,and this may result in improved solubility and dissolution rate as compared with crystalline drug.Solid dispersion can be prepared by either fusion or solvent method[2].

Thrapeutic equivalence in the treatment of hypertension:Can lercanidipine and nifedipine GITS be considered to be interchangeable?

AIM: To undertake a review of the evidence that nifedipine GITS and lercanidipine are therapeutically equivalent in the management of essential hypertension.METHODS: A systematic review of the published literature was prompted by the findings of two meta-analyses which indicated that there was a lower incidence of peripheral(ankle) oedema with lercanidipine. However,neither meta-analysis gave detailed attention to comparative antihypertensive efficacy or cardiovascular protection. Accordingly,a systematic,detailed and critical review was undertaken of individual published papers. The review started with those studies incorporated into the 2 meta-analyses and then all other salient and directly relevant papers identified through the following search criteria: all randomized controlled trials in which the therapeutic profile and antihypertensive effects of lercanidipine were directly compared with those of nifedipine GITS(in hypertensive patients). The searchstrategy was focused on the reports of clinical trials of lercanidipine vs nifedipine GITS,which were identified through a systematic search of PubMed(from 1966 to October 2012),Embase(from 1980 to October 2012) and the Cochrane library(from 1 October 2008 to end October 2013). The search combined terms related to lercanidipine vs nifedipine GITS(including MeSH search using calcium antagonists,calcium channel blockers and dihydropyridines).RESULTS: With regard to blood pressure(BP) control and the consistency of BP control throughout 24-h,there is limited published evidence. However,two studies using 24 h ambulatory blood pressure monitoring clearly identified the dose-dependency of BP lowering with lercanidipine and its variably sustained 24-h efficacy. In contrast,there is evidence of a consistent antihypertensive effect throughout 24 h with nifedipine GITS. The incidence of the most common "side effect",i.e.,peripheral(ankle) oedema can be estimated as follows. For every 100 patients treated with lercanidipine,2.5 will report oedema compared to 6 patients treated with nifedipine GITS. However,98 or 99 patients will continue treatment with nifedipine GITS,compared with 99.5 patients on lercanidipine. Finally,with regard to outcome studies of cardiovascular(CV) morbidity and mortality,there is definitive outcome evidence for nifedipine GITS but there is no evidence that treatment with lercanidipine leads to reductions in CV morbidity and mortality.CONCLUSION: There is no evidence in terms of longterm BP control and CV protection to justify the contention that lercanidipine is therapeutically equivalent to nifedipine GITS.

Evaluation Procedure for Quality Consistency of Generic Nifedipine Extended-Release Tablets Based on the Impurity Profile

A procedure to evaluate the quality consistency of generic drugs based on the impurity profile and the similarity analysis methods was presented in this paper. Nifedipine extended-release tablets from six generic factories of China were used to evaluate the uniformity with the original drug in the study. The procedure includes: choice of chromatographic methods, data collection and conformity test, evaluation of intra-batch similarity of drugs, evaluation of generic drugs with the original drug and weighted similarity evaluation of generic drugs. The data were collected via high-performance liquid chromatography (HPLC), and then calculated by correlation coefficient, cosine, principal component analysis (PCA) and hierarchical clustering analysis (HCA). It is more suitable to use peak areas as the vector when calculating the similarity of impurity profile. After weighting the peak areas of the unspecified impurities in further evaluation of the generic quality, the generic level of different factories was differentiated and the best generic factory was picked out.

Improving Flow Property of Nifedipine Loaded Solid-Lipid Nanoparticles by Means of Silica for Oral Solid Dosage Form

In this study, a new formulation of silica nanocomposite containing nifedipine (NI) loaded freeze-dried solid-lipid nanoparticles (NI-SLNs) and silica have been developed with improved flowability of powders, which can lead to the formulation of a widely acceptable oral dosage form. The stable NI-SLNs were prepared using two phospholipids, hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol mixed with 2.5% w/v trehalose as a cryoprotectant followed by lyophilization. We employed various grades of two types of silica, such as fumed and precipitated. Silica improved the poor flow property of NI-SLNs to good category as per USP-29. In addition, most of the silica nanocomposites showed the satisfactory results in their physicochemical properties such as particle size, polydispersity index, zeta potential, and recovered potency by around 100 nm, 0.3, -50 mV, and 80%, respectively. Furthermore, it was found that NI-SLNs were easily released form nanocomposites within 30 min, therefore, suggesting an improvement of drug dissolutions. Among them, precipitated silica cooperated fairly in improving the powder characteristics as well as the physicochemical, morphological, and pharmaceutical properties.

Effect of nifedipine combined with Magnesium Sulfate on oxidative stress,hemorheology,platelet active substances and renal function in patients with pregnancy-induced hypertension

Objective: To investigate effect of nifedipine combined with Magnesium Sulfate on levels of oxidative stress, blood rheology, platelet active substance and renal function in patients with pregnancy-induced hypertension. Methods: A total of 99 cases of patients with pregnancy-induced hypertension were selected as the study object, according to random data table, they were divided into control group (n=50) and observation group (n=49), patients in control group were treated with Magnesium Sulfate, while patients in the observation group received Magnesium Sulfate combined with nifedipine treatment, levels of blood pressure and oxidative stress, blood rheology, platelet activity and renal function index before and after treatment of both groups were compared. Results: There were no significant difference of the level of DBP, SBP, Tac, MDA, SOD, high/low shear blood viscosity, PV, HCT, CD62P, CD63, GPⅡb/Ⅲa, SCr and BUN before treatment between control group and the observation group. Compared with intragroup before treatment, the levels of DBP, SBP, MDA, high/low shear blood viscosity, PV, HCT, CD62P, CD63, GPⅡb/Ⅲa, SCr and BUN after treatment of the two groups were significantly decreased, and the levels of the observation group after treatment was significantly lower than those in the control group, the difference was statistically significant;Compared with level of SOD and Tac, after treatment, the levels of SOD and Tac of the two groups were significantly higher than those in the same group before treatment, and levels of the observation group was significantly higher than in the control group, the difference was statistically significant. Conclusion: Nifedipine combined with magnesium sulfate treatment of pregnancy-induced hypertension, which can effectively reduce the blood pressure level of patients, improve the levels of oxidative stress, blood rheology and platelet active substance, protect renal function, with an important clinical value.

Effect of nifedipine in combined with magnesium sulfate on the hemorheology and coagulation indicators in patients with gestational hypertension

Objective:To explore the effect of nifedipine in combined with magnesium sulfate on the hemorheology and coagulation indicators in patients with gestational hypertension.Methods:A total of 90 patients with gestational hypertension were included in the study and randomized into the observation group and the control group with 45 cases in each group. The patients in the observation group were given magnesium sulfate in combined with nifedipine, while the patients in the control group were only given magnesium sulfate. The patients in the two groups were continuously treated for 2 weeks. The blood pressure, hemorheology indicators, and coagulation indicators before and after treatment in the two groups were detected and compared.Results: SBP, DBP, whole blood high, moderate, and low shear viscosity, plasma viscosity, and HCT after treatment in the two groups were significantly reduced when compared with before treatment (P<0.05). The levels of the above indicators after treatment in the observation group were significantly lower than those in the control group (P<0.05). PT, APTT, and TT after treatment in the two groups were significantly elevated when compared with before treatment (P<0.05), while Fib was significantly reduced (P<0.05). PT, APTT, and TT after treatment in the observation group were significantly higher than those in the control group (P<0.05), while Fib was significantly lower than that in the control group (P<0.05). Conclusions:Nifedipine in combined with magnesium sulfate can significantly stabilize the blood pressure level in patients with gestational hypertension, and improve the hemodynamic and coagulation indicators, with a significant efficacy.

Development and characterization of nifedipine-amino methacrylate copolymer solid dispersion powders with various adsorbents

Solid dispersions of nifedipine(NDP), a poorly water-soluble drug, and amino methacrylate copolymer(AMCP) with aid of adsorbent, that is, fumed silica, talcum, calcium carbonate,titanium dioxide, and mesoporous silica from rice husks(SRH), were prepared by solvent method. The physicochemical properties of solid dispersions, compared to their physical mixtures, were determined using powder X-ray diffractometry(PXRD) and differential scanning calorimetry(DSC). The surface morphology of the prepared solid dispersions was examined by scanning electron microscopy(SEM). The dissolution of NDP from solid dispersions was compared to NDP powders. The effect of adsorbent type on NDP dissolution was also examined. The dissolution of NDP increased with the ratio of NDP:AMCP:adsorbent of 1:4:1 when compared to the other formulations. As indicated from PXRD patterns, DSC thermograms and SEM images, NDP was molecularly dispersed within polymer carrier or in an amorphous form, which confirmed the better dissolution of solid dispersions. Solid dispersions containing SRH provided the highest NDP dissolution, due to a porous nature of SRH, allowing dissolved drug to fill in the pores and consequently dissolve in the medium.The results suggested that solid dispersions containing adsorbents(SRH in particular) demonstrated improved dissolution of poorly water-soluble drug when compared to NDP powder.

Formulation development of nifedipine controlled-release coated tablets

Due to frequent administration of oral nifedipine tablet, controlled or sustained release of the drug will improve patient compliance, stable blood level and side effect decrement [1,2].Various extended release nifedipine products have been commercially available. In this study, extended release tablets of this drug were formulated using sodium alginate,hydroxypropylmethylcellulose (HPMC) as controlled release matrix materials.

Formulation, optimization & evaluation of mouth dissolving film of nifedipine by using design of experiment

The oral mucosa is vascularized,drugs can be absorbed directly and can enter the systemic circulation without firstpass metabolism[1].This advantage can be used in preparing products with increased oral bioavailability of molecules that undergo first pass metabolism.Thus oral mucosa is an attractive site for drug delivery[2,3].The objective of this research work is to formulate mouth dissolving film of nifedipine for enhanced bioavailability.nifedipine is used to treat hypertension and angina pectoris.

Effects of Isoprenaline，Phenylephrine on Heart and Influence of Nifedipine on These Effects

In a perfused isovolumetrically contracting rat heart model, the effects of isoprenaline(IPN) and phenylephrine (PE) on myocardial contraction and relaxation were investigated,and the influence of nifedipine on these effects was studied. Both IPN and PE increased the myocardial contraction and improved its relaxation, but some differences existed.Nifedipine (10 nmol/L)substantially inhibited the PE-mediated inotropic effect, but in case of IPN-mediated inotropic ones, it did not.It was assumed that there may be various types of slow channels, one was activated by IPN,and the other, by PE.

硝苯呲啶(Nifedipine)的临床应用进展

目前临床上用硝苯吡啶(心痛定)治疗高血压病及冠心病已较普遍,随着对其药理作用的深入认识,其应用范围不断扩大。本文介绍近年来临床用途的某些进展。一、高血压病本药的特点是见效快.

Preparation and Antidiabetic Effect of Orally Administered Nifedipine‐Loaded Solid Lipid Nanoparticles in Fructose-Induced Diabetic Rats

The use of Nifedipine (NI), a dihydropyridine calcium channel blocker, is limited due to its poor aqueous solubility. However, NI loaded solid-lipid nanoparticles (NI-SLN) are known to exhibit suitable pharmacokinetic properties and good biocompatibility. The present investigation was designed to evaluate the effects of NI-SLN on glucose homeostasis, lipid metabolism and liver function in fructose-induced diabetic rats. NI-SLN was prepared by high pressure homogenization technique followed by lyophilization with trehalose as cryoprotectant. Diabetes was induced into rats by the administration of fructose (10%) in drinking water for six weeks. After induction of diabetes, rats were divided into four groups for the oral ingestion of NI, NI-SLN and/or vehicles and their effects on blood glucose levels, oral glucose tolerance test (OGTT), lipid profile, biochemical parameters, electrolytes and histopathology were observed. Single dose administration and treatment with NI-SLN showed significant glucose lowering efficacy in fructose-induced diabetic rats. Although NI and NI-SLN did not alter the fasting blood glucose level in normal rats, diabetic rats treated with NI-SLN resulted in significant reduction in glucose level for 24 hr. In OGTT, NI-SLN exhibited significant antihyperglycemic activity in both normal and diabetic rats. So, NI-SLN has better glucose lowering efficacy than that of pure NI in diabetic rats. The survival rates in rats among the treatment groups were 100%. Treatment with NI-SLN significantly improved lipid profiles than NI alone and the effect was dose-dependent. Administration of NI-SLN significantly reduced uric acid, creatinine levels and maintained a good cationic balance. After two weeks of NI-SLN treatment, hepatocytes regained their normal architecture, and the beneficial effect could be correlated with the reduction of SGOT and total bilirubin levels. Therefore, NI-SLN was found to be useful for the enhancement of bioavailability and exhibited profound antidiabetic activity in rats. The results of the study suggested that NI-SLN exerted better improvement in glucose levels, lipid profiles and organ protection than pure NI and might have some beneficial effects in the management of diabetic patients.