Efficacy and safety of the 200–300 mg sustained release formulation of diltiazem administered once daily in patients with stable angina

The aim of this multicentre randomised double blind study was to compare the efficacy and safety of the 200–300 mg sustained release diltiazem formulation administered once daily (200–300 SR) with standard diltiazem (D) given three or four times daily to patients with stable angina. Patients aged 59 years, with a reproducible exercise test on placebo, were randomised to 4 weeks of treatment with 200–300 SR (n=70) or D (n=74). The initial dosage was 200 mg in the 200–300 SR group and 60 mg t.i.d. in the D group, increased to 300 mg once daily or 60 mg q.i.d., respectively, if ergometric parameters, which were always measured at the end of the dosing period, had not improved after two weeks. After 4 weeks of treatment, the antianginal efficacy at rest was comparable in the 200–300 SR and the D group; there was a prolongation of the total duration of exertion of 14% and 18% respectively (P<0.01 vs placebo for both groups with no intergroup difference). A dose-effect relation was found with both formulations.The 200–300 SR formulation gave full 24 hour anti-ischaemic protection when administered once daily. Its efficacy and safety were comparable to those of standard diltiazem t.i.d. or q.i.d. in patients with stable angina. The once daily administration should improve treatment compliance.     

Antihypertensive efficacy of twice daily controlled release diltiazem using 24 hour intra-arterial blood pressure monitoring

The aim of the study was to examine the efficacy of a new controlled release formulation of diltiazem administered in a twice-daily dose in patients with essential hypertension using 24 hour intra-arterial ambulatory blood pressure monitoring.Sixteen patients (2 female) of mean age 53 years with mild to moderate essential hypertension, defined as a supine resting diastolic cuff blood pressure 95 mm Hg, were recruited to a sequential dose ranging study of controlled release (CR) diltiazem. After a six week run-in period without any anti-hypertensive medication, intra-arterial blood pressure monitoring with 60° tilt, isometric handgrip and bicycle exercise testing were performed. Patients were then treated for one week with CR diltiazem 120 mg b.i.d. If supine resting diastolic cuff blood pressure fell by <10 mm Hg compared to the last run-in value and remained >90 mm Hg, the dose was increased to 240 mg b.i.d. for a week, and if necessary to 360 mg b.i.d. for a week. Patients continued for further one month on the dose of CR diltiazem at which they achieved target blood pressure reduction. At the end of this maintenance treatment, 24 hour intra-arterial blood pressure monitoring was repeated.Twelve patients were satisfactorily controlled on 120 mg b.i.d. CR diltiazem, three on 240 mg twice daily and one on 360 mg twice daily. During rest and exercise, blood pressure and heart rate were significantly lower after treatment with CR diltiazem than before treatment. The hypotensive effect of diltiazem was maintained throughout the 12 hour dosing interval and the early morning blood pressure response was blunted. No adverse effects or ECG abnormalities were reported.It was concluded that CR diltiazem 120 mg, administered twice daily to a total daily dose of between 240 mg and 720 mg, is effective and well tolerated in the treatment of mild to moderate essential hypertension.     

Formulation of sustained release bioadhesive minitablets containing solid dispersion of levofloxacin for once daily ocular use

This study aimed to increase ocular residence time of levofloxacin by formulation into zero-order sustained release mucoadhesive minitablets for once daily administration using a hydrophobic–hydrophilic polymeric matrix. Levofloxacin was first formulated into solid dispersion with different ratios of Eudragit^® RS then the resulting solid dispersion was mixed with different concentrations of Carbopol^® and other excipients to be finally compressed into minitablets. A 2⁴ full factorial design was employed to estimate the effects and interactions of two formulation factors, and to establish their relationships with selected responses in the developed minitablets. The studied factors were: drug to Eudragit^® RS ratio, and percent of Carbopol^® in the minitablets. Sixteen ocular minitablets formulations were prepared and evaluated for the cumulative percentages drug release at 6, 12, and 24?h, as well as mucoadhesion time, mucoadhesive strength, and swelling index as response variables. After optimizing the responses, the optimized formulation was found to be stable on sterilization using gamma-irradiation and storage at 40?°C/75% RH for six months. In vivo testing of the optimized formulation showed that the minitablets extended levofloxacin release up to 24?h without causing any ocular irritation. The optimized formulation exhibited superior microbiological activity compared to the commercial product.     

控释硝苯地平降压效应谷／峰比率的临床研究

目的　探讨计算控释硝苯地平治疗原发性高血压患者降压效应谷/峰比率（T/　PR）的最佳方法和该药的平稳指数(SI)　。方法　轻、中度原发性高血压患者32例,每天早晨服控释硝苯地平(nifedipine　GITS)　30　mg,治疗前及4　wk后作动态血压监测,分别以2　h个体法和整组法计算T/PR并计算该药的SI　。结果　4　wk治疗后患者偶测血压和动态血压的降低幅度分别为(24±12)/(12±8)　mmHg和(14.5±3.9)/(11.2±3.1)　mmHg;　个体法计算的收缩压和舒张压的T/PR分别为0.65±0.23和0.66±0.25,　而整组法则分别为0.62和0.68;　该药的收缩压和舒张压SI分别为3.74和3.77　。结论　控释硝苯地平可24　h有效平稳地降压;其降压平稳作用可通过T/PR和SI反映。     

Left ventricular hypertrophy in hypertensive patients in Indian primary care: prevalence and effect of treatment with sustained release indapamide

Objective: Epidemiologic studies indicate an ethnic determinant of left ventricular hypertrophy (LVH), but its prevalence in hypertensive Asian Indians at diagnosis is not known. The observation that LVH regression reduces cardiovascular risk independent of blood pressure, suggests that initial antihypertensive treatment, which also regresses LVH is a desirable goal. This study investigates the prevalence of LVH and its regression with indapamide sustained release (Natrilix SR) in untreated Indian hypertensive patients managed in the primary care setting.

Design and methods: Randomly selected physicians serving a defined population recruited untreated hypertensive patients to determine prevalence of LVH. All patients then received indapamide SR treatment for 6months. LVH was assessed by echocardiography. All measurements were centralized and interpreted by a single blinded observer.

Main outcome measures: The primary treatment outcomes were the percentage of patients whose LVH regressed with treatment and the number of patients who achieved a blood pressure below 140/90 mmHg.

Results: Of the 86 patients recruited, 21 (24.4%, 95% confidence interval (CI) 15.3-33.8) had LVH. There were 11 cases (26.2%) in men, 10 (22.7%) in women, and 15 (32.6%) in those above 50years. Treatment regressed LVH in 16 (76.2%, 95%CI, 58.0-94.4) by a mean of 25.4?g/m² (95%CI, 2.8-47.7, p?<?0.05). Blood pressure was controlled in 71 (82.6%, 95%CI, 74.5–90.6) patients.

Conclusion: Prevalence of LVH in untreated Indian hypertensive patients is similar to that in white western populations. Initial indapamide SR treatment is effective in both controlling blood pressure and regressing LVH in the primary care setting.     

利多卡因缓释胶丸皮下植入的药代动力学

目的：研究利多卡因缓释胶丸（ＬＳＲＰ）在兔和大鼠体内的药代动力学。方法：运用高效液相色谱法（ＨＰＬＣ）测定ＬＳＲＰ在血浆和组织中的浓度。结果：发现兔皮下植入ＬＳＲＰ（２０，４０，８０ｍｇ·ｋｇ－１）后，血浆药物浓度—时间曲线符合缓释制剂的一室开放模型。３种剂量的ＬＳＲＰ吸收半衰期Ｔａ１／２均较利多卡因注射液（ＬＴ，１０ｍｇ·ｋｇ－１，ｓｃ）明显延长。３种剂量ＬＳＲＰ的峰浓度（Ｃｍａｘ）分别为０．２４±０．０９，１．２５±０．２３，５．６５±０．１０ｍｇ·Ｌ－１，而ＬＩ（１０ｍｇ·ｋｇ－１，ＳＣ）的Ｃｍａｘ为２．１８±０．３２ｍｇ·Ｌ－１。４０ｍｇ·ｋｇ－１ＬＳＲＰ经大鼠皮下植入后，在局部皮下组织中利多卡因浓度明显高于血浆、脑、心、肝和肾组织中浓度，并在给药后４８ｈ仍能维持在１．１８μｇ·ｇ－１水平。结论：ＬＳＲＰ经皮下植入后的缓释效果明显。提示ＬＳＲＰ能延长利多卡因的局麻、镇痛作用，并可能减轻其全身毒性。     

硝苯地平缓释片联合依那普利治疗老年人原发性高血压60例疗效观察

目的观察硝苯地平缓释片(纳欣同)联合依那普利治疗老年人原发性高血压的临床疗效。方法将老年原发性高血压患者180例随机分为A、B、C组各60例。A组予纳欣同口服,每次20mg,每天1～2次;B组予依那普利片口服,每次10mg,每天2次;C组予纳欣同联合依那普利治疗,纳欣同用法用量同A组,依那普利片用法用量同B组。治疗后比较3组临床疗效及不良反应。结果 C组总有效率为96.7%高于A组的66.7%和B组的60.0%,差异均有统计学意义(P<0.01)。C组与A组不良反应发生率比较差异无统计学意义(P>0.05)。但各组患者均可耐受,不影响治疗。结论纳欣同联合依那普利治疗老年人原发性高血压疗效显著,且不良反应轻微,值得推广应用。     

聚乳酸-乙醇酸共聚物降解行为对缓控释制剂药物释放行为影响的研究进展

在以聚乳酸–乙醇酸共聚物（PLGA）为辅料的药物缓控释制剂中,药物的释放行为主要取决于PLGA聚合物的降解行为。PLGA的降解行为受骨架结构、环境因素和剂型因素等影响。对PLGA的降解机制进行剖析,并综述影响PLGA降解行为的相关因素,包括PLGA的单体聚乳酸与聚乙醇酸的比例、相对分子质量、pH值、结晶度、温度、药物的类型和基质包封药物后的剂型等,同时论述了其对缓控释制剂药物释放行为的影响。     

缓释控释制剂的释放度测定方法的研究进展

目的　介绍缓、控释制剂的体外释放度测定方法 ,使其能更好地模拟体内状态。方法　综述最近的中外文献中有关缓释、控释制剂的体外释放度测定实验方法 ,实验条件的选择及影响因素。结果　体外释放度实验条件如释放介质的 pH值、离子强度、增溶剂、表面活性剂和释放仪器等可影响缓、控释制剂的体外释放度。结论　根据不同药物选择尽可能接近体内状态的方法     

Efficacy of a new once daily hydromorphone formulation in comparison with twice daily administration in chronic pain: a randomized,double-blind,cross-over study

Objective Efficacy and safety of a novel multiple-unit hydromorphone once daily (HOD) was compared to an established hydromorphone twice daily (HTD) regimen in patients with moderate-to-severe chronic pain.

Design and methods The results from a randomized, double-blind, multicenter, cross-over trial in patients (n?=?37) with chronic malignant or non-malignant pain are reported. The primary efficacy parameter was current pain on 0–100?mm VAS assessed four times daily and prior to intake of rescue medication (immediate-release hydromorphone) throughout the last 5 days with each treatment (after an 8?day build-up period to avoid carry-over effects). Total daily dose of hydromorphone (TDD: 8–32?mg/day) was kept stable during the double-blind treatment phase.

Results The difference observed in mean current pain (?0.92?mm VAS) over the 5?day assessment period between HOD and HTD (28.44?mm vs. 29.36?mm VAS) was found to lack clinical relevance, as the 95% CI (?4.10 to 2.28?mm VAS) did not exceed the prespecified limit for non-inferiority of 9?mm VAS. Results from the full analysis set were consistent with per protocol data confirming robustness, as did the data for 12?h recalled pain assessed at 08:00?h and 20:00?h, showing no significant differences between once and twice daily medication. Both treatments produced effective and stable pain control with only minor day-to-day and intra-day fluctuations. Switching between treatments was suitable, considering both efficacy and safety, as no relevant or significant differences in adverse events were seen (25.0% HOD, 24.3% HTD). Most frequently typical side-effects of opioid therapy were observed, such as nausea, vomiting and headache.

Conclusion Although this study was of short duration and included a limited number of patients, the results confirm that the new HOD is as effective and safe as the established HTD.     

空服与饱服大剂量烟酸缓释片的药动学

目的 :研究健康志愿者口服烟酸缓释片 (1 50 0mg)的药动学。 方法 :1 8名健康志愿者随机分成两组 ,一组禁食 1 2h后 ,空服烟酸缓释片 1 50 0mg。另一组进食统一餐后 ,口服烟酸缓释片 1 50 0mg。比较两组的药动学参数。 结果 :烟酸缓释片的体内过程符合具有一级吸收的一室模型 ,其主要的药动学参数Tmax,Cmax和AUC0→∞ 分别为 (3 .2± 0 .3)h和 (3 .2± 0 .3)h ;(5 .3± 1 .4)mg·L- 1 和 (5 .5± 1 .0 )mg·L- 1 ;(43 .4± 1 3 .9)mg·h·L- 1 和 (46 .2± 1 0 .2 )mg·h·L- 1 。结论 :为临床合理用药提供了参考资料     

Ivermectin-loaded microparticles for parenteral sustained release: in vitro characterization and effect of some formulation variables

Ivermectin (IVM) is a BCS II drug with potent antiparasitic activity in veterinary applications. In this study, poly(lactide-co-glycolide) (PLGA) and poly(DL-lactide) (PLA) Ivermectin-loaded microparticles were prepared by the simple emulsion (O/W) solvent evaporation method in order to obtain sustained release formulations for parenteral applications. The effects of polymer end-groups (ester or free acid) and the addition of the hydrophilic polyvinylpyrrolidone polymer (PVP) in in vitro drug release profiles were also studied. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis showed that IVM was present in an amorphous state or as a molecular dispersion within the polymers or theirs mixtures with PVP and that a PVP-drug complex was formed. Drug entrapment efficiency in the microparticles (>90%) was independent of the polymer composition, the end groups and the presence of PVP. However, microscopic (SEM) observations showed that the addition of PVP led to more porous microparticles accompanied by the increased rates of drug release.     

动态血压监测评价复方替米沙坦的降压疗效

目的以24 h动态血压监测评价复方替米沙坦治疗轻中度原发性高血压患者的疗效。方法选择28例轻中度高血压患者,予以复方替米沙坦1~2片(每片含替米沙坦40 mg,氢氯噻嗪12.5 mg),po,qd,治疗8 wk,分别于治疗前后行24 h动态血压监测并计算其谷峰比值、平滑指数后进行比较分析。结果治疗8 wk后24 h平均收缩压、舒张压,日间平均收缩压、舒张压,夜间平均收缩压、舒张压与治疗前比较均有显著性降低(P<0.01),收缩压、舒张压负荷也有显著降低(P<0.01)。收缩压谷峰比值为62.4%,舒张压谷峰比值为65.6%,收缩压平滑指数为1.08±0.36,舒张压平滑指数为1.13±0.22。结论复方替米沙坦具有良好的降压效果及满意的谷峰比值、平滑指数,临床使用安全。     

氟尿嘧啶植入剂在原发性晚期上皮性卵巢癌术中的应用效果

目的 探讨氟尿嘧啶植入剂在原发性晚期上皮性卵巢癌（PAEOC）肿瘤细胞减灭术中的临床疗效。方法 回顾性分析安徽医科大学第一附属医院2007年6月至2012年12月收治并成功随访的162例PAEOC患者的临床资料,根据手术关腹前是否植入缓释氟脲嘧啶植入剂将患者分为试验组（术中腹腔植入缓释氟尿嘧啶600 mg）80例和对照组（术中未植入氟尿嘧啶植入剂）82例。观察两组患者的化疗副反应、术后并发症及生存率。结果 术后两组化疗副反应差异无统计学意义（P>0.05）;试验组与对照组近期生存率差异无统计学意义（χ²=2.865,P=0.091）,而生存率的远期效应,试验组高于对照组,差异有统计学意义（χ²=4.911,P=0.027）。结论 术中植入氟尿嘧啶植入剂是一种安全、有效的腹腔局部化疗方法,可提高患者的远期生存率。     

Antihypertensive efficacy of indapamide SR in hypertensive patients uncontrolled with a background therapy: the NATIVE study*

ABSTRACT

Objectives: Antihypertensive monotherapy rarely achieves blood pressure (BP) control. NATIVE (NATrilix SR use in combInation antihypertensiVe thErapy) evaluated indapamide sustained release (SR) in hypertensive patients receiving background therapy.

Research design and methods: Patients remaining hypertensive (systolic BP [SBP], 145–180?mmHg; diastolic BP [DBP], 95–105?mmHg) while receiving an angiotensin-converting enzyme (ACE) inhibitor (n = 709), β-blocker (n = 629), calcium-channel blocker (CCB; n = 493), angiotensin II type 1 receptor blocker (ARB; n = 75), α-blocker (n = 29) or other therapy (n = 6) were enrolled, recruited by physicians from 228 centres in Pakistan. Indapamide SR 1.5?mg was administered daily for 3 months with background therapy. BP was assessed every 2 weeks, and blood glucose and total cholesterol were evaluated at baseline and study end in a patient subgroup. Adverse events were also recorded.

Main outcome measures and results: Of 2073 enrolled patients (49% males; mean age 51 years), 1941 received indapamide SR and background therapy. SBP and DBP decreased significantly (SBP, 166 ± 16?mmHg at baseline vs. 132 ± 12?mmHg at 3 months; DBP, 102 ± 8?mmHg vs. 83 ± 6?mmHg; both p < 0.0001 vs. baseline). Patients uncontrolled with an ACE inhibitor, β-blocker, CCB or ARB achieved an SBP/DBP decrease of 34 ± 15/19 ± 9, 33 ± 17/19 ± 10, 33 ± 15/18 ± 8 or 35 ± 16/20 ± 12?mmHg, respectively (all p < 0.0001). In all, 84% of patients achieved target SBP (≤?140?mmHg) and 61% achieved BP normalisation (SBP <?140, DBP <?90?mmHg). The absence of placebo control may lead to an overestimation of the extent of the BP reduction achieved. Glucose and cholesterol levels were unaffected by indapamide SR. Four percent of patients experienced side-effects, which were mild-to-moderate in severity.

Conclusions: In patients with hypertension despite antihypertensive therapy, indapamide SR significantly reduced BP with a good acceptability profile. Indapamide SR may represent an effective additional therapy for patients who do not achieve BP goals with other antihypertensive agents.     

谷峰比值和平滑指数在降压药物疗效评价中的应用

目的 :探讨谷峰比值合理计算方法 ,并比较其与平滑指数反映降压药物降压作用的稳定性。方法 :结合乐卡地平在高血压病人中的疗效研究 ,6 0例病人分别在治疗wk 0 ,6 ,8末进行 3次 2 4h动态血压检测。以不同方法计算服药后峰 /谷效应值、谷峰比值和平滑指数 ,并比较其重复性。结果 :以 2h时间段进行计算 ,峰 /谷效应值下降最少 ,重复性增加明显。以治疗有效病人为对象计算谷峰比值为正态分布 ,分布相对集中。治疗wk 6末和wk 8末相比 ,平滑指数重复性优于谷峰比值。结论 :建议在降压药疗效评价中取降压幅度最大的相邻 2h时间段计算峰效应值 ,下次服药前 2h时间段计算谷效应值 ,选择治疗有效病人计算谷峰比值 ,并增加平滑指数来更稳定地反映药物的平稳降压作用     

Gallopamil slow release: a double blind study of twice daily versus once daily treatment in chronic stable angina

Summary The clinical efficacy of a new slow release preparation of the calcium antagonist gallopamil was assessed in 20 patients by diary cards and treadmill exercise tests. A single blind phase of two week periods of placebo, gallopamil 100 mg o.d. and gallopamil 100 mg b.i.d., blinded to the patient, was followed in 18 patients by a double blind comparison of gallopamil 100 mg od versus 100 mg b.i.d.Angina frequency and trinitrin consumption per week were both significantly less on high dose (2.7 and 1.7) than on low dose (5.4 and 3.4) respectively. Treadmill total exercise time was longer on high dose (523 s) than low dose (449 s). Other exercise test parameters showed similar improvements on high dose treatment.Gallopamil was well tolerated. PR interval correlated best with plasma gallopamil level, while exercise test parameters correlated best with the log plasma level of its major metabolite nor-gallopamil.     

The effect of secoverine hydrochloride on stimulated sigmoid motility: a double-blind, placebo controlled cross-over study in irritable bowel syndrome.

The effect of oral secoverine hydrochloride on neostigmine-stimulated sigmoid motility in 12 patients with irritable bowel syndrome was studied in a double-blind placebo-controlled cross-over study. Both spontaneous and stimulated motor activity were significantly reduced by the compound in comparison with placebo. The most sensitive indices were the frequency of wave activity, maximum amplitude and motility index. Two patients reported mild dizziness after secoverine.     

Pharmacokinetic evaluation of an azithromycin controlled release dosage form in healthy human volunteers: a single dose study

Azithromycin (AZI) follows a two-compartment model pharmacokinetically. The purpose of this study was to evaluate the in vivo performance of a controlled release (CR) formulation of AZI, which would eliminate the risk of high peak plasma concentrations obtained within 2–3 h after peroral administration of immediate release (IR) products. The study was conducted in twelve healthy male human volunteers to compare an experimental NIPER product (CR tablets) with Vicon^® (IR tablets) at the same dose level as a single-dose, randomized, one-period, two-treatment, and parallel-study. Concentrations of AZI in serum samples were assessed using the validated HPLC method. From the serum concentration–time profiles various pharmacokinetic parameters (AUC_0–96, AUC_0–inf, C_max and T_max) were calculated for both products. Results showed that the high peak concentration obtained by administration of a conventional IR formulation were eliminated with the CR product. A mean dosage form index (DI) of 1.17 with fluctuations of 7.57% was obtained with the CR product at steady state level, indicating reduced fluctuations at the steady state serum concentrations. Elimination of the pronounced peak as well as fluctuations reduced or minimized AZI adverse effects associated with the IR product.