The incubation time of relapses after treatment of multibacillary leprosy with rifampicin containing regimens

In order to determine the duration of follow-up needed to evaluate the efficacy of short-course bactericidal regimens for multibacillary leprosy, information is needed on the incubation time of relapses after stopping treatment. Several groups of patients, who had been on rifampicin-containing regimens, were followed up for periods ranging from 4 to 10 years, Two groups of relapses were observed: early relapses occurring within 3.5 years after stopping treatment, with a median incubation time of 1 year and 10 months (upper limit of 95% confidence interval: 2 years); and late relapses occurring more than 3.5 years after stopping treatment, with a median incubation of 5 years. Early relapses are probably due to insufficient treatment, and late relapses to persisting bacilli or to reinfection. It is concluded that the efficacy of short-course RMP-containing therapeutic regimens can be evaluated by observing the occurrence of early relapses, 50% of which occur before 2 years after the end of therapy.Corresponding author.     

Chemical synovectomy vs. radioactive synovectomy for the treatment of chronic haemophilic synovitis: a prospective short-term study

Between January 1992 and December 1994, a prospective study was performed in two centres comparing chemical synovectomy using repeated weekly injections (range, 1–17) of Rifampicin (Group R) vs. radioactive synovectomy using 1–2 injections of Yttrium-90 (Group Y). The study was performed on 38 joints in a total of 35 haemophilic patients suffering from chronic haemophilic synovitis unresponsive to 3 months of conservative treatment (substitution therapy with the deficient coagulation factor plus a rehabilitation protocol). Group R included 18 patients with an average age of 9 years, with an average follow-up time of 25 months. In Group R, 19 joints were treated: nine knees, four elbows and six ankles. Group Y included 17 patients with an average age of 18 years, with an average follow-up time of 23 months. In Group Y, 19 joints were treated: 14 knees, two elbows and three ankles. The joints were evaluated according to the frequency of bleeding episodes and the Pettersson radiographic score. On the basis of the radiographic scale at the time of the synoviortheses, the joints were categorized as stage I (0 points), stage II (1–2 points), stage III (3–7 points), stage IV (8–10 points) and stage V (11–13 points). The overall results showed that in Group R, bleeding decreased in 12 joints, remained the same in six and worsened in one. In Group Y, bleeding decreased in 11 joints, remained the same in seven and worsened in one. In both Groups, bleeding was controlled best if joints were in stages I and II. In stages III, IV and V, synoviorthesis should not be carried out in haemophilia because it is not effective. Use of radioactive substances in persons under the age of 9 years has been discouraged in the past and therefore only Rifampicin was used in this age group. However, in patients over 9 years of age, this study showed similar decrease of bleeding in both treatment groups. Taking into account the advantages and disadvantages of both agents, we suggest the use of Rifampicin in elbows and ankles but prefer Yttrium-90 for the knees.     

抗结核固定剂量复合制剂的抗结核活性研究

目的对不同配方的抗结核固定剂量复合制剂的体内外抗结核活性进行研究并对其抗结核作用进行评估。方法体外活性用2倍稀释法检测最低抑菌浓度（MIC），体内活性以半数动物存活时间为指标观察药物对实验性结核病的疗效。结果2药或3药复合中的各药物对结核分枝杆菌王H378，Rv、牛型结核杆菌（Ravenal）和草分枝结核杆菌（M．phlei）的MIC绝大多数都低于药物单独应用时的MIC；体内抗结核作用显示，2药复合和3药复合及其复合制剂对实验性结核病均表现出显著的治疗作用，并明显优于各配方中相应药物单独应用时的作用。结论2药复合和3药复合及其制剂在体内外均具有显著抗结核作用，且不同厂家的同一产品的抗结核作用未见显著差异。     

抗结核药缓释涂层在兔脊柱结核模型体内的释药性能及组织分布研究

目的 :观察抗结核药缓释涂层在兔脊柱结核模型体内的释药性能及组织分布特性。方法 :选取新西兰大白兔(雌雄不限)体重3.00±0.25kg,通过椎体钻孔、浸注结核杆菌法构建并筛选脊柱结核模型120只,按"异烟肼(INH,H)、利福平(RFP,R)和吡嗪酰胺(PZA,Z)"给药剂型及途径不同,将模型分为4组,每组各30只:A组,缓释材料组,病灶局部置入缓释抗结核药缓释涂层(300mg/kg)+自体髂骨;B组,局部给药组,病灶局部置入HRZ药物晶体(H,12.5mg/kg;R,12.5mg/kg;Z,25.0mg/kg);C组,灌喂给药组,每日固定时间灌喂给药(H,12.5mg/kg/d;R,12.5mg/kg/d;Z,25.0mg/kg/d);D组,假手术灌药组,每天固定时间给药(剂量:H,12.5mg/kg/d;R,12.5mg/kg/d;Z,25.0mg/kg/d)。四组单次给药剂量相同,其中A、B两组单次给药,C、D两组研究期间连续多次给药。采用高效液相色谱法测定给药后(7d、14d、28d、84d)各组静脉血、腰大肌以及骨组织(病灶椎体)中H、R及Z的药物浓度,绘制药物浓度-时间曲线,观察其释药性能及组织分布特性。结果:4组单次给药剂量相同,A、B两组HRZ各药的给药总剂量均显著小于C、D两组(P0.01)。A组术后(7d、14d、28d、84d)腰大肌及骨组织中H、R及Z的药物浓度均显著高于C、D两组(P0.01)。A组术后(7d、14d、28d、84d)静脉血中H、R及Z药物浓度均极低或检测不到(P0.05)。A组在腰大肌及骨组织中的药物浓度-时间曲线平缓,无突释现象出现。A组腰大肌H(14.22±1.07μg/ml)、R(12.66±1.12μg/ml)、Z(28.93±1.30μg/ml)的浓度和骨组织中H(12.46±0.29μg/ml)、R(10.34±0.32μg/ml)及Z(26.21±0.82μg/ml)的浓度在给药后第7d时最高,至给药后第84d时H、R及Z的浓度降至最低,此时病灶骨组织中H(6.69±1.42μg/ml)、R(6.28±0.77μg/ml)及Z(19.88±0.90μg/ml)的浓度在各检测时间点均≥10倍的最低抑菌浓度。B组术后7d时腰大肌H(8.19±1.98μg/ml)、R(16.87±3.03μg/ml)、Z(91.18±11.12μg/ml)及骨组织H(5.70±1.25μg/ml)、R(13.06±1.26μg/ml)、Z(79.00±8.68μg/ml)中的药物浓度较高,此后急剧下降,至术后28d时腰大肌及骨组织中已检测不到药物(H、R及Z)浓度。B组静脉血中的药物(H、R及Z)浓度极低或检测不到。C、D两组静脉血、腰大肌及骨组织在各检测时间点均可测得药物(H、R及Z)浓度。C组及D组骨组织中药物(H、R及Z)的浓度均维持在相对平稳的较低水平。结论:缓释HRZ材料在兔脊柱结核病灶局部释药性能满意,组织分布特征为病灶局部高药物浓度而外周低药物浓度。     

HPLC测定人血清中利福平的浓度

目的　建立测定血清中利福平浓度的高效液相色谱法 ,并应用于临床。方法　采用Nova -pakC18色谱柱 (4 μm ,15 0nm× 3.9mm) ,以甲醇 - 0 .0 2mol·L-1醋酸钠 (6 2∶4 0 )为流动相 ,紫外检测波长 334nm ,测定口服利福平 4d以上的患者血清中利福平的浓度。结果　血清中利福平在 0 .5～ 16 .0 μg·ml-1范围内浓度与峰面积线性关系良好 (r=0 .9992 ) ,平均回收率为99 .4 3% ,日内、日间RSD <5 .0 %。结论　所用方法准确、灵敏 ,用血量少 ,适用于治疗药物监测 ,为临床用药提供数据参考     

制剂中利福平晶型的确定

目的确定制剂中利福平的晶型.方法利用粉末X-射线衍射方法测定不同晶型的利福平原料,结合文献数据,总结出利福平各晶型的主要特征衍射峰;直接测定利福平胶囊内容物或片剂研细的固体粉末的粉末X-射线衍射图谱,根据图谱中存在的利福平主要特征衍射峰,确定制剂中利福平的晶型.结果利福平晶体的主要特征衍射峰(2θ)分别为8.79°和14.48°(Ⅰ型结晶),1 5.84°和20.06°(Ⅱ型结晶),18.36°(SV型结晶);制剂中的辅料不干扰对主要特征衍射峰的判断;国内5个企业的12批利福平片和37个企业的88批利福平胶囊中的利福平均为Ⅰ型结晶.结论本方法可方便地判断制剂中利福平的晶型.     

复合三联抗结核药聚乳酸-羟基乙酸缓释微球的制备及体外释药特性

目的 :制备复合异烟肼(H)、利福平(R)、吡嗪酰胺(Z)的聚乳酸-羟基乙酸(HRZ/PLGA)缓释微球,观察其理化性质和体外缓释特性。方法:以PLGA(450mg)为载体,避光条件下称取H(40mg)、R(60mg)、Z(125mg),采用复乳-溶剂挥发法制备HRZ/PLGA缓释微球,应用扫描电镜观察微球的形态特征;应用高效液相色谱法(HPLC)测定其载药量、包封率;采用溶出法、HPLC于3h、6h、12h、1d、2d、3d、6d、9d、12d、15d、20d、25d、30d、40d、50d测定H、R、Z三种药物的浓度,观察其是否均大于10倍最低抑菌浓度(MIC),计算其日均释药率、累计释药率。结果:HRZ/PLGA微球在电镜下观察呈圆球形,平均粒径为10.3±4.7μm;H、R、Z三种药物的载药量分别为(18.02±0.36)%、(22.46±0.24)%、(21.68±0.37)%,包封率分别为(54.79±1.13)%、(72.35±0.39)%、(67.21±0.68)%;体外缓释试验显示微球缓释前12d左右,三种药物的累计缓释度均超过了50%,日均释药率分别为5.05%、4.89%、6.86%;第12天后三药的缓释基本趋于稳定,日均释药率分别为0.17%、0.26%、0.16%;三种药物缓释到50d时均大于10倍MIC。结论:HRZ/PLGA微球具有优良的载药及药物缓释效果,是一种理想的复合抗结核药物缓释系统。     

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Background:

Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.

Methods:

Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).

Results:

Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C_max), 91.43 ± 30.82 μg·h⁻¹ ·ml⁻¹, 55.49 ± 37.58 μg·h⁻¹ ·ml⁻¹, 96.50 ± 47.24 μg·h⁻¹ ·ml⁻¹, 101.47 ± 33.07 μg·h⁻¹ ·ml⁻¹, respectively, for area under the concentration-time curve (AUC_{0−24 h}).

Conclusions:

Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).     

Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice

Rifampicin (RIF), a typical ligand of human pregnane X receptor (PXR), powerfully induces the expression of cytochrome P450 3A4 (CYP3A4) in humans. Although it is thought that RIF is not a ligand of rodent PXR, treatment with high-dose RIF (e.g. more than 20?mg/kg) increases the expression of CYP3A in the mouse liver. In this study, we investigated whether the induction of CYP3A by high-dose RIF in the mouse liver is mediated via indirect activation of mouse PXR (mPXR). The results showed that high-dose RIF increased the expression of CYP3A11 and other PXR-target genes in the liver of wild-type mice but not PXR-knockout mice. However, the results of reporter gene and ligand-dependent assembly assays showed that RIF does not activate mPXR in a ligand-dependent manner. In addition, high-dose RIF stimulated nuclear accumulation of mPXR in the mouse liver, and geldanamycin and okadaic acid attenuated the induction of Cyp3a11 and other PXR-target genes in primary hepatocytes, suggesting that high-dose RIF triggers nuclear translocation of mPXR. In conclusion, the present study suggests that high-dose RIF stimulates nuclear translocation of mPXR in the liver of mice by indirect activation, resulting in the transactivation of Cyp3a11 and other PXR-target genes.     

利福霉素钠与利福平治疗肺结核安全性评价

目的 比较利福霉素钠和利福平在治疗肺结核中的安全性.方法 792例肺结核患者分为利福霉素钠组(393例)和利福平组(399例),治疗2个月后评价其安全性.结果 利福霉素钠不良反应发生率(12.47％),较利福平(18.29％)低,严重不良反应发生率:利福霉素钠为1.78％,利福平为5.76％,差异有统计学意义;主要表现为肝损伤、过敏反应、肾功能损伤、血细胞减少和消化道不适.结论 利福霉素钠的不良反应发生率和严重程度小于利福平,若患者不能耐受利福平,可考虑利福霉素钠作为替代治疗.