β-内酰胺酶抑制剂复方制剂非临床研究技术指南

β-内酰胺酶抑制剂复方制剂在临床上被广泛应用于治疗耐药菌所致感染,由于早期β-内酰胺酶抑制剂的抑酶谱较 窄,抑酶谱更广泛的酶抑制剂在不断研发之中。与一般抗菌药物临床前研究不同,β-内酰胺酶抑制剂复方制剂的临床前研究需 明确β-内酰胺类药物或酶抑制剂本身的抗菌谱与抗菌活性,尤其是明确酶抑制剂是否具有抗菌活性。需要确定合适的β-内酰胺 类药物与酶抑制剂复方制剂,以及适用的不同酶型的目标病原菌。本文主要介绍新型β-内酰胺酶抑制剂复方制剂临床前研究方 法。临床前研究阶段的β-内酰胺酶抑制剂复方制剂研究包括体外研究和体内研究两部分,前者主要为体外药效学研究和体外药 动学/药效学(pharmacokinetic/pharmacodynamic, PK/PD)研究,常用研究方法包括β-内酰胺类药物和β-内酰胺酶抑制剂复方制剂最 低抑菌浓度测定、最低杀菌浓度测定、抗生素后效应测定及时间杀菌曲线。后者主要为动物药动学研究、感染动物药效学研究 和感染动物药动学/药效学研究。在动物药动学/药效学研究中,需考虑β-内酰胺类药物与酶抑制剂的相互影响。这些研究方法的 应用旨在阐明β-内酰胺酶抑制剂复方制剂两组分药效学特点、药动学相似与否、PK/PD指数及其临床前PK/PD靶值,为进入临 床试验阶段目标适应症及剂量选择提供依据。     

The impact of fixed‐dose combination versus free‐equivalent combination therapies on adherence for hypertension: a meta‐analysis

Nonadherence to antihypertensive medication is considered as a reason of inadequate control of blood pressure. This meta‐analysis aimed to systemically evaluate the impact of fixed‐dose combination (FDC) therapy on hypertensive medication adherence compared with free‐equivalent combination therapies. Articles were retrieved from MEDLINE and Embase databases using a combination of terms “fixed‐dose combinations” and “adherence or compliance or persistence” and “hypertension or antihypertensive” from January 2000 to June 2017 without any language restriction. A meta‐analysis was performed to parallel compare the impact of FDC vs free‐equivalent combination on medicine adherence or persistence. Studies were independently reviewed by two investigators. Data from eligible studies were extracted and a meta‐analysis was performed using R version 3.1.0 software. A total of nine studies scored as six of nine to eight of nine for Newcastle‐Ottawa rating with 62 481 patients with hypertension were finally included for analysis. Results showed that the mean difference of medication adherence for FDC vs free‐equivalent combination therapies was 14.92% (95% confidence interval, 7.38%–22.46%). Patients in FDC group were more likely to persist with their antihypertensive treatment, with a risk ratio of 1.84 (95% confidence interval, 1.00–3.39). This meta‐analysis confirmed that FDC therapy, compared with free‐equivalent combinations, was associated with better medication adherence or persistence for patients with hypertension. It can be reasonable for physicians, pharmacists, and policy makers to facilitate the use of FDCs for patients who need to take two or more antihypertensive drugs.     

Clindamycin phosphate 1.2%/benzoyl peroxide 3% fixed‐dose combination gel versus topical combination therapy of adapalene 0.1% gel and clindamycin phosphate 1.2% gel in the treatment of acne vulgaris in Japanese patients: A multicenter,randomized, investigator‐blind,parallel‐group study

Adapalene 0.1% (ADA) with clindamycin phosphate 1.2% (CLNP; ADA + CLNP) and the fixed‐dose combination containing CLNP and benzoyl peroxide 3% (CLNP/BPO 3%) are strongly recommended for the early treatment of acne vulgaris in Japan. Here, we compare the early efficacy and safety of CLNP/BPO 3% with Japanese standard topical use of ADA + CLNP in the treatment of acne vulgaris. In this phase IV, multicenter study, 351 patients were randomized to receive CLNP/BPO 3% or ADA + CLNP for 12 weeks. The primary end‐point was percentage change from baseline in total lesion (TL) counts at week 2. Secondary end‐points included the percentage change from baseline in TL, inflammatory and non‐inflammatory lesion (IL and non‐IL) counts, Investigator's Static Global Assessment (ISGA), quality of life (QoL [Skindex‐16]) and patient preference. Local tolerability scores and adverse events were also recorded. CLNP/BPO 3% provided a significantly greater percentage reduction from baseline in TL compared with ADA + CLNP at week 2, and week 4. Compared with ADA + CLNP, CLNP/BPO 3% was superior at reducing IL (but not non‐IL) over weeks 2–12, was more effective at improving patient QoL and ISGA, and scored higher in patient‐preference assessments. Both treatments were well tolerated; adverse drug reactions occurred more frequently in patients receiving ADA + CLNP (37%) than in those receiving CLNP/BPO 3% (17%). In conclusion, CLNP/BPO 3% showed greater efficacy for the early treatment of acne vulgaris in Japan, with a more favorable safety profile compared with ADA + CLNP.     

The antimalarial agent artesunate possesses anticancer properties that can be enhanced by combination strategies

Artemisinins are a class of compounds that are first-line treatment options for malaria. They also have potent antiproliferative activity, which makes them potential anticancer drugs. We have previously demonstrated anticancer activity of a number of these compounds in vitro; however, cytotoxic activities were compromised by drug-induced cell cycle arrests. In this study, we have explored further the activity of the clinical lead artemisinin-drug artesunate (ART), used either alone or in combination with established chemotherapy. Also, by using a cell line expressing polyploidy character, have also explored the impact of cell cycle arrest in determining overall drug activity. Results showed that ART caused dose-dependent decreases in cell number, which were associated with either increased cytotoxicity or cytostasis. Cytostasis appeared to be a consequence of a simultaneous arrest at all phases of the cell cycle, a deduction that was supported by molecular profiling, which showed reductions in cell cycle transit proteins. ART appeared to maintain cells in this arrested state; however, reculturing these treated cells in drug-free medium resulted in significant reductions in viabilities. We also showed that ART maintained activity in polyploidy cells, and that an impressive enhancement to its activity was achievable through a combination with the immunomodulatory drug lenalidomide. Taken together, these observations indicate ART and its related compounds may be effective for the treatment of tumours, and that activity is related to schedule. Therefore, it is important to carefully select the most appropriate schedule to maximise ART efficacy.     

复方氯己定达克罗宁乳膏含量测定方法研究

目的建立反相高效液相层析(RP-HPLC)法同时测定复方氯己定达克罗宁乳膏中两种成分含量的方法,用于制定复方氯己定达克罗宁乳膏的质量标准。方法采用C18(250 mm×4.6 mm,5μm)色谱柱,流动相,乙腈∶0.05moL/L磷酸二氢钾溶液(含0.07%庚烷磺酸钠,0.4%三乙胺,用磷酸调pH至3.0),流速1.0 mL/min,检测波长284 nm,柱温25℃。结果盐酸氯己定、盐酸达克罗宁的线性范围分别为0.100 03～2.000 60μg和0.015 18～0.303 60μg,相关系数均为0.999 99,回收率(n=9)分别为99.83%和99.89%,相对标准偏差(RSD)分别为0.41%和0.14%。结论该方法简便、准确,可作为控制复方氯己定达克罗宁乳膏中盐酸达克罗宁、盐酸氯己定含量的质量标准。     

Update on the role of alpha-agonists in glaucoma management

Glaucoma is the second most common cause of world blindness (following cataract) with estimated cases reaching 79.6 million by 2020. Although the etiology of glaucoma is multi-factorial, intraocular pressure (IOP) is the only modifiable factor in glaucoma management proven to alter the natural course of the disease. Among various classes of IOP-lowering medications currently available, alpha-adrenergic receptor agonists are used either as monotherapy, as second-line therapy, or in fixed combination with beta-blockers. Non-selective adrenergic agonists such as epinephrine and dipivefrin are infrequently used today for the treatment of glaucoma or ocular hypertension, and have been replaced by the alpha-2-selective agonists. The use of apraclonidine for IOP reduction in glaucoma or OHT is limited due to a high rate of follicular conjunctivitis. The alpha-2-selective agonist in use today is brimonidine. The brimonidine–purite formulations are preferred to brimonidine–benzalkonium chloride (BAC) formulations due better tolerability while maintaining similar efficacy. Brimonidine is also effective when used in combination with a beta-blocker. Using brimonidine–timolol fixed combination (BTFC) as first-line therapy has an added potential for neuroprotection. This would be a valuable strategy for glaucoma treatment, for patients who are intolerant of prostaglandin analogs, or for patients where prostaglandin analogues are contraindicated as first-line therapy, such as in patients with inflammatory glaucoma.