Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children

Introduction: New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple challenges limit timely access to new MDR-TB treatments in children.

Areas covered: Diagnosis of MDR-TB in children remains a barrier, with few children with MDR-TB diagnosed and treated. Other barriers to timely access to new and repurposed drugs are discussed, and include delayed initiation of paediatric trials, limited funding for paediatric drug development, fragmented regulatory systems and operational challenges. The status of access to current repurposed and novel drugs is presented.

Expert commentary: More timely initiation of paediatric trials is needed and paediatric work should happen and be funded in parallel with each phase of adult trials. Better quality data, increased regulator resources and expertise, harmonization of regulatory requirements across borders/organisations and registration fee waivers would improve registration timelines. Improved diagnosis, recording and reporting will establish better demand. Improved systems for procurement and supply chain management would reduce in-country operational barriers to getting medications to children. The challenges must be addressed to ensure timely and equitable access to new drugs and regimens that are urgently needed for effective, safe and shorter treatment of children with MDR-TB.     

耐药结核病的流行和监测现状

结核分枝杆菌的耐药性已成为全球关注的重大公共卫生挑战。根据世界卫生组织(World Health Organization, WHO)的统计,我国是全球22个结核病(tuberculosis, TB)高负担国家之一,也是全球27个耐多药结核病(multi-drug resistant TB, MDR-TB)高负担国家之一。耐药结核病(drug resistant TB, DR-TB)是中国结核病防治工作的三大挑战之一,如若耐药结核病的流行不能得到有效控制,将会影响我国“2035年终止结核病流行目标”的顺利实现。结核病耐药性监测对于指导合理使用抗生素起着至关重要的作用,耐药监测是评估结核病防治规划实施效果的有效指标。1994年,WHO和国际防痨及肺部疾病联合会(International Union Against Tuberculosis and Lung Disease, UNION)共同开展了一项全球性的结核病耐药性监测项目,我国除参与该项目外,同时积极开展了多次全国结核病流行病学调查,并成功开展了全国结核病耐药性基线调查,为制定科学防治结核病的策略措施提供重要参考依据。     

An update on pharmacotherapy for the treatment of fibromyalgia

Introduction: Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised.

Areas covered: Publications describing randomized controlled trials and long-term extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review.

Expert opinion: Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials.     

Beijing genotype of Mycobacterium tuberculosis is significantly associated with linezolid resistance in multidrug-resistant and extensively drug-resistant tuberculosis in China

Linezolid (LNZ) is a promising antimicrobial agent for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). To investigate the efficacy of LNZ among MDR-TB and XDR-TB in China, the LNZ susceptibility of 158 MDR-TB isolates from the national drug resistance survey was determined by the minimum inhibitory concentration method. The 158 MDR-TB isolates were also sequenced in the 23S rRNA, rplC and rplD genes conferring LNZ resistance and were typed using spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Overall, the prevalence of LNZ-resistant isolates was 10.8% (17/158) among MDR-TB isolates circulating in China. Beijing genotype was significantly associated with LNZ resistance in MDR-TB and XDR-TB (odds ratio = 4.66, 95% confidence interval 1.03–21.16; P = 0.033). In addition, a higher frequency of LNZ-resistant isolates was observed among XDR-TB strains (60%) compared with the MDR (5.6%; P < 0.001) and pre-XDR groups (12.2%; P = 0.004). Mutations in 23S rRNA and rplC were responsible for only 29.4% of LNZ-resistant M. tuberculosis among MDR-TB isolates, and a novel non-synonymous substitution His155Asp in rplC was first identified to be contributing to low-level LNZ resistance (2 μg/mL) in M. tuberculosis. The unsatisfactory correlation between mutant genotypes highlights the urgent need to investigate another mechanism for LNZ resistance that has not yet been described.     

莫西沙星和左氧氟沙星治疗耐药性肺结核的效果及安全性观察

目的：研究对比莫西沙星和左氧氟沙星治疗耐药性肺结核的临床疗效及其安全性。方法选取2011年6月-2014年6月接受药物治疗的肺结核患者82例,所有患者随机分为莫西沙星组（试验组）与左氧氟沙星组（对照组）各41例。对照组患者给予基础药物以及左氧氟沙星治疗,试验组患者给予基础药物以及莫西沙星治疗,比较2组患者的痰菌转阴率、临床治疗效果以及不良反应情况。结果试验组用药12个月后痰菌转阴率为90.24%明显高于对照组的73.17%（P ＜0.01）。试验组治疗总有效率为87.80%明显高于对照组的70.73%（P ＜0.05）。试验组总不良反应率为12.20%明显低于对照组的26.82%,差异均有统计学意义（P ＜0.05）。结论治疗耐药性肺结核时,莫西沙星比左氧氟沙星具有更好的临床疗效。     

An update on emerging drugs for fibromyalgia treatment

Introduction: Fibromyalgia (FM) is a chronic disorder whose symptoms of pain, fatigue, sleep disturbances and depression have a devastating effect on patients’ lives as it limits their ability to engage in everyday working and social activities, and make it difficult to maintain normal relationships with family, friends and employers. None of the currently available drugs are fully effective against the whole spectrum of symptoms. The aim of this narrative review is to summarise the data relating to the new therapeutic options that have become available over the last few years.

Areas covered: Increasing efforts by the pharmaceutical industry have led to the introduction of new investigational drugs and new formulations of older drugs, and studies have been carried out in order to investigate the possibility of using drugs that are currently used for other diseases.

Expert opinion: Slight improvements in the health of FM patients treated with drugs targeting a range of molecular mechanisms have been observed, but there is still no single drug that is capable of offering substantial efficacy against all of the characteristic symptoms of FM. The identification of new and improved therapies for FM requires consideration of the heterogeneity of the condition, which suggests the existence of different patient subgroups, a relationship between central and peripheral aspects of the pathophysiology, and the need for combined treatment with drugs targeting multiple molecular mechanisms.     

结核丸联合环丝氨酸治疗耐药性肺结核效果及对患者炎性因子水平的影响

目的 探讨结核丸联合环丝氨酸治疗耐药性肺结核的临床效果以及对患者炎性因子水平的影响。方法 将西安市胸科医院自2015年1月-2017年12月确诊的耐药性肺结核患者106例作为研究对象,按随机法分为观察组和对照组各53例,观察组使用结核丸联合环丝氨酸进行治疗,对照组仅使用环丝氨酸进行治疗,对比观察两组患者的临床疗效和体内炎性因子水平的变化情况。结果 治疗后两组患者痰细菌学转阴率分别为66.04%和62.26%,组间比较差异无统计学意义。治疗后观察组患者病灶吸收有效率为86.79%,明显高于对照组的73.58%,差异有统计学意义（P<0.05）。治疗后两组患者干扰素-γ（INF-γ）水平明显升高,白介素-4（IL-4）、C反应蛋白（CRP）和肿瘤坏死因子-α（TNF-α）水平均明显降低,同组治疗前后比较差异有统计学意义（P<0.05）;其中观察组患者改善程度明显优于对照组,差异有统计学意义（P<0.05）。结论 使用结核丸联合环丝氨酸治疗耐药性肺结核患者可有效提高患者治疗效果,降低机体内炎性反应,可推广使用。     

黄精汤及制剂治疗肺结核和耐药性肺结核临床研究

目的：观察黄精汤及制剂治疗肺结核和耐药性肺结核的疗效。方法：新诊108例患者随机分为黄精汤及制剂组（治疗组57例）和2ERHZ/4RH化疗组（对照组51例）,45例耐药患者为耐药治疗组（治疗方法同治疗组）,观察3组治疗后肺部病灶、血沉、PPD试验、痰菌检、肝肾功能及主要症状体征的变化和安全性。结果：3组患者治疗后证候积分较之治疗前均明显减少（P〈0.01）。治疗组、耐药治疗组症状疗效、临床疗效与对照组等效性比较差异有统计学意义（P〈0.05）。对照组疗程6~12个月,平均（8.5±2.3）个月,肝肾异常率为25.49%,治疗组、耐药治疗组,疗程均3～5个月,平均（3.5±1.2）个月,肝肾异常率均0,与对照组比较差异均有统计学意义（P〈0.05）。结论：黄精汤及制剂是一组疗程短、安全、有效的治疗肺结核和耐药性肺结核的中药,具2ERHZ/4R化疗等效。     

Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects

Drug resistance in Mycobacterium tuberculosis arises from the man-made selection of mutants that result from spontaneous chromosomal alterations. Preventing the development of drug-resistant TB through a good control program based on directly observed treatment, short-course, is of paramount importance. Established multidrug-resistant (MDR)-TB requires alternative specific chemotherapy, comprising drugs with higher cost and greater toxicity delivered on a programmatic basis. The development of new anti-TB drugs would help to prevent and treat MDR-TB. Notably, moxifloxacin and gatifloxacin are being tested for shortening treatment in Phase III trials, while three novel compounds, TMC-207, OPC-67683 and PA-824 are in Phase II studies for both drug-susceptible and drug-resistant disease. The roles of surgery and immunotherapy in the management of MDR-TB require further evaluation. The recent emergence of extensively drug-resistant TB poses a serious challenge to the global control of TB. In order to combat extensively drug-resistant TB, strengthening of directly observed treatment, short-course and drug-resistance programs, alongside other strategies, including the development of newer diagnostics and drugs, is mandatory.     

乳酸左氧氟沙星序贯疗法治疗耐多药肺结核的临床研究

研究乳酸左氧氟沙星序贯疗法对耐多药肺结核(MDR-PTB)的疗效。对18例经Bactec-460法和改良罗氏法痰培养证实的MDR-PTB患者采用3AHPVX／18DVX方案治疗[A阿米卡星(0．4～0．6)g／d．H异烟肼(0．3～0．4)g／d,P对氨基水杨酸钠(8～12)g／d．V乳酸左氧氟沙星(0．4～0．6)g／d．X为根据既往用药及耐药报告所选药物．D帕司烟肼(0．8～1．2)g／d]．即前3个月强化期采用AHPV静脉用药冲击疗法．后18个月巩固期采用DVX口服用药的序贯疗法．观察其短期疗效。结果显示．上述治疗12个月后18例患者痰菌阴转率83．33％(15／l8)．X线胸片总有效率88．89％(16／18)。病人依从性、耐受性均显示良好。提示乳酸左氧氟沙星序贯疗法治疗MDR-PTB具有较好的短期疗效。     

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Introduction: Gastrointestinal stromal tumor (GIST) is the most common nonepithelial malignancy of the GI tract. With the discovery of KIT and later platelet-derived growth factor α (PDGFRA) gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST.

Areas covered: This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans.

Expert opinion: It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.     

利奈唑胺抗结核临床疗效

目的 观察利奈唑胺(噁唑烷酮类抗菌药)对肺结核的疗效.方法 3例利奈唑胺治疗肺结核临床疗效的病例,并附系统性相关文献复习.结果 1例确诊和2例临床诊断肺结核患者,在接受利奈唑胺600 mg每日2次静脉滴注的单药治疗后,均在短期内(2天)迅速缓解高热、咳嗽、咳痰和周身不适等临床症状;1例患者用药2周后,肺部阴影明显吸收.国外采用利奈唑胺治疗肺结核多为联合用药,且患者为多重耐药的结核菌感染,最长疗程达28个月.已检索到的报告病例,经利奈唑胺治疗后,痰菌全部阴转.结论 利奈唑胺具有抗结核作用,单药使用即可改善症状.     

抗结核药物的作用机制及结核分枝杆菌的耐药机理

结核病是一个严重的全球性疾病,随着艾滋病病毒及耐药结核菌的出现及播散成为结核病控制的又一个威胁。虽然我们有结核疫苗及抗结核药物,但控制结核病仍是一件很棘手的事情。多重耐药结核菌的不断出现给结核病的治疗带来很大的困难。为有效控制耐药结核病,我们必须了解结核菌的耐药机理。本文讨论了抗结核药物的作用机制及结核菌的耐药机理。结核菌耐药机理的阐明对耐药菌的快速分子诊断及新药的开发有重要的意义。     

真菌耐药的研究进展

伴随着免疫功能低下患者的不断增多,深部真菌感染的发生率急剧升高,并发展为该类患者死亡的主要原因之一。现有常用的抗真菌药物品种有限,耐药性已成为困扰临床抗真菌治疗的严重问题。为克服真菌耐药,广大医疗工作者开展了大量的基础研究和临床实践,不断取得新的研究进展。本文针对真菌感染的流行病学、真菌耐药的流行病学、真菌耐药的机制,以及克服真菌耐药的策略四个方面做一综述。     

An update on the use of rifapentine for tuberculosis therapy

Introduction: Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial.

Areas covered: This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented.

Expert opinion: Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.     

利奈唑胺治疗耐药结核的研究进展

利奈唑胺是一种新型恶唑烷酮类抗菌药物,在体外对耐多药结核菌有抗菌作用,其临床疗效已得到一系列临床研究证明.本文综述其抗菌作用、临床疗效及不良反应等研究进展.     

An update on risk factors for drug-induced arrhythmias

A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ‘‘effect amplifiers’’ which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, T_peak–T_end/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias.     

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.

Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.

Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.     

Finafloxacin for the treatment of urinary tract infections

Introduction: In the past decade, the indiscriminate use of fluoroquinolones in the prophylaxis and treatment of urinary tract infections (UTIs) has led to an increase of antibiotic resistance patterns. Finafloxacin is a new generation fluoroquinolone with interesting preclinical characteristics and pH-related efficacy.

Areas covered: This review summarizes finafloxacin’s safety profile and prospectively evaluates its specific use in the treatment of UTIs. This article was based on a Medline English literature search.

Expert opinion: In vitro and in vivo studies have shown that finafloxacin expresses its full antibacterial activity in acidic environments and is able to exert significant bactericidal effects in difficult-to-treat infections. Finafloxacin has a broad antibacterial spectrum and efficient pharmacokinetic absorption. Moreover, it undergoes extensive tissue distribution, resulting in good antibacterial activity for daily dosages from 400 to 800 mg. This novel compound has also been successfully tested on biofilm-related Escherichia coli. Finafloxacin has demonstrated a good safety and tolerability profile in humans when administered orally or intravenously and is thus an interesting compound for the treatment of UTIs. However, further prospective randomized clinical trials will be necessary to confirm these preliminary results before definitive conclusions can be made.