Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now!

Thioridazine (TDZ) has been shown to have in vitro activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, to promote the killing of intracellular MDR and XDR strains and to cure the mouse of antibiotic-susceptible and -resistant pulmonary tuberculosis (TB) infections. Recently, TDZ was used to cure 10 of 12 XDR-TB patients in Buenos Aires, Argentina. At the time of writing, it is being used for the therapy of non-antibiotic-responsive terminal XDR-TB patients in Mumbai, India, on the basis of compassionate therapy and although it is too early to determine a cure, the patients have improved appetite, weight gain, are afebrile and free of night sweats, and their radiological picture shows great improvement. Because XDR-TB is essentially a terminal disease in many areas of the world and no new effective agents have yet to yield successful clinical trials, global clinical trials for the therapy of XDR-TB are urgently required.     

耐药肺结核患者结核分枝杆菌菌型分布及耐药研究

目的 研究肺结核耐药患者结核分枝杆菌菌型分布及耐药情况。方法 收集2011年4月至2012年7月肺结核患者痰液标本,分离培养后进行菌种鉴定和药敏试验。结果 人结核分枝杆菌约占83.91%,牛结核分枝杆菌约占15.70%;患者对一线抗结核药物耐药率显著高于对二线抗结核药物耐压率,差异有统计学意义(P<0.05);一类抗结核药物单一耐药率显著高于二类抗结核药物(χ²=4.281,P<0.05)。结论 肺结核耐药患者菌型以人结核分枝杆菌最多,对一线抗结核药物的耐药率显著高于对二线抗结核药物的耐药率。     

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.     

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.     

Multiple drug resistant tuberculosis: aetiology, diagnosis and outcome.

Tuberculosis is an increasing problem worldwide both in terms of disease burden and resistance to conventional antibiotic therapy. Studies of outbreaks involving resistant strains have highlighted the need for both improved infection control and the rapid provision of accurate susceptibility data. Each patient should undergo a risk assessment for possible resistance and those in whom risk factors exist should be investigated by means of rapid molecular techniques or other phenotypic methods, so that appropriate management can be instituted with minimal delay. The ultimate outcome will vary according to whether the patient is immunosuppressed, the time taken to make a diagnosis, the severity of disease as well as the degree of resistance. The prognosis can be improved when adequate antibiotic therapy is started as soon as resistance is suspected. Adjuncts to conventional treatment, such as surgery and perhaps immunotherapy may be considered when response to antimicrobial chemotherapy has been suboptimal.     

Current and developing therapies for the treatment of multi drug resistant tuberculosis (MDR-TB) in India

Introduction: India accounts for 25% of the global burden of MDR-TB. In 2016, the India’s Revised National TB Control Programme reported a success rate of 46% among 19,298 MDR-TB patients treated under the programme. This suboptimal treatment outcome warrants an urgent need for newer drugs and newer regimens in the treatment of MDR-TB. India requires new shorter, cheap, safe and effective anti-TB regimen to treat MDR-TB.

Areas covered: We used different search strategies to obtain relevant literature from PubMed, on Indian experiences of developing therapies for the treatment of MDR-TB. Further information from the Central TB Division Government of India on programmatic management of resistant TB was collected.

Expert opinion: In 2016 WHO recommended a shorter MDR-TB regimen of 9–12 months (4–6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E /5 Mfx-Cfz-Z-E) may be used instead of longer regimens. Currently, conducting trials involving newer drugs such as bedaquiline, have been proposed. The regimen will be of a shorter duration containing isoniazid, prothionamide, bedaquiline, levofloxacin, ciprofloxacin, ethambutol and pyrazinamide (STREAM regimen). To successfully treat MDR-TB one requires new classes of antibiotic and newer diagnostic tests. This represents an enormous financial and technical challenge to the programme managers and policy makers.     

耐多药结核病的流行病概况及控制策略

结核病在全球大幅回升不仅严重危害人类的健康,也给社会和经济带来了巨大的损失。随着耐多药结核的出现,结核病防控面临着严峻的考验。本文从耐多药结核的流行病学、发生机制、发生原因、诊断、治疗及控制策略等方面进行综述,为耐多药结核的控制工作提供依据。     

The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s)

The no-observed-adverse-effect-level (NOAEL) is an important part of the non-clinical risk assessment. It is a professional opinion based on the design of the study, indication of the drug, expected pharmacology, and spectrum of off-target effects. There is no consistent standard definition of NOAEL. This is based, in part, on the varied definitions of what constitutes an adverse effect. Toxicologists, either investigating or reviewing, have not been consistent in defining an effect as either adverse or acceptable. The common definition of NOAEL, "the highest experimental point that is without adverse effect," serves us well in general discussions. It does not, however, address the interpretation of risk based on toxicologically relevant effects, nor does it consider the progression of effect with respect to duration and/or dose. This paper will discuss the issues and application of a functional definition of the NOAEL in toxicology evaluations.     

降钙素原检测对于耐药结核病的预测价值

目的观察血清降钙素原（PCT）在抗结核治疗时的动态变化,及早发现耐药患者。方法选择300例初治接受正规抗结核药物治疗的涂阳培阳肺结核患者,治疗前均做罗氏比例法药敏试验和血清PCT检测,并于抗结核治疗期间每个月做血清PCT检测,分析结核分枝杆菌耐药和敏感患者PCT动态变化规律,以便及早发现耐药患者。结果耐药组和敏感组肺结核患者治疗前血清PCT差异无统计学意义（P〉0.05）,治疗后1个月、2个月时2组血清PCT均降低,但组间差异无统计学意义（P〉0.05）,治疗3、4和6个月时耐药组无下降,与敏感组相比差异显著（P〈0.01）。结论血清PCT可作为肺结核患者抗结核治疗疗效评估指标,并对耐药结核有预测作用。     

The global status of HIV drug resistance: clinical and public-health approaches for detection, treatment and prevention

Antiretroviral therapy (ART) scale-up in resource limited settings (RLS) has been successful, utilizing a standardized population-based approach to ART delivery. An unintended consequence of treatment scale-up is the inevitable emergence of HIV drug resistance (HIV DR) in populations even when patient adherence to ART is optimally supported. HIV DR has the potential to undermine the dramatic gains that ART has had in reducing the morbidity and mortality of HIV-infected patients in RLS. Sustaining and expanding ART coverage in RLS will depend upon the ability of ART programs to deliver ART in a way that minimizes the emergence of HIVDR. Fortunately, current evidence demonstrates that HIVDR in RLS has neither emerged nor been transmitted to the degree that had initially been feared. However, due to a lack of standardized methodologies, HIVDR data from RLS can be difficult to interpret and may not provide the programmatic evidence necessary for public health action. The World Health Organization has developed simple, standardized surveys that generate comparable results to assess acquired and transmitted HIVDR for routine public health implementation in RLS. These HIVDR surveys are designed to be implemented in conjunction with annual monitoring of program and site factors known to create situations favorable to the developments of HIV DR.     

氟喹诺酮类药物治疗耐药肺结核的成本效果分析

目的 比较和探讨3种氟喹诺酮类药物(氧氟沙星、左氧氟沙星、莫西沙星)治疗耐药肺结核(MDR-TB)的经济效果和最佳治疗方案.方法 将经痰培养检查证实的108例耐药肺结核患者完全随机分为3组,各36例,同期进行临床研究,3组除均给予一定量的利福喷丁、吡嗪酰胺、对氨基水杨酸异烟肼、丙硫异烟胺、链霉素外,在抗痨方案上分别加入氧氟沙星、左氧氟沙星、莫西沙星,再运用药物经济学的成本-效果分析方法进行评价.结果 治疗15个月后,在痰菌转阴率、X线病灶吸收率比较中,左氧氟沙星与莫西沙星效果相近,优于氧氟沙星;不良反应发生等指标各组间比较无统计学意义(P＞0.05).各组间的医疗费用差异有统计学意义(P＜0.05).结论 左氧氟沙星是治疗耐药肺结核的最佳治疗方案.     

Medicinal mushrooms for glycemic control in diabetes mellitus: history, current status, future perspectives, and unsolved problems (review)

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia with defects in insulin secretion and/or insulin resistance. Despite great efforts that have been made in the understanding and management of diabetes, its prevalence continues to grow. Recent discoveries have opened up an exciting opportunity for developing new types of therapeutics from medicinal mushrooms to control DM and its complications. To date, more and more active components including polysaccharides and their protein complexes, dietary fibers, and other compounds extracted from fruiting bodies, cultured mycelium, or cultured broth of medicinal mushrooms have been reported as to having anti-hyperglycemic activity. These compounds exhibit their antidiabetic activity via different mechanisms. This article presents an overview of the multiple aspects of diabetes mellitus and the efficacy and mechanism of medicinal mushrooms for glucose control in diabetes, including the inhibition of glucose absorption, protection of beta-cell damage, increase of insulin release, enhancement of antioxidant defense, attenuation of inflammation, modulation of carbohydrate metabolism pathway, and regulation of insulin-dependent and insulin-independent signaling pathways. However, there is insufficient evidence to draw definitive conclusions about the efficacy of individual medicinal mushrooms for diabetes. In addition, the wide variability, the lack of standards for production, and the lack of testing protocols to assess product quality are still problems in producing medicinal mushroom products. Moreover, well-designed randomized controlled trials with long-term consumption are needed to guarantee the bioactivity and safety of medicinal mushroom products for diabetic patients.     

Drug resistance patterns,treatment outcomes and factors affecting unfavourable treatment outcomes among extensively drug resistant tuberculosis patients in Pakistan; a multicentre record review

BackgroundExtensively drug resistant tuberculosis (XDR-TB) is considered as a major threat to global health. This study aimed to analyse the treatment outcomes and identify the factors significantly associated with unfavourable treatment outcomes among XDR-TB patients.MethodsWe conducted a retrospective observational study at 10 Programmatic Management Units of the National Tuberculosis Control Program of Pakistan. The Electronic Nominal Recording Reporting System records were used to collect data of all eligible XDR-TB patients registered at the study sites between March 2012 and August 2018. Treatment outcomes were analysed as per the standard criteria. Factors associated with unfavourable treatment outcomes were analysed by using multivariate binary logistic regression analysis.ResultsOut of the total 184 patients, 59 (32.1%) completed their treatment successfully. Whereby, 83 patients (45.1%) died, 24 (13%) had treatment failure, and 11 (6%) were lost to follow-up. Treatment outcomes were not evaluated in 7 (3.8%) patients. Factors significantly associated with unfavourable treatment outcomes included; conventional therapy with bedaquiline, unfavourable interim treatment outcomes and occurrence of adverse drug events (negative association).ConclusionTreatment success rate in the study cohort was sub-optimal (i.e., <75%). The poor success rate and high mortality are concerning, and requires immediate attention of the program managers and clinicians.     

The evolution of drug development in schizophrenia: past issues and future opportunities.

Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored.     

莫西沙星与左氧氟沙星对耐多药肺结核病的治疗效果

目的 评价新一代氟喹诺酮类药物莫西沙星对耐多药肺结核病(MDR-PTB)的治疗作用.方法 132例 MDR-PTB患者随机分为2组:治疗组(Ⅰ组)用莫西沙星0.4 g,每日1次;对照组(Ⅱ组)用左氧氟沙星0.4 g,每日1次,疗程12月,同时辅以其他抗痨药物治疗,126例完成疗程.结果 治疗组痰菌阴转率明显高于对照组(P＜0.05),影像吸收率、副作用2组间差异无显著性(P＞0.05).结论 莫西沙星是一种安全、有效的抗MDR-PTB药物.     

Epidemiological features of drug resistant tuberculosis in Harare, 1994 to 1996

OBJECTIVES: To characterise the prevalence, clinical and radiological features of drug resistant tuberculosis in selected patients with pulmonary tuberculosis in Harare between 1994 and 1996. DESIGN: A retrospective review of medical and microbiological records. SETTING: Beatrice Road Infectious Diseases Hospital, Harare, Zimbabwe. SUBJECTS: 381 smear-positive tuberculosis patients who had samples submitted to the National Tuberculosis Reference Laboratory for culture and susceptibility testing. MAIN OUTCOME MEASURES: Prevalence of resistance of isolated cultures of Mycobacterium tuberculosis to anti-tuberculosis drugs; clinical, radiological and microbiological response to treatment with recommended anti-tuberculosis regimens. RESULTS: Resistance to one or more drugs was detected in 16 isolates (16/165, 9.7%), single drug resistance in five (3.0%) and resistance to two or more drugs in 11 (6.7%). There were no distinctive clinical or radiological features of drug-resistant tuberculosis, although a higher percent of drug resistant cases had evidence of pleural disease (25% vs 2.5%, p = 0.005). Neither past history of tuberculosis or known or suspected HIV infection was associated with the presence of drug resistance. CONCLUSIONS: In spite of the resurgence of tuberculosis and the high prevalence of HIV infection in Zimbabwe, the rates of drug resistance have remained relatively low, even among a selected population at high risk of resistance. A significant proportion of cases of drug-resistant tuberculosis appear to be due to new transmission of drug resistant strains, which reinforces the importance of maintaining a surveillance system for the monitoring of drug susceptibility. Ongoing prospective studies should provide more reliable estimates of the prevalence and determinants of drug resistance in Zimbabwe.     

The California Substance Abuse Research Consortium: origins,history, and issues

When research results are passively presented in the policy world, especially when policy is tied to politics, researchers are often surprised and disappointed that officials do not attend to the obvious applications of their work. Active, timely, bidirectional exchange of information among parties is crucial. However, many contextual influences inhibit exchange efforts and must be recognized and understood in order to be overcome. Obstacles include "political entropy," bureaucratic "deference to hierarchy," media distortions, failure to reimburse provider staff in-service training, and comfort by all with the "way things are." Countering these contextual negative influences requires at least two "champions" (one from the government agency involved and one from academia), persuasion via reason, use of contemporary, politically correct rhetoric, building support through the most important constituencies, and, finally, pluck, persistence, and the ability to adapt to the inevitably changing context. This article discusses each of these aspects and describes examples of problems and solutions that have occurred throughout the history of substance abuse research and information exchange within the context of one key California effort, first known as the State Epidemiology Work Group, and later as the Substance Abuse Research Consortium.