Newly developed drugs invented to treat tuberculosis in clinical trial

Tuberculosis (TB) is a leading cause of morbidity and mortality in more than one-third of the world population. Its impact on global health is a result of decades of neglect for such an important infectious disease, lack of resources for national TB control programs, poor case detection, and inadequate/inappropriate therapy in high-burden countries. The worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health due to inadequacy of long and cumbersome tuberculosis (TB) therapy. Treatment regimens consist of at least four drugs with different mechanisms of action. Several new molecules in clinical development hasencouraged the scientific community to discover new drug targets and new drug candidates. Therefore, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death. Nowadays, various new investigational drugs, such as bedaquine (TMC207), nitroimidazoles (PA-824, OPC-67683), diamines (SQ109), oxazolidinones (Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858) and fluoroquinolones (moxifloxacin and gatifloxacin), have entered clinical trials and are in progress to be developed for the treatment of MDR-TB. In this perspectivearticle, an overview of the new anti-TB drugs with different structures that are either being clinically used or in advanced stages clinical stages as well as of preclinical development are presented. This review provides snapshots of the efforts that are being made in the development of new drugs as lead anti-TB agents. Finally, it is crucial to improve the connection between research and development institutes, industries, drug control authorities, and international policy-making bodies to deliver efficacious therapies for patients who are suffering from TB.     

Inhaled Drug Delivery for Tuberculosis Therapy

One third of the world population is infected with tuberculosis (TB), and new infections occur at a rate of one per second. The recent increase in the emergence of drug-resistant strains of Mycobacterium tuberculosis and the dearth of anti-TB drugs is threatening the future containment of TB. New drugs or delivery systems that will stop the spread of TB and slow down or prevent the development of drug-resistant strains are urgently required. One of the reasons for the emergence of drug-resistant strains is the exposure of mycobacteria to sub-therapeutic levels of one or more antibiotics. Lung lesions containing large numbers of bacteria are poorly vascularized and are fortified with thick fibrous tissue; conventional therapy by the oral and parenteral routes may provide sub-therapeutic levels of anti-TB drugs to these highly sequestered organisms. Administering drugs by the pulmonary route to the lungs allows higher drug concentrations in the vicinity of these lesions. Supplementing conventional therapy with inhaled anti-TB therapy may allow therapeutic concentrations of drug to penetrate effectively into lung lesions and treat the resident mycobacteria.     

Myoinositol and methyl stearate increases rifampicin susceptibility among drug-resistant Mycobacterium tuberculosis expressing Rv1819c

The alarming increase in multidrug resistance, which includes Bedaquiline and Delamanid, stumbles success in Tuberculosis treatment outcome. Mycobacterium tuberculosis gains resistance to rifampicin, which is one of the less toxic and potent anti-TB drugs, through genetic mutations predominantly besides efflux pump mediated drug resistance. In recent decades, scientific interventions are being carried out to overcome this hurdle using novel approaches to save this drug by combining it with other drugs/molecules or by use of high dose rifampicin. This study reports five small molecules namely Ellagic acid, Methyl Stearate, Myoinositol, Rutin, and Shikimic acid that exhibit synergistic inhibitory activity with rifampicin against resistant TB isolates. In-silico examinations revealed possible blocking of Rv1819c—an ABC transporter efflux pump that was known to confer resistance in M. tuberculosis to rifampicin. The synergistic anti-TB activity was assessed using a drug combination checkerboard assay. Efflux pump inhibition activity of ellagic acid, myoinositol, and methyl stearate was observed through ethidium bromide accumulation assay in the drug-resistant M. tuberculosis clinical strains and recombinant Mycobacterium smegmatis expressing Rv1819c in coherence with the significant reduction in the minimum inhibitory concentration of rifampicin. Cytotoxicity of the active efflux inhibitors was tested using in silico and ex vivo methods. Myoinositol and methyl stearate were completely non-toxic to the hematological and epithelial cells of different organs under ex vivo conditions. Based on these findings, these molecules can be considered for adjunct TB therapy; however, their impact on other drugs of anti-TB regimen needs to be tested.     

Phenothiazines as anti-multi-drug resistant tubercular agents

Pulmonary tuberculosis (TB) has again become a global problem: it infects 2.2 billion people world-wide, caused the deaths of over 3 million last year and will produce over 8 million new cases of TB this coming year. Although effective therapy is widely available for antibiotic susceptible strains of Mycobacterium tuberculosis, current drugs are relatively useless against multi-drug resistant infections (MDRTB). Mortality is almost complete within two years regardless of therapy, and in the case of co-infection with HIV/AIDS, mortality is 100% within a few months of diagnosis especially the M. tuberculosis strain in XDRTB. As of the time of this writing no new effective anti-TB drugs have been made available by the pharmaceutical industry and XDRTB. Because TB is an intracellular infection of the non-killing macrophage of the lung, any agent that is to prove effective must have activity against MDRTB and XDRTB strains that have been phagocytosed by the human macrophage. This review intents to provide cogent in vitro, ex vivo and in vivo evidence that supports the use of a variety of commonly available phenothiazines for the therapy of MDRTB and XDRTB, especially when the prognosis of the infection is poor and the use of the recommend agents can take place along lines of "compassionate therapy". In addition, we will describe the macrophage assay as indispensable when an agent is to be further studied for its effectiveness as an anti-TB drug. In vitro studies if not complemented by ex vivo studies will for the most part be dead-ended since few agents that have activity in vitro have any activity against phagocytosed M. tuberculosis.     

Emerging therapeutic targets in tuberculosis: post-genomic era

Every minute, somewhere in the world four people die from tuberculosis (TB), yet it has been nearly 40 years since a novel drug was introduced to treat this disease. The ever increasing number of TB cases together with the advent of multi-drug resistant (MDR) TB, has stimulated the search for novel anti-TB agents. An array of novel drug targets is provided by the mycobacterial cell wall, whose integrity is essential for bacterial viability. Over the years researchers have identified potential drug targets that are associated with the synthesis of various cell wall constituents. This classic approach, together with the unravelling of the Mycobacterium tuberculosis genome sequence, has placed TB drug research in an unprecedented position. An entire new set of genetic and bioinformatic tools for probing potential drug targets is now available. As therapies using first-line drugs like isoniazid (INH) or rifampin in combination with second-line drugs, like ethambutol (EMB) still continues, a number of substituted fluoroquinolones are being considered as the new generation of anti-TB drugs for their favourable pharmacokinetic profile and excellent oral bioavailability. In this review, the future of anti-TB drugs is discussed with reflection on the structure and biosynthesis of cell wall constituents that are potential drug targets. The importance and relevance of the M. tuberculosis genome sequence for the development of novel anti-TB drugs, have also been underscored.     

The challenges of pharmacokinetic variability of first-line anti-TB drugs

Introduction: Inter-individual variations in the pharmacokinetics (PK) of anti-TB drugs are known to occur, which could have important therapeutic implications in patient management.

Areas covered: We compiled factors responsible for PK variability of anti-TB drugs reported from different settings that would give a better understanding about the challenges of PK variability of anti-TB medications. We searched PubMed data base and Google scholar from 1976 to the present using the key words ‘Pharmacokinetics’, ‘pharmacokinetic variability’, ‘first-line anti-TB therapy’, ‘Rifampicin’, ‘Isoniazid’, ‘Ethambutol’, ‘Pyrazinamide’, ‘food’, ‘nutritional status’, ‘HIV’, ‘diabetes’, ‘genetic polymorphisms’ and ‘pharmacokinetic interactions’. We also included abstracts from scientific meetings and review articles.

Expert commentary: A variety of host and genetic factors can cause inter-individual variations in the PK of anti-TB drugs. PK studies conducted in various settings have adopted different designs, PK sampling time points, drug estimation methodologies. Hence comparison and interpretation of these results should be done with caution More phamacogenomic studies in different patient populations are needed for further understanding.     

Drug-resistant tuberculosis: what are the treatment options?

Drug-resistant tuberculosis (DR-TB) is an emerging global health threat as treatment involves complex multiple drug regimens, which are longer and more toxic than standard therapy and yet have worse outcomes. In the presence of resistance to one or more first-line drugs, an alternative regimen should be designed. A major problem is the almost complete lack of published evidence regarding the optimal drug combinations and duration of treatment for the different types of DR-TB. Current principles, some of which are based on expert opinion, are that at least three new anti-TB agents should be added to a failing regimen and four agents when multidrug resistance is suspected. All first-line oral anti-TB agents to which the Mycobacterium tuberculosis strains are susceptible should be used, plus one fluoroquinolone. In addition, one injectable anti-TB agent and one or more second-line oral anti-TB agents should be added to the regimen until the target number of drugs is reached. The duration of treatment depends on the type of drug resistance, the type and number of drugs used in the regimen, and the extent of the disease. All forms of DR-TB should receive daily, not intermittent, therapy and all doses should be directly observed. Because of the high rate of adverse drug effects, careful monitoring and appropriate management of these adverse reactions are important to achieve successful treatment. Supportive measures, such as adequate nutrition along with emotional and social supports, are an important part of the treatment. Careful consideration is required when dealing with pregnant or lactating women and HIV co-infected patients, as well as in treatment of extrapulmonary DR-TB.     

Oral colon-specific drug delivery of protein and peptide drugs

With the advent of new technologies and radical growth in the field of biotechnology, dozens of protein and peptide drugs have been marketed. However, there are several challenges for successful delivery of such molecules. A number of routes have been used for the delivery of these fragile molecules by exploring various novel delivery technologies, including microspheres, liposomes, gel spheres, nano-spheres, niosomes, microemulsions, use of permeation enhancers, use of protease inhibitors, etc. But the route that has attracted the attention of worldwide drug delivery scientists is the oral route due to its various advantages. Even though the proteolytic activity is higher in a few segments of the gastrointestinal tract (GIT), this route has certain segments that have lower proteolytic activity, for example, the colon. The colon has captured attention as a site for the delivery of these molecules because of its greater responsiveness to absorption enhancers, protease inhibitors, and novel bioadhesive and biodegradable polymers. Although the success rate of these approaches, when used alone is pretty low, when used in combinations, these agents have demonstrated wonders in increasing the drug bioavailability. This review focuses on the challenges, pharmaceutical concepts, and approaches involved in the delivery of these fragile molecules, specifically to the colon. This review also includes studies conducted on colonic targeting of such drugs. Further studies may lead to improvements in therapy using protein/peptide drugs and refinements in the technology of colon-specific drug delivery.     

Insights into the pharmacokinetic properties of antitubercular drugs

Introduction: The furiously advancing cases of multidrug-resistant tuberculosis (TB) along with the recent emergence of total drug resistant TB and TB-AIDS comorbidity present an increased threat to global public health. Knowledge of pharmacokinetic properties helps in selecting an appropriate anti-TB dosage regimen to achieve optimal results in patients.

Areas covered: This article provides a brief compilation of the information available regarding published pharmacokinetic data for anti-TB drugs and may act as a single window for investigators/medical practitioners in this field. The information regarding absorption, tissue distribution, elimination and pharmacokinetic interactions of the first- and second-line anti-TB drugs and candidate drugs under clinical trials is discussed.

Expert opinion: Pharmacokinetic properties such as poor absorption, too short biological half-life, extensive first-pass metabolism, drug-food and drug-drug related interactions are not attractive for prospective anti-TB drugs and significantly contribute to treatment failure and further resistance. The long duration, monotonous and multidrug treatment plan leads to poor patient compliance and resulted in a greater occurrence of anti-TB drug resistance worldwide. Few new agents, which are in development phase, are considering the aspect of shortening duration of the treatment regimen and provide a boost in therapy that is sorely needed.     

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care.     

Tuberculosis drug targets

Despite the availability of the BCG vaccine and chemotherapy, tuberculosis (TB) remains a leading infectious killer worldwide. The recent rise of TB and especially the alarming increase of drug-resistant TB call for urgent need to develop new anti-TB drugs. Lengthy chemotherapy and increasing emergence of drug-resistant strains pose a significant problem for effective control. The need for a lengthy TB therapy is a consequence of the presence of persistent Mycobacterium tuberculosis, not effectively killed by current anti-TB agents. A list of new drug candidates along with proposed targets for intervention is described. Recent advances in the knowledge of the biology of the organism and the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of mycobacterial metabolism, persistence, virulence and cell wall synthesis would be attractive targets. It is expected that the application of functional genomics tools, such as microarray and proteomics, in combination with modern approaches, such as structure-based drug design and combinatorial chemistry to biology-based targets, will lead to the development of new drugs that are not only active against drug-resistant TB but also can shorten the course of TB therapy.     

抗体药物偶联物及其在恶性血液系统肿瘤治疗中的应用

单克隆抗体靶向治疗是目前临床肿瘤治疗的热点。针对抗体分子大而组织穿透性差以及临床使用剂量大、生产成本高的问题,抗体的小型化和高效性设计已成为抗体药物研发的新趋势。近年来,单抗与细胞毒性药物的结合物被称为抗体药物偶联物(antibody-drug conjugates,ADCs),已加入到抗癌药物的行列中,成为新型的抗体药物而受到广泛关注。泛义的ADC通常由抗体、接头(linker)和效应分子等3部分组成。根据效应分子的不同,可将ADC分为化学免疫偶联物、免疫毒素、放射性免疫偶联物等3类。ADC被内化进入细胞后,通过细胞内的化学和酶解作用释放出细胞毒性物质,细胞毒性物质则通过抑制蛋白合成、解聚微管蛋白或断裂双链DNA等作用而对靶细胞产生杀伤作用。近年来,FDA已经批准2种ADC药物上市,有多种处于II～III期临床试验阶段,取得了显著的临床效果,吸引了越来越多的制药企业争相竞逐。本文介绍ADC的过去和现状,结合临床肿瘤应用中的实际问题,探讨其将来的发展趋势。     

Application of the EIIP/ISM bioinformatics concept in development of new drugs

The development of a new therapeutic drug is a complex, lengthy and expensive process. On average, only one out of 10,000 - 30,000 originally synthesized compounds will clear all the hurdles on the way to becoming a commercially available drug. The process of early and full preclinical discovery and clinical development for a new drug can take twelve to fifteen years to complete, and cost approximately 800 million dollars. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we reviewed the application of the EIIP/ISM bioinformatics concept for the development of new drugs. This approach, connecting the electron-ion interaction potential of organic molecules and their biological properties, can significantly reduce development time through (i) identification of promising lead compounds that have some activity against a disease by fast virtual screening of the large molecular libraries, (ii) refinement of selected lead compounds in order to increase their biological activity, and (iii) identification of domains of proteins and nucleotide sequences representing potential targets for therapy. Special attention is paid in this review to the application of the EIIP/ISM bioinformatics platform along with other experimental techniques (screening of a phage displayed peptide libraries, testing selected peptides and small molecules for antiviral activity in vitro) in development of HIV entry inhibitors, representing a new generation of the AIDS drugs.     

Adverse reactions of anti-tuberculosis drugs in hospitalized patients: incidence, severity and risk factors

BACKGROUND: Tuberculosis (TB) has been a common chronic infectious disease in human communities. Besides disease-related complications, there could be serious adverse reactions due to anti-tuberculosis (anti-TB) drug therapy. OBJECTIVES: To assess the incidence and severity of adverse drug reactions (ADRs) induced by anti-TB drugs. To determine possible covariates associated with detected ADRs. METHODS: All patients with respiratory TB admitted to a teaching hospital who received anti-TB drugs during the research period entered the study and were monitored for ADRs. Socio-demographic and medical history of patients were used as independent covariates. The relationship between independent covariates with frequency and severity of ADRs was analysed using multivariate logistic regression. Preliminary analyses of the Mann-Whitney, Chi-square, Kruskal-Wallis and the Fisher's exact tests were applied to determine factors unlikely associated with the independent variables. RESULTS: Among 204 patients admitted, there were 92 patients (45.1%) with ADRs induced by anti-TB drugs. Patients with a previous history of anti-TB drugs usage (OR = 5.81, 95% confidence interval [95%CI]: 1.31-25.2), patients with a history of drug allergy (OR = 6.68, CI: 1.28-36.2), those from Afghani ethnic (OR = 4.91, 95%CI: 1.28-18.30) as well as smoker patients with concurrent diseases (OR = 19.67, CI: 1.24-341.51) had a higher rate of ADR incidence. Being female (OR = 1.63, 95%CI: 1.96-36.40) and having previous history of ADR (OR = 17.46, 95%CI: 1.96-20.42) were identified as risk factors. CONCLUSION: Anti-TB drugs could cause severe and frequent adverse effects. Females, those with a previous history of ADRs to anti-TB drugs and Afghani patients, should be considered as high-risk groups.     

抗结核药物最新进展

结核病是病死率仅次于艾滋病的全球第二大感染性疾病。当前结核病的控制面临一系列挑战。世界卫生组织推荐的结核治疗方案疗程长,对敏感菌和耐药菌感染分别需6个月、20个月的持续治疗。现有抗结核一线化疗药仍为四十多年前所开发,品种有限,选择余地小。此外,多耐药结核病(MDR-TB)及广泛耐药结核病(XDR-TB)的流行,严重阻碍了结核病控制的进展。严峻的结核病防治形势急需抗结核新药的出现。近十年来,抗结核化疗新药研发在沉寂多年后取得了较明显进展。本文介绍了近年上市与处于临床及临床前研究阶段的抗结核新药。     

Recent overview of ocular patents

Ocular drug therapy has always been considered as a major challenge in the field of drug delivery. The presence of blood ocular barriers and efflux pumps has imposed a great concern as well. Various vision threatening disorders require a long term therapy of drug molecules, especially for the diseases that affect the posterior segment. Pharmaceutical companies and other research institutes have adopted a multidisciplinary approach to meet the current challenges which is evidenced by the trends seen in the published and filed U.S. patents. Various strategies have been employed to achieve long term sustained and targeted delivery for both the anterior and the posterior segments of the ocular diseases. These strategies include formulating drugs into implant, micro or nanoparticulate systems and hydrogel-based systems. Transporter targeted approach has also allowed scientists to deliver drugs to both the segments of the eye. Recent developments such as delivery of drugs utilizing ultrasound, iontophoresis and microneedle based devices have been promising. Genebased therapeutics has opened a new avenue for vision threatening disorders. In all, the current developments in the entire field have been very exciting for finding out new strategies to treat vision threatening disorders.     

Derivatives of 3-isoxazolecarboxylic acid esters: a potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis

New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC50's > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3- isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development.     

Stereochemistry at the forefront in the design and discovery of novel anti-tuberculosis agents

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.