New drugs for tuberculosis: current status and future prospects

This article reviews two classes of compounds that have advanced into phase II and III clinical trials, long-acting rifamycins and fluoroquinolones, and a number of other drugs that have entered or may enter clinical development in the near future.     

New drugs for tuberculosis treatment

Available data on anti-tuberculosis drug research reveal different properties of the agents and provoke speculation about future directions. Higher doses of the rifamycins are promising and are currently being evaluated in regimens of shorter duration that the isoniazid plus rifampin-based, six-to-nine month-course therapy. Moxifloxacin and gatifloxacin might shorten tuberculosis treatment as well, possibly in combination with rifapentine, while SQ109 could enhance the activity of rifampin-containing regimens. On the other hand, co-administration of moxifloxacin and PA-824 could be active against latent tuberculosis, whereas linezolid, PA-824 and TMC207 are candidates for a rifampin-free regimen in multidrug-resistant and extensively-resistant tuberculosis. Unfortunately, shorter than existent treatment regimens based on the new agents discussed here are likely to take at least another decade to be fully developed and implemented in clinical practice.     

New diagnostics for latent and active tuberculosis: state of the art and future prospects

Tuberculosis (TB) continues to be the world's most important infectious cause of morbidity and mortality among adults. Nearly 9 million people develop TB disease each year, and an estimated 1.6 million die from the disease. Despite this enormous global burden, case detection rates are low, posing serious hurdles for TB control. Conventional TB diagnosis continues to rely on antiquated tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In this review, we describe recent advances in the diagnosis of latent and active TB, and detection of drug resistance. Although the perfect test will not be ready for large-scale roll-out and integration into routine TB care services for some time, substantial progress has been made in expanding the TB diagnostic product pipeline. With the resurgence of interest in the development of new tools for TB control, and the recent influx of funding and political support, it is likely that the next few years will see the introduction of new diagnostic tools into routine TB control programs.     

Treatment of active tuberculosis: challenges and prospects

This article reviews the basic principles of drug treatment of tuberculosis, individual pharmacologic agents, current treatment recommendations, and several special situations that clinicians are likely to encounter in medical practice.     

Rotavirus vaccines: current prospects and future challenges

Rotavirus is the most common cause of severe diarrhoea in children worldwide and diarrhoeal deaths in children in developing countries. Accelerated development and introduction of rotavirus vaccines into global immunisation programmes has been a high priority for many international agencies, including WHO and the Global Alliance for Vaccines and Immunizations. Vaccines have been developed that could prevent the enormous morbidity and mortality from rotavirus and their effect should be measurable within 2-3 years. Two live oral rotavirus vaccines have been licensed in many countries; one is derived from an attenuated human strain of rotavirus and the other combines five bovine-human reassortant strains. Each vaccine has proven highly effective in preventing severe rotavirus diarrhoea in children and safe from the possible complication of intussusception. In developed countries, these vaccines could substantially reduce the number and associated costs of child hospitalisations and clinical visits for acute diarrhoea. In developing countries, they could reduce deaths from diarrhoea and improve child survival through programmes for childhood immunisations and diarrhoeal disease control. Although many scientific, programmatic, and financial challenges face the global use of rotavirus vaccines, these vaccines-and new candidates in the pipeline-hold promise to make an immediate and measurable effect to improve child health and survival from this common burden affecting all children.     

Vaccination against tuberculosis: current status and future promise

Tuberculosis remains a major health threat. The currently available vaccine, bacille Calmette-Guérin (BCG), provides insufficient protection, and multi-drug-resistant strains are on the rise. A novel vaccine with higher efficacy is needed for satisfactory control of the disease. Currently, several novel vaccine candidates are being tested in preclinical models with promising outcome, but none with overwhelming success. The final decision as to whether an efficacious vaccine can be designed will have to await the outcome of a clinical trial comprising the most promising candidates identified by experimental animal studies.     

Treatment of latent tuberculosis infection: challenges and prospects

This article reviews the treatment of latent tuberculosis infection in HIV-seropositive and HIV-seronegative persons.     

Clinical immunology: past, present and future challenges and prospects.

Over the past four decades, immunology has undergone a revolution changing from a largely phenomenological science into a deeply analytical and technical field. Questions concerning the primary cell involved in cell-mediated immunity, the mechanisms responsible for antibody diversity as well as the molecules used by the network of immunological cells to communicate with one another that could barely be asked in the 1950s, have been definitely answered. A major contributor to this revolution in immunological knowledge has been the scientist focussing on patient-oriented clinical immunology, a form of clinical research requiring the presence of the patient or materials freshly derived from the patient. This type of research has led to the discovery of new diseases, the definition of new infectious agents causing disease and the delineation of functional defects using applied variables on mononuclear cells removed from the patient. Moreover, this type of research is absolutely required to test hypotheses concerning the pathogenesis of disease in humans and to provide the scientific basis for the development of new approaches to therapy. As I look to the future, there are great threats to patient-oriented clinical research. The road ahead seems long and daunting. Nevertheless, I am encouraged that the patient-oriented clinical research scientist in the future will make major contributions to the use of the immune system in preventing human disease, in the development of immunological methods for diagnosis, and in the use of immune intervention to provide a new perspective for the prevention of allograft rejection, and for the treatment of neoplastic, immunodeficiency, and autoimmune disease.     

Anticoagulation: New challenges,old drugs

Effective atrial fibrillation (AF) management requires attention to adequate rate control, consideration for the need to maintain sinus rhythm, and deliberation regarding proper anticoagulation to prevent thromboemboli. When properly used, warfarin anticoagulation in patients with AF at high risk for stroke reduces stroke incidence markedly. Unfortunately, proper anticoagulation with warfarin is not easy. An anticoagulant drug for which there are few interactions with other drugs, food, or supplements; for which there can be uniform dosing; for which routine International Normalized Ratio monitoring is not required; and for which there is a lower risk for bleeding, will gain widespread and rapid acceptance. In two large randomized trials comparing fixed-dose ximelagatran with warfarin in noninferiority studies, ximelagatran appears to be as effective at preventing stroke and thromboembolic events as warfarin (based on intention-to-treat analysis) and with similar, if not better, long-term risk.     

Gene therapy for monogenic liver diseases: clinical successes,current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.     

EGFR靶向药物在结直肠癌中的研究进展

结直肠癌是常见的消化系恶性肿瘤,传统的化疗和放疗效果均不甚理想.表皮生长因子受体(EGFR)q%号转导通路在结直肠癌细胞的增殖、血管生成、侵袭、转移等方面有重要作用.因此,针对EGFR的靶向药物已陆续开发,并应用于结直肠癌治疗的临床实践.本文就EGFR靶向药物在结直肠癌中的研究现状及其相关问题进行综述.     

Development of antituberculous drugs: current status and future prospects

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)     

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

Resistance in Mycobacterium tuberculosis arises from man-made selection of genetic mutants that result from spontaneous chromosomal alterations. Thus, drug-resistant tuberculosis (TB) is generally due to inappropriate treatment regimen, poor drug quality, erratic drug supply and poor patient adherence to treatment, reflecting failure in the implementation of an effective TB control programme. Multidrug-resistant TB (MDR-TB) usually denotes bacillary resistance to at least isoniazid and rifampicin. Proper implementation of the directly observed treatment, short-course (DOTS) strategy should achieve a high cure rate for disease and curtail the development of drug resistance. Innovations in reinforcement of this strategy should further facilitate its delivery and enhance its effectiveness. However, established MDR-TB is notoriously difficult to treat, and necessitates the use of alternative specific antituberculosis chemotherapy regimens. These regimens comprise combination use of second-line antituberculosis drugs, that are generally more costly and toxic, and have to be given for longer durations. The fluoroquinolones, better tolerated by patients, have a pivotal role in MDR-TB treatment. Optimal delivery of these treatment regimens mandates a programmatic basis which is now included under the Stop-TB Drug-Resistance Programme(s). The key components embrace political commitment, quality-assured drug susceptibility testing, reliable supply of quality drugs, delivery of chemotherapy under directly observed settings, and a sound recording and reporting system to monitor the individual treatment outcome of patient and overall performance of the TB control programme. Adjunctive surgery in selected MDR-TB patients help to improve their treatment success. Further exploration is required regarding the use of immunotherapy. The recent emergence of extensively drug-resistant TB (XDR-TB), representing MDR-TB with additional bacillary resistance to fluoroquinlones and one or more of the second-line injectable drugs -kanamycin, amikacin and capreomycin, threatens the global control of TB. Given the escalating size of the problem of MDR-TB and XDR-TB worldwide, gigantic instillation of resources is required for control of this formidable challenge, largely through more accurate and rapid drug susceptibility testing (especially for rifampicin and fluoroquinolone), regular drug-resistance surveillance, development of new antituberculosis drugs and other therapeutic modalities, intensive infection control, especially in HIV care settings, as well as strengthening of currently functioning DOTS and Drug-Resistance Programmes.     

Transition: a future promise for children and adolescents with special health care needs and disabilities

Transitions are a part of everyone's life experience. Most young people with special health care needs and disabilities (SHCN/D) become independent partners in adult society, but some need deliberate guidance and support. This latter group is growing in number. Through a new consensus statement from the American Academy of Pediatrics and the U.S. Federal Government (Healthy People 2010), society is recognizing the need to assist young people with SHCN/D in attaining their potential in adulthood. This article discusses the growing number of young people with SHCN/D, their desires for their transition, the definition and areas of transition that should be addressed, and the key elements of successful transition programs. The article ends with a suggested list of actions a health care professional can undertake to foster a successful transition and a selected list of helpful resources for health professionals, families, and young people with SHCN/D.     

Current status and future prospects for new therapies for pulmonary tuberculosis

PURPOSE OF REVIEW: Nowadays tuberculosis is becoming a worldwide problem, and according to the World Health Organization, which declared tuberculosis a global health emergency in 1993, each year 8 million people worldwide develop the active disease and almost 3 million die. RECENT FINDINGS: Due to this problem there is an urgent need for new strategies and drugs to fight against this disease. In this context, this review describes promising new classes of compounds against tuberculosis that are under study, as well as promising drugs that may soon be introduced onto the market. Another subject reported in this review is inhaled therapy, an important route under study for delivering antitubercular drugs directly to the lungs. SUMMARY: The implications of new drugs and inhaled therapy in tuberculosis treatment are fewer toxic side-effects, improved pharmacokinetics properties, extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains, and a reduction in the total treatment time.     

Current challenges and future prospects in oral anticoagulant therapy

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed‐dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex ‘real‐world’ patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.