Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 11, Issue 2, 2011

The World Health Organization (WHO) estimates that 2 billion people, or one-third of the world's population, are infected with M. tuberculosis. From this seedbed of latent infection, 9.4 million new cases of active disease and 1.3 million deaths were attributed to tuberculosis in 2008 [1]. Disease due to M. tuberculosis is most common in developing nations, both in absolute numbers and incidence of new cases. Twenty-two countries account for 80 % of all cases of tuberculosis; India and China are responsible for 23 % and 17 % of cases, respectively. In general, the highest incidence of disease is found in the countries of sub-Saharan Africa where HIV infection has contributed to extraordinary increases in case rates. The global incidence of tuberculosis is increasing slightly, though population growth is resulting in higher numbers of cases each year. Declines in incidence in the developed world have been offset by increasing rates in the HIV-ravaged. In 2009, about 3 million people became newly infected with HIV, half of whom were young adults (<24 year old) with the majority residing in developing countries [1]. Interventions are urgently needed to decrease the burden of both HIV and Tuberculosis globally. In this issue, Zeier and Nachega as well as Slogrove and colleagues [2,3] report the global status of antiretroviral therapy (ART) to include topical issues such as when to start and with what treatment regimens in adults and children, respectively. The 2009 US Department of Health and Human Services (DHHS) and WHO HIV treatment guidelines are swinging towards earlier treatments at the threshold in both adults and children. Encouragingly, with the assistance of US President's Emergency Plan For AIDS Relief (PEPFAR), UN Global Funds and other, great progress have been made by providing ART to 4 million of HIV-infected globally over the last few years, about another 7 million other are still in need. However, the sad reality today is that for one HIV-infected patient started on ART, about 3 other individuals are becoming HIV-infected. So treatment efforts alone are not sustainable to dramatically control the HIV epidemic. Combined treatment and prevention efforts should be high on the global agenda. An exciting and optimistic development in the field is that effective ART in the highly adherent patient greatly reduce the likelihood of sexual transmission from infected individuals to their sexual partners. As a result, most treatment guidelines in the developed world recommend that infected partners of HIV-discordant couples should be started on ART regardless of their CD4 T-cell count, but further encourage the consistent use of other prevention methods such as condoms. More than ever, excellent ART adherence is being considered to be critical because of the benefit it can provide for the individual (decrease likelihood of viral replication, drug resistance and disease progression) but also as a prevention tool (Prevention of Sexual Transmission). The currently debated “test-and-treat” mathematical model in which universal HIV testing with immediate HIV ART for infected persons would be incorporated with other prevention strategies is likely to continue to be controversial for some time. However, if this model is feasible and affordable, it could potentially reduce HIV incidence and mortality to less than one case per 1,000 people per year by 2016. But achieving full access to these interventions for all at-risk populations may prove to be more difficult than any mathematical model could predict. There is an urgent need to validate assumptions used in such model by research which are already underway both in resource-rich and limited settings. The global status of HIV drug resistance is also addressed by Hong and colleagues [4]. Furthermore, Nachega and colleagues, review the current practices of management of active adult tuberculosis in the era of HIV pandemic and issues such when to start antiretroviral therapy in TB-HIV co-infected patients, drug-drug interactions and Tuberculosis Immune Reconstitution Syndrome (TB-IRIS) are discussed [5]. On the other hand, Marais and colleagues address several issues related to childhood tuberculosis, a somewhat neglected disease [6]. They provide an overview of current treatment practices, presenting the authors personal perspectives on issues related to the treatment of childhood tuberculosis, together with a brief synopsis of potential future treatment options. Another very important trend in tuberculosis epidemiology is the growing problem of drug-resistant tuberculosis as well as the challenge of managing TB-HIV co-infected patients. Multidrug resistant (MDR) or extensively resistant (XDR) strains of tuberculosis are an emerging global threat. Indeed, a global survey of resistance performed by the WHO and the International Union Against Tuberculosis and Lung Disease found that the median prevalence of primary drug resistance was 10 %, and the median prevalence of acquired resistance was 36 %. Moreover, ‘hot spots’ of drug-resistant tuberculosis were identified on all continents. The most notable of these are in the former Soviet nations where multidrug-resistant tuberculosis, defined as resistance to at least rifampicin and isoniazid, is identified in 10 to 20 % of all cases. Multidrug-resistant tuberculosis treatment is exceedingly difficult, since the drugs used are less effective, more costly, and poorly tolerated due to drug-related side effects. Furthermore, failure to control the spread of drug resistant tuberculosis has led to the outbreak of extensively drug resistant tuberculosis, which is defined as multidrug-resistant tuberculosis plus resistance to fluoroquinolones and at least one injectable second-line agent (capreomycin, amikacin, or kanamycin). Extensively drug-resistant tuberculosis been responsible for high rates of mortality in HIV-infected individuals in South Africa and is reported in more than 70 countries globally. Drug-resistant tuberculosis (MDR or XDR) will likely continue without effective implementation of directly observed therapy, short-course (DOTS) [6]. The development of new, safe and effective treatment options will ameliorate the burden of disease for HIV and drug resistant tuberculosis. The article by Derendorf and colleagues demonstrates that appropriate quantitative model-based concepts (socalled pharmacometrics) applied during drug development can identify the optimal dosage regimens for new antiretroviral or tuberculosis treatments by providing essential dose-exposure-response relationship information. This approach has successfully been used for example to predict the appropriate dosing regimen for the new non-nucleoside reverse transcriptase inhibitor (NNRTI), GW 420867X, and for the novel CCR5 chemokine receptor antagonist, maraviroc. Pharmacometrics is a useful method for optimizing drug combination regimens to prevent emergence of resistance during ARV treatment [7]. For example, it could be predicted that co-administration of an optimized dose of the nucleoside reverse transcriptase inhibitor (NRTI), zidovudine together with tenofovir or abacavir can prevent development of resistance against either drug. Most of the drugs currently used to treat tuberculosis have been introduced into clinical practice decades ago, and therefore knowledge about their pharmacokinetics and PK-PD relationship unfortunately is scarce. Pharmacometric approaches have been extremely useful in dosage optimization of these drugs, such as by providing a clear rationale for the use of a high-dose rifampin and rifapentine regimen [7]. Currently, the management of patients affected by these infections is far from ideal, especially in developing countries. Global effort and mobilization for timely diagnostic, treatment and prevention of both tuberculosis and HIV must remain an essential part of the strategy to combat this deadly partnership.....

Since the identification of the Human Immunodeficiency Virus (HIV) as the cause of the syndrome of Acquired Immunodeficiency Syndrome (AIDS), there has been an evolution of compounds targeting the replication of the virus in an effort to delay clinical progression. In this review, we revise the mechanism of action of the different groups of drugs. We shortly revisit the older and perhaps lesser used as well as the more recently approved drugs and mention some of the compounds still under investigation.

Introduction: HIV-1 infection is a major problem for children in lower income countries. The benefit of early antiretroviral (ARV) therapy started within 12 weeks of life is well documented. Although the development of new drug classes give alternative options for highly treatment experienced patients there is inadequate pharmacokinetic knowledge regarding the already established ARV classes in infants and children. Also, there are many practical challenges to administering these agents to children. Method and Results: The challenges of current widely available treatment regimens in the light of new vertical transmission prevention guidelines are discussed. The dynamic physiological changes affecting pharmacokinetics in infancy and childhood are reviewed. New antiretroviral drugs in the established drug classes are presented. The new drug classes of entry inhibitors (including co-receptor binding inhibitors and fusion inhibitors), integrase inhibitors and other novel drug classes under development are described and relevant pediatric studies are reviewed. Work on novel drug delivery systems with potential to enhance adherence, improve drug exposure and reduce side-effects are discussed. Conclusion: The established benefits of ARV therapy in children of all ages can be enhanced by appropriate pharmacokinetic data on established antiretroviral agents and child-friendly drug formulations. Besides new suppressive treatment options in treatment experienced patients with multi-class resistant virus the new drug classes provide potential for novel means of disease modification and reduction of vertical transmission. Novel drug classes and delivery systems in development provide potential for further reduction in vertical transmission of HIV, rapid virological suppression and improved neurological outcomes in children and adults.

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 HIV DR. Fortunately, current evidence demonstrates that HIV DR in RLS has neither emerged nor been transmitted to the degree that had initially been feared. However, due to a lack of standardized methodologies, HIV DR 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 HIV DR for routine public health implementation in RLS. These HIV DR surveys are designed to be implemented in conjunction with annual monitoring of program and site factors known to create situations favorable to the development of HIV DR.

The global impact of the HIV epidemic on the prevention and management of tuberculosis has resulted in added levels of complexity for physicians and other health- care workers caring for these patients. In addition to the usual difficulties associated with drug toxicities and regimen adherence, the concomitant treatment of HIV and tuberculosis is complicated by drug interactions between antiretroviral agents and the antituberculous containing rifampin-based regimens, and the frequent occurrence of the tuberculosis-associated immune reconstitution inflammatory syndrome (TBIRIS). Currently, the best antitubercular regimens include a rifamycin, usually rifampin, because of the high cost of rifabutin. Two nucleosides combined with efavirenz is the best antiretroviral alternative for patients who are receiving rifampin. Issues regarding the duration of anti-tubercular therapy before starting antiretroviral therapy (ART) need further clarification. The standard recommendation of waiting 8 weeks before starting ART is accompanied by significant morbidity and mortality, and has recently been challenged by data suggesting that 2 weeks is adequate. Ongoing studies looking at concomitant anti-inflammatory therapies for prevention of TB-IRIS may allow initiation of therapy for both diseases nearly simultaneously. The increase rates of M(X)DR tuberculosis isolates is not only testimony to the technical inability of the currently available tools for diagnosis and treatment of resistant TB but also the massive structural, social, political and economical constraints that most affected countries face. There is a critical need for novel antituberculous agents, but before they are made freely available, widespread investments in tuberculosis control programs are needed in order to ensure the application of practical and cost-effective community-based directly observed therapy and thus to protect these novel agents from the same fate as the current first line agents.

Childhood tuberculosis (TB) continues to be a neglected disease in areas where limited resources restrict the focus of national TB control programmes to only the most infectious sputum smear-positive cases. However, appreciation that children contribute a significant proportion to the global TB disease burden and suffer severe TB-related morbidity and mortality is growing. The World Health Organization (WHO) published guidelines on the management of paediatric TB in 2006 and child friendly drug formulations have been made available to deserving nations via the Global Drug Facility (GDF) since 2008. These advances also served to emphasize the considerable programmatic barriers that remain in resource- limited settings. This review provides an overview of current treatment practices, presenting the authors personal perspectives on issues related to the treatment of childhood TB, together with a brief synopsis of potential future treatment options.

Drug development continues to be time consuming, expensive and less efficient, while drug therapy is often administered at suboptimal levels. This is particularly true with anti-infectives for HIV and tuberculosis. The application of pharmacometric principles and models to drug development and pharmacotherapy will improve the drug approval process and selection of optimal dosage regimens or therapeutic combinations. In this review we mainly focus on the utilities of pharmacometrics in the dose selections of anti-retroviral and anti-tubercular drugs. We will examine how pharmacometrics have been useful in the area of dose selections, preclinical to clinical scaling, subpopulation selections, combination therapies, adherence assessments, and resistance prevention dosing strategies.

Poor adherence to combined antiretroviral therapy (cART) has been shown to be a major determinant of virologic failure, emergence of drug resistant virus, disease progression, hospitalizations, mortality, and health care costs. While high adherence levels can be achieved in both resource-rich and resource-limited settings following initiation of cART, long-term adherence remains a challenge regardless of available resources. Barriers to optimal adherence may originate from individual (biological, socio-cultural, behavioral), pharmacological, and societal factors. Although patients and providers should continuously strive for maximum adherence to cART, there is accumulating evidence that each class of antiretroviral therapy has specific adherence-drug resistance relationship characteristics allowing certain regimens more flexibility than others. There is not a universally accepted measure for cART adherence, since each method has distinct advantages and disadvantages including cost, complexity, accuracy, precision, intrusiveness and bias. Development of a real-time cART adherence monitoring tool will enable the development of novel, pre-emptive adherence-improving strategies. The application of these strategies may ultimately prove to be the most cost-effective method to reduce morbidity and mortality for the individual and decrease the likelihood of HIV transmission and emergence of resistance in the community.

The progress of transcription is synthesized by complex molecules, among which DNA-dependent RNA polymerase (RNAP) is the central enzyme. The prokaryotic RNAP is a large protein composed of core subunits (α2,β and β') and a σ factor that is required for specific recognition of the promoter site and the initiation of transcription. Despite its ubiquity, structural and functional similarities, bacterial RNAPs do not share extensive sequence homology with eukaryotic RNAPs. Bacterial RNAP an attractive target for the development of anti-bacterial drugs as its inactivation would lead to bacterial cell death. This review will present the state of knowledge on the assembly and function of RNAP subunits in bacteria with special focus on insights provided by structural analysis of a key component σ factor. Thorough retrospection has been provided for better understanding of progress and problems in targeting RNAP by traditional chemical compounds. Recent progress using innovative strategies including structural biology and phage based screening, especially the antisense technology, has shed light on developing the first set of macro-molecule RNAP inhibitors. In particular, exploration on targeting RNAP σ70 for realization of broad-spectrum antisense bactericidal effect in gram negative bacteria presents the first successful example of PNA-peptide conjugate showing attractive potential as conventional broad-spectrum antibiotics, in which possible way the antisense antibiotics might develop into to meet the range and type of usage in future health care.

Aims: Global figures clearly demonstrate inadequacy of current diabetes care: every 10 seconds one patient dies of diabetes-related pathologies. Nephropathy is the leading secondary complication of the disease. Nutritional supplement by chromium-picolinate is assumed to have beneficial therapeutic effects. However, potential toxic effects reported increase concerns about safety of chromium-picolinate. The experimental design aimed at determining, whether the treatment with clinically relevant doses of chromium-picolinate can harm through DNA damage and extensive alterations in central detoxification / cell-cycle regulating pathways in treatment of diabetes. Methods: Well-acknowledged animal model of db/db-mice and clinically relevant doses of chromium-picolinate were used. As an index of DNA-damage, measurement of DNA-breaks was performed using “Comet Assay”-analysis. Individual and group-specific expression patterns of SOD-1 and P53 were evaluated to give a clue about central detoxification and cell-cycle regulating pathways under treatment conditions. The study was performed in a double-blind manner. Results: Experimental data revealed highly individual reaction under treatment conditions. However, group-specific patterns were monitored: highest amount of damaged DNA - under the longest treatment with high doses, in contrast to groups with low doses of chromiumpicolinate. Comet patterns were intermediate between untreated diabetised and control animals. Expression patterns demonstrated a correlation with subcellular imaging and dosage-dependent suppression under chromium-picolinate treatment. Conclusions: This article highlights possible risks for individual long-term effects, when chromium-picolinate is used freely as a therapeutic nutritional modality agent without application of advanced diagnostic tools to predict risks and individual outcomes. Targeted measures require a creation of new guidelines for advanced diabetes care.

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed.