Synthetic investigational new drugs for the treatment of tuberculosis

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.     

Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy

Importance of the field: Malaria infection during pregnancy is a major public health problem worldwide, with 50 million pregnancies exposed to the infection every year. Approximately 25,000 maternal deaths and between 75,000 and 200,000 infant deaths could be prevented each year by effective malaria control in pregnancy. Antimalarial drug treatment and prevention has been hampered by the appearance of drug resistance, which has been a particular problem in pregnancy due to the inherent safety issues.

Areas covered in this review: New antimalarial drugs and combinations are being studied but there is not yet sufficient information on their efficacy or, more importantly, on their safety in pregnancy. This article provides an overview of the relevance of the topic and reviews the current antimalarial drugs recommended for pregnancy, as well as the guidelines for both treatment and prevention in women living in endemic areas and for travellers.

What the reader will gain: Updated information on the drugs currently used for malaria treatment and prevention in pregnancy, including new drugs under development, is provided. The gaps on efficacy and safety information for use during pregnancy are also discussed.

Take home message: Prevention and case management of malaria during pregnancy is based on risk–benefit criteria and poses one of the greatest challenges to current malaria control.     

Selective drug deposition in lungs through pulmonary drug delivery system for effective management of drug-resistant TB

Introduction: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is a major health issue and continues to be a global health concern. Despite significant advancements in treatment modalities, ~1.6 million deaths worldwide occur due to TB infection. This is because of tuberculosis reservoirs in the alveoli making it a challenge for the formulation scientist to target this.

Area covered: This review recent investigations on the forefront of pulmonary drug delivery for managing MDR-TB and XDR-TB. Novel delivery systems like liposomes, niosomes, employing carbohydrate, and -coated molecules via conjugation to selectively deliver the drugs to the lung TB reservoir via pulmonary administration are discussed.

Expert opinion: Poor patient adherence to treatment due to side effects and extended therapeutic regimen leads to drug-resistant TB. Thus, it is essential to design novel strategies this issue by developing new chemical entities and/or new delivery systems for delivery to the lungs, consequently reducing the side effects, the frequency and the duration of treatment. Delivery of drugs to enhance the efficacy of new/existing anti-TB drugs to overcome the resistance and enhance patient compliance is underway.     

Biodegradable synthetic polyesters in the technology of controlled dosage forms of antihypertensive drugs – the overview

ABSTRACT

Introduction: Arterial hypertension is a disease of civilization that requires long-term treatment. Recently, growing interest in natural and synthetic polymers as drug delivery vehicles in controlled release dosage forms for improving the efficacy of treatment has been observed.

Areas covered: This review introduces biodegradable synthetic polyesters as macromolecular carriers of antihypertensive drugs. Although various, synthetic and natural polymer-drug conjugates and/or polymeric carriers of anticancer drugs are currently under preclinical and clinical studies, there is no such data for antihypertensive drugs. Therefore, it seems appropriate to use such materials for the treatment of hypertension.

Expert opinion: There are currently only a few studies describing the use of synthetic polyesters in the arterial hypertension therapy. In order to the fact that there is a high demand for new, effective antihypertensive dosage forms, further studies for such drug carriers are certainly expected. Synthetic polyester carriers could improve the drug bioavailability and its pharmacokinetic properties by altering the pharmaceutical dosage form. This property is particularly useful for drugs with proven pharmacological action, but with limited application due to their inappropriate pharmacological properties. The development of new polymeric materials and technologies affords the opportunity to produce novel synthetic polyester DDSs.     

HIV integrase inhibitors: a new era in the treatment of HIV

Introduction: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming ‘standard’ drugs in the treatment of both naïve as well as heavily pretreated individuals with HIV.

Areas covered: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.

Expert opinion: Due to their outstanding data of efficacy, tolerability, safety – shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals – INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.     

The safety and tolerability of the second-line injectable antituberculosis drugs in children

ABSTRACT

Introduction: A growing number of children globally are being treated for multidrug-resistant tuberculosis (MDR-TB). The second-line injectable antituberculosis medications amikacin, kanamycin and capreomycin, traditionally a mainstay of MDR-TB treatment, cause important adverse effects including permanent sensorineural hearing loss, nephrotoxicity, electrolyte abnormalities, injection pain and local injection site complications.

Areas covered: To characterize the safety and tolerability of the second-line injectables in children treated for MDR-TB, we reviewed data on the mechanism of injectable associated adverse effects, risk factors for their development, and the incidence of injectable-associated adverse effects in adults and children treated for MDR-TB.

Expert opinion: Despite a substantial evidence base in adults demonstrating the frequent and potentially serious adverse effects of second-line injectables, important knowledge gaps remain. Improved characterization of the incidence of injectable-associated adverse effects will inform rational guidance on monitoring children with TB on injectables. Eliminating the need for injectables in MDR-TB treatment regimens is a high priority, and will rely on the use of novel antituberculosis TB drugs. Strategies to reduce the risk of adverse effects of injectables, if used, deserve evaluation. This includes evaluation of potentially otoprotective medications N-acetylcysteine or aspirin, high frequency hearing screening for earlier detection of ototoxicity and therapeutic drug monitoring.     

Linezolid in South Africa: The regulatory authority’s role in supporting access to improved treatment regimens for drug-resistant tuberculosis

Abstract

The rising incidence of drug-resistant tuberculosis (DR-TB) in South Africa is cause for concern, with doctors having limited treatment options to offer patients who face excruciating side-effects from existing medications, and poor odds of treatment success. With several newer drugs showing efficacy against DR-TB, increased possibilities exist to stem the tide of the epidemic, shorten treatment duration, and improve outcomes. To take advantage of this potential TB treatment revolution, countries must rapidly facilitate access to existing and future drugs. This requires co-ordinated action from governments, and particularly regulatory authorities, in promoting early access to new treatments, tackling intellectual property and price barriers, expediting regulatory approval, adopting and implementing up-to-date TB management policies, and engaging with research and development processes for new regimens. Doctors Without Borders expended great effort to obtain a less expensive version of the drug, linezolid, for its DR-TB pilot program in Khayelitsha, South Africa. This piece describes that experience, and subsequently offers recommendations for policy reforms which could help South Africa more rapidly access other new TB drugs in the future. The South African experience may be of relevance to other countries seeking advice on how to facilitate access to new treatments and tackle their TB epidemics.     

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series

Introduction: Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD).

Areas covered: The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term.

Expert opinion: To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics – with treatment duration ranging from 1 to 14 months – provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.     

Fotemustine for the treatment of melanoma

Introduction: Melanoma is a rare but very aggressive form of cancer. Survival in melanoma varies widely depending on the stage of the tumor. In metastatic melanoma, prognosis is usually poor and the treatment is based on chemotherapy. So far, dacarbazine has been the drug of reference, with an average response rate of 15 – 20% when used as a monotherapy. As single drugs go, fotemustine is considered the second-best treatment, after dacarbazine.

Areas covered: This review of the scientific literature focuses on the use of fotemustine in patients with cutaneous melanoma and discusses its clinical efficacy and safety.

Expert opinion: Fotemustine is a nitrosurea that has proved its efficacy in metastatic melanoma and particularly on cerebral metastases, given its high lipophilicity, facilitating its active penetration in all tissues including the central nervous system. However, overall response rates are low, with only few complete remissions and short response durations.     

InforMatrix: ADP antagonists in acute coronary syndromes

Introduction: InforMatrix is an interactive matrix model, in which pharmacotherapeutic strategies are supported in a rational manner, by means of a transparent selection methodology.

Areas covered: In this paper, InforMatrix is applied to ADP antagonists, including clopidogrel, prasugrel and ticagrelor. These drugs are important additions to the treatment of acute coronary syndromes. The drugs are compared using the following selection criteria: efficacy, safety, tolerability, ease of use, applicability and cost. All direct comparative studies, as well as placebo-controlled or double-blind comparisons with other drugs, were used in the assessment.

Expert opinion: By means of the interactive program, users may assign their own individual weight to each criterion and to the properties of the individual drugs, which stimulates concrete discussions on the relative importance of the various aspects of the drugs. When applied to ADP antagonists, the discussion focuses on the documentation of relative efficacy, safety and acquisition cost. The extensive clinical experience with clopidogrel must be balanced against the potential advantages of the other two compounds concerning efficacy. In those countries where generic clopidogrel is available, there are also major differences in acquisition cost between generic clopidogrel and patented prasugrel and ticagrelor. The interactive program provides the opportunity to quantify existing differences in opinion on the (importance of) various properties of the drugs, which greatly facilitates concrete discussions and rational formulary decision making.     

Pixantrone for the treatment of aggressive non-Hodgkin lymphoma

Importance of the field: At present there is no standard treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma who progress following second-line therapy. Anthracyclines are highly active drugs, but their use in this setting is limited by cumulative cardiac toxicity. Pixantrone is a new aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. This compound has been developed to minimize cardiac toxicity without reducing efficacy.

Areas covered in this review: This review summarizes the preclinical and clinical trial data for the use of pixantrone for the treatment of aggressive non-Hodgkin lymphoma.

What the reader will gain: An overview of the mechanism of action of pixantrone, preclinical data, clinical efficacy, safety data and future developments for this compound.

Take home message: Pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive non-Hodgkin lymphoma. The pixantrone application will be submitted to the regulatory authorities in the USA and in Europe.     

Pregabalin for the treatment of postsurgical pain

Importance of the field: Multimodal postoperative pain management targeted at diminishing harmful outcomes should include pregabalin in cases that need opioid reduction and when the risk of developing chronic neuropathic postsurgical pain is present. Gabapentanoids have grown in importance due to their opioid-sparing effects. They may also contribute to the prevention of chronic postsurgical pain.

Areas covered in this review: We reviewed the literature regarding the use of gabapentanoids and their role in treatment modalities in acute postsurgical pain. Dosing, therapeutic efficacy, side effects, and their role within a multimodal regimen are discussed. Particular emphasis is placed on their ability to provide an opioid-sparing effect, as well as on their potential for inhibiting chronic neuropathic pain. A Pubmed search of pregabalin, gabapentin, acute pain, multimodal analgesia, chronic postsurgical pain, and neuropathic pain between 2000 and 2010 was done. Relevant articles – including randomized controlled trials, retrospective trials, case series, case reports, and review articles – were filtered to include those that relate to postsurgical pain.

What the reader will gain: Readers will gain an increased appreciation of the role of pregabalin in postsurgical pain in patients at risk of developing chronic pain.

Take home message: Pregabalin is a safe and effective medication that may decrease perioperative opioid use in patients with more acute neuropathic pain than acute inflammatory pain. When surgery involves more neuropathic-type acute pain there is growing evidence that pregabalin may decrease the incidence of chronic pain.     

An overview of early drug development for endometriosis

Introduction: Endometriosis is an estrogen-dependent chronic disease of women of fertile age requiring chronic therapy. Although available drugs have good efficacy and safety profiles, some patients experience partial or no improvement of pain with conventional treatment and recurrence of symptoms after discontinuation of the therapies. For these reasons, many new compounds are currently under investigation for the treatment of endometriosis.

Areas covered: This review offers the reader a complete and updated overview on emerging therapies for the treatment of endometriosis. The authors describe, in detail, the laboratory and clinical studies on these therapies and highlight the potential advantages and limitations associated with the administration of these new agents.

Expert opinion: Gonadotropin-releasing hormone antagonists are the most intriguing emerging agents for the treatment of patients with endometriosis. It should be noted that while there are a number of drugs under investigation, a large majority of these new compounds have only been investigated in laboratory studies with more extensive research required to better elucidate their efficacy and safety profiles.     

Antituberculosis therapy for 2012 and beyond

Introduction: In terms of human suffering, tuberculosis has a huge impact on global society, making it arguably the most important infectious disease in history. Despite the devastating impact on society, the tools to fight tuberculosis are very limited. Current standard therapy has been used for over 40 years and threats, such as the HIV epidemic and drug-resistant strains, undermine efforts to control the disease. New drugs are needed to address the challenges faced globally.

Areas covered: Current therapy is briefly reviewed in this paper and then new doses and combinations of existing drugs are presented. New candidate drugs are also discussed, along with the potential benefits and pitfalls of each of the compounds and approaches to therapy.

Expert opinion: Despite the need to develop new drugs, the ability of programs to deliver existing therapies must not be neglected. Directly observed therapy and a standard basic level of care for all patients with tuberculosis, regardless of where they reside, is imperative, and will ensure that new drugs and regimens will have the greatest possible impact. New combination regimens, including PA 824 and TMC207, in combination with existing drugs, are very exciting – not only because of their ability to shorten treatment regimens in pan-susceptible cases, but also because they can be used among drug-resistant strains. Although an effective vaccine will probably be necessary to eliminate tuberculosis, new drugs and combination regimens have the potential to save millions of lives before tuberculosis is finally eliminated.     

Emerging drugs and alternative possibilities in the treatment of tuberculosis

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.     

Emerging drugs for venous thromboembolism

Importance of the field: Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, is a frequent and serious condition. Anticoagulant (AC) drugs are necessary and effective for primary prevention, treatment of acute phase and prevention of recurrences. The currently available ACs have several drawbacks which have prompted the search for new drugs.

Areas covered in this review: We analysed the advantages and disadvantages of the emerging ACs in comparison to currently available ACs by reviewing the available results of drugs that have Phase III clinical trials for prevention and treatment of VTE, published between 2003 and September 2009.

What the reader will gain: The reader will get information on efficacy and safety of new ACs in comparison to the standard treatment for prevention of VTE after elective major orthopaedic surgery and on the prospects of their use for treatment of VTE.

Take home message: These new ACs will be an important step forward for an easier, effective and safe prophylactic and therapeutic treatment of VTE. Some grey areas in their use require, however, a careful consideration and an accurate post-marketing investigation.