Combination chemotherapy for hepatitis B virus: the path forward?

Hepatitis B virus (HBV) was identified as a cause of viral hepatitis more than 30 years ago and hepatitis B vaccines have been available for almost 20 years, but HBV infection continues to be a global health problem, responsible for about 1.2 million deaths annually. By the end of this year, almost 400 million people--about 5% of the world's population and more than ten times the number infected with human immunodeficiency virus (HIV)--will be infected with HBV. Chemotherapy remains the only treatment option for controlling chronic HBV infection once acquired, but none of the many different chemotherapeutic strategies used in the past has proven consistently successful. Prospects for successful treatment of HBV have improved dramatically during the past decade due to the development of new, well tolerated and efficacious anti-HBV drugs, and to advances in our understanding of HBV replication and pathogenesis. The newer anti-HBV drugs are capable of reducing viral loads very rapidly, but the initial response is invariably followed by very much slower elimination of residual virus. As more effective anti-HBV drugs become available, the emergence of drug resistance during the slower phase of HBV elimination will probably become the most significant obstacle in the way of eventual control of HBV infection. Experience with HIV indicates that combination chemotherapy may suppress or eliminate drug resistance and methods for pre-clinical and clinical assessment of anti-HBV drug combinations are being developed. Basic research into mechanisms of drug action and interaction should assist in the design and optimisation of combination chemotherapy for HBV infection, for which additional new anti-HBV drugs will undoubtedly be required in future.     

Combination therapy for multiple sclerosis: the treatment strategy of the future?

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterised by demyelination and axonal loss in the CNS. Although new immunomodulatory therapies including interferon-beta and glatiramer acetate became available during the last decade, these therapies are only partially effective. There is a continuing need to develop more effective treatment strategies to combat the chronic and progressive aspects of the disease. In view of the complex pathophysiology underlying the MS disease process, combination therapy offers a rational therapeutic approach. Combining immunomodulatory agents with different mechanisms of action that promote synergistic or additive effects represents an important objective in MS therapeutic research. Ultimately, the optimal therapies will likely include strategies that promote repair and limit tissue destruction in combination with anti-inflammatory interventions.     

Combination therapy: the Holy Grail for the treatment of postmenopausal osteoporosis?

Agents for the treatment of osteoporosis are divided into broad categories according to whether the predominant effect is to inhibit bone resorption (antiresorptive drugs) or stimulate bone formation (osteo-anabolic drugs). However, due to the coupling of these two components of bone remodeling, drugs that inhibit bone resorption generally also reduce bone formation, and those that stimulate bone formation also increase bone resorption. Since these synchronous changes may limit the beneficial effects of treatment, researchers have undertaken a search for combinations of antiresorptive and osteo-anabolic drugs given concurrently, sequentially, intermittently, or cyclically that could partially or totally uncouple bone resorption and bone formation. This offers the potential for greater increases in bone mineral density (BMD), restoration of lost structural elements, and perhaps greater reduction in fracture risk than monotherapy with currently approved drugs. While some methods of combining drugs have been shown to enhance BMD response and perhaps extend the duration of osteo-anabolic effects compared to monotherapy, none have been proven to provide greater reduction of fracture risk. Upon completion of a course of osteo-anabolic therapy with daily subcutaneous parathyroid hormone, antiresorptive therapy must be started in order to prevent subsequent loss of BMD.     

Multi-level governance: The way forward for European illicit drug policy?

Illicit drug policy has long been an area that has attracted international policy intervention, however, the European Union has declared it an area of subsidiarity, leaving ultimate control to national governments. Nevertheless, European Union preoccupation with the illicit drug issue and international drug trafficking and organised crime concerns have ensured that continued and increased cooperation in illicit drug policy is never off the agenda. This article examines the history of European integration in contrasting areas of policy and considers both the desirability and the viability of an increasingly harmonised drug policy for Europe. Finally, it proposes a model of integrated illicit drug policy that is strongly connected to developing patterns of European social policy, calling on multi-level governance and close involvement at the level of the citizen.     

New fixed dose chemical combinations: the way forward for better diabetes type II management?

Introduction: Diabetes type II is a complex disease with unclear pathophysiology. Lack of adherence and high cost of medicines invariably make the management of diabetes type II highly challenging. Newer fixed drug combinations (FDC) are cost effective and can improve the medication adherence thereby prevent the complications of diabetes. Safety and efficacy of newer FDCs are not well established in all populations. Moreover, extrapolating the efficacy and safety data globally may not be pragmatic. Our review will discuss newer chemical combinations available for the treatment of diabetes type II.

Areas covered: In the present review, the authors discussed the newer FDCs available as add on therapy to the existing pharmacological interventions of diabetes type II that have shown promising results in various randomised trials with regard to efficacy and safety.

Expert opinion: Safety and efficacy data of newer FDCs available as an adjuvant therapy to conventional pharmacological interventions in diabetes type II revealed that fewer new FDCs are promising with their high efficacy and low adverse effect. However, there is a need to explore the place in therapy to establish the utility of FDC in diabetes type II management.     

The dosing and monitoring of vancomycin: what is the best way forward?

We have evaluated the literature to review optimal dosing and monitoring of intravenous vancomycin in adults, in response to evolving understanding of targets associated with efficacy and toxicity. The area under the total concentration–time curve (0–24 h) divided by the minimum inhibitory concentration (AUC₂₄/MIC) is the most commonly accepted index to guide vancomycin dosing for the treatment of Staphylococcus aureus infections, with a value of 400 h a widely recommended target for efficacy. Upper limits of AUC₂₄ exposure of around 700 (mg/L).h have been proposed, based on the hypothesis that higher exposures of vancomycin are associated with an unacceptable risk of nephrotoxicity. If AUC₂₄/MIC targets are used, sources of variability in the assessment of both AUC₂₄ and MIC need to be considered. Current consensus guidelines recommend measuring trough vancomycin concentrations during intermittent dosing as a surrogate for the AUC₂₄. Trough concentrations are a misleading surrogate for AUC₂₄ and a poor end-point in themselves. AUC₂₄ estimation using log-linear pharmacokinetic methods based on two plasma concentrations, or Bayesian methods are superior. Alternatively, a single concentration measured during continuous infusion allows simple AUC₂₄ estimation and dose-adjustment. All of these methods have logistical challenges which must be overcome if they are to be adopted successfully.     

Gene therapy for renal disorders: what are the benefits for the elderly?

Chronic renal failure is one of the major health problems for the elderly. Currently, about 50% of all patients receiving chronic dialysis for end-stage renal disease (ESRD) are aged 65 years or older. Their first-year mortality rate is as high as 30%. The leading causes of ESRD in the elderly are diabetic nephropathy, hypertension and large vessel diseases, and glomerulonephritis. The elderly are also prone to developing acute renal failure induced by ischaemic injury or nephrotoxic drugs. Gene transfer in experimental animals have been tested in all of these conditions, as well as in animal kidney transplantation models, with various degrees of success. However, there are many obstacles to be overcome before gene therapy can be tested clinically for renal disorders. In particular, the major challenges include determining how to prolong and control transgene expression or antisense inhibition and how to minimise the adverse effects of viral or nonviral vectors. Once these problems are solved, gene therapy will have a role in treating age-related renal impairment.     

Therapeutic drug monitoring-based dosing of TNF inhibitors in inflammatory bowel disease: the way forward?

ABSTRACT

Introduction: Secondary loss of response to anti-tumor necrosis factor (TNF) therapy remains a challenge in the clinical management of inflammatory bowel disease (IBD) patients. A frequently observed reason for secondary loss of response to TNF blockers is inadequate drug exposure and sub-therapeutic serum drug concentrations.

Areas covered: This review presents an overview of recent research on therapeutic drug monitoring (TDM)-based dosing with anti-TNF agents in IBD. The role of reactive and proactive TDM and different approaches on how to optimize anti-TNF treatment are discussed.

Expert opinion: Due to variations within and between patients, the ‘one size fits all’ theory does not apply to all IBD patients receiving anti-TNF agents. Timing of TDM (i.e. reactive versus proactive) is a matter of debate. Both strategies might optimize anti-TNF treatment, although most trials did not show a clinical benefit compared to conventional dosing up to now. So-called dashboard systems might have an additive value in the optimization of anti-TNF treatment, since these tools enable clinicians to really personalize anti-TNF treatment.     

Hypothesis: cannabinoid therapy for the treatment of gliomas?

Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer. Current therapeutic strategies for the treatment of glioblastoma multiforme are usually ineffective or just palliative. During the last few years, several studies have shown that cannabinoids-the active components of the plant Cannabis sativa and their derivatives--slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.     

Angiogenesis: the new potential target for the therapy of psoriasis?

Angiogenesis is a hallmark of chronic inflammation such as psoriasis. Unraveling the pathogenesis of psoriasis shows that several proangiogenic mediators are activated and highly expressed during psoriasis. Vascular endothelial growth factor, hypoxia- inducible factor, tumor necrosis factor, interleukin-8 and angiopoietins are considered to be the main players responsible for the strong vessel formation in psoriasis. The proangiogenic milieu in the skin seems to result from a proinflammatory immune response initiated by T helper cells. Interestingly, several small molecules as well as modern biologics used for systemic therapy of psoriasis have been shown to provide not only immune regulatory effects but also influence endothelial cell biology. Thus, direct targeting of angiogenesis may not only help to understand psoriasis pathogenesis but also to develop new strategies to treat psoriasis with therapeutics that halt the angiogenesis required for the inflammatory disease.     

Is chemical genetics the new frontier for malaria biology?

Malaria is a global disease, causing at least 500 million clinical cases and more than one million deaths each year. Moreover, drug-resistant Plasmodium falciparum, the organism that causes most malaria-associated deaths, has become a major problem. Therefore, discovery and investigation of novel targets for anti-malarial drug design is essential to combat this disease. The malarial genome has been sequenced, revealing approximately 5500 genes. The current post-genomic challenge is functionally to evaluate the essential genes and validate them for therapeutic design. Unfortunately, standard genetics techniques are limited in scope because of low transfection efficiency and a lack of knockdown techniques, thereby rendering the analysis of essential genes difficult.     

Euphorbiaceae diterpenes: plant toxins or promising molecules for the therapy?

Most of the species of Euphorbiaceae are known to be toxic and poisonous plants because their milky latex has strong skin irritant activity, and chronic exposure can result carcinogenic effect. The toxic constituents of Euphorbiaceae species are specific diterpenes, called in common as phorboids. These compounds (tigliane, ingenane and daphnane derivatives) possess extreme pro-inflammatory and tumour promoting effects due to the activation of protein kinase C enzyme. The present article gives a survey about the present estimation of Euphorbiaceae diterpenes on the basis of own experimental results and literature data. The study tries to answer the question whether these compounds can be regarded as plant toxins or they may have therapeutic relevance? It was concluded that one group of diterpenes, such as most of phorbol and ingenol esters can be considered exclusively as toxins without any possible medicinal use. The other group of diterpenes comprises compounds, which display toxicity, but in adequate dose they have therapeutic perspective (e.g. the resiniferatoxin with capsaicine-like effect). The third group of compounds such as diterpenes of non-phorboid type with macrocyclic or polycyclic structures do not have toxic effect or this property is markedly reduced, however demonstrate interesting biological activities (anti-MDR, antiproliferative and tubulin-interacting effects). Thus, these compounds may be promising lead compounds for natural product based drug developments.