Expert opinion on emerging drugs
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Acute myeloid leukaemia (AML) is the most common form of leukaemia in young adults. Although 75-85% of patients will achieve complete remission after induction chemotherapy, the long-term survival is still < 50% at 5 years. Chemotherapy has increased in intensity in recent years and is perceived to have reached the limit of toxicity. ⋯ More selective delivery of chemotherapeutic agents is also feasible using humanised monoclonal antibodies, with the intriguing possibility of increasing treatment delivery without increasing the toxicity. However, despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathognomic genetic event to act as a drug target. This review discusses the drugs presently under investigation in Phase II or Phase III trials in AML.
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Drugs that inhibit or poison the function of topoisomerase (topo) enzymes are one of the mainstays of cancer chemotherapy, and include some of the most widely used anticancer drugs. A major effort is going into improving the broad deficiencies of established agents: for topo I inhibitors, this includes better lactone stability than for camptothecin; for topo II inhibitors lower cardiotoxicity than for existing anthracycline/anthraquinone analogues and for both classes, ways to counteract cell efflux mechanisms. ⋯ This review covers 24 drugs (6 topo I inhibitors, 12 topo II inhibitors and 6 dual topo I/II inhibitors) at various stages of clinical development. Although many of the latter class are at an early stage of development, despite a lack of detailed structural biology on the target enzymes, the research area is vigorous and has the potential to open up specific new drug design approaches.
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Medical treatment of endometriosis relies on drugs that suppress ovarian steroids and induce an hypoestrogenic state that causes atrophy of ectopic endometrium. Gonadotrophin-releasing hormone (GnRH) analogues, danazol, progestogens and oestrogen-progestin combinations have all proven effective in relieving pain and reducing the extent of endometriotic implants. However, symptoms often recur after discontinuation of therapy and hypoestrogenism-related side effects limit the long-term use of most medications. ⋯ A fundamental objective of research in endometriosis treatment is to develop new therapeutic approaches based on the findings from experimental studies on the aetiopathogenesis of the disease; current research is focusing on anti-inflammatory drugs and modulators of the immune system. TNF-binding protein-1 and IL-12 have proved effective in reducing endometriotic lesions in animal models, while pentoxifylline and INF-alpha 2b have shown encouraging results in clinical studies. This area may be of paramount importance in the near future in order to develop a therapy that could prevent or eradicate endometriosis rather than merely relieving the symptoms.
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Cystic fibrosis (CF) is one of the most common life-shortening inherited disorders. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene disrupt the localisation and function of the cAMP-mediated chloride channel. ⋯ This review explores the current understanding of the nature of the different mutant CFTR forms and the potential for repair of the chloride channel defect. High-throughput screening, pharmacogenomics and proteomics bring recent technological advances to the field.
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Coronary artery disease (CAD) is the leading cause of mortality and morbidity among adults in the Western world. Coronary artery bypass grafting and percutaneous coronary interventions (PCI) have gained widespread acceptance for the treatment of symptomatic CAD. There has been an explosive growth worldwide in the utilisation of PCI, such as balloon angioplasty and stenting, which now accounts for over 50% of coronary revascularisation. ⋯ Several potential targets for inhibiting restenosis are currently under investigation including platelet activation, the coagulation cascade, VSMC proliferation and migration, and ECM synthesis. In addition, new approaches for local drug therapy, such as drug eluting stents, are currently being evaluated in preclinical and clinical studies. In this article, we critically review the current status of drugs that are being evaluated for restenosis at various stages of development (in vitro, preclinical animal models and human trials).