The therapeutic potential of novel anticoagulants

For several decades, conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin (coumadin). Although used widely and effectively, heparin and warfarin display liabilities which have prompted the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins (LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and more recently, approval for their use in the USA. Paralleling the development of LMWHs, but lagging behind in terms of clinical development, has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors, exert their effects independent of either antithrombin III (ATIII) or heparin co-factor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases), direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of these natural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant factor (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents have been and are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness (and sometimes relative ineffectiveness compared with conventional therapy) in arterial and venous thromboembolic disorders has been demonstrated. These novel anticoagulents are curently being tested or will for their validity and potential as new antithrombotic agents acting via direct enzyme inhibition. In doing so, it is hoped that the clinician will in future be able to turn to proven specific anticoagulant interventions, targeted at each respective thrombotic state.     

The therapeutic potential of novel cardiotonic agents

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as β-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca²⁺mobilisation (upstream mechanism). These agents are associated with the risk of Ca²⁺ overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca²⁺ overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca²⁺ ions (central and/or downstream mechanisms). Novel Ca²⁺ sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca²⁺ sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.     

The therapeutic potential of novel antiangiogenic therapies

Promising new antiangiogenic strategies are emerging for the treatment of cancer. Numerous candidate drugs that target vascular endothelial growth factor, vascular endothelial growth factor receptors, integrins, matrix metalloproteinases and other blood vessel targets are being developed and tested in clinical trials. This review highlights the numerous drugs in clinical trials and expands on potential new approaches to inhibiting angiogenesis. These approaches include gene therapy, vaccine strategies and antiangiogenic radioligands. New insight has been gained from completed Phase III trials with antiangiogenic drugs and some of the major obstacles include design of trials, dosing, toxicities and resistance. This review will discuss these barriers and methods by which they can be overcome.     

The therapeutic potential of novel antiangiogenic therapies

Promising new antiangiogenic strategies are emerging for the treatment of cancer. Numerous candidate drugs that target vascular endothelial growth factor, vascular endothelial growth factor receptors, integrins, matrix metalloproteinases and other blood vessel targets are being developed and tested in clinical trials. This review highlights the numerous drugs in clinical trials and expands on potential new approaches to inhibiting angiogenesis. These approaches include gene therapy, vaccine strategies and antiangiogenic radioligands. New insight has been gained from completed Phase III trials with antiangiogenic drugs and some of the major obstacles include design of trials, dosing, toxicities and resistance. This review will discuss these barriers and methods by which they can be overcome.     

The therapeutic potential of novel cardiotonic agents

During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as beta-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca(2+) mobilisation (upstream mechanism). These agents are associated with the risk of Ca(2+) overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca(2+) overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca(2+) ions (central and/or downstream mechanisms). Novel Ca(2+) sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca(2+) sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.     

The therapeutic potential of novel anti-migraine acute therapies

Introduction: Migraine is a highly disabling neurovascular disorder. ‘The complex and multifactorial properties of migraine pathogenesis provide the opportunity to identify new therapeutic targets from a wide range of receptors.

Areas covered: In this editorial, the authors focus on future pharmacological interventions for acute migraine including: 5-HT receptors and their agonists, calcitonin gene-related peptide receptors and their antagonists, PAC1 receptors and their antagonists, glutamate receptors and some of their antagonists as well as transient receptor potential channels and their antagonists. The authors also discuss preventative treatments for migraine that are currently in development.

Expert opinion: Future pharmaceutical research that looks at the well-known mechanisms involved in the pathophysiology of migraine should aim to overcome the existing limitations of each pharmacological class and their side effects. There has lately been particular interest in the role of glutamate receptors, particularly metabotropic glutamate receptors, in the pathophysiology of migraine. These receptors may be potentially viable drug targets for migraine in the future.     

The therapeutic potential of novel aromatase inhibitors in breast cancer

For over 20 years, aromatase inhibitors have played a role in the treatment of breast cancer. However, until relatively recently, their utility has been limited by a lack of selectivity and significant toxicity. Several second and third generation aromatase inhibitors which are highly selective for the aromatase enzyme have reached clinical trials this decade. As a result of these initial studies, aromatase inhibitors are now established as second line agents in the treatment of postmenopausal women with advanced breast cancer. They are now under evaluation in several other settings, including adjuvant and neoadjuvant therapy, and as part of combination treatment in premenopausal women. This review focuses on recent and ongoing clinical trials and the effect these have had on the clinical use of aromatase inhibitors.     

The plasma coagulation cascade: potential targets for novel anticoagulants in major lower limb surgery

Strategies for prevention of venous thromboembolism in orthopaedic patients undergoing major lower limb surgery include pharmacological prophylaxis. Over the last three decades, the search for new safe and effective approaches for the prevention of venous thromboembolism in these patients has continued. Increased understanding of the haemostatic process has led to a clearer appreciation of the mechanisms of action of antithrombotic drugs already in use as well as the identification of new targets for novel drug development. As a result, the development of new anticoagulants has advanced rapidly over recent years. The molecular targets of several novel anticoagulants, and their effectiveness in early Phase II and Phase III trials are reviewed.     

The therapeutic and diagnostic potential of FKBPL; a novel anticancer protein

The immunophilin family of proteins has a vast number of roles regulating a variety of biological processes through protein-protein interactions. A relatively new and divergent member of this family, FK506-binding protein like (FKBPL), is emerging as a key player in the DNA damage response, steroid receptor signalling and more recently, control of tumour growth where it regulates response to endocrine therapy in addition to acting as a novel antiangiogenic protein. As a new therapeutic peptide based on FKBPL approaches clinical trials, this article highlights a unique approach to targeting tumours that are resistant to current antiangiogenic therapies and supports the role of FKBPL as a novel prognostic and predictive biomarker, distinct from its other family members.     

Imidazoline receptors, novel agents and therapeutic potential

The initial realization that agents containing an imidazoline structure may interact with a distinct class of receptors, has led to a major class of cardiovascular agents, which now has the potential to enter a third generation. There is now general acceptance that there are three main imidazoline receptor classes, the I(1) imidazoline receptor which mediates the sympatho-inhibitory actions to lower blood pressure, the I(2) receptor which is an important allosteric binding site of monoamine oxidase and the I(3) receptor which regulates insulin secretion from pancreatic beta cells. Thus all three represent important targets for cardiovascular research. Interestingly, an I(1)- receptor candidate has been cloned (IRAS, imidazoline receptor antisera selected) which is a homologue of the mouse cell adhesion integrin binding protein Nischarin. There has been range of new agonists and antagonists with very high selectivity for I(1), I(2) and I(3) receptors developed. Three different endogenous ligands have been characterized including agmatine (decarboxylated arginine), a range of beta-carbolines including harman and harmane, and more recently imidazoleacetic acid-ribotide. The imidazoline field has recently seen an enormous diversification with discoveries that I(1) and I(2) receptors also play a role in cell proliferation, regulation of body fat, neuroprotection, inflammation and some psychiatric disorders such as depression. This diversification has continued with the addition of effective agents with imidazoline affinity in the fields of cancer, pain and opioid addiction, stress, cell adhesion, epilepsy and appetite. The imidazoline field has maturated considerably with a range of highly selective leader molecules, candidate receptors and endogenous ligands. We are therefore only at the threshold of an exciting new era as we begin to understand the diverse and complex nature of their function.     

The therapeutic potential of flavonoids

Four most widely investigated flavonoids, flavopiridol, catechins, genistein and quercetin are reviewed in this article. Flavopiridol is a novel semisynthetic flavone analogue of rohitukine, a leading anticancer compound from an Indian tree. Flavopiridol inhibits most cyclin-dependent kinases and displays unique anticancer properties. It is the first cyclin-dependent kinase inhibitor to be tested in Phase II clinical trials. Catechin and its gallate are major ingredients in green tea and their anti-oxidant and cancer preventive effects have been widely investigated. A Phase I study of green tea extract GTE-TP91 has been conducted in adult patients with solid tumours. Similarly, genistein is a major ingredient in soybean and has been shown to prevent cancer and have antitumour, anti-oxidant and anti-inflammatory effects. Two antibody-genistein conjugates, B43-genistein and EGF-genistein, are currently in clinical development for the treatment of acute lymphoblastic leukaemia and breast cancer, respectively. Finally, most recent updates of quercetin are briefly described.     

The therapeutic potential of flavonoids

Four most widely investigated flavonoids, flavopiridol, catechins, genistein and quercetin are reviewed in this article. Flavopiridol is a novel semisynthetic flavone analogue of rohitukine, a leading anticancer compound from an Indian tree. Flavopiridol inhibits most cyclin-dependent kinases and displays unique anticancer properties. It is the first cyclin-dependent kinase inhibitor to be tested in Phase II clinical trials. Catechin and its gallate are major ingredients in green tea and their anti-oxidant and cancer preventive effects have been widely investigated. A Phase I study of green tea extract GTE-TP91 has been conducted in adult patients with solid tumours. Similarly, genistein is a major ingredient in soybean and has been shown to prevent cancer and have antitumour, anti-oxidant and anti-inflammatory effects. Two antibody-genistein conjugates, B43-genistein and EGF-genistein, are currently in clinical development for the treatment of acute lymphoblastic leukaemia and breast cancer, respectively. Finally, most recent updates of quercetin are briefly described.     

The therapeutic potential of leptin

Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood–brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.     

The therapeutic potential of lactoferrin

Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.     

The therapeutic potential of phytoestrogens

Phytoestrogens, such as the soya isoflavones genistein and daidzein, are currently being extensively investigated through both molecular, preclinical and clinical studies to determine their potential health benefits. Phytoestrogens may protect against chronic diseases such as hormone-dependent cancer (e.g., breast and prostate cancer), cardiovascular disease and osteoporosis. Investigations of phytoestrogen metabolism and bioavailability are also of great relevance. Conversion by gut microflora of daizein to its isoflavan metabolite equol, which is a more potent oestrogen and anti-oxidant, occurs only in some individuals (about 35% of subjects tested are equol excretors). This has considerable implications for daidzein bioavailability and also for cancer risk. Oxidative damage has been implicated in the development of heart disease and cancer and soya phytoestrogens have been reported to decrease plasma F₂-isoprostane concentrations (biomarker for in vivo lipid peroxidation) and increase low density lipoprotein oxidation resistance. This anti-oxidant action of phytoestrogens could potentially contribute to their therapeutic efficacy. The findings from the current ongoing studies are all likely to contribute to determining the potential use of phytoestrogens as therapeutic agents.     

The therapeutic potential of lactoferrin

Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.     

The therapeutic potential of phytoestrogens

Phytoestrogens, such as the soya isoflavones genistein and daidzein, are currently being extensively investigated through both molecular, preclinical and clinical studies to determine their potential health benefits. Phytoestrogens may protect against chronic diseases such as hormone-dependent cancer (e.g., breast and prostate cancer), cardiovascular disease and osteoporosis. Investigations of phytoestrogen metabolism and bioavailability are also of great relevance. Conversion by gut microflora of daizein to its isoflavan metabolite equol, which is a more potent oestrogen and anti-oxidant, occurs only in some individuals (about 35% of subjects tested are equol excretors). This has considerable implications for daidzein bioavailability and also for cancer risk. Oxidative damage has been implicated in the development of heart disease and cancer and soya phytoestrogens have been reported to decrease plasma F(2)-isoprostane concentrations (biomarker for in vivo lipid peroxidation) and increase low density lipoprotein oxidation resistance. This anti-oxidant action of phytoestrogens could potentially contribute to their therapeutic efficacy. The findings from the current ongoing studies are all likely to contribute to determining the potential use of phytoestrogens as therapeutic agents.     

The therapeutic potential of leptin

Many studies have reported the difficulty most subjects have in maintaining weight loss. Leptin is a cytokine-like protein made in adipose tissue and is transported into the brain by the blood-brain barrier where it inhibits food intake by altering the expression of hypothalamic neurotransmitters. The discovery of leptin raised the hope that a natural compound had been found that could cause weight loss without adverse effects. However, the majority of obese people have high levels of circulating leptin and it is not surprising that clinical trials published so far have shown that leptin only works effectively to suppress food intake in subjects who are hyperphagic as a result of low leptin levels. Obesity secondary to leptin deficiency is rare, most being associated with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels in the CNS may be required. However, there is evidence that the leptin transport mechanism is saturated at low plasma leptin concentrations, limiting the effectiveness of peripherally-administered hormone. It is concluded that for leptin to have therapeutic potential, it either needs to be modified or the transport system by which leptin enters the brain needs to be upregulated to allow leptin to enter the brain more easily. To achieve effective weight loss, it may also be necessary to overcome central leptin insensitivity by developing agents that act downstream of leptin action.