Drugs

Ansell, Jack; Bergqvist, David

doi: 10.2165/00003495-200464001-00002pmid: 15586622

Significant advances in the pharmacological prophylaxis of venous thromboembolism have occurred since warfarin and unfractionated heparin were introduced for this indication nearly 60 years ago. Despite these advances, coumarin derivatives such as warfarin remain the only orally active anticoagulants available for prophylaxis in venous thromboembolism. Although administered orally, coumarin derivatives are not convenient to use, because they have narrow therapeutic indexes and require routine coagulation monitoring and dose adjustment. This is inconvenient for patients and physicians and costly for the healthcare system. Low-molecular-weight heparins, which are administered in fixed or weight-adjusted doses and do not require monitoring, are widely used for the prevention of venous thromboembolism in patients in both the hospital and the outpatient setting. However, these drugs must be given subcutaneously, which can be difficult for outpatients and resource-intensive for in-hospital use. Likewise, fondaparinux, the synthetic pentasaccharide, must be administered subcutaneously. Consequently, there remains a need for new orally active anticoagulants that can be given in fixed doses and do not have a narrow therapeutic index, so that coagulation monitoring is unnecessary. Because such agents would be more convenient for patients and physicians, they would probably expand the use of prophylaxis in venous thromboembolism in those at risk, and would simplify treatment of patients with established venous thromboembolism.

Killestein, Joep; Uitdehaag, Bernard; Polman, Chris

doi: 10.2165/00003495-200464010-00001pmid: 14723555

This is an exciting time for cannabinoid research. Evidence suggests that cannabis (marijuana) can alleviate symptoms like muscle spasticity and pain in patients with multiple sclerosis (MS). Interest in the field of cannabinoids has been strengthened by the identification and cloning of cannabinoid receptors located in the central nervous system and the peripheral immune organs, and by the discovery of the endogenous cannabinoid ligands. Cannabinoids are also efficacious in animal models of MS. However, there have been only ten published clinical reports on the use of cannabis in MS, involving 78 individuals worldwide, and the results have been equivocal. Researchers encounter a number of difficulties in designing clinical studies that use cannabinoids. From the studies reporting the use of cannabinoids in MS patients with spasticity, the somewhat better designed studies failed to demonstrate objective improvement. Therefore, convincing evidence that cannabinoids are effective in MS is still lacking.

Haas, Sylvia

doi: 10.2165/00003495-200464001-00003pmid: 15586623

Venous thromboembolism is a serious illness that affects patient morbidity and mortality and presents a significant management challenge to healthcare providers world-wide. Despite major achievements in the significant reduction of thromboembolic complications, the most common therapies currently used for prevention and treatment of venous thromboembolism — heparins and vitamin K antagonists such as warfarin — have several limitations. In particular, unfractionated heparin and warfarin show significant inter-patient variability in pharmacokinetics and pharmacodynamics, which makes regular coagulation monitoring necessary. Furthermore, only warfarin is suitable for long-term use, as it is administered orally. A new class of anticoagulants has been developed that directly target thrombin, a key enzyme in the blood coagulation cascade. Unlike warfarin and heparin, these direct thrombin inhibitors are able to inhibit fibrin-bound thrombin and so produce more effective inhibition of coagulation. Importantly, some members of this class of drugs have been developed for oral administration. Ximelagatran, which is converted to its active form melagatran, has predictable pharmacokinetics and pharmacodynamics. Therefore, ximelagatran can be administered in fixed doses with no need for coagulation monitoring. Its efficacy and safety profile have been demonstrated in preclinical and clinical studies. As the first oral agent in the new class, direct thrombin inhibitors, ximelagatran has significant potential for improving the prevention and treatment of venous thromboembolism.

Abdel-Hamid, Ibrahim

doi: 10.2165/00003495-200464010-00002pmid: 14723556

Rapid (premature) ejaculation (RE) is a very common sexual disorder. This condition may be primary or secondary to underlying disease. Control of RE has been primarily focused on behavioural therapy, topical anaesthetics, tricyclic antidepressants and selective serotonin reuptake inhibitors; however, an approved treatment does not exist.

Dahl, Ola

doi: 10.2165/00003495-200464001-00004pmid: 15586624

Venous thromboembolism after total hip replacement or total knee replacement represents a significant complication of these surgical techniques, with profound clinical and economic consequences. As the detection of venous thromboembolism is particularly difficult in this setting, its prevention with thromboprophylactic agents is the most appropriate strategy. The anticoagulants currently used for thromboprophylaxis in orthopaedic surgery are injectable low-molecular-weight heparins (LMWHs) and oral coumarin derivatives such as warfarin. Orthopaedic surgery provides a good model with which to investigate the antithrombotic potential of novel agents, because of the relatively high venous thromboembolism event rates, and the opportunity to detect and quantify bleeding.

Gill, Sharlene; Goldberg, Richard

doi: 10.2165/00003495-200464010-00003pmid: 14723557

Advanced colorectal cancer is a significant cause of worldwide cancer-related mortality. For the majority of patients, palliative chemotherapy can yield substantial improvements in survival. Fluorouracil has been the mainstay of treatment in this setting for the past few decades. The relatively recent availability of new combinations with active agents such as irinotecan and oxaliplatin makes this a promising and hopeful time for the treatment of metastatic colorectal cancer, with median survivals now approaching 18–21 months. For patients presenting with resectable metastases, the goal of therapy is surgery with a curative intent. There exists the potential for this approach to be extended also to a greater proportion of patients whose cancer may be rendered resectable following effective neoadjuvant chemotherapy. In addition, an improved understanding of molecular predictors for treatment response and toxicity may facilitate the future selection of individualised treatments for a given tumour profile. Further improvements in the management of advanced disease will continue to be pursued through the ongoing development of multimodality approaches and the incorporation of novel targeted agents with innovative chemotherapy combinations.

Eriksson, Bengt

doi: 10.2165/00003495-200464001-00005pmid: 15586625

Patients who undergo orthopaedic surgery are at substantially increased risk for venous thromboembolic events. These include proximal and distal deep vein thrombosis, with the former more likely to lead to pulmonary embolism and fatal complications. Anticoagulants are routinely used for venous thromboembolism prophylaxis in patients undergoing total hip or total knee replacement surgery. Although current treatments offer effective prophylaxis, they have disadvantages. Warfarin is limited by the requirement for coagulation monitoring to ensure effective and safe use. Similarly, low-molecular-weight heparins (LMWHs) have disadvantages, including the need for parenteral administration. This article brings together data from clinical trials of the novel oral direct thrombin inhibitor, ximelagatran, in the prevention of venous thromboembolism in patients undergoing elective total hip or total knee replacement. The ximelagatran clinical trial programme in orthopaedic surgery has focused primarily on five large multicentre studies in Europe (the Melagatran Thromboprophylaxis in Orthopaedic surgery II and III and Expanded Prophylaxis Evaluation Surgery Study studies) and in the United States (the Exanta Used to Lessen Thrombosis A and B studies), which enrolled more than 8000 patients. In addition, the USA clinical trial programme included three other trials that investigated ximelagatran in orthopaedic surgery; two of these studies focused on prevention of venous thromboembolism after total knee replacement, and one study investigated prevention of venous thromboembolism after total hip replacement. These studies compared ximelagatran with the LMWHs dalteparin and enoxaparin and with warfarin, and were designed to reflect regional differences in venous thromboembolism prophylaxis and to build on findings from previous studies. Generally, ximelagatran has been shown to possess comparable or greater efficacy relative to comparators. The timing and dose of ximelagatran have been shown to be important determinants of its efficacy and safety. As ximelagatran can be given in fixed oral dosing without coagulation monitoring, it is an attractive choice for the prevention of venous thromboembolism in major elective orthopaedic surgery.

Eriksson, Henry

doi: 10.2165/00003495-200464001-00006pmid: 15586626

Despite the effectiveness of anticoagulant therapy for the treatment of acute venous thromboembolism and the prevention of recurrent venous thromboembolism, existing antithrombotic therapies are suboptimal. Unfractionated heparin, low-molecular-weight heparin (LMWH) and warfarin have practical limitations and carry the risk of treatment-related adverse events that restrict their clinical benefits and reduce cost-effectiveness. Efforts to achieve optimal venous thromboembolism prophylaxis by modifying the intensity of oral warfarin treatment have produced equivocal results, and there is a need for new, efficacious antithrombotic drugs providing predictable, well-tolerated oral dosing without the need for coagulation monitoring. Such agents would ideally have no significant food or drug interactions, and be suitable for both short- and long-term treatment. Ximelagatran, the first oral direct thrombin inhibitor, has the potential to fulfill many of the unmet needs in the management of venous thromboembolism.

Wheeler, Anthony

doi: 10.2165/00003495-200464010-00004pmid: 14723558

Voluntary muscle is the largest human organ system. The musculotendinous contractual unit sustains posture against gravity and actuates movement against inertia. Muscular injury can occur when soft tissues are exposed to single or recurrent episodes of biomechanical overloading. Muscular pain is often attributed to a myofascial pain disorder, a condition originally described by Drs Janet Travell and David Simons. Among patients seeking treatment from a variety of medical specialists, myofascial pain has been reported to vary from 30% to 93% depending on the subspecialty practice and setting. Forty-four million Americans are estimated to have myofascial pain; however, controversy exists between medical specialists regarding the diagnostic criteria for myofascial pain disorders and their existence as a pathological entity.

Agnelli, Giancarlo

doi: 10.2165/00003495-200464001-00007pmid: 15586627

Current antithrombotic therapies are associated with various practical limitations and risks that restrict their utility in the management of venous thromboembolism. The coagulation factor, thrombin, has been the focus of extensive investigation as a pharmacological target in efforts to improve the management of venous thromboembolism. Hirudin, desirudin, bivalirudin and argatroban are direct thrombin inhibitors that have been launched for limited indications as anticoagulants. Their usefulness for long-term prophylaxis is limited by a requirement for parenteral administration, restricted licensing and bleeding/tolerability profile. Ximelagatran — which, after oral administration, is rapidly converted to its active form, melagatran — is the first oral direct thrombin inhibitor and the first new oral anticoagulant to become available in 60 years. Clinical studies have shown that melagatran/ximelagatran, without coagulation monitoring, is effective and well tolerated for the prevention of venous thromboembolism after hip replacement and knee replacement surgery. Ximelagatran is also effective in the acute treatment of venous thromboembolism and long-term secondary prevention of recurrent venous thromboembolism, the prevention of stroke in patients with atrial fibrillation and in the prevention of cardiovascular events after myocardial infarction. Oral direct thrombin inhibitors have a promising role in the management of venous thromboembolism and other associated medical conditions.