Advanced Stages Of Clinical Testing Research Articles

PROTACs: Walking through hematological malignancies.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small molecule inhibitors, PROTACs have proven highly effective in targeting undruggable proteins and those bearing mutations. Because of these considerations, PROTACs have increasingly become an emerging technology for the development of novel targeted anticancer therapeutics. Interestingly, many PROTACs have demonstrated a great potency and specificity in degrading several oncogenic drivers. Many of these, following extensive preclinical evaluation, have reached advanced stages of clinical testing in various cancers including hematologic malignancies. In this review, we provide a comprehensive summary of the recent advances in the development of PROTACs as therapeutic strategies in diverse hematological malignancies. A particular attention has been given to clinically relevant PROTACs and those targeting oncogenic mutants that drive resistance to therapies. We also discus limitations, and various considerations to optimize the design for effective PROTACs.

COVID-19 vaccines

The COVID-19 pandemic is the most important public health challenge facing humankind in the 3rd millennium to date. It also has myriad of economic, political and social implications. In addition to behavioral measures, vaccines are the solution to limit the number of cases of infections. The scientific community has mobilized exemplary, and with the financial and regulatory support of states, in less than a year since the sequencing of the SARS-CoV-2 genome, dozens of vaccines have reached advanced stages of clinical testing, some of which being already authorized for use in vaccination campaigns unprecedented in history. This paper reviews the anti-COVID vaccines currently in use, along with some having the potential to be authorized soon. The mechanisms of immunogenic action of vaccines and the platforms that enabled their development are discussed. Results from clinical trials investigating the efficacy and safety of vaccines are presented. The success of stopping the pandemic through vaccination currently depends on several factors. The availability of vaccines, in sufficient quantities to vaccinate billions of people, is a challenge. Some of the vaccines have restrictive storage conditions, making it difficult to use them in less developed parts of the world. People’s acceptance of immunization is also a decisive factor. The hesitant attitude towards vaccination is not a new phenomenon, and it seems that important refusal rates are also being reached towards COVID‑19 vaccination. Nondiscriminatory attitudes, nonmandatory vaccination and education campaigns are considered to be optimal strategies for increasing the acceptance rate of vaccination. In order to achieve herd immunity, it’s important that high percentages of the population be vaccinated. How high this level should be is unknown yet. Also, there are many questions that we have not yet answered. The emergence of viral variants, on which vaccines are less effective, is one of the most important impediments that have arisen against successful curbing the pandemic.

Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Drug Repurposing in Parkinson's Disease.

The development of an intervention to slow or halt disease progression remains the greatest unmet therapeutic need in Parkinson's disease. Given the number of failures of various novel interventions in disease-modifying clinical trials in combination with the ever-increasing costs and lengthy processes for drug development, attention is being turned to utilizing existing compounds approved for other indications as novel treatments in Parkinson's disease. Advances in rational and systemic drug repurposing have identified a number of drugs with potential benefits for Parkinson's disease pathology and offer a potentially quicker route to drug discovery. Here, we review the safety and potential efficacy of the most promising candidates repurposed as potential disease-modifying treatments for Parkinson's disease in the advanced stages of clinical testing.

Immunotherapy for prostate cancer: False promises or true hope?

Prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related death for men in the United States. Despite the approval of several new agents for advanced disease, each of these has prolonged survival by only a few months. Consequently, new therapies are sorely needed. For other cancer types, immunotherapy has demonstrated dramatic and durable treatment responses, causing many to hope that immunotherapies might provide an ideal treatment approach for patients with advanced prostate cancer. However, apart from sipuleucel-T, prostate cancer has been conspicuously absent from the list of malignancies for which immunotherapies have received recent approval from the US Food and Drug Administration. This has left some wondering whether immunotherapy will "work" for this disease. In this review, the authors describe current developments in immunotherapy, including approaches to engage tumor-targeting T cells, disrupt immune regulation, and alter the immunosuppressive tumor microenvironment. The authors then describe the recent application of these approaches to the treatment of prostate cancer. Given the Food and Drug Administration approval of 1 agent, and the finding that several others are in advanced stages of clinical testing, the authors believe that immunotherapies offer real hope to improve patient outcomes for men with prostate cancer, especially as investigators begin to explore rational combinations of immunotherapies and combine these therapies with other conventional therapies. Cancer 2016;122:3598-607. © 2016 American Cancer Society.

An Updated Review on Liposome Drug Delivery System

Liposomes, sphere-shaped vesicles consisting of one or more phospholipids bilayers. Today, they are a very useful reproduction, reagent, and tool in various scientific disciplines, including mathematics and theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. A number of clinical studies have now demonstrated the superiority of liposomal drug formulations over conventional delivery systems. Liposomes characterize an advanced technology to deliver active molecules to the site of action, and at present, several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles to ‘second-generation liposome's’, in which long-circulating liposome's are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposome with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. Antineoplastic agents, doxorubicin, daunorubicin and cytarabine, are in advanced stages of clinical testing in humans. One or more of these should prove to be a medically useful and commercially viable product within the next few years. This paper summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations in respect to industrial applicability and regulatory requirements concerning liposomal drug formulations based on FDA and EMEA documents.

Is there a role for angiogenesis inhibition in prostate cancer?

Prostate cancer is the most common male cancer and one of the most common causes of cancer death among men in European countries. In the last years, a large number of new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, others are still in an advanced stage of clinical testing. In this review, we provide an overview on new substances which act via modulation or inhibition of angiogenesis. Results and limitations from clinical studies as well as future needs for improvement of those agents in CRPC are critically discussed.

Preparing for microbicide introduction, rollout, and sustained access.

Two topical vaginal microbicide candidates for HIV prevention are at an advanced stage of clinical testing, with efficacy results from three clinical trials expected within the next 2 years. Therefore, preparations for introducing and ensuring access to these products in the event that they are proven safe and effective now require increased attention. Microbicides are expected to fill an important global public health need for HIV prevention options for women. They have been developed almost exclusively with public and private funding through academic and nongovernmental institutions and minimal involvement of commercial pharmaceutical partners. Efficient and rapid introduction of a new public health technology requires a broad range of expertise and collaborations, some of which are new to the microbicide field as products are at last completing late-stage pivotal licensure studies. Strong leadership, political commitment, and considerable financial investments will be required to ensure successful distribution as well as uptake and continued access to this new product class. This paper highlights work conducted since 2000 by scientists, advocates, and public health officials to prepare for microbicide introduction, and discusses some of the needed actions to ensure that products will become readily accessible to the women who need them.

Stem Cells as an Emerging Paradigm in Stroke 3

Cell-based therapy continues to grow as a new field to explore investigational treatments for stroke. Leaders from academia and industry convened an inaugural meeting in 2007 with members of the National Institutes of Health and Food and Drug Administration (FDA) to generate consensus-based guidelines on the development of cell therapies for stroke, entitled “Stem Cells as an Emerging Paradigm in Stroke” (STEPS).1 These guidelines focused on preclinical studies that are considered important as part of a development program to support clinical testing of cell therapies. The STEPS meeting also provided recommendations on the conduct of early-stage clinical trials. Given the rapid advances in the field, a second meeting was held in 2009 to update and expand these guidelines, which were published as STEPS 2.2 In December 2011, investigators in academia, industry leaders, and members of the National Institutes of Health and FDA gathered at a third meeting, STEPS 3, to discuss emerging data on the mechanisms of action of cell therapy, the barriers to successful translation from animal models to patients, and the design of current clinical trials for acute and chronic stroke. Since the prior STEPS meeting, there are now several active cell therapy platforms for stroke and other neurological disorders, in stages that range from preclinical to clinical trials, and with sponsors that include industry, the National Institutes of Health, and the California Institute of Regenerative Medicine. As the field continues to progress and as pilot clinical studies are starting to show safety for some cell types, it has become necessary to formulate a new set of guidelines that address topics not covered in prior STEPS publications. Specifically, the current document reflects a compilation of recommendations that focus on more advanced stages of clinical testing, as well as the testing of cell therapies in a broader …

Editorial Commentary: Intussusception and Rotavirus Vaccination--Balancing Risk Against Benefit

An association between intussusception, a form of bowel obstruction, and live oral rotavirus vaccines was first identified with Rotashield, a rhesus-human reassortant rotavirus vaccine that was recommended for routine immunization of US infants in 1998 [1]. During the first year after vaccine introduction, a cluster of intussusception cases temporally linked to Rotashield vaccination was reported to the US Vaccine Adverse Event Reporting System (VAERS), a national passive reporting system [2]. This prompted a national case-control study, which confirmed the association between Rotashield and intussusception [3], with the greatest risk (an approximately 37-fold increase) occurring 3–7 days after the first vaccine dose. A smaller increase was seen in the second week after dose 1 and during the first week after dose 2. The excess risk of approximately 1 intussusception case in 10 000 Rotashield recipients led to withdrawal of the vaccine from the US market in 1999 [4]. Because of the legacy of Rotashield, the 2 other live oral rotavirus vaccines in advanced stages of clinical testing at the time—a pentavalent bovine-human reassortant vaccine (RV5, RotaTeq, Merck.) and a monovalent human vaccine (RV1, Rotarix, GSK Biologicals)—each underwent large clinical trials of approximately 60 000–70 000 infants specifically to assess the risk of intussusception [5, 6]. No elevated risk was found 42 and 30 days after vaccination after any of the 3 doses of RV5 and either of the 2 doses of RV1, respectively, in these trials. This facilitated licensure of both products and a recommendation for universal use in the United States and around the world. The World Health Organization (WHO) recommends both RV5 and RV1 for global use and encourages postlicensure monitoring to further assess the intussusception risk during routine programmatic use [7]. In this issue, Carlin et al present an elegant analysis of postlicensure intussusception data from Australia that has several notable strengths [8]. First, given that different states in Australia exclusively implemented either RV5 or RV1 with a relatively equitable national distribution of the 2 vaccines, this evaluation was able to evaluate risk with both vaccines during contemporaneous use in demographically similar populations. Second, robust and nationally representative evidence could be generated because of a relatively comprehensive capture of intussusception cases through examination of hospital discharge databases (with review of case records to restrict analysis to cases that met the highest Brighton Collaboration level 1 diagnostic certainty) and because of the availability of immunization data though a national registry with a near-complete (>98%) capture of vaccines provided through the National Immunization Program. Third, both the case-series and case-control methods were used to assess intussusception, and the consistency of estimates from both approaches provides additional reassurance about the validity of the findings. Fourth, the authors present side-by-side data on both the excess number of intussusception cases that might be caused by vaccination against the expected reduction in rotavirus hospitalizations, so that the risks could be interpreted in the context of benefits. Last, a range of sensitivity analyses were conducted around various assumptions and parameters that informed the analysis, with none influencing the overall conclusions substantially. The results show that in Australia both rotavirus vaccines are associated with an increased risk of intussusception in the first 3 weeks after the first vaccine dose and the first week after the second dose, with the greatest risk in the first week after dose 1. An increased intussusception risk in the first week after dose 1 of RV1 was also documented in a previous smaller study from Australia and in 2 separate evaluations in Mexico [9–11]. In Received 1 July 2013; accepted 5 July 2013; electronically published 19 August 2013. Correspondence: Walter A. Orenstein, MD, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30338 (dmill06@emory.edu). Clinical Infectious Diseases 2013;57(10):1435–7 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit532

Signal transduction inhibitors in treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

Novel therapeutic approaches for the treatment of castration-resistant prostate cancer

Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour

Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

Abstract PL01-02: The Breast International Group (BIG): Building on an accelerated path to tailored adjuvant cancer therapy

Abstract The Breast International Group (BIG) : building an accelerated path to tailored adjuvant cancer therapy M. Piccart-Gebhart Today only 1 in 20 oncologic drugs that are tested in human subjects are ultimately shown to be efficacious and approved for widespread use. The vast majority of novel agents fail in advanced stages of clinical testing. Preliminary data suggests that the success rate is only marginally better for the family of targeted kinase inhibitors. After more than 40 years of clinical research in breast cancer, hormonal receptors and HER-2 status are the only predictive therapeutic markers that are routinely used in clinical decision-making. These markers have good negative predictive values but unsatisfactory positive predictive values. There is an exciting array of novel targeted therapies designed to inhibit aberrant pathways in the cancer cell currently in clinical testing. Many of these agents may only be effective in patients with specific molecular alterations. However, demonstrating differential activity in breast cancer subtypes and developing reliable predictive assays to select patients for novel targeted therapy remains a great challenge. The traditional model of establishing initial activity in patients with advanced refractory disease with subsequent retrospective biomarker discovery and validation in the adjuvant setting has failed to establish truly tailored therapies for use in the clinic. As a result, efforts are underway to move the discovery and validation of predictive biomarkers into earlier phases of drug development in the neoadjuvant setting. The NeoBIG program is being developed by the Breast International Group (BIG) to accelerate biomarker discovery and drug development in early breast cancer. Under this platform, a series of neo-adjuvant randomized phase II clinical trials (each with 300-600 patients) will be concomitantly launched to evaluate promising novel targeted therapies in different molecular breast cancer subtypes. Short-term endpoints, including pathological remission, proliferation markers, and imaging response, will be used to establish efficacy. These studies will integrate emerging technologies, such as genomics, proteomics, metabolomics, pharmacogenetics and functional imaging, to develop predictive markers of efficacy that can be validated in a subsequent adjuvant registration trial. In addition to addressing the need for accelerated development of more effective and less toxic therapies, modern trials should lead to an improved mechanistic understanding of the underlying biology of disease in specific patient populations. The NEO-BIG program will collaborate with basic science laboratories to improve our understanding of the biology of HER2 positive, triple negative and luminal B cancers. Citation Format: Martine J. Piccart-Gebhart. The Breast International Group (BIG): Building on an accelerated path to tailored adjuvant cancer therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr PL01-02

Konzepte der klinischen Testung biologischer Wirkstoffe am Beispiel der Vakzination

Biologische Wirkstoffe (Biologika) umfassen eine sehr heterogene Gruppe neuartiger Substanzen, die ihnen eigene, hoch spezifische Charakteristika aufweisen, in denen sie sich klar von den klassischen Chemotherapeutika unterscheiden. Die heute gültigen Konzepte klinischer Testung neuer Medikamente in der Onkologie basieren vollständig auf den Erfahrungen, die mit zytotoxischen Wirkstoffen gemacht wurden, und berücksichtigen daher Aspekte, die beim Einsatz von biologischen Wirkstoffen von essenzieller Bedeutung sind, nur unvollständig oder gar nicht. Dies kann im Extremfall dazu führen, dass Biologika, die ein Potenzial zur Wirksamkeit gegen Tumoren aufweisen, in klinischen Studien nicht erfolgreich getestet oder gar nicht erst in Studien eingebracht werden. Um die Zahl von biologischen Wirkstoffen zu vergröβern, die erfolgreich durch alle Phasen der klinischen Prüfung gebracht werden können, ist es notwendig, die heute gültigen Konzepte klinischer Testung zu überdenken und so anzupassen, dass sie den spezifischen Anforderungen der getesteten Biologika gerecht werden. Wichtig ist, dass eine wirkstoffspezifische Anpassung von Konzepten klinischer Prüfung keinesfalls mit einem Absenken der hohen gültigen Standards für Sicherheit und Qualität verbunden ist. Die wichtigsten Argumente für einen Paradigmenwechsel in der klinischen Prüfung sollen hier anhand der therapeutischen Tumorimpfungen, als Stellvertreter für biologisch wirksame Therapien, verdeutlicht werden.

Standardized definitions of failure modes for female condoms

Definitions of male condom failure modes are now well documented, and failure events are usually reported as the proportion of the total number of condoms used and the proportion of men/couples who experience an event. The lack of standardized definitions for female condom (FC) failure has led to variability in reporting and hence difficulties in making comparisons across studies. As a result, the World Health Organization convened a technical review committee meeting in January 2006 through which the members compiled and agreed to a standard list of terms and definitions for each of the failure modes. These failure modes apply to FCs currently marketed or in advanced stages of clinical testing. They were designed to assist in the review and comparative assessment of different FCs.

Effective tailor-made force field parameterization of the several Zn coordination environments in the puzzling FTase enzyme: opening the door to the full understanding of its elusive catalytic mechanism

Protein farnesyltransferase (FTase) is very promising anticancer drug target, with several drugs in advanced stages of clinical testing. However, in spite of the thrilling achievements in the development of farnesyltransferase inhibitors (FTIs) over the past few years, the farnesylation mechanism remains, to some degree, a mystery. This work reports the determination and validation of three sets of molecular mechanical parameters specifically tailored to accurately account for the very specific nature of the several Zn coordination spheres formed during the unclear catalytic pathway of this puzzling metalloenzyme, and built on the top of recent experimental and theoretical results that have dramatically changed the way how the farnesylation mechanism is perceived. Extensive validation studies with 14 FTase crystallographic structures, EXAFS data, DFT, and QM/MM theoretical calculations are presented.

The status of new anticoagulants

Currently available anticoagulants include heparin, low-molecular weight heparin, fondaparinux and warfarin. Despite advances with low-molecular weight heparin and fondaparinux, the currently available agents have limitations that have provided the impetus for the development of new drugs for prevention and treatment of both venous and arterial thromboembolism. Novel anticoagulants targeting specific steps in coagulation are in various stages of development. This paper reviews the pharmacology of these new agents and describes the results of clinical trials with new anticoagulants in more advanced stages of clinical testing.

New anticoagulants.

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.

New anticoagulants: beyond heparin, low-molecular-weight heparin and warfarin.

The limitations of traditional anticoagulants, heparin and warfarin, have prompted the development of new anticoagulant drugs for prevention and treatment of both venous and arterial thromboembolism. After a brief review of thrombogenesis and its regulation, this paper focuses on new anticoagulant agents in more advanced stages of clinical testing.