Cafer Adiguzel

Drug and dietary interactions of the new and emerging oral anticoagulants

Oral warfarin is associated with extensive food and drug interactions, and there is a need to consider such interactions with the new oral anticoagulants (OACs) dabigatran etexilate, rivaroxaban and apixaban. A literature survey was conducted using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with dabigatran etexilate, rivaroxaban and apixaban. Clinical experience regarding food interactions is currently limited. Regarding drug–drug interactions, dabigatran requires caution when used in combination with strong inhibitors or inducers of P‐glycoprotein, such as amiodarone or rifampicin. Rivaroxaban (and possibly apixaban) is contraindicated in combination with drugs that strongly inhibit both cytochrome P450 3A4 and P‐glycoprotein, such as azole antimycotics, and caution is required when used in combination with strong inhibitors of only one of these pathways. Important drug interactions of the new OACs that can lead to adverse clinical reactions may also occur with non‐steroidal anti‐inflammatory drugs and antiplatelet drugs, such as aspirin and clopidogrel. Over‐the‐counter (OTC) medications and food supplements (e.g. St. John’s Wort) may also interact with the new OACs. Given the common long‐term use of drugs for some chronic disorders, the frequent use of OTC medications and the need for multiple treatments in special populations, such as the elderly people, it is essential that the issue of drug interactions is properly evaluated. New OACs offer significant potential advantages to the field of venous thromboprophylaxis, but we should not fail to appreciate their lack of extensive clinical experience.

Survival of Heparins, Oral Anticoagulants, and Aspirin after the Year 2010

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants, and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. The development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, glycoprotein IIb/IIIa inhibitors, and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains as the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa, and XIIIa), recombinant forms of serpins (antithrombin, heparin cofactor II, and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin, and site-specific serine protease inhibitor complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and anti-IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa and antithrombin agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the postsurgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the U.S. Food and Drug Administration did not approve the orally active antithrombin agent ximelagatran for several indications. The synthetic pentasaccharide (fondaparinux) has undergone an aggressive clinical development. Unexpectedly, fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated cyclooxygenase (COX)-1 and P2Y (12) receptors as targets for new drug development. Prasugrel, a novel thienopyridine, cangrelor, and AZD 6140 represent newer P2Y (12) antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas prasugrel requires metabolic activation. Though clinically effective, recent results have prompted a closure of a large clinical trial with prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin, and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond 2010.

Differentiating Low-Molecular-Weight Heparins Based on Chemical, Biological, and Pharmacologic Properties : Implications for the Development of Generic Versions of Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

Pregnancy Outcome in Women with Antiphospholipid Antibodies: Report on a Retrospective Study

Antiphospholipid syndrome (APS) represents a serious risk factor in pregnancy resulting in several complications, leading to fetal loss and hemostatic complications. In this dedicated report, we describe our experiences in the treatment of pregnancies in patients with APS. The retrospective data from 140 pregnant women were investigated, and the treatment results of 121 patients were recorded. We studied two groups of patients receiving different treatment. The first group (N = 78) received the standard therapy with low-weight-molecular heparin (dalteparin 5000 U or certoparin 3000 U daily) and aspirin (100 mg daily) and in the second group (N = 43) an additional 0.2 g/kg intravenous immunoglobulin (IVIG). Outcomes were 74.3% and 83.7% live births in the first group and in the second group, respectively. The abortion rate was similar in both groups (11.5% vs. 11.6%). The late complication rate was lower in the second group (5.8% vs. 14.1%, P < 0.05) than in the group with standard therapy. Interestingly, we found a trend to higher percentage (> 12%) of natural killer (NK) cells in patients with pregnancy complications (60% vs. 12%, P < 0.05). Our retrospective data shows an improvement of late pregnancy complications by additional use of IVIG. It is possible that IVIG influences higher NK cell activity in patients with previous pregnancy complications.

European Community and US-FDA Approval of Recombinant Human Antithrombin Produced in Genetically Altered Goats

Thrombin and factor Xa play a central role in thrombogenesis in both medical and surgical patients. Antithrombin (AT) is the key inhibitor, which controls the action of these enzymes in hypercoagulable states. The AT concentrates prepared from human blood have been used to treat patients with thrombotic disorders and heparin resistance. The AT concentrates are prepared from pooled human plasma and beside limited supply, suffer from viral and other biological contaminants. The availability of recombinant human AT (rhAT) obtained from genetically engineered goats provide a biologically equivalent product that can be used in practically all indications where human AT is indicated including heparin resistance. Moreover, because of its high affinity to heparin and related drugs, recombinant AT can also be developed in further indications. On review of the preclinical and clinical data on the safety and efficacy, the European Union and U.S. Food and Drug Administration (US-FDA) have recently approved the use of rhAT in specified clinical indications.

Are All Low Molecular Weight Heparins Equivalent in the Management of Venous Thromboembolism

Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism

BackgroundThe prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available.MethodsMEDLINE and EMBASE databases were searched to identify relevant original articles.ResultsLow-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding.ConclusionsParenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.

Contaminant in the Recalled Unfractionated Heparin Preparations: Where is the Problem?

In a recently held press conference, the USFDA (United States Food and Drug Administration) briefed the press that the potential contaminant in the recalled Baxter product is a heparin-like substance. The USFDA commented that heparin-like molecules have been identified using high-tech methods. No specifics regarding these contaminants were given. The manufacturing process of heparin is such that other heparin-like contaminants, such as the dermatan sulfate, heparan sulfate, and chondroitin sulfate are removed effectively. These represent the main contaminants in heparin. However, these contaminants are unlikely to produce any allergic effects, nor the reported adverse reactions, because some of the antithrombotic drugs contain significant amounts of these heparin-like substances. Because of the carbohydrate nature of the contaminants identified by a special method of nuclear magnetic resonance (NMR), it is quite disturbing to note that such contaminants may have inadvertently been added to the recalled heparin. Heparin-like materials have been isolated from the shellfish, marine plants, bones, or skin of mammalian origin for several therapeutic purposes. Although structurally similar, these heparin-like substances exhibit different biochemical and pharmacologic effects. There are also various protein contaminants that can be expected along with the carbohydrates. Thus, it is likely that besides the carbohydrate contaminants, some unknown protein contaminants may also be present in these products. The statement that a heparin-like material was identified using high-tech methods is ambiguous and misleading. Such statements should be specific and clear regarding the methods used and the nature In late January, Baxter Healthcare Corporation voluntarily recalled the following lots of heparin: 107054, 117085, 047056, 097081, 107024, 107064, 107066, 107074, and 107111. These products were labeled as heparin 1000 U/mL in 10 mL vials and heparin 1000 U/mL in 30 mL vials. The reason for this recall was the reported adverse reactions, which were associated with the use of these heparin batches. These included abdominal pain, hypotension, burning, chest pain, diarrhea, dizziness, dyspepsia, dyspnea, arrhythmia, flushing, headache, hyperthyroidism, hypoesthesia, increased lacrimation, loss of consciousness, malaise, nausea, pallor, palpitation, paresthesia, pharyngeal edema, restlessness, vomiting, stomach discomfort, tachycardia, thirst, trismus, unresponsiveness to stimuli, and drug ineffectiveness. These adverse reactions were reported in hundreds of patients treated with these heparins in the USA. Initially 19 deaths were linked with the use of the recalled heparins. However, this figure has now reached 81, and it is likely that it will go even higher. These multiple adverse reactions were later attributed to heparin manufactured by Baxter’s [Deerfield, IL] suppliers using Chinese raw material from SPL Changzhou, China. Subsequently, Baxter recalled all of the remaining lots and doses of its heparin sodium injection multidose, single dose vials, and Hep-lock heparin flush product.

Structural and functional characterization of low-molecular-weight heparins: impact on the development of guidelines for generic products.

Low-molecular-weight heparins (LMWHs) are poly-pharmacologic drugs used to treat thrombotic and cardiovascular disorders. Recently, several generic versions of branded LMWHs have been introduced. Although generic versions of LMWHs exhibit similar profiles, marked differences in their biological and pharmacologic properties have been demonstrated. Several studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs and also underscore the importance of further pharmacologic studies involving animal and human clinical trials. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) are currently developing guidelines for the acceptance of complex biological drugs including LMWHs. The US FDA considers these drugs as follow-on agents whereas the EMEA classifies these drugs as biosimilar agents. Until clear guidelines are developed, generic interchange of LMWHs may not be feasible.

Reduced Immunogenic Potential of Membrane Filtered Bovine Thrombin Preparations for Hemostatic Application

There is concern that exposure to bovine thrombin can result in the development of antibodies, usually against factor V/Va, which can lead to hemostatic abnormalities. It is thought that purer preparations of bovine thrombin might be less immunogenic. Utilizing newer methods including a membrane filtration step, bovine crude thrombin is further purified into thrombin 4A and 4B preparations which exhibit a higher specific activity and are devoid of some of the protein contaminants. Bovine crude thrombin and its purified versions were administered intravenously to individual groups of rabbits using standard immunologic protocols. Antiserum was drawn from each rabbit and the pooled antisera were purified to obtain the IgGs using protein G affinity columns. The results suggest that the reported purification process, including filtration, resulted in the removal of most of the antigens found in crude thrombin, and that none of these preparations generated any detectable antibodies against bovine factor V related antigens.