Sebastian Harder

Clinically important drug interactions with anticoagulants. An update.

SummaryCoumarin derivatives combine 3 unfavourable properties which make them prone to potentially life threatening drug-drug interactions: (i) high protein binding; (ii) cytochrome P450 dependent metabolism; and (iii) a narrow therapeutic range.An entire list of drugs which are supposed to interact with coumarins (mostly with warfarin) comprises about 250 different compounds. Noteworthy are the interactions with cardiovascular or antilipidaemic drugs which are often coadministered with coumarins: amiodarone, propafenone and fibrates. Cardiovascular drugs which are obviously devoid or proven to be devoid of an interaction are angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, β-blockers and cardiac glycosides. There are several other drugs which enhance the hypopro-thrombinaemic response to coumarins by various mechanisms: inhibitors of the elimination of the eutomer S-(−)-warfarin (e.g. miconazole, phenylbutazone), combined with protein binding displacement (e.g. sulfinpyrazone, phenylbutazone), synergistic hypoprothrombinaemia (e.g. cefazoline). Furthermore, bleeding complications may occur with drugs affecting platelet function [aspirin (acetylsali-cylic acid) and several nonsteroidal anti-inflammatories (NSAIDs)]. Strong inducers of coumarin metabolism are rifampicin (rifampin) and carbamazepine. Biphasic interactions may occur where a drug first enhances the hypoprothrombinaemic response to a coumarin but has a sustained inducing effect on coumarin metabolism (e.g. phenytoin or sulfinpyrazone).The complex response of coumarins to concomitant drug therapy makes it difficult to predict the occurrence and degree of a deterioration of anticoagulant control in individual patients. For clinical practice, it seems advisable that one should monitor for changes in prothrombin time when adding or deleting any newly approved drug or any drug suspected (e.g. on the basis of this review) to cause an interaction to patients on coumarin therapy. The onset of the adverse prothrombin time response might be from between 1 to 2 days up to 3 weeks (in case of phenprocoumon) after starting a concomitant drug regimen. With amiodarone, an adverse prothrombin time response might occur up to 2 months after initiating therapy.For heparins, only a drug interaction with aspirin or nitroglycerin seems clinically relevant due to the possibility of coadministration during acute cardiac events. Both drugs are shown to enhance the activated partial thromboplastin time response to heparin.

Breast carcinoma during pregnancy

Breast carcinoma during pregnancy (BCP) is a difficult clinical situation, as it appears to put the health of the mother in conflict with that of the fetus.

Clopidogrel but not aspirin reduces P‐selectin expression and formation of platelet‐leukocyte aggregates in patients with atherosclerotic vascular disease*

Formation of platelet‐leukocyte aggregates via the CD62 ligand represents an important mechanism by which leukocytes contribute to thrombotic events. In a cross‐sectional study, we investigated platelet‐leukocyte aggregate formation and markers indicative for platelet, leukocyte, and endothelial activation (CD62, activated fibrinogin receptor glycoprotein IIb/IIIA [PAC‐1], CD11b/CD18 [MAC‐1], and soluble intercellular adhesion molecule 1) in 44 patients with atherosclerotic vascular disease and peripheral occlusions receiving clopidogrel (n = 12), aspirin (n = 17), their combination (n = 8), or no treatment (n = 7), as well as in a group of healthy subjects (n = 9). Whole‐blood flow cytometry was performed before (baseline) and after stimulation with thrombin receptor‐activating peptide or adenosine diphosphate. Both at baseline and after stimulation, untreated patients and those receiving aspirin monotherapy exhibited significantly higher levels of platelet CD62 expression (baseline CD62: untreated, 22% [median]; with aspirin, 16%) and had higher rates of platelet‐leukocyte aggregate formation (monocyte‐platelet‐leukocyte aggregates at baseline: untreated, 27%; with aspirin, 16%) when compared with patients receiving clopidogrel alone (baseline CD62: 10% [P < .05]; monocyte‐platelet‐leukocyte aggregates: 13% [P < .05]) or combined with aspirin (baseline CD62: 5% [P < .05]; monocyte‐platelet‐leukocyte aggregates: 7% [P < .05]). Up‐regulation of MAC‐1 on monocytes after stimulation with thrombin receptor‐activating peptide and adenosine diphosphate was significantly lower in patients treated with clopidogrel and aspirin. Plasma levels of soluble intercellular adhesion molecule 1 were significantly lower in the group of healthy subjects (median, 186 ng/mL) when compared with those in untreated patients (median, 352 ng/mL) (P < .05), whereas intercellular adhesion molecule 1 levels in treated patients were similar for any antiplatelet regimen (aspirin, 262 ng/mL; clopidogrel, 274 ng/mL; combination therapy, 273 ng/mL) but significantly lower than those in untreated patients. This is the first report showing that platelet‐leukocyte aggregate formation is enhanced in atherosclerotic vascular disease but was found to be reduced in patients receiving clopidogrel.

Effects of the Oral, Direct Factor Xa Inhibitor Rivaroxaban on Platelet‐Induced Thrombin Generation and Prothrombinase Activity1

Rivaroxaban (BAY 59‐7939) is an oral, direct factor Xa inhibitor in advanced development. This study was undertaken to investigate its effects on thrombin generation. In this placebo‐controlled, randomized, crossover study, 12 healthy subjects received rivaroxaban (single 5‐ or 30‐mg dose) or placebo. Thrombin generation was investigated by measuring the endogenous thrombin potential and prothrombinase‐induced clotting time. Maximal effect of rivaroxaban was observed 2 hours after drug administration: prothrombinase‐induced clotting time was prolonged 1.8 and 2.3 times baseline after rivaroxaban 5 and 30 mg, respectively. Collagen‐induced endogenous thrombin potential was reduced by ∼80% and ∼90% compared with baseline after rivaroxaban 5 and 30 mg, respectively, and tissue factor‐induced endogenous thrombin potential was reduced by ∼40% (5 mg) and ∼65% (30 mg), respectively. Thrombin generation remained inhibited for 24 hours. There was a close correlation between plasma concentration of rivaroxaban and prolongation of prothrombinase‐induced clotting time and reduction in endogenous thrombin potential. Rivaroxaban strongly inhibits platelet‐induced thrombin generation, after activation of either platelets or the coagulation pathway, even in the presence of minimal factor Xa inhibition in plasma.

Avoidance of Bleeding During Surgery in Patients Receiving Anticoagulant and/or Antiplatelet Therapy: Pharmacokinetic and Pharmacodynamic Considerations

Perioperative management of chronically anticoagulated patients and/or patients treated with antiplatelet therapy is a complex medical problem. This review considers the pharmacokinetic and pharmacodynamic properties of commonly used antiplatelet and anticoagulant drugs with special emphasis on loss of effects after discontinuation and possible counteracting (or antidote) strategies. These drugs are aspirin (acetylsalicylic acid), ticlopidine/clopidogrel, abciximab, tirofiban and eptifibatide, heparin (unfractionated and low-molecular-weight), warfarin and direct thrombin inhibitors. Since the pharmacological mechanisms of some of these drugs are based on irreversible or slowly reversible effects, their pharmacokinetic profiles are not necessarily predictive for their pharmacodynamic profiles. A close and direct relationship between plasma concentrations and effects is seen only for the glycoprotein (GP) IIb/IIIa inhibitors tirofiban and eptifibatide with a fast off-rate for dissociation from the GPIIb/IIIa receptor, and for direct thrombin inhibitors (hirudin and argatroban). For other compounds, drug concentrations in plasma and pharmacodynamic effects are not closely correlated because of, for example, irreversible binding to their target (aspirin, Clopidogrel and abciximab), inhibition of the generation of a subset of clotting factors with differing regeneration and degradation rates (coumarins) or sustained binding to the vascular wall (heparins).Surgery in patients on anticoagulant and/or antiplatelet therapy may be categorised as: (i) elective versus urgent; and (ii) cardiopulmonary bypass (CPB) versus non-CPB. Monotherapy with Clopidogrel or aspirin need not be discontinued in elective non-CPB surgery, and temporary discontinuation of warfarin should be accompanied by preoperative intravenous heparin only in selected high-risk patients. Vitamin K as an antidote for warfarin should only be used subcutaneously and solely in urgent/emergency surgery. In elective surgery requiring CPB (coronary artery bypass grafting), it is recommended to discontinue aspirin 7 days preoperatively in patients with a low risk profile. Patients requiring urgent CPB surgery (e.g. after failure of a percutaneous coronary angioplasty with or without coronary stent deployment) are usually pretreated with several antiplatelet agents (e.g. aspirin and Clopidogrel, together with a GPIIb/IIIa inhibitor) together with unfractionated or low-molecular-weight heparin. With judicious planning, urgent/emergency cardiac surgery can be safely performed on these patients. Delaying surgery (e.g. for 12 hours in patients treated with abciximab) should be considered if possible. Standard heparin doses should be given to achieve optimal anticoagulation for CPB. Prophylactic use of aprotinin (intraand/or postoperatively), aminocaproic acid or tranexamic acid should be considered. Early (in the operating theatre prior to chest closure) and judicious use of replacement blood products (platelets) should be commenced when clinically indicated.

Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P‐selectin expression in a human ex vivo in vitro model

Formation of platelet‐leukocyte aggregates (PLA) through the CD62 ligand is an important mechanism by which leukocytes contribute to thrombosis and inflammation. We investigated the formation of PLA in human subjects after stimulation with thrombin receptor activating peptide and adenosine diphosphate (ADP) after treatment with clopidogrel and after in vitro application of the platelet glycoprotein IIb/IIIa complex antagonist abciximab. Expression of CD62 was significantly reduced 30% to 50% with clopidogrel, depending on the type and concentration of the inducer, but addition of abciximab led to a significant approximately 30% increase in CD62 expression whenplatelets were stimulated by ADP. Formation of PLA decreased significantly with clopidogrel to 55% to 75% of the baseline value, whereas addition of abciximab caused a significant increase in PLA in ADP‐stimulated samples before but not after administration of clopidogrel. The increase in formation of PLA after in vitro addition of abciximab was not paralleled by a decrease in platelet microaggregates and is therefore presumed not caused by enhanced availability of platelets. To our knowledge, this is the first report showing that clopidogrel reduces formation of PLA. The findings also suggest intersection between an “outside‐in” signal generated by abciximab and stimulation of platelet P2T12 purinergic receptors that augments degranulation and increases formation of PLA but is inhibited by clopidogrel.

Measurement of theophylline absorption from different regions of the gastro-intestinal tract using a remote controlled durg delivery device

SummaryThe absorption of a theophylline solution containing 80–120 mg doses delivered to different sites in the gastro-intestinal tract has been determined in 3 male volunteers using a remote controlled drug release system (HF-capsule). There was no difference between the stomach, ileum and the colon in the amount of theophylline absorbed (AUC). The T1/2abs of theophylline absorbed via the colon was prolonged when compared with that entering via the upper gastro-intestinal tract. The results provide a rational basis for the further development of theophylline formulations and are indispensable for planned development and to account for variation in the bioavailability of retarded release drug preparations.

Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas

IntroductionScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients.MethodsWe have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks.ResultsNo hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients.ConclusionOur results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.

Clinical Pharmacokinetics of Sevoflurane

Sevoflurane is a comparatively recent addition to the range of inhalational anaesthetics which has been recently released for clinical use. In comparison to older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more rapid uptake and induction than the ‘older’ inhalational agents, improved control of depth of anaesthesia and faster elimination and recovery. The more rapid pharmacokinetics are a result of the low blood/gas partition coefficient of 0.69. With an oil/gas partition coefficient of 47.2, the minimum alveolar concentration (MAC) of sevoflurane is 2.05%. Two to 5% of the drug taken up is metabolised by the liver. The pharmacokinetics of sevoflurane do not change in children, obese patients or patients with renal insufficiency.The pharmacokinetics and pleasant odour of sevoflurane make mask induction feasible, which is an obvious advantage in paediatric anaesthesia. The hepatic metabolism of sevoflurane results in the formation of inorganic fluoride. Upon contact with alkaline CO2 absorbent, a small amount of sevoflurane is degraded and a metabolite (compound A) is formed and inhaled in trace amounts. Whether inorganic fluoride or compound A are nephrotoxic is presently a matter of controversy.

Novel oral anticoagulants: clinical pharmacology, indications and practical considerations.

BackgroundNovel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost–benefit relations compared with traditional vitamin K antagonists or no therapy.AimThis review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.