Amiodarone concentrations in plasma and fat tissue during chronic treatment and related toxicity.

AIMS: To determine if amiodarone, highly lipophilic, accumulates in excess with respect to dose in fat tissue during long-term administration, and study if plasma and fat tissue concentrations are correlated with adverse effects. METHODS: Trough concentrations of amiodarone and N-desethyl-amiodarone were measured simultaneously in plasma and fat tissue, in 30 consecutive patients treated with amiodarone for 3 months to 12 years. Subcutaneous adipose tissue was obtained by needle aspiration from lumbar and abdominal areas. Concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Plasma levels of amiodarone and N-desethyl-amiodarone were significantly correlated with daily maintenance doses (R= 0.52, P= 0.003). Amiodarone concentrations in fat tissue were four to 226 times (mean 55) higher than in plasma, and well correlated with plasma levels (R= 0.68, P < 0.001). Concentrations of amiodarone and N-desethyl-amiodarone in adipose tissue did not significantly increase with higher total cumulated doses or longer treatment duration. Nine of 12 patients who had received amiodarone for > or =2 years developed clinically important adverse effects, predominantly hypothyroidism (n= 6), compared with two of 18 patients treated for less time (relative risk 6.75; 95% confidence interval 1.8, 26). The incidence of those adverse effects was not significantly associated with amiodarone concentrations, whether in plasma or in adipose tissue. CONCLUSIONS: We found no evidence of excessive or unexpected accumulation of amiodarone in fat tissue on long-term administration. Late amiodarone adverse effects, particularly hypothyroidism, are associated with longer exposure times, but do not seem to be explained by higher concentrations in plasma or in fat tissue.

Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study.

BACKGROUND AND OBJECTIVES: Paracetamol (acetaminophen) has occasionally been reported to interact with warfarin. The primary end-point of this study was to investigate whether paracetamol initiation potentiates the anticoagulant effect of warfarin and the mechanism of the interaction. DESIGN AND METHODS: In a double-blind placebo-controlled, randomized, cross-over study, 20 patients on stable oral anticoagulant therapy with warfarin for at least 1 month were randomized to receive placebo or paracetamol 1g four times daily for 14 days. International Normalized Ratio (INR) and clotting factors activities were measured before the first administration and then on days 2, 4, 7, 9, 11,14. RESULTS: Mean INR rose rapidly after the start of paracetamol and was significantly increased within one week of paracetamol intake compared to placebo, p=0.0002. The INR values reached a mean maximum of 3.45+/-0.78 with paracetamol versus 2.66+/-0.73 with placebo (p=0.03), corresponding to a maximum increase from baseline of 1.20+/-0.62 with paracetamol versus 0.37+/-0.48 with placebo (p<0.001). Together with the rise in INR on paracetamol treatment there were significant reductions in the vitamin K-dependent clotting factors II, VII, IX and X. INTERPRETATION AND CONCLUSIONS: The most plausible hypothesis to explain the in vivo interaction is that paracetamol (or its metabolites) interfere with enzymes involved in vitamin K-dependent coagulation factor synthesis. Paracetamol at 4 g daily (a dose higher than that used in clinical practice) potentiates the anticoagulant response produced by warfarin. Clinicians should be aware of this clinically significant and underestimated interaction.

Pharmacokinetic-pharmacodynamic modeling of the effect of triamcinolone acetonide on central macular thickness in patients with diabetic macular edema.

PURPOSE: To develop a population model capable of describing the profile of the effect of intravitreal triamcinolone acetonide in the treatment of diabetic diffuse macular edema. METHODS: The results of 51 injections in 37 eyes (33 patients) with diffuse diabetic macular edema were studied, by using population pharmacokinetic-pharmacodynamic modeling, without triamcinolone concentration measurements. This approach was supported by the pharmacokinetic hypothesis that the intravitreal triamcinolone concentration decreases in accordance with an exponential biphasic equation. Central macular thickness (CMT), measured by optical coherence tomography was chosen as the pharmacodynamic parameter. RESULTS: The pharmacodynamic profile of the effect of triamcinolone on CMT was characterized by a curve in three phases: a fast decrease, a steady state, and a relapse. The confidence interval of most of the estimated parameters of the model was narrow. The mean estimated half-life of triamcinolone +/- SD was 15.4 +/- 1.9 days, and the mean maximum duration of its effect (+/-SD), 140 +/- 17 days. CONCLUSIONS: Pharmacokinetic-pharmacodynamic modeling using CMT constitutes a valid alternative to pharmacokinetic studies. This approach worked excellently in the present study, and the results are consistent with those published for the intraocular pharmacokinetics of triamcinolone acetonide in the human eye. The authors conclude that this type of investigation is of interest, as it avoids intraocular measurements as far as possible.

Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors: a dose-mediated deleterious effect.

BACKGROUND: By inhibiting prostaglandin synthesis, aspirin can interfere with both arterial functional and angiotensin-converting enzyme inhibitor (ACEI) properties and be deleterious in chronic heart failure (CHF). AIM: Our aim was to prospectively evaluate the effect of aspirin on arterial functional properties in CHF patients treated with ACEIs. METHODS AND RESULTS: Over three consecutive treatment periods of 7 days, 18 patients received placebo, followed by aspirin 100 mg/day, and then aspirin 325 mg/day. Single blind prospective assessment of reflected wave and time reflection by radial applanation tonometry; pulse wave velocity; blood pressure; thromboxane B2 (TxB2) and prostaglandins in plasma and urine was performed. Aspirin 325 mg/day induced a significant increase in augmentation index of reflected wave (P<0.0001 and P=0.0013 vs. placebo and aspirin 100 mg, respectively) and a significant decrease in reflected wave traveling times (P=0.0007 vs. placebo). Aspirin 100 mg/day produced a similar, though non-significant, trend in these parameters compared with placebo. Both aspirin treatments produced a statistically significant decrease in serum TxB2 (P<0.0001) but did not have an effect on the metabolite of prostaglandin I2 (P=0.136). CONCLUSION: This study demonstrates the existence of a dose-mediated deleterious effect of aspirin upon arterial functional properties in CHF patients treated with ACEI.

Management of oral anticoagulant in clinical practice: a retrospective study of 187 patients.

Oral anticoagulant (OA) therapy is widely used in elderly patients because of the increase of indications with age (venous thromboembolism and atrial fibrillation). A particularity of France is to administer three different OAs (warfarin and more often fluindione or acenocoumarol). In an attempt to assess the particularities of managing all three OAs in elderly patients in clinical practice, we studied the modalities of anticoagulation of 187 consecutive OA therapy patients (mean age = 74.4 years) hospitalized in an Internal Medicine department (95 patients on OA at admission and 92 patients initiated on OA during hospitalization). Patients aged 75 years or older more often required a low dosage of OA than those aged younger than 75, irrespective of the OA (warfarin and more often fluindione or acenocoumarol). Ambulatory patients aged 75 years or older were more susceptible to receive acenocoumarol than were ambulatory patients younger than 75 years (respectively 30/67 vs 8/28, respectively), whereas fluindione was prescribed at the same frequency in ambulatory patients and hospitalized patients, regardless of age group (> or =75: 32/67; <75: 19/28). In hospitalized patients with OA induction, fluindione was prescribed as often in patients younger than 75 than in patients aged 75 years or older (40/47 vs 35/45, respectively). On admission, international normalized ratio was in the target range in 26 of the 95 patients (27.4%) and was >3 in 51 of the 95 patients (51.6%). OA therapy was stopped during hospitalization in 35 patients (36.8%). In conclusion, we have a picture of the practice of anticoagulation with three different OA therapies. Although it is usually recommended to prescribe long half-time OA therapy (2), it appears that short half-time therapy such as acenocoumarol still represents an important number of OA prescriptions in France, especially in ambulatory and elderly patients. International normalized ratio is not in the target range as often as expected in clinical practice, and elderly patients require specific modalities of OA therapy management, such as half dose initiation, use of long-half-life OA, and close monitoring.

Does paracetamol potentiate the effects of oral anticoagulants?: a literature review.

Paracetamol (acetaminophen) is the analgesic and antipyretic therapy of choice for patients receiving oral anticoagulation. It is widely used by patients in both prescription and over-the-counter products, resulting in frequent co-prescription with oral anticoagulants, especially in elderly patients. Indeed, older patients are the most likely to receive this combination of drugs because indications for both oral anticoagulation and analgesic therapy increase with age. For many years reports have presented evidence both for and against the idea that paracetamol may potentiate the anticoagulant effect of oral anticoagulants, thus increasing haemorrhagic risk in patients receiving this combination of drugs. This issue has continued to be a matter of debate in recent publications. No clear practical conclusion can be drawn from the studies because of methodological bias and the lack of clinical relevance. No prospective, randomised study assessing the effect of paracetamol on the anticoagulant effect of oral anticoagulants as used in clinical practice (i.e. the types of patients and dosages used in clinical practice) are available in the literature. The implications are considerable since on the one hand, the ingestion of paracetamol may be a cause of altered anticoagulation in patients who regularly take oral anticoagulation and who may have a haemorrhagic risk factor; and on the other hand, paracetamol might be the analgesic drug of choice that can be used without the need for any restrictions in patients receiving oral anticoagulant drugs. A comprehensive search of Medline and EMBASE for studies and case reports from 1966-2002 was performed in order to review the available literature on the interaction between paracetamol and oral anticoagulant drugs. In conclusion, the potential interaction between oral anticoagulant drugs and paracetamol is an important unanswered question, due to the growing incidence of the concomitant use of these drugs and the possible bleeding implications. The association between paracetamol and the occurrence of excessive INR values remains controversial due to lack of prospective clinical studies assessing the effect of the prescription of paracetamol in patients receiving long-term oral anticoagulation in clinical conditions. Such a study is currently ongoing.

Defining the role of calcium channel antagonists in heart failure due to systolic dysfunction.

Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations. Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure. There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a 'class b' effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents. Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized clinical trials that assessed mortality as the primary endpoint. First generation CCAs have direct negative inotropic effects and even sustained release formulations have not proved any beneficial effect upon survival. With second generation CCAs, some benefit on hemodynamic parameters has been observed but none on survival, alone or in combination with ACE inhibitors. It is noteworthy that although amlodipine had a neutral effect on morbidity and mortality in large, randomized, placebo-controlled trials in patients with heart failure, the drug was well tolerated. There is no specific indication for CCAs (first or second generation) in patients with systolic heart failure, alone or in combination with ACE inhibitors, but amlodipine may be a considered in the management of hypertension or coronary artery disease in patients with heart failure.

Aspirin for the prevention of cardiovascular events in the elderly.

Aspirin (acetylsalicylic acid), the most widely used antiplatelet drug, is clinically effective for the prevention of vascular ischaemic events. Very few primary or secondary prevention trials address the benefit-risk ratio of aspirin in the elderly. In secondary prevention, it is generally accepted that the beneficial effect of aspirin in the general patient population, demonstrated by randomised controlled trials, can be extrapolated to the elderly. Elderly patients are at relatively high risk for the development of vascular disease and might also be expected to derive substantial benefit from regular aspirin administration. However, there is no consensus about the definition of elderly and no specific prospective trial conducted in elderly subjects is available. Retrospective studies in the elderly found that the benefit provided by aspirin in older patients was similar or increased compared with younger individuals. In primary prevention, the potential benefit of antiplatelet agents must be balanced against the risk of bleeding, which is higher in older patients. The risk-benefit trade-off from the use of low-dose aspirin in the elderly is not yet established and caution should be exercised when using aspirin in primary prevention. In conclusion, aspirin should only be given for primary and secondary prevention in the elderly after a comprehensive evaluation of an individual patient's thrombotic and haemorrhagic risk has been conducted.

D-dimer can predict survival in patients with chronic atrial fibrillation.

High mean levels of D-dimers (DD), markers of fibrin product and degradation, have been reported in patients with atrial fibrillation. In order to determine the predictive value of DD, 125 consecutive patients (mean age, 78 years) with chronic atrial fibrillation without acute disease were prospectively included. DD were quantified by Liatest at inclusion. Patients were followed for a mean duration of 2 years. DD and age at inclusion were significantly higher in patients who would die (n = 54) than in those who would not (n = 65). After multiple analysis of variance, age was not significantly related to prognosis (P = 0.36); low DD (P = 0.03) and oral anticoagulant therapy (P = 0.0192) were independently related to survival. In conclusion, a single determination of DD can strongly predict survival over the following 2 years. It may contribute to the risk stratification and perhaps to the choice of the antithrombotic therapy in high-risk patients with elevated DD.

Clinical trials in paediatric oncology. Recommendations for the development of new anticancer agents.

Childhood and adolescent cancers are rare diseases. Despite the progress in treatment (more than two-thirds of all cases are cured), cancer remains the leading cause of death by disease in children older than 1 year. Access to new drugs that are more efficacious or better tolerated is therefore an important public health priority. The objective of our round table was thus to take inventory of the situation and to propose recommendations aimed at facilitating coordinated, rational and more rapid access to new treatments. The active participation of paediatric oncologists, parents, pharmaceutical companies and regulatory authorities proved not only necessary but very constructive. Pharmaceutical companies have developed very few new anticancer agents for children during the past 10 years. The round table identified current trends that appear propitious: the mobilisation of parents and patients' associations; European initiatives to encourage companies to assess drugs in children; regulatory initiatives to guide drug development; and the existence of structured clinical research networks in paediatric oncology, including for the development of early treatment. The round table recommends the following measures to improve access to new treatments for children and adolescents with cancer: 1. Conduct preclinical paediatric evaluation of all anticancer agents that begin the development process for adults (research and validation of treatment targets; pharmacological evaluation in relevant experimental models) to help choose the agents to study in children. 2. Initiate paediatric clinical development before the first application for authorization for adults is filed, when sufficient safety and tolerability data are available, that is, after the phase I trials in adults and optimally during the phase II trials. 3. Optimise paediatric clinical evaluation by defining development plans early and by reducing the duration of studies (enlargement of the early treatment research network to ensure adequate recruitment; new evaluation methods; better extrapolation of pharmacological data from adults to children for dose-finding). 4. Improve information to and participation of parents and patients in clinical research for new treatments. The prerequisite for the success of this project became rapidly clear to all the round-table participants: cooperation and partnership between specialists and other scientists from academia, parent associations, pharmaceutical companies and regulatory authorities. Only with such cooperation can progress in treatment occur and new hopes for recovery be fulfilled.

[What are the criteria for evaluation and prevention of venous thromboembolism?]. / Quel critère d'évaluation en prévention de pathologie veineuse thromboembolique?

Venous thromboembolism occurs frequently in both medical and surgical units. Although we possess the therapeutic means to prevent this condition, the question is how to assess the benefit induced by a treatment in relation to the haemorrhagic risk? The primary evaluation criteria and the evaluation method must be correctly chosen. While phlebography is the reference method for diagnosing deep venous thrombosis, the limitations associated with this method have led to the promotion of other diagnostic techniques, and clinical criteria or composite criteria are increasingly used. These different approaches--with their respective advantages and limitations--will be developed.

[From the chemical product to the authorization of drug marketing]. / De l'entité chimique à l'autorisation de mise sur le marché d'un médicament.

A great number of highly qualified specialists are involved in the drug development process, mainly chemists, galenic and pharmacokinetic experts, pharmacologists and toxicologists. The 7 to 15 years development process implies preclinical studies in thousands of animals as well as clinical studies in about 3,000 patients. Various mandatory studies, regulatory requirements as well as a drug assessment process lead to the possible marketing authorization approval. The drug assessment process usually leads to a sound assessment of pharmaceutical quality of clinical benefit in each indication proposed; yet, occasionally, the assessment of safety is incomplete. Performing phase IV studies, collecting pharmacovigilance data is a requirement in the future. The prescriber of a newly approved drug must remain highly watchful.

Which treatment for patent foramen ovale in cryptogenic stroke?

The management of a patient with a cryptogenic stroke and a patent foramen ovale (PFO) depends on the existence of identifiable causes of stroke, on the PFO characteristics, on the characteristics of the patient, on the contraindications to antithrombotic therapy, and on the preference of the patient. There is no consensus on the management of a patient with a cryptogenic stroke and a PFO, but the algorithm presented in this article seems reasonable to these authors.

Low molecular weight heparin for the prevention of deep venous thrombosis: a suitable monitoring in elderly patients?

Monitoring of anti-Xa activity (aXa) levels is not routinely required in patients receiving enoxaparine at prophylactic dosages, since aXa is supposed to stay below the manufacturer's recommended range in patients treated for venous thrombosis (0.5-1 IU/ml). In order to aXa in elderly subjects receiving prophylactic enoxaparin, 68 consecutive patients (mean age 82.5 +/- 10.7 years) hospitalized in a medical department receiving 4000 IU enoxaparin daily subcutaneously for the prevention of venous thromboembolic disease were studied. After the first injection of enoxaparin, the aXa of 57.4% patients was superior to 0.5 IU/ml while 69.4% had an aXa higher than 0.5 after 8.4 +/- 1.2 days. A negative relationship between aXa and body weight and a trend towards a positive correlation between aXa and age but not with creatinine clearance were noted. Our findings question the opportunity to monitor aXa in elderly patients receiving 4000 IU enoxaparin as antithrombotic prophylaxis.

Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial.

OBJECTIVE: To evaluate prospectively the efficacy and safety of 1 intravitreal injection of 4 mg of triamcinolone acetonide for refractory diffuse diabetic macular edema. DESIGN: Interventional case series. PARTICIPANTS: Fifteen patients with bilateral diabetic macular edema unresponsive to laser photocoagulation. In all patients, one eye received the injection, and the other served as a control. INTERVENTION: Intravitreal injection of 4 mg of triamcinolone acetonide under subconjunctival anesthesia. MAIN OUTCOME MEASURES: The main outcome measure was central macular thickness (CMT) at 1, 3, and 6 months, measured by optical coherence tomography. Secondary outcomes were Early Treatment Diabetic Retinopathy Study (ETDRS) scores, intraocular pressure, and cataract progression. RESULTS: In this preliminary report, we give the results for 12 patients who had a follow-up of at least 3 months. Seven of them were followed up for 6 months. Before injection, CMT was 509.6+/-143.5 microm (mean +/- standard deviation [SD]) in injected eyes, versus 474.4+/-82.6 microm in control eyes. Four weeks after injection, it was 207.3+/-44.2 microm in injected eyes and 506.7+/-122.4 microm in control eyes (P<0.001, bilateral Wilcoxon test for paired samples), and after 12 weeks, 207+/-96.7 microm and 469.3+/-117.6 microm, respectively (P = 0.005). The difference between the CMTs of injected and control eyes was no longer significant at 24 weeks because of the recurrence of macular edema in 5 of 12 injected eyes. Before triamcinolone injection, the ETDRS score was 47.8+/-13 (mean +/- SD; range, 28-66) in injected eyes, versus 51.9+/-14.6 (range, 31-71) in control eyes. Twelve weeks thereafter, the corresponding values were 52.7+/-10.8 (range, 34-70) and 50.8+/-14.3 (range, 29-69), respectively, and at 24 weeks, 54.7+/-7.6 (range, 47-68) and 50.6+/-18.4 (range, 28-71). At no time was the difference between the ETDRS scores for injected and control eyes significant. In 6 of the 12 injected eyes, intraocular pressure exceeded 25 mmHg, and was controlled by topical medication. CONCLUSION: Intravitreal injection of triamcinolone effectively reduces macular thickening due to diffuse diabetic macular edema, at least in the short term. Further studies are required to demonstrate that it provides visual benefit.

Enhanced saquinavir exposure in human immunodeficiency virus type 1-infected patients with diarrhea and/or wasting syndrome.

The protease inhibitor saquinavir was administered to 100 human immunodeficiency virus type 1 (HIV-1)-infected patients as a single 600-mg oral dose (hard gelatin capsules) with a standard breakfast, including 200 ml of grapefruit juice, during an open-label trial to assess whether diarrhea and/or wasting syndrome has consequences on its pharmacokinetics. Three groups of patients were enrolled: group 1, asymptomatic patients (n = 30); group 2, AIDS symptomatic patients without body weight loss or diarrhea (n = 37); and group 3, AIDS symptomatic patients with severe body weight loss and/or diarrhea (n = 33). Clinical and biological data (covariates) were collected. A population approach was performed with three blood samples per patient to estimate the mean population pharmacokinetic parameters (clearance [CL]/oral bioavailability [F], V/F, k(a), and lag time) and the derived ones (k(el), C(max), T(max), and area under the curve [AUC]). The relationships between groups, exposure (i.e., estimated individual post hoc AUCs), and covariates were explored by using multiple linear regressions. A significant increase in median AUCs (165, 349, and 705 ng. h. ml(-1) for groups 1, 2, and 3, respectively [P < 0.0001]) was observed. The enhancement in saquinavir exposure could be due to the destruction of the transporters in enterocytes and/or to the enlargement of their tight junctions, allowing a paracellular crossing of saquinavir as the illness spreads. Because of grapefruit juice intake by every patient, no implication of CYP3A4 could be assessed. These results strongly suggest that, despite its low intrinsic oral bioavailability, saquinavir can be considered as a relevant treatment for HIV-1-infected patients with diarrhea and/or wasting syndrome. This must be evaluated in a long-term period.