Unexpectedly long half-life of metformin elimination in cases of metformin accumulation.

INTRODUCTION: In a study of the oral administration of a single dose of metformin to healthy participants, the estimated half-life (t½ ) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation. METHODS: We systematically reviewed all the data on plasma and erythrocyte metformin assays available in our centre. We then selected patients with a plasma metformin concentration ≥ 5 mg/l and in whom the metformin concentration had been remeasured once or more at least 5 days after admission. RESULTS: Twelve patients met the aforementioned criteria. All but one of these patients displayed generally severe lactic acidosis on admission (mean ± sd pH and lactate: 6.88 ± 0.35 and 14.8 ± 6.56 mmol/l, respectively) and 11 were treated with dialysis. The mean ± sd time interval between the first and last blood sample collections for metformin measurement was 8.3 ± 3.2 days (range 5-14 days). Five days after the first sample had been collected, metformin was still detectable in plasma and in erythrocytes in all patients. Metformin remained detectable for up to 13 days (both in plasma and in erythrocytes). The estimated mean terminal t½ for metformin in plasma and erythrocytes was 51.9 and 43.4 h, respectively. CONCLUSIONS: The prolonged elimination of accumulated metformin (even after dialysis therapy) challenges the traditional view that the drug clears rapidly because of a short half-life in plasma.

[Low-molecular-weight heparin-induced bullous haemorrhagic dermatosis associated with cell-mediated hypersensitivity]. / Dermatose bulleuse hémorragique associée à une réaction d'hypersensibilité retardée sous héparine de bas poids moléculaire.

BACKGROUND: Heparin-induced bullous hemorrhagic dermatosis is a rare, recently described side-effect of subcutaneous heparin injection. We describe a patient simultaneously presenting distant haemorrhagic bullae and eczematous reaction at the low molecular-weight heparin (LMWH) injection sites. PATIENTS AND METHODS: Subcutaneous enoxaparin sodium was initiated in a 51-year-old patient and was replaced a few days later by tinzaparin sodium. Forty-eight hours later, annular, erythematous and vesicular plaques appeared at the injection sites (thighs). Small hemorrhagic bullae were noted on the abdominal skin at the same time. Skin biopsies revealed respectively eczematous dermatitis and an intraepidermal blister filled with red blood cells. Direct immunofluorescence was negative. Standard laboratory investigations and coagulation studies were unremarkable. Skin lesions disappeared ten days after discontinuation of LMWH. Patch tests and intradermal tests were negative. DISCUSSION: The case described herein shares the stereotypical clinical picture previously reported, namely small, multiple, haemorrhagic bullae on normal skin, appearing at remote sites five to 21 days after the start of subcutaneous heparin treatment. Despite the absence of clear management guidelines, it is obviously tempting to stop the heparin if there are too many bullae for fear of more clinically significant and dangerous mucous membrane lesions. The underlying physiopathological mechanism is poorly understood; no coagulation abnormalities were recorded. In addition, our patient presented an eczematous reaction at the injection sites, raising the possibility of a type IV hypersensitivity reaction. The association of these two cutaneous side effects of heparin is perhaps not purely coincidental.

Valvular heart disease in patients with Parkinson's disease treated with pergolide. Course following treatment modifications.

UNLABELLED: Valvular heart abnormalities have been reported in patients with Parkinson's disease (PD) treated with pergolide. However, the incidence and severity of these abnormalities vary from study to study and their course after drug withdrawal has not been systematically assessed. OBJECTIVES: To estimate the frequency and severity of valvular heart abnormality and its possible reversibility after drug withdrawal in a case-control study. METHODS: All PD patients in the Amiens area treated with pergolide were invited to attend a cardiologic assessment including transthoracic echocardiography. Thirty PD patients participated in the study. A second echocardiography was performed (median interval: 13 months) after pergolide withdrawal (n=10 patients). Controls were age- and sex-matched non-PD patients referred to the cardiology department. RESULTS: Compared to controls, aortic regurgitation (OR: 3.1; 95% IC: 1.1-8.8) and mitral regurgitation (OR: 10.7; 95% IC: 2.1-53) were more frequent in PD patients (tricuspid: NS). The number of affected valves (n=2.4+/-0.7) and the sum of regurgitation grades (n=2.8+/-1.09) were higher (p=0.008 and p=0.006, respectively) in the pergolide group. Severity of regurgitation was not correlated with pergolide cumulative dose. A restrictive pattern of valvular regurgitation, suggestive of the role of pergolide, was observed in 12/30 (40%) patients including two with heart failure. Pergolide was discontinued in 10 patients with valvular heart disease, resulting in a lower regurgitation grade (p=0.01) at the second transthoracic echocardiography and the two patients with heart failure returned to nearly normal clinical examination. This study supports the high frequency of restrictive valve regurgitation in PD patients treated with pergolide and reveals that a significant improvement is usual when the treatment is converted to non-ergot dopamine agonists.

[Mouth ulcers induced by enteric-coated mycophenolate sodium (Myfortic]. / Ulcérations buccales après prise de mycophénolate de sodium (Myfortic).

BACKGROUND: Mycophenolate sodium (Myfortic) is an enteric-coated formulation of the immunosuppressant therapy mycophenolic acid. We report a case of diffuse mouth ulceration in a patient treated with Myfortic presenting recurrence after another dose of drug. PATIENTS AND METHODS: We report the case of a 26-year-old female patient with systemic lupus erythematosus, initially treated with corticosteroids and mycophenolate mofetil, but which was stopped because of varicella-zoster dissemination and leucopoenia. She consulted for mouth ulcers occurring two weeks after the introduction of Myfortic. There were no signs of opportunist infection or lupus activity. Mucosal ulcerations disappeared when Myfortic was stopped. Several weeks later, the patient presented recurrence of mouth ulcerations after another treatment of Myfortic. DISCUSSION: Myfortic is a new enteric-coated formulation of mycophenolic acid developed to reduce gastrointestinal upset associated with Cellcept. In certain cases, Cellcept toxicity can present as a number of oral ulcerations. Direct toxicity is involved in these cases. This side effect has never been described with Myfortic. In our case, the distinctive characteristic is that the patient was never treated with Cellcept without mucosal toxicity despite equivalent systemic mycophenolic acid exposure.

[The best of clinical cardiovascular pharmacology in 2005]. / L'essentiel de 2005 en pharmacologie clinique cardiovasculaire.

Although the year 2005 has reinforced the therapeutic advances of 2004, with confirmation of certain concepts, the 'coxib affair' has continued to provoke arguments between pharmaceutical companies, licensing agencies as well as patients, some of whom have amalgamated into consumer groups to reject en masse placing any responsibility on the prescribers in favour of an attack on the drug licensing process itself. Among the cardiovascular drugs that will soon be licensed, only ivabradine in stable angina, and remodulin in primary pulmonary arterial hypertension are new. The therapeutic advances in 2005 regarding platelet aggregation and blood coagulation have been significant, in the human, scientific and commercial context, while hypertension has not been ignored. Another new development is the ever more precise notion of the metabolic syndrome, a target of choice for the pharmaceutical industry. The potential range of applications has been widened to include obesity, hypertension, diabetes, HDL cholesterol... The licensing authorities find themselves facing a hurdle to overcome, with novel combinations of drugs (ACE inhibitors, calcium blockers/statins, statins/aspirin, ARA2/calcium blockers...).

Parkinsonism and/or cognitive impairment with valproic acid therapy: a report of ten cases.

BACKGROUND: Valproic acid (VPA) is commonly prescribed and is generally considered to have a good safety profile. Severe neurological side effects, such as acute encephalopathy or tremor, are well-known. Parkinsonian syndromes and cognitive impairment have been very rarely reported with this drug. METHODS: Ten cases of reversible parkinsonism associated with VPA in 6 women and 4 men, associated with marked cognitive impairment in six cases, are described. These side effects sometimes occurred after several years of good tolerability. RESULTS: All patients had serum levels within the therapeutic range (50-100 microg/ml). Symptoms improved several weeks or months after discontinuation of VPA therapy in every case. CONCLUSIONS: Several cases of parkinsonian syndromes have been reported in the literature, but usually in children or young adults. These symptoms had an insidious and progressive onset. Clinical features can mimic Parkinson's disease and may be confusing, especially when they occur in older patients. The mechanism of these disorders is currently unknown, but several hypotheses have been proposed. Despite the good safety of VPA therapy for several years, a drug-induced mechanism of parkinsonism or cognitive impairment must be considered in all patients treated with VPA, as discontinuation of the drug can induce significant improvement of the patient's neurological and mental status.

[Extrapyramidal adverse effects of veralipride (Agreal), a drug used to treat hot flushes: a propos of 17 cases]. / Troubles extrapyramidaux sous véralipride (Agréal), traitement symptomatique des bouffées de chaleur: à propos de 17 cas.

PURPOSE: Extrapyramidal disorders associated with veralipride therapy are rarely reported and often due to a drug misuse. METHODS: We evaluated cases of extrapyramidal disorders associated with veralipride. Cases were extracted from the regional pharmacovigilance centre of Amiens database. From January 1, 1995 to September 30, 2004, cases were selected on the basis of the occurrence of extrapyramidal disorders under veralipride therapy. RESULTS: Seventeen cases of veralipride-induced extrapyramidal disorders were found. They consist of 16 menopausal women and one old man with LH-RH antagonist-induced hot flushes. Mean age was 61 years (48-73). Adverse effects were acute dyskinesia (n=2) or parkinsonian syndrome, which occurred after several months or years of treatment (n=15). Parkinsonism was associated with other extrapyramidal symptoms in 8 cases: tardive dyskinesia (n=6), postural tremor (n=3), myoclonia (n=1), and trunk dystonia (n=1). In all cases, outcome was favorable after drug discontinuation. In most cases the tablet-free interval was not respected: this may lead to prolonged striatal D2 receptors blockade. It must be added that the diagnosis was often delayed and patients were considered as suffering from idiopathic Parkinson's disease. CONCLUSIONS: Prescribers should be aware that veralipride is a neuroleptic and could induce potentially severe extrapyramidal disorders. Increase veralipride prescription is expected due to the recent restriction of hormonal replacement therapy for menopause. The physicians should also use veralipride according to the Summary of the Product Characteristics.

[The best of clinical pharmacology in 2004]. / L'essentiel de 2004 en pharmacologie clinique cardiovasculaire.

The year 2004 was not marked by major pharmacological advances, but by confirmation of previous "evidence". Several innovative drugs for stable angina (ranolazine, ivabradine), some interesting results in acute coronary syndrome (PROVE IT study), some classic concepts (cannabinoid receptors and their antagonists such as rimonabant) applied to novel indications (treatment of obesity), hopes for the "sartans" revived in the light of new evidence (VALUE study), advances in the management of diabetes and hypertension (ASCOT and CARDS studies), nebivolol which is not just a betablocker but also produces the NO radical (is this why it decreased the mortality of heart failure in the elderly in the SENIOR study?). In contrast, although Chronadalate did not live up to expectations for coronary insufficiency, the year was marked above all by the much heralded withdrawal of Vioxx for increasing cardiovascular risk. The old adage: primum non nocere springs to mind.

Impact of inflammation and oxidative stress on vascular calcifications in chronic kidney disease.

Vascular and/or valvular calcifications in patients with chronic kidney disease (CKD) appear to indicate a poor prognosis in terms of overall survival and cardiovascular morbidity and mortality. Inflammation and oxidative stress represent new features of the arterial and/or valvular calcification process. However, only limited observational and epidemiological data are available in these areas. Therefore, the link between inflammation, oxidation and vascular and/or valvular calcifications deserves careful consideration in CKD patients, since they may become targets for the development of new therapeutic strategies.

[Angioedema and angiotensin converting enzyme inhibitors: a report of 19 cases]. / Angio-oedèmes et inhibiteurs de l'enzyme de conversion de l'angiotensine: à propos de 19 cas.

PURPOSE: Inhibitors of angiotensin-converting enzyme are worldwide used and are a real progress for the treatment of systemic hypertension or cardiac failure and are a real progress. The most common adverse side effect is cough. Angioedema is a sudden and localized edema involving the deeper cutaneous and mucosa tissue lappers. 0.1-0.5% of patients treated by ACE inhibitors could develop angioedema. MATERIALS AND METHODS: We report a series of 19 cases, recruited in the Parmacovigilance Center of the University Hospital of Amiens from 1997 to 2003. RESULTS: All the patients had a facial swelling edema at initial presentation. Intestinal mucosa or preputial are misleading localisations. In 1/3 of cases, angioedema appeared after the first administration, in 1/3 of cases it appeared with a delay of 1-2 years. The oropharynx localisation with glottic involvement may need an airway intervention. One patient died from pulmonary distress at home. CONCLUSION: The pathophysiology is current unknown although there is increasing evidence for bradykinin accumulation involvement. The treatment by ACE inhibitors must be broken off; angiotensin II antagonists may be an alternative treatment, but has to be introduced carefully.

Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.

OBJECTIVES: Although the existence of a deep compartment for metformin has long been hypothesized, there is still little direct information concerning metformin distribution in individual tissues in man. The only available study involves chronic metformin therapy. In that study, the measurement of metformin in erythrocytes provided a reliable indicator of metformin distribution and of potential accumulation. To determine the kinetics of metformin in plasma and in erythrocytes after acute oral administration, we performed the present study in healthy subjects after a single oral dose of metformin and compared the pharmacokinetics parameters in erythrocytes to those in plasma. METHODS: Six nondiabetic participants took the study dose of 850 mg metformin at 8: 00 AM after a non-standardized breakfast (i.e., as recommended in clinical practice). Blood samples were collected for metformin measurement in plasma and in erythrocytes at 0, 1, 2, 3, 4, 6, 9, 24, 33, 48, 57, and 72 h. RESULTS: Maximum metformin concentration was attained at 3.0 +/- 0.3 h in plasma and 4.7 +/- 0.5 h in erythrocytes. This difference was not significant. Metformin concentrations peaked at a maximum almost 6 times higher in plasma than in erythrocytes (1.7 +/- 0.1 and 0.3 +/- 0.0 mg/l, respectively). However, because the elimination half-life of metformin was much longer in erythrocytes (23.4 +/- 1.9 h vs. 2.7 +/- 1.2 h), there was no difference in area under the curve between plasma and erythrocytes. The distribution volume (plasma) was calculated to be 146 +/- 11 l. Plasma and erythrocytes concentration-time curves showed that metformin was not detectable in plasma 24 hours after the oral administration, while it remained detectable in erythrocytes up to 48 hours. Metformin concentrations crossed approximately 13 hours after having reached their maximum values in plasma, approximately 16 h after metformin intake. CONCLUSION: Having demonstrated the rapid elimination of metformin from plasma and its slow disappearance from erythrocytes, the presents results should contribute to adjustment of metformin dosage to renal function, assessment of drug compliance, and retrospective analysis (when blood samples are drawn with delay) of the link between metformin and development of lactic acidosis. Most importantly, the present findings should help to ascertain the optimal dosage of metformin, particularly in elderly patients.

[The best of clinical pharmacology in 2002]. / L'essentiel de 2002 en pharmacologie clinique et thérapeutique.

The results of several large therapeutic cardiovascular trials were reported in 2002. The LIFE study concluded that losartan is superior compared to atenolol in terms of prevention of cardiovascular morbidity and mortality, the benefit being for CVA without changing the incidence of myocardial infarction. The OPTIMAAL study stated the disappointing results of post-infarct losartan. The IONA study represents a first demonstration with nicorandil of benefit not only in angina crises but equally on cardiac morbidity and mortality. The HPS study confirms the benefit of a statin in secondary prevention but for the first time, no matter what the initial level of LDL-cholesterol. Finally in the LIPS study, it is reported that statins reduce major cardiovascular events after coronary angioplasty. The year 2002 was marked elsewhere by imagination after the publication of the RAVEL study on coated stents delivering anti-proliferative drugs in order to avoid coronary restenosis. Three drugs were the subject of work confirming their potential significance in cardiovascular pathology: a) ezetimibe, representing a new class of cholesterol lowering drugs with which the association with statins seems especially synergic, b) nesiritide recombinant type B natriuretic peptide, whose significance was confirmed in acute cardiac insufficiency. c) levosimendan (calcium sensitisor) which moreover can be a significant treatment in cardiac decompensation as suggested by the LIDO study with a follow up of 180 days. By contrast, omapatrilate did not confirm its potential superiority over ACE inhibitors in the treatment of cardiac insufficiency. Some encouraging data were reported in 2002 in the field of therapeutic angiogenesis as much at the myocardial level as in lower limb arteritis. Finally, 2002 was marked by the publication of the WHI study which intensified suspicions regarding hormonal substitution treatment, confirming the advantage of not only secondary but perhaps primary cardiovascular prevention.

[Intracranial hemorrhages associated with oral anticoagulant therapy. Analysis of 38 cases]. / Hémorragies intracrâniennes associées à un traitement anticoagulant oral. Analyse de 38 observations.

The major risk of oral anticoagulant therapy is haemorrhage potentially affecting all organs. Bleeding in the central nervous system is a rare but severe complication of anticoagulant therapy. This study aimed to analyse a series of intracranial haemorrhages. This series from the Regional Pharmacovigilance Center of Amiens included spontaneously reported and retrospectively collected cases from January 1999 to December 2000. During this period, 38 cases of intracranial bleeding possibly related to oral anticoagulant administration were reported; 19 women and 19 men, median age 69.5 (29 to 87) years. In 34% of the cases, patients died and in 18% neurologic sequelae were still present at the time of the evaluation. In 21 cases (62%), the INR (International Normalized Ratio) was higher than the therapeutic range recommended for the indication. Among the most frequent risk factors, hypertension and recent minor trauma are highlighted in this series. In 17 cases, oral anticoagulants were associated with potentially potentiating drugs. Mental status changes or headache were prominent early symptoms which had often been present for days. Our data confirm that anticoagulant-associated intracranial haemorrhages are not rare, can be severe, potentially fatal and are probably underestimated by physicians. The fact that more than 50% of patients in this series were overanticoagulated at the time of bleeding suggests that many cases of intracranial haemorrhage could be prevented by improved anticoagulation control. Epidemiological studies are needed in order to prospectively evaluate the incidence of this type of complication and its avoidance. The value of anticoagulation clinics can be discussed.

[Oxidative stress, atherogenesis and cardiovascular risk factors]. / Stress oxydant, athérogenèse et facteurs de risque cardiovasculaire.

Cardiovascular diseases are the main cause of mortality in the western world. It is widely accepted that atherosclerosis, the first etiology, is influenced by free radicals and the oxidizing stress that they cause. In the oxidative theory of atherosclerosis, the atheromatous lesion is initiated by oxidation of two density lipoproteins (LDL), a process still known as lipid peroxidation. Oxidized LDL have many effects on the cells of the vessel wall which, provide an explanation to most of the cellular and tissular changes observed in the plaque. The vascular complications of hypercholesterolaemia, diabetes, hyperhomocysteinemia, hypertension and smoking may, in part, be secondary to oxidizing stress that impairs endothelial function and modify the lipids in the intima of the vessels. The aim of this paper is to review the modes of free radical production, to determine the role of oxidizing stress in the development of atherosclerosis and to show how the different risk factors may initiate atheroma through oxidizing stress.

[The best of 2001. Clinical pharmacology]. / L'essentiel de 2001 en pharmacologie clinique.

In the field of cardiovascular pharmacology the year 2001 has been marked by the demonstration of the clinical significance of new anti-thrombotics and by the interesting results with anti-endothelins. Whereas the failure of oral antiGPIIb-IIIa has been confirmed, melagatran (an anti-thrombin administered orally) and pentasaccharide (a new subcutaneous anti-Xa) have proved their efficacy in the prevention of venous thromboembolic disease compared to low molecular weight heparins, with an acceptable incidence of unwanted effects. Anti-endothelins under development have variable mechanisms of action from one drug to another. Their efficacy in cardiac insufficiency, pulmonary artery hypertension and arterial hypertension is suggested by clinical studies investigating small population; a more important study in decompensated cardiac insufficiency has not however shown a reduction of the morbidity and mortality with one of these drugs. The clinical significance of angiotensin II receptor antagonists has been confirmed for the indications which they share with ACE inhibitors (cardiac insufficiency, prevention of diabetic nephropathy). However, there are not enough comparative trials for these indications between these two classes in order to draw conclusions about the equivalence or superiority of one or the other. Of help elsewhere has been a re-interpretation of the mode of action of arterial wall drugs, and the inflammatory theory of atherosclerosis, putting the accent for example on the reduction of C reactive protein with a statin, or on the anti-inflammatory effect of aspirin. However, one study has not shown any benefit in giving a short course of corticosteroids in unstable angina. A very prominent event in the year 2001 remains the withdrawal of cerivstatin due to fatal rhabdomyolysis. The consequences go far beyond this drug, as its withdrawal justifies a fresh examination of the risk-benefit ratio for all the statins, with the probable corollary of a halt in the escalation of prescriptions. In this context, the new ezetimibe-type cholesterol absorption inhibitors could be a future solution.