Pitfalls in cefepime titration from human plasma: plasma- and temperature-related drug degradation in vitro.

While developing a high-pressure liquid chromatography assay for cefepime in plasma, we observed significant drug degradation at 20 and 37 degrees C but not at 4 degrees C. This plasma-related degradation persisted after protein removal. This warrants caution regarding cefepime assays for pharmacokinetic and pharmacodynamic studies of cefepime in vitro and in vivo.

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t½) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t½ of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t½ of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t½ of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Intrauterine growth restriction is associated with structural alterations in human umbilical cord and decreased nitric oxide-induced relaxation of umbilical vein.

INTRODUCTION: Intrauterine growth restriction (IUGR) affects ∼8% of all pregnancies and is associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiovascular diseases in adulthood. Despite identification of several risk factors, the mechanisms implicated in the development of IUGR remain poorly understood. In case of placental insufficiency, reduced delivery of oxygen and/or nutrients to the fetus could be associated with alterations in the umbilical circulation, contributing further to the impairment of maternal-fetal exchanges. We compared the structural and functional properties of umbilical cords from growth-restricted and appropriate for gestational age (AGA) term newborns, with particular attention to the umbilical vein (UV). METHODS: Human umbilical cords were collected at delivery. Morphological changes were investigated by histomorphometry, and UV's reactivity by pharmacological studies. RESULTS: Growth-restricted newborns displayed significantly lower growth parameters, placental weight and umbilical cord diameter than AGA controls. Total cross-section and smooth muscle areas were significantly smaller in UV of growth-restricted neonates than in controls. Maximal vasoconstriction achieved in isolated UV was lower in growth-restricted boys than in controls, whereas nitric oxide-induced relaxation was significantly reduced in UV of growth-restricted girls compared to controls. CONCLUSION: IUGR is associated with structural alterations of the UV in both genders, and with a decreased nitric oxide-induced relaxation in UV of newborn girls, whereas boys display impaired vasoconstriction. Further investigations will allow to better understand the regulation of umbilical circulation in growth-restricted neonates, which could contribute to devise potential novel therapeutic strategies to prevent or limit the development of IUGR.

Combination therapy with venlafaxine and carbamazepine in depressive patients non-responding to venlafaxine : pharmacokinetic and clinical aspects

Résumé L'antidépresseur chiral venlafaxine (VEN) est à la fois un inhibiteur de la récapture de la sérotonine et de la noradrénaline. Le CYP2D6 et le CYP3A4 contribuent à son métabolisme stéreosélectif. Dix patients génotypés au CYP2D6 et dépressifs (F32x et F33x, ICD-10) ont participé à cette étude ouverte sur les conséquences pharmacocinétiques et pharmacodynamiques d'une « augmentation » avec la carbamazepine chez des non-répondeurs à la venlafaxine. Après une première période de traitement de quatre semaines avec VEN (195 - 52 mg/ jour), le seul patient qui présentait un déficience génétique de CYP2D6 (poor metaboliser), avait les taux plasmatiques de S-VEN et R-VEN les plus élevés, tandis que ceux de R-0-déméthyl-VEN étaient les plus bas dans ce groupe. Comme seulement 4 patients ont été des répondeurs après 4 semaines de traitement, 6 patients ont été inclus dans la deuxième période de traitement combiné VEN et carbamazépine. Cinq patients non-répondeurs ont complété cette deuxième période d'étude de quatre semaines. Chez l'unique non-répondeur au traitement combiné, on pouvait observer à la fin de la période d'étude une diminution importante des deux énantiomères de VEN, 0-desmethy'lvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) et N, 0-didesmethylvenlafaxine (NODV) dans le plasma. Cela suggère un manque de compliance chez ce patient, mais une induction métabolique par la carbamazepine ne peut pas être exclue entièrement. L'administration de la carbamazepine (moyen ± s.d. (range) ; 360 ± 89 (200-400) mg/jour)) pendant quatre semaines n'a pas eu comme résultat une modification significative des concentrations plasmatiques des énantiomères de VEN et de ses métabolites 0- et N-démethylés chez les autres patients. En conclusion, ces observations préliminaires suggèrent qu'une combinaison de VEN et de carbamazepine représente une stratégie intéressante par son efficacité, sa tolérance et l'absence de modifications pharmcocinétiques, mais ces résultats devraient être vérifiés dans une plus grande étude.

Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.

A sample of 15 patients participating in an injectable methadone trial and of 15 patients in an oral methadone maintenance treatment, who admitted injecting part or all of their methadone take-home doses, were compared to 20 patients in maintenance treatment who use methadone exclusively by mouth. The present study confirms the poorer general health, the higher levels of emotional, psychological or psychiatric problems, the higher use of illicit drugs, and the higher number of problems related to employment and support associated with the use of the intravenous mode of administration of methadone. As expected, due to the shunt of metabolism in the gut wall and of the liver first-pass effect, higher concentration to dose ratios of (R)-methadone, which is the active enantiomer, were measured in the intravenous group (23% increase). This difference reached an almost statistically significant value (P = 0.054). This raises the question whether the effect of a higher methadone dose could be unconsciously sought by some of the intravenous methadone users.

Laparoscopic surgery for coeliac artery compression syndrome: current management and technical aspects.

Objectives: The study aims to assess the feasibility and midterm outcome of trans-peritoneal laparoscopy for coeliac artery compression syndrome (CACS).Design: Retrospective chart review involving four European vascular surgery departments and two surgical teams.Materials and methods: charts for patients who underwent laparoscopy for symptomatic CACS between December 2003 and November 2009 were reviewed. Preoperative computed tomography (CT) angiography and postoperative duplex scan and/or CT angiography were performed.Results: Eleven consecutive patients (nine women) with a median age of 52 years (interquartile range: 42.5-59 years) underwent trans-peritoneal laparoscopy for CACS. All patients had a history of postprandial abdominal pain; weight loss exceeded 10% of the body mass in eight cases. Preoperative CT angiography revealed coeliac trunk stenosis >70% in all cases. One patient had additional aortitis and inferior mesenteric artery occlusion, while another patient presented with an occluded superior mesenteric artery. Two conversions occurred (one difficult dissection and one aorto-hepatic bypass needed for incomplete release of CACS). The median blood loss was 195 ml (range: 50-900 ml) and median operative time was 80 min (interquartile range: 65-162.5 years). Symptoms improved immediately in 10/11 patients (no residual stenosis) while one remained unchanged despite a residual stenosis treated by a percutaneous angioplasty. Symptoms reappeared in one patient due to coeliac axis occlusion. The mean follow-up period was 35 +/- 23 months (range: 12-78 months).Conclusion: Our study demonstrates that trans-peritoneal laparoscopy for treating median arcuate ligament syndrome is safe and feasible. Additional patients and a longer follow-up are needed for long-term assessment of this laparoscopic technique. (C) 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Accès des patients agés aux urgences: evolution démographique et perspectives médico-ethiques [Access of elderly patients in the emergency department: demographic evolution and ethical perspectives].

Due to actual demographic evolution, emergency departments have to face a dramatic increase in admissions of elderly people. The peculiar medical and socio-demographic characteristics of these old patients emphasize the need of specific decision processes and resources allocation. An individual-based approach, related to significant ethical values, should allow better diagnostic and therapeutic attitudes. Such a way to admit, evaluate and treat older patients implies an active collaboration with patients and their relatives, but also with all medical interveners, including in particular primary care physicians.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

Circadian glomerular function: from physiology to molecular and therapeutical aspects.

Life on earth is rhythmic by essence due to day/night alternation, and many biological processes are also cyclic. The kidney has a special role in the organism, controlling electrolytes and water balance, blood pressure, elimination of metabolic waste and xenobiotics and the production of several hormones. The kidney is submitted to changes throughout 24 h with periods of intense activity followed by calmer periods. Filtration, reabsorption and secretion are the three components determining renal function. Here, we review circadian changes related to glomerular function and proteinuria and emphasize the role of the clock in these processes.