Elisabeth Polard

Postural Instability and Consequent Falls and Hip Fractures Associated with Use of Hypnotics in the Elderly A Comparative Review

The aim of this review is to establish the relationship between treatment with hypnotics and the risk of postural instability and as a consequence, falls and hip fractures, in the elderly.A review of the literature was performed through a search of the MEDLINE, Ingenta and PASCAL databases from 1975 to 2005. We considered as hypnotics only those drugs approved for treating insomnia, i.e. some benzodiazepines and the more recently launched ‘Z’-compounds, i.e. zopiclone, zolpidem and zaleplon.Large-scale surveys consistently report increases in the frequency of falls and hip fractures when hypnotics are used in the elderly (2-fold risk). Benzodiazepines are the major class of hypnotics involved in this context; falls and fractures in patients taking Z-compounds are less frequently reported, and in this respect, zolpidem is considered as at risk in only one study. It is important to note, however, that drug adverse effect relationships are difficult to establish with this type of epidemiological data-mining. On the other hand, data obtained in laboratory settings, where confounding factors can be eliminated, prove that benzodiazepines are the most deleterious hypnotics at least in terms of their effects on body sway. Z-compounds are considered safer, probably because of their pharmacokinetic properties as well as their selective pharmacological activities at benzodiazepine-1 (BZ1) receptors. The effects of hypnotics on balance, gait and equilibrium are the consequence of differential negative impacts on vigilance and cognitive functions, and are highly dose- and time-dependent. Z-compounds have short half-lives and have less cognitive and residual effects than older medications.Some practical rules need to be followed when prescribing hypnotics in order to prevent falls and hip fractures as much as possible in elderly insomniacs, whether institutionalised or not. These are: (i) establish a clear diagnosis of the sleep disorder; (ii) take into account chronic conditions leading to balance and gait difficulties (motor and cognitive status); (iii) search for concomitant prescription of psychotropics and sedatives; (iv) use half the recommended adult dosage; and (v) declare any adverse effect to pharmacovigilance centres. Comparative pharmacovigilance studies focused on the impact of hypnotics on postural stability are very much needed.

Clinically significant drug interactions with cholinesterase inhibitors a guide for neurologists

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer’s disease. These drugs are also being used off label to treat severe cases of Alzheimer’s disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors.The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors.A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.

Safety of Calcium Dobesilate in Chronic Venous Disease, Diabetic Retinopathy and Haemorrhoids

The aim of the present review is to consider the adverse effects and the safety profile of calcium dobesilate. Calcium dobesilate (Doxium™) is a veno-tonic drug, which is widely prescribed in more than 60 countries from Europe, Latin America, Asia and the Middle East for three main indications: chronic venous disease, diabetic retinopathy and the symptoms of haemorrhoidal attack.Data sources used for this review comprise the international literature (1970–2003), a postmarketing surveillance (PMS) report for calcium dobesilate from OM Pharma (Geneva, Switzerland) covering the period 1974–1998, and periodic safety update reports (PSUR) covering the period 1995–2003 from the French Regulatory authorities pharmacovigilance database and OM Pharma. Data from the PMS report for 1974–1998 indicated that adverse events with calcium dobesilate did not occur very frequently and had the following distribution in terms of frequency: fever (26%), gastrointestinal disorders (12.5%), skin reactions (8.2%), arthralgia (4.3%), and agranulocytosis (4.3%). No deaths were attributed to calcium dobesilate in the PMS report. Using data on product use in the Swiss Compendium we estimated the prevalence of agranulocytosis to be 0.32 cases/million treated patients, i.e. ten times less than the calculated prevalence of agranulocytosis in the general population. Most adverse events are type B, i.e. rare and unrelated to the pharmacological properties of calcium dobesilate.This review concludes that the risk of an adverse effect with calcium dobesilate 500–1500 mg/day is low and constant over time. The recently raised problem of agranulocytosis (a total of 13 known cases drawn from all data sources) appears to be related to methodological bias. Such a review reinforces the need for a strong international pharmacovigilance organisation using similar methods to detect and analyse the adverse effects of drugs.

Psychomotor and cognitive effects of piribedil, a dopamine agonist, in young healthy volunteers

Piribedil is a dopamine agonist acting on D2 and D3 central nervous system dopamine receptors. This drug has been administered to 12 young healthy male volunteers (age 22 ± 2 years) according to a single center randomized, double‐blind, two ways cross‐over, placebo controlled trial, including a washout period of one week. Placebo and piribedil were administered by a single intravenous infusion over 2 h (3 mg). Psychomotor performance and cognitive functions were assessed through a standardized and computerized psychometric tests battery and a continuous electroencephalogram (EEG) mapping. Piribedil improved simple reaction time (P=0.02), immediate (P=0.045 and 0.004), and delayed free recall (P=0.05), dual coding test (P=0.02) and increased theta and fast beta waves on the EEG (P < 0.05 and 0.001, respectively). No deleterious effect was observed on the tests exploring attention and concentration via the other procedures. It is concluded that a single intravenous perfusion of piribedil 3 mg improves alertness and the information processing speed within the central nervous system, in healthy volunteers.

Non steady state and steady state PKS Bayesian forecasting and vancomycin pharmacokinetics in ICU adult patients.

The pharmacokinetics of vancomycin was investigated in adult ICU patients after the first administration and at steady state. Then the predictive performance of a two-compartment Bayesian forecasting program was assessed in these patients by using population-based parameters and three non steady state vancomycin concentrations as feedback information. Finally a prospective investigation was carried out to search potential covariates. At steady state, a significant decrease (around 30%) in clearance (CL) was observed, while creatinine clearance (CLcr) was stable and a significant increase (around 30%) in volume of distribution (V(SS)) was observed. A two-fold increase in elimination half-life was found. CL was weakly correlated with CLcr at onset of therapy and at steady state. The Bayesian program tended to overpredict vancomycin peak and trough concentrations. A larger mean prediction error and a poorer precision were observed when population-based parameter estimates were used (no feedback) compared to feedback prediction, but the differences were not significant. Mechanical ventilation and concurrent opioid therapy may be pertinent covariates of vancomycin pharmacokinetics. The current work has shown that vancomycin pharmacokinetics in ICU patients displayed a significant variability and a significant change in both clearance and distribution during the course of therapy. Further investigation is necessary to clarify these findings. Moreover, the use of the Bayesian forecasting PKS program in our patients led to a prediction with low bias but rather poor precision. This outcome highlights the need to implement a population modeling approach, to determine the vancomycin pharmacokinetic parameters and covariates in our ICU patients, and to apply this information to provide more accurate concentration predictions.

Complicated Atazanavir-Associated Cholelithiasis: A Report of 14 Cases

Fourteen human immunodeficiency virus (HIV)-infected patients receiving an atazanavir (ATV)-based antiretroviral regimen developed complicated cholelithiasis. ATV was found in biliary calculi in 8 of 11 cases: infrared spectrometry analysis of calculi revealed that ATV made up a median of 89% (range, 10%-100%) of the total calculus composition. Development and management of ATV-associated cholelithiasis are discussed.

In vitro and in vivo evaluation of polylactide and polylactide-co-glycolide microspheres of morphine for site-specific delivery

Abstract The aim of using opioid drugs such as morphine in chronic pain is optimal pain relief with a minimum of side effects. After the discovery that opioids could produce analgesia when administered intrathecally or extradurally, there has been particular interest in their administration by these routes and other site-specific routes. Controlled release systems of morphine are not currently available for parenteral routes. So, the design of a controlled release system for this analgesic was undertaken. To reach this goal, morphine-loaded microspheres (MLMs) made with polylactide and polylactide-co-glycolide polymers were prepared by the solvent evaporation process. MLMs were characterized by optical and scanning electron microscopy, by their drug contents and in vitro release kinetics. MLMs were then administered via subcutaneous injection in rabbits. The in vivo results, in accordance with the in vitro release studies, showed: (i) a controlled release of morphine avoiding high plasma levels; and (ii) an extended release of morphine.

Brand name to generic substitution of antiepileptic drugs does not lead to seizure-related hospitalization: a population-based case-crossover study

Sequential pattern mining algorithms are widely used to explore care pathways database, but they generate a deluge of patterns, mostly redundant or useless. Clinicians need tools to express complex mining queries in order to generate less but more significant patterns. These algorithms are not versatile enough to answer complex clinician queries. This article proposes to apply a declarative pattern mining approach based on Answer Set Programming paradigm. It is exemplified by a pharmaco-epidemiological study investigating the possible association between hospitalization for seizure and antiepileptic drug switch from a french medico-administrative database.There is still controversy on brand‐to‐generic (B‐G) antiepileptic drugs (AEDs) substitution.

131I-Labeled Lipiodol-Induced Interstitial Pneumonia: A Series of 15 Cases

BACKGROUND The drug (131)I-labeled lipiodol is used as internal radiotherapy for unresectable hepatocellular carcinoma. Although the drug was considered safe during preapproval studies, we observed several cases of interstitial pneumonia following its administration. METHODS Cases were retrospectively identified through the drug safety unit database of Rennes University Hospital. RESULTS From 1994 to 2009, interstitial pneumonia developed in 15 patients following (131)I-labeled lipiodol administration, with an estimated prevalence of 15.5 cases (95% CI, 7.7-23.2) per 1,000 treated patients. Mean age of the patients was 60 ± 8 years, and the male to female ratio was 6.5:1. All patients had cirrhosis, mainly related to long-term alcohol intoxication (n = 12). Most (n = 10) cases occurred after the second (131)I-labeled lipiodol injection. The median delay between last (131)I-labeled lipiodol administration and first respiratory symptoms was 30 days (interquartile range, 16.5-45 days). All patients presented with shortness of breath. Physical examination mostly revealed fever (n = 11) and bilateral crackles (n = 12). Chest CT scan showed bilateral ground-glass opacities (n = 8) with septal thickening, retraction, or both (n = 8). BAL (n = 7) was remarkable for increased neutrophils (n = 4) or CD8(+) T cell count (n = 3). Despite corticosteroids, 12 (80%) patients died, mostly of untractable respiratory failure (n = 9). Median delay between last (131)I-labeled lipiodol injection and death was 63 days (interquartile range, 34-129 days). CONCLUSIONS Interstitial pneumonia may be a serious and not uncommon complication of (131)I-labeled lipiodol administration.

Passage à la chronicité d’une toux : quels mécanismes ?

Resume Introduction Dans certaines situations, telles les toux post-virales ou post-coqueluchoides, le clinicien est confronte a une toux chronique non productive que ne peuvent expliquer ni une inflammation sous-jacente, ni une erosion de l’epithelium, ni une broncho-constriction. Cette toux subaigue ou chronique constitue un veritable syndrome (toux maladie) cause et entretenu par le systeme nerveux central (SNC) et ses efferences ortho et parasympathiques, siege d’un reajustement fonctionnel ou interviennent des mecanismes de plasticite neuronale (intervention des recepteurs de type NMDA au glutamate). Etat des connaissances Les neurones situes dans la zone expiratoire des centres de la respiration (le complexe Pre-Boetzinger du tronc cerebral) font l’objet d’un apprentissage a la decharge (firing) , du fait d’une stimulation repetee des recepteurs NMDA ; ce phenomene est similaire au phenomene de potentialisation a long terme (PLT) base moleculaire de la memoire et de la neosynaptogenese. Ces donnees suggerent l’interet potentiel d’un antagonisme precoce des mecanismes d’amplification et donc de perennisation du reflexe de toux. Perspectives Une piste plus recente est envisageable, faisant intervenir les recepteurs de type 4 a la serotonine (5HT 4 ) antagonisant la depression respiratoire induite par les opiaces (fentanyl). Une surstimulation ou une surexpression de ces recepteurs, toujours dans la zone de Pre-Boetzinger, pourrait contribuer a l’accentuation du reflexe de toux. Conclusions Ces phenomenes d’amplification d’un reflexe meritent consideration car ils sont accessibles a la therapeutique, et antagonises precocement, devraient limiter l’extension de la toux chronique.