Hervé Allain

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.

Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze.

Antidepressants are usually prescribed for the treatment of depression but more recently have also been recommended for the treatment of anxiety disorders. The purpose of this study was to investigate the anxiogenic- or anxiolytic-like effects of an acute administration of antidepressants (serotonergic and noradrenergic compounds) in male Wistar rats submitted to the elevated plus-maze. Fluoxetine (2.5, 5, 10, 15mg/kg), paroxetine (0.1, 0.5, 3, 12mg/kg) and desipramine (2.5, 5, 10mg/kg) or their vehicles were administered intraperitoneally 30min prior to testing. Diazepam (0.5, 1.5, 2.5mg/kg) was used as a positive comparator for anxiolytic effect. In comparison with control animals, the percentage of time the rats treated with fluoxetine (5 and 10mg/kg) and paroxetine (3 and 12mg/kg) spent in the open arms decreased. The percent of inactive time spent in the open arms also decreased in rats given fluoxetine (5 and 10mg/kg) and paroxetine (12mg/kg). Desipramine was inactive on all these parameters. In conclusion, acute treatment with fluoxetine and paroxetine, but not with desipramine, produced a pattern of anxiety behavior. Thus, the pharmacological mechanism appears to be due more to serotonergic than adrenergic neurotransmission. The elevated plus-maze exhibits good sensitivity for detecting anxiogenic effects of antidepressant drugs and the conventional parameters are sufficient and reliable for detecting such effects.

Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.

Effects of a new slow release formulation of caffeine on EEG, psychomotor and cognitive functions in sleep-deprived subjects

Caffeine is a widely‐consumed psychoactive substance whose stimulant effects on mood, attention and performance are largely recognised. The central nervous system pharmacodynamic profile of a single oral dose of a new slow release (SR) caffeine formulation (600 mg) was assessed in a randomised, double‐blind, crossover, placebo‐controlled study. Twelve young, health, male, sleep‐deprived (for 36 h) subjects were studied using EEG and various measures of psychomotor and cognitive functions, including critical flicker fusion (CFF), choice reaction task (CRT), tracking, continuous performance task (CPT), Stroop test, body sway and subjective evaluation (Stanford Sleepiness Scale). Caffeine significantly ( < 0/05) antagonised the detrimental effects of sleep‐deprivation on EEG (i.e. produced a significant decrease in delta and theta relative power and a significant increase in alpha and beta (12–40 Hz) relative power) and psychomotor performance (significant increase in speed of reaction on the CRT and Stroop tests, significant decrease in body sway, significant increase in accuracy of the CPT and significant reduction in subjective sedation) compared to placebo. The effect peaked 4 h after dosing and was maintained until the end of sleep deprivation (i.e. 24 h after dosing). In conclusion, the present results demonstrate that a single dose of caffeine SR possesses alerting effects which are able to reverse the deleterious effect of 36 h sleep deprivation for at least 24 h. Copyright

Antidepressants and cognition: comparative effects of moclobemide, viloxazine and maprotiline

The respective effects of three antidepressant drugs (moclobemide, 450 mg/j; viloxazine, 300 mg/j; maprotiline, 150 mg/j) on vigilance, attention, and memory were compared. Young depressed outpatients (n=46) entered a double-blind, randomised, monocentre clinical trial lasting for 6 weeks. Drug actions were assessed through the regular determination of critical flicker fusion point (CFF), reaction times (SRT), and a battery to measure memory components. None of the three drugs caused deterioration in cognitive functions. On the other hand, moclobemide improved both vigilance and attention (CFF, SRT) and some crucial components of memory (general memory scores, delayed word recall, recognition of familiar faces). This effect was rapid, stable, and superior to those of viloxazine and maprotiline. It may be explained by moclobemides selective and reversible inhibition of monoamine oxidase A, as well as by the lack of any anticholinergic action.

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.

Simultaneous quantitative assay of six HIV protease inhibitors, one metabolite, and two non-nucleoside reverse transcriptase inhibitors in human plasma by isocratic reversed-phase liquid chromatography

A rapid (less than 30 min), sensitive, and specific liquid chromatography method for simultaneous assay of nine antiretroviral drugs in human plasma is described. This technique allows therapeutic drug monitoring of six approved protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and two approved non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). Assays were performed after diethyl ether liquid–liquid extraction from 250-&mgr;L plasma samples. Chromatographic separation was achieved on an X-TERRA (Waters; Saint Quentin, France) column using a 58% water (with 3 mmol/L pyrrolidine) and 42% acetonitrile mobile phase. Three ultraviolet wavelengths were used for detection with a diode array detector. This method allowed quantitative assay of all nine antiretroviral drugs within a concentration range of 25 ng/mL to 9000 ng/mL. The method has been validated extensively and has been in routine use in our laboratory for several months for drug monitoring in plasma samples from patients treated with antiretroviral drugs.

Fecal incontinence with normal anal canal pressures: where is the pitfall?

ObjectiveOne third of subjects who suffer from fecal incontinence are found to have values within the normal range when anal manometry is performed. For these patients, one hypothesis is that impaired rectal adaptation to distension may occur. The aim of our study was to analyze anorectal responses to rectal isobaric distension in this population.MethodsThis was a prospective study conducted in 51 consecutive incontinent patients (45 female, six male) divided into two groups according to their functional anal state: absence (19 patients aged 55 ± 6 yr) or presence of manometric anal weakness (32 patients aged 59 ± 2 yr). The subjects were submitted to two randomized modes of rectal isobaric distension (tonic, phasic) with an electronic barostat. Anal pressures, perception, and volumes of the rectum were recorded at six different preselected pressures.ResultsAs compared with those having anal weakness, patients with no anal weakness retained higher mean pressures at both upper (36.9 ± 2.2 vs 22.9 ± 1.4 mm Hg; p= 0.01) and lower parts (41.0 ± 2.0 vs 23.3 ± 1.4 mm Hg; p= 0.002) of the anal canal, similar perception scores, but much lower rectal volumes (68.5 ± 5.5 vs 121.8 ± 7.0 ml; p= 0.008) in response to rectal isobaric distension.ConclusionsA decrease in rectal adaptation could be involved in fecal leakage in patients with no anal manometric weakness.

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.