Danièle Bentué-Ferrer

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.

Simultaneous determination of 12 beta-lactam antibiotics in human plasma by high-performance liquid chromatography with UV detection: application to therapeutic drug monitoring.

ABSTRACT A rapid and specific high-performance liquid chromatography method with UV detection (HPLC-UV) for the simultaneous determination of 12 beta-lactam antibiotics (amoxicillin, cefepime, cefotaxime, ceftazidime, ceftriaxone, cloxacillin, imipenem, meropenem, oxacillin, penicillin G, piperacillin, and ticarcillin) in small samples of human plasma is described. Extraction consisted of protein precipitation by acetonitrile. An Atlantis T3 analytical column with a linear gradient of acetonitrile and a pH 2 phosphoric acid solution was used for separation. Wavelength photodiode array detection was set either at 210 nm, 230 nm, or 298 nm according to the compound. This method is accurate and reproducible (coefficient of variation [CV] < 8%), allowing quantification of beta-lactam plasma levels from 5 to 250 μg/ml without interference with other common drugs. This technique is easy to use in routine therapeutic drug monitoring of beta-lactam antibiotics.

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.

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.

Comparative Efficacies of Antibiotics in a Rat Model of Meningoencephalitis Due to Listeria monocytogenes

ABSTRACT The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to Listeria monocytogenes in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (P < 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 ± 0.5 log10 CFU/ml for amoxicillin-gentamicin, 5.0 ± 0.4 log10 CFU/ml for trovafloxacin, and 5.8 ± 0.5 log10 CFU/ml for TMP-SMX;P < 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 ± 0.8 and 2.7 ± 0.8 log10 CFU/ml, respectively) but more active than TMP-SMX (4.4 ± 0.6 log10 CFU/ml; P< 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment ofListeria infections may be warranted.

Alzheimer's disease: the pharmacological pathway

The current pharmacological treatment of Alzheimers disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing β‐amyloid and τ‐rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti‐apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti‐amyloid substances, (5) anti‐protein aggregation and (6) lipid‐lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Five-Year Follow-Up of Early Lisuride and Levodopa Combination Therapy versus Levodopa Monotherapy in de novo Parkinson’s Disease

The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson’s disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson’s disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson’s Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.