Louis Merle

Predicting and Preventing Adverse Drug Reactions in the Very Old

The size of the elderly population has been increasing steadily for several years. Individuals in this age group often have several concomitant diseases that require treatment with multiple medications. These drugs, for various reasons and especially as a consequence of potential accumulation, may be associated with adverse reactions. Of the numerous factors that can favour the occurrence of these adverse drug reactions, the most important are the pathophysiological consequences of aging, particularly as these apply to the very old.Although absorption of drugs is not usually reduced in the elderly, diffusion, distribution and particularly elimination decline with age. Furthermore, while hepatic metabolic function is fairly normal, renal function is usually markedly depressed in very old individuals, and this can translate into clinical consequences if it is not taken into account. This is why, before administration of any drug in the elderly, evaluation of glomerular filtration rate is essential. Validated estimations such as those obtained from the classical Cockcroft-Gault formula or from more recent methodologies are required.In addition to reductions in various organ functions, factors connected with very old age such as frailty, falls, abnormal sensitivity to medications and polypathology, all of which tend to be more common in the last years of life, all directly impact on adverse drug reaction occurrence.Given these characteristics of the elderly population, the best way to reduce the prevalence of adverse drug reactions in this group is to limit drug prescription to essential medications, make sure that use of prescribed agents is clearly explained to the patient, give drugs for as short a period as possible, and periodically re-evaluate all use of drugs in the elderly.

Inappropriate Medications in the Elderly

The aging of the world population is a new medical challenge for the 21st century. There has been a striking increase in the proportion of elderly people, especially the very old, over the past decades. The elderly are living longer due, in part, to improved standards of living and the availability of social aid and medical care. Although some people reach a very old age completely free of physical ailments, most elderly people have several chronic diseases. Modern pharmacotherapy can slow down and delay the consequences of these ailments up to the eighth decade of life, but thereafter the complications of these diseases will usually become clinically significant. This often results in the administration of several drugs simultaneously.

Impact of Hospitalisation in an Acute Medical Geriatric Unit on Potentially Inappropriate Medication Use

Background and objectivePotentially inappropriate medication use is a major safety issue in the elderly and may cause a substantial proportion of drug-related hospital admissions. Hospitalisation could result in a change in the quantity and type of drugs, but its effect on potentially inappropriate drug use is still unknown. The aim of this study was to estimate the potentially inappropriate medication prevalence in patients ≥70 years of age at admission to and at discharge from an acute medical geriatric unit, and to identify the factors associated with no longer being a potentially inappropriate drug user at hospital discharge.MethodsA prospective drug surveillance study was undertaken in 2018 elderly patients (≥70 years of age) admitted to an acute medical geriatric unit in Limoges University Hospital, France. Prescribing patterns were established at admission and at discharge. Potentially inappropriate medication use was evaluated according to a list derived from the Beers criteria and adapted to French practice. “To be no longer a potentially inappropriate drug user at discharge” was defined as using at least one potentially inappropriate medication at admission and not using it at discharge.ResultsThe numbers of drugs used at admission/discharge were 6.2 ± 3.1/5.4 ± 2.5. The prevalence of potentially inappropriate medication use decreased from 66% (95% CI 63.8, 68.0) at admission to 43.6% (95% CI 41.3, 45.9) at discharge. At discharge, 535 subjects were no longer potentially inappropriate medication users. Multivariate analysis showed that no longer being a potentially inappropriate medication user was associated with the number of drugs used (4–6 drugs vs ≤3 odds ratio [OR] 1.20; 95% CI 0.86, 1.68; 7–9 drugs vs ≤3 OR 1.37; 95% CI 0.97, 1.93; ≥10 drugs vs ≤3 OR 1.64; 95% CI 1.10, 2.44), age (80–89 years vs 70–79 years OR 1.38; 95% CI 1.03, 1.85; ≥90 years vs 70–79 years OR 1.69; 95% CI 1.22, 2.83), cerebral vasodilator use (OR 2.87; 95% CI 2.31, 3.57), analgesic use (OR 1.54; 95% CI 1.06, 2.25) and concomitant use of psychotropic drugs of the same therapeutic class (OR 1.94; 95% CI 1.29, 2.92).ConclusionHospitalisation in geriatric services results in a reduction in potentially inappropriate medication use. Improved pharmacological education of practitioners, especially with regard to drug adverse effects, is desirable to improve management of geriatric patients.

Buprenorphine withdrawal syndrome in a newborn

A pregnant woman who was addicted to heroin rapidly withdrew from illicit drugs after the onset of a 4 mg/day buprenorphine treatment. In the newborns blood, urine, and meconium 20 hours after birth, high concentrations of buprenorphine and its metabolite norbuprenorphine were detected, with a higher buprenorphine/norbuprenorphine ratio than in adults, possibly as a consequence of immature hepatic function; no illicit drugs were found. The child had a weak withdrawal syndrome on the second day of life and recovered rapidly. The measured buprenorphine daily dose ingested by the newborn through mothers milk was very low (3.28 μg) and probably had little pharmacologic effect because no withdrawal signs could be noted when maternal feeding was later abruptly interrupted. Further investigations are required to determine whether buprenorphine can be considered to be a good alternative to methadone in the treatment of pregnant heroin addicts to prevent marked withdrawal syndromes in newborns.

Médicaments potentiellement inappropriés aux personnes âgées: intérêt d'une liste adaptée à la pratique médicale française

Drug induced adverse effects are frequently encountered in geriatrics. Their occurrence can be limited by an adapted prescription. Potentially inappropriate medications are drugs with an unfavourable benefit to risk ratio when other safer or more efficient therapeutic alternatives are available. An expert consensus allowed us to establish a new list of potentially inappropriate medications for people aged 75 or over, taking into account French prescribing habits. The drugs or the drug-classes proposed in this list are, generally speaking, and when possible, to be avoided in the elderly, but can be prescribed at times, under special clinical conditions, provided that the benefit to risk ratio is assessed. The French list proposed here could be considered as (i) an epidemiological tool for evaluating the quality of drug prescription in geriatrics and as (ii) a prescription guide suggesting an alternative treatment whenever a therapeutic alarm is raised. This guide could be used both as a base for the education of prescribers and as a way of increasing patients awareness. This French list should be kept up-to-date so as to remain adapted to the evolution of the knowledge on the effect of drugs in the elderly and of the pharmaceutical market.

Paraoxonase 1 192/55 Gene Polymorphisms in Alzheimer's Disease

Abstract: An esterase, paraoxonase 1 (PON1), protects against organophosphate neurotoxicity and decreases lipoprotein oxidation. Two polymorphisms of PON1 [192 (R or Q) and 55 (M or L)] exist and are associated with coronary artery disease. We have previously shown that serum PON1 activity (PON1a) is lower in vascular dementia (VaD) than in Alzheimers disease (AD), suggesting that PON1a may distinguish VaD from AD. As PON1 polymorphism modifies PON1a, we determined 192 and 55 PON1 polymorphisms by sequence‐specific primer PCR in 64 healthy subjects (HS; mean age: 79.5 ± 6.3 years; 38 women) and in 72 patients (mean age: 80.2 ± 6.8 years; 51 women) undergoing cognitive evaluations. According to DSM‐IV/NINCDS/ADRDA/NINDS/AIREN criteria, 45 patients (mean age: 80.0 ± 7.2 years, 34 women) had AD and 27 patients (mean age: 79.8 ± 6.6 years, 16 women) had VaD. We also measured serum PON1a by spectrophotometry. No significant differences in phenotype distributions among the three study groups were detected by χ2 test. Among the variables, age, sex, and phenotypes 192 and 55, logistic regression selected only polymorphism 192, but not 55, as a discriminating factor between AD and VaD (p < 0.05). Substitution of serum PON1a for genotype yielded a similar result. PON1 polymorphism 192 appears to be a reliable marker to distinguish patients with AD from patients with VaD and from healthy subjects. Changes in 192 polymorphism distributions in AD and in VaD may at least partially explain the significant difference in PON1a in these two types of dementia.

Paraoxonase 1 Activity: A New Vascular Marker of Dementia?

Abstract: Paraoxonase 1 (PON1), an A‐esterase with peroxidase‐like activity present on the surface of HDL, decreases the peroxidation of LDL. Serum PON1 activity (PON1a) decreases with aging and in disorders associated with a high risk of adverse cardiovascular events (acute myocardial infarction, diabetes mellitus, and chronic renal failure). The implication of vascular factors in Alzheimer‐type dementia (ATD) is strongly suspected. We measured PON1a by spectrophotometry using the paraoxon substrate in 180 healthy subjects (controls; mean age: 75.3 ± 8.9 years; 98 women) and 154 patients admitted for cognitive testing. According to criteria, 45 patients had mild cognitive impairments (MCI; mean age: 75.6 ± 9.3 years; 28 women), 60 had ATD (mean age: 75.6 ± 8.3 years; 47 women), and 49 had vascular dementia (VaD; mean age: 77.5 ± 7.2 years; 33 women). Mean PON1a was lower in VaD (0.25 ± 0.1 U/mL) than in controls or ATD (both 0.41 ± 0.2 U/mL, p < 0.01). Mean PON1a values in MCI (0.34 ± 0.2 U/mL) and ATD (0.41 ± 0.2 U/mL) were not significantly different. In multiple linear regression, PON1a was negatively correlated with male sex, age, and VaD, and positively correlated with ATD (each correlation p < 0.001). As shown in other high‐risk cardiovascular disorders, PON1a seems to be a reliable marker of VaD. Its modification in Alzheimers disease supports the implication of vascular risk factors in this type of dementia.

Quality of Phenobarbital Solid-dosage Forms in the Urban Community of Nouakchott (Mauritania)

Summary:  Purpose: Epilepsy is a major public‐health problem in Africa. The quality of available drugs is a limiting factor for an adequate management. The aim of this study was to describe the proportion of poor‐quality phenobarbital (PB) solid‐dosage forms and evaluate the factors associated with its quality in Nouakchott (Mauritania).

Inhibition of human serum arylesterase by metal chlorides.

The inhibition of arylesterase (paraoxonase, EC 3.1.8.1) by metal chlorides was studied with both pooled human serum (A phenotype) and purified enzyme, using phenyl acetate as substrate. Inhibition data were analysed with the Hill equation. Results obtained with whole serum and purified enzyme were very similar. On the basis of the Hill coefficient, n(H), three groups of inhibitors were distinguished: (1) Cu(2+) and Hg(2+) for which n(H)=1, suggesting a single binding site (probably the free cysteine at position 283); these metals were mixed inhibitors, with more affinity for the free enzyme than for the enzyme-substrate complex; (2) Mn(2+), Co(2+), Ni(2+), Zn(2+), and Cd(2+) for which n(H)>1, suggesting several cooperative binding sites; (3) La(3+), for which n(H)<1. Within groups (1) and (2) the inhibiting potency followed the order of the periodic table. For the 3d elements the inhibiting order followed the Irving-Williams series, with the classical exception of Cu(2+). Only Zn(2+) was inhibitory at its physiological concentration.

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross‐sectional study

To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimers disease (AD) or other dementia in France.