[Interfering RNA and antisense oligonucleotide treatments currently available in France: An update]. / Les traitements par ARN interférents et par oligonucléotides antisens actuellement disponibles en France : une mise au point.

The arrival of anti-Covid-19 RNA vaccines in 2020 should not obscure the fact that for several years we have already had treatments based on interfering RNA or antisense oligonucleotides in a number of rare diseases with a very poor prognosis such as transthyretin amyloidosis, acute hepatic porphyria, primary hyperoxaluria, spinal muscular atrophy or familial hyperchylomicronemia. If their performance, unlike that of vaccines, is for the moment only qualified as moderate therapeutic progress (moderate clinical added value) in the therapeutic strategies against these diseases, it should be taken into account that their initial evaluation was penalized by a certain number of unfavorable factors: trials of small numbers, therapeutic modalities to be refined, the lack of hindsight on their long-term effects but especially the choice of the moment of the initiation of the treatment in the natural evolution of the sickness. This choice is not trivial because it is hard to imagine that the products used could, beyond a simple stabilization of the disease installed, allow its regression as soon as certain lesions formed are irreversible. This is why their very early implementation, possibly based on genetic screening, is an avenue to be seized in the interest of patients. But, in the competitive context of innovations in the field, interfering RNAs and antisense oligonucleotides will have to reckon with gene therapy and genome editing using the CRISPR-Cas 9 technique.

[Perception of medication risk by the public and role of the media]. / Rapport 22-09. Perception du risque médicamenteux par le public et rôle des médias.

Opinion polls regularly show that the vast majority of French people have a positive perception of the efficacy and safety of using medicines, including vaccines. Distrust or hostility towards them is only the fact of a small minority of the population, but active and noisy on social networks and overvalued by the media and public authorities. However, the pandemic due to Covid 19 (SARS-CoV-2) has confirmed to what extent the perception of drug risk by the public is unstable, sometimes irrational, how many and complex the determinants of this perception are and what role as a public resonance, fears play out in the media. We can even implicitly see the general underlying tendency of our society, which is to grant primacy to risk to the detriment of profit in the assessment of a technological innovation. The risk tree often masking the forest of efficiency. This polarization of minds on risks, associated with an overestimation of low probabilities, testifies to the impregnation of our mores by the ideology of precaution. To which are added distorting factors such as naturalistic prejudice, cultural relativism and the planetary extension of social networks which instantly spread false information that is more viral and better remembered than the true ones, hampering communication based on science data. Promoting the correct perception of drug risk requires recalling both the benefits and the risks linked to action but also those linked to inaction; to clarify institutional messages by making them as factual as possible; to limit the number of public broadcasters to achieve greater consistency in their messages; to have the frankness to sometimes say that we do not know, medicine by nature being practiced in a context of uncertainty. The Academy calls for an ambitious educational policy for young people: training in critical thinking and the acquisition of the basics of drug risk should be introduced from middle school. The Academy also believes that the public is entitled to expect quality-controlled information from the media, away from rumors, by calling on indisputable experts and by favoring objective data over subjective testimonies based on personal experiences.

[Potentially inappropriate prescriptions for the elderly: a study of health insurance reimbursements in Southeastern France]. / Prescriptions médicamenteuses potentiellement inadaptées chez les personnes âgées : une étude en Provence-Alpes-Côte d'Azur à partir des données de remboursements de l'Assurance maladie.

BACKGROUND: This study conducted in the region of Provence-Alpes-Côte d'Azur (PACA) sought to assess the feasibility of constructing and using indicators of potentially inappropriate prescriptions for the elderly from health insurance reimbursement data. We present and discuss different indicators of inappropriate prescriptions for people aged 70 years or older (at-risk prescriptions, dangerous or at-risk coprescriptions, absence of necessary coprescriptions) and reports their prevalence in PACA. METHODS: The indicators were constructed from the French list of inappropriate prescriptions, national agency guidelines, and the advice of experts in the field. The indicators selected were applied to the databases of the PACA Salaried Workers' Health Insurance Fund for 2008 for all recipients aged 70 years or older and compared according to age, sex, chronic disease status, and, after standardization for age and sex, according to district of residence. RESULTS: In January 2009, 500,904 recipients aged 70 years or older were identified in the data base of the Salaried Workers' Health Insurance Fund, 60.8% of whom were women and 52.1% of whom had approved coverage for a chronic disease. The potentially inappropriate prescriptions most frequently observed here, in decreasing order, were: prescription of an NSAID without the coprescription of gastric protection (28.1%); long-term benzodiazepine treatment (21.5%); prescription of long half-life benzodiazepine (14.9%), and long-term treatment with NSAIDs (11.6%). Overall, the prevalence of each increased significantly with age and was higher among women and people with chronic diseases. Significant variations were also observed between the different districts of PACA. CONCLUSION: Our results confirm that a substantial proportion of elderly people receive potentially inappropriate prescriptions. They also suggest that health insurance reimbursement data could be used in some prescription domains for monitoring trends in the potentially inappropriate prescriptions in the populations of various territories, provided that specific limitations are considered.

Feedback and lessons from the prescription of rimonabant, a drug to be used under strict guidelines, in southeastern France, March 2007 through June 2008.

BACKGROUND: To provide feedback on the initial market authorization of rimonabant, a drug to be used under strict guidelines, we conducted a study with information from the National health insurance reimbursements database for southeastern France. The aims of this study were to: (1) describe the characteristics of subjects who have had one rimonabant prescription reimbursed; (2) study the frequency of prescriptions that did not comply with reimbursement criteria; (3) study the frequency of prescriptions for patients simultaneously treated with antidepressants; and (4) analyse the factors associated with both types of prescription (patient and prescriber characteristics). METHODS: Using the database of drug reimbursements maintained by the southeastern France general health insurance fund, we studied the characteristics of outpatients with at least one reimbursement for rimonabant, compared them to the rest of the population, and analysed compliance with the indications, contraindications, and regulations for rimonabant prescription with multivariate logistic regressions. RESULTS: A total of 10,510 beneficiaries (0.28%) had at least one rimonabant reimbursement. Among them, 55.7% were treated for diabetes. For at least 62.4% of rimonabant beneficiaries, the reimbursement regulations were not respected: this was significantly more frequent among women less than 57 years old, subjects with no chronic diseases, and when the prescriber was not an endocrinologist; 11.4% of rimonabant beneficiaries also received an antidepressant treatment. CONCLUSION: Despite the specific status of rimonabant regarding its reimbursement modalities, these results suggest that some prescribers get around reimbursement instructions and that a significant percentage of prescriptions did not respect an important contraindication. Tools to follow up the prescriptions of new drugs with strict guidelines for use should be developed and physicians should be better informed and trained regarding specific prescription regulations.

Antiplatelet therapy for primary prevention in diabetes.

Aspirin is currently recommended by ADA (American Diabetes Association) for the diabetic patients over 40 years of age and without cardiovascular disease. This recommendation is at odds with drug approval for aspirin. The main explanation is the absence of appropriate trials assessing the usefulness of aspirin in such patients. Two assumptions, central to these guidelines are that diabetes is a coronary risk equivalent, and that aspirin benefit/risk ratio is similar in diabetic patients than in coronary disease patients. Unfortunately, vascular risk level is variable in diabetic patients. Patients with new onset diabetes have lower cardiovascular risk than patients with established cardiovascular disease. Smoking habits markedly increase the risk. Benefits may be lower in diabetic patients since aspirin resistance is common in these patients. Haemorrhagic risk may be higher since diabetes is a risk factor for haemorrhagic stroke. Awaiting trial evidence, aspirin therapy should be considered in diabetic patients with a very high risk, such as smokers, patients with long diabetes duration, or atherosclerotic plaques at echography.

Effects of folate supplementation in hyperhomocysteinemic pigs.

OBJECTIVES: The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia. BACKGROUND: We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions. METHODS: Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS: Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state, 19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four months). CONCLUSIONS: In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.

Association of mild hyperhomocysteinemia with cardiac graft vascular disease.

In non-transplant patients mild hyperhomocysteinemia is an independent risk factor for vascular disease. The aim of this study was to determine whether hyperhomocysteinemia is associated with graft vascular disease. Fasting total plasma homocysteine was assessed in 18 patients with graft vasculopathy and 18 transplanted patients without graft vasculopathy matched for age, sex and the time since transplant. All were on cyclosporin. Graft vasculopathy was defined at coronary angiography as stenoses > or = 25%, or aneurysms. We found that hyperhomocysteinemia ( > or = 15 micromol/l) is common among transplanted heart recipients and significantly more frequent in the patients with graft vasculopathy (17/18 versus 11/18). Accordingly, the mean homocysteinemia was significantly higher in the group with graft vasculopathy (23.6+/-7.8 versus 16.9+/-7.1 micromol/l, P=0.01). The elevation of homocysteine plasma levels in the heart transplant recipients has probably multiple causes. The main cause seems to be renal failure. Additional causes could be azathioprine treatment or genetic polymorphisms. These results suggest that besides the immunological factors, homocysteine can play an additional role in the pathogenesis of graft vascular disease.

Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients.

We conducted a randomized, placebo controlled, double-blind, cross-over study, to assess the effects of a 4-week fluvastatin therapy on plasma markers of endothelial activation or injury in 20 transplanted heart recipients. The levels of thrombomodulin and von Willebrand factor antigen were higher at baseline in cardiac transplant recipients than in age and sex-matched healthy controls. Plasma total cholesterol showed a 21% reduction on fluvastatin therapy (p = 0.0001). Fluvastatin treatment had no significant effect on creatininemia, plasma cyclosporine, PAI-1 antigen, PAI-1 activity, tPA antigen, and Von Willebrand factor. However, fluvastatin produced a significant decrease of plasma thrombomodulin (66.7 ng/ml on placebo versus 58.8 ng/ml on fluvastatin, p <0.001), suggesting a rapid improvement of endothelial injury in these patients.

Inappropriateness and variability of antibiotic prescription among French office-based physicians.

OBJECTIVE: To describe oral antibiotic prescription in the community. DESIGN: Audit of anti-infective prescribing in office-based medical practice. SETTING: Center of France, in the Loiret, a 600,000 inhabitant administrative division. MAIN OUTCOME MEASURES: Clinical hypothesis and antimicrobial drugs used as well as daily doses and durations of treatment. RESULTS: Respiratory tract infections with a presumed viral etiology accounted for 36% of prescriptions. In children, a high percentage of antibiotic prescriptions were underdosed as compared to clinical recommendations, particularly in acute otitis media. The variability of the daily dose was high, with coefficients of variation over 40% in acute otitis media or acute tracheobronchitis. Whatever the clinical hypothesis, the duration of treatment was close to 8 days. In acute otitis media, the coefficient of variation was 14%, the lowest for all diagnoses. CONCLUSION: Our investigation identified two main areas for improving antimicrobial drug prescribing: (1) reduction of useless prescriptions in respiratory tract infections with a presumed viral etiology, and (2) increasing the prescribed daily dose of antimicrobials to the recommended levels.

Guidelines for clinical studies assessing the efficacy of drugs for the management of acute low back pain.

In this paper we propose guidelines for clinical trials aimed at assessing the efficacy of drugs for acute non-specific low back pain (LBP) with or without radicular pain, preliminary to their approval and registration. To this end, consensus statements were obtained from a group of experts in the fields of rheumatology, clinical medicine, public health and epidemiology. EBM resources were systematically used as references. Four diagnostic categories were defined: type 1--LBP with no radiation; type 2--LBP radiating no further than the knee; type 3--LBP radiating beyond the knee, but with no neurologic signs; and type 4--LBP radiating to a specific and entire leg dermatome, with or without neurologic signs. Studies should be designed on the basis of the claimed indications for the drug, but must be double-blinded whatever the indication. The duration of the study may be shorter for LBP type 1 or 2 (one week) than for LBP types 3 and 4 (up to one month), depending on the aim of the study and the indications for the drug. The comparator may be inactive (placebo) or active (for a superiority trial, e.g., versus paracetamol). Specific inclusion and exclusion criteria have been defined here for each category. An appropriate wash-out period for any drugs that could affect the pain status should be planned. Paracetamol may be allowed as rescue medication. The primary endpoint should be based on a validated pain assessment tool that may be either generic (type 1 or 2) or oriented (back and knee for types 3 and 4). Secondary endpoints could include the assessment of functional performance; the duration of any period of bed-rest; work limitation; a global assessment comprising pain at rest, standing and walking; the time elapsed before epidural injection, the prescription of other therapeutic agents, or surgery; and the use of rescue medication. Adverse events (AE) should be monitored systematically using a methodology that reflects the mode of action of the tested drug. With the application of these guidelines, LBP could serve as an appropriate disease for testing analgesic drugs. Rigorous evaluation may also help to improve the management of acute LBP.

Lack of evidence of ketoprofen kinetic changes during the oestrous cycle in rats.

This study was designed to document possible changes in ketoprofen kinetics in female rats related to the stage of the oestrous cycle. At 3 different stages of the oestrous cycle (proestrus, oestrus or dioestrus), 3 different groups of 5 animals each received a single 10 mg/kg intraperitoneal dose of ketoprofen and blood samples were taken at 0.25, 0.5, 0.75, 1, 2, 4, 8, 12 and 24 h after administration. Ketoprofen pharmacokinetic parameters (Cmax, T1/2 alpha and beta, AUC and MRT) were calculated. Our data did not reveal any significant differences in ketoprofen kinetics related to the oestrous cycle.

Medico-economic analysis of diacerein with or without standard therapy in the treatment of osteoarthritis.

This 9-month pragmatic study compared 2 therapeutic regimens in the management of osteoarthritis of the hip and knee. Patients received either diacerein 100 mg/day plus standard osteoarthritic therapy for 6 months, followed by a 3-month monitoring period without diacerein, or standard therapy alone for the entire 9-month period. A total of 207 patients with osteoarthritis of the knee and hip were enrolled. Improvements in Lequense's functional index and quality-of-life scores (revised Arthritis Impact Measurement Scales Health Status Questionnaire and Nottingham Health Profile), and decreases in nonsteroidal anti-inflammatory drug and analgesic consumption were significantly greater with diacerein plus standard therapy than with standard therapy alone. The overall assessment of therapy by patients was good or excellent for 60% of those who received diacerein plus standard therapy, compared with 26% who received standard therapy alone. Medical and paramedical procedures carried out in addition to those stipulated in the protocol (medical consultations, physiotherapy, nursing, etc.), osteoarthritis-related, were fewer and less costly in the diacerein plus standard therapy group than in the standard therapy group. The average outpatient cost (in 1995 French francs) of osteoarthritis treatment in the standard therapy group was FF2272 compared with FF2360 in the diacerein plus standard therapy group. The cost-effectiveness ratios per point scored on Lequesne's index were FF1893 for the standard therapy group and FF1072 for the diacerein plus standard therapy group, leading to a saving of 43% with diacerein plus standard therapy. The marginal cost (additional cost corresponding to the clinical benefit obtained by adding diacerein to standard treatment) was FF88 per point scored on Lequesne's index.

A chronobiological study of delta-amino levulinic acid urinary excretion.

Determination of urinary delta-amino levulinic acid (ALA) is now systematically used in occupational health to detect an excessive exposure to lead in professionally exposed workers. However, to determine whether circadian changes of the urinary excretion of ALA alter the significance of the test, we quantified the ALA levels in the urine of 19 healthy young adults. Urine samples were taken every 3 hr between 0700 and 2300 hr and ALA levels were determined by a spectrocolorimetric method. The data indicated that the 24-hr mean ALA level was: 1.81 mg/g creatinine. The peak values (2.24 +/- 0.24) were obtained between 1400 and 1700 hr whereas the lowest ALA levels were found between 2200 and 0300 hr. Cosinor analysis revealed a significant circadian rhythm while no significant difference could be found according to sex. Possible explanations of our findings are discussed.

Are there circadian variations of polymorphonuclear phagocytosis in man?

Eleven male subjects were investigated to detect a possible circadian rhythm of the polymorphonuclear phagocytosis. Both cell activity and serum opsonins were studied for numerical detection of granulocytes having ingested at least one particle and for the mean number of ingested particles per cell. No significant temporal differences (ANOVA and cosinor) were found.

Delivering generics without regulatory incentives? Empirical evidence from French general practitioners about willingness to prescribe international non-proprietary names.

France presents a unique situation in which the take-off of a generic drug market depends, out of regulatory incentives, on whether physicians choose a prescription method (international non-proprietary names, INN) that can lead to the delivery of these drugs and on whether patients accept them. This paper is aimed at pointing out factors explaining general practitioners' (GPs') willingness to prescribe in INN through data collected from a South-Eastern France representative sample of 600 GPs in March 2002. The main results shed light on the key-role played by GPs' information about drugs and the source which they take it from, by GPs' volume of services and caseloads, and slightly by socio-economic characteristics of patients.

[Factual medicine]. / La médecine factuelle.

It is well known that a number of medical interventions are still based on personal practitioner impression, non-systematic clinical experience or pathophysiologic rationale rather than solid scientific evidence, even when available. Evidence based medicine consists in systematically finding, appraising and using validated research results as a basis for clinical decision making. Access to evidence is essentially provided by randomized clinical trials. One can hope that medical practice supported by the best available evidence about diagnosis, prognosis and therapy will lead to some improvement in patient care. Nevertheless, the field of grey zones is still so large in clinical practice (where incertainty is mainly the rule) that evidence based medicine remains for the moment a positive mental attitude more than a pragmatic and generalizable approach.

[Critical reflections on innovation, therapeutic progress and economics of health]. / Réflexions critiques sur l'innovation, le progrès thérapeutique et l'économie de la santé.

Innovation should not be likened to progress and cost, true innovation should be clearly distinguished from false, novelty for novelty's sake should be avoided, and medicoeconomic evaluations should be interpreted with caution as they are often too precocious and overfavourable. It seems preferable (taking into account examples of statins, anti-Cox 2 NSAIDs, antiTNFs, recombinants...) that therapeutic innovation, as concerns both the prescriber and the evaluator, should give rise to critical reflection rather than to blind enthusiasm and scientistic belief. Delayed use, focusing on real or potential dangers, can be as deleterious for our patients' health as precipitate or generalized use while only considering increased efficacy. Innovation is extremely desirable, particularly when it seems to correspond to a health requirement of prior concern. However, it should be evaluated with a cool head, without prejudice, and even with a hint of scepticism to act as a counterbalance. It should be used with discernment, without improper extrapolation to patients for whom it is not necessary. Careful assessment of the sanitary and economic consequences of therapeutic innovation--which constitute a source of expenditure or economy--should be a permanent concern of health authorities. They must be evaluated using reliable and partly independent data from firms and paying agencies.

[Choice of doses in the treatment of osteoporosis]. / Le choix des doses dans les traitements de l'ostéoporose.

The choice of dosing of osteoporosis drugs should lie upon appropriate studies, indicating particularly the minimal efficient dosing which is, in this area, of a particular importance. Because of technical difficulties in the realisation, very few studies have been reported at the present time. From a practical point of view, the good choice of dosing of anti osteoporotic drugs must be studied from dose-response relationship curvus at the beginning of phase III clinical studies. From literature, it appears that the supposed optimal dosing of anti osteoporotic drugs have frequently been assessed empirically or from studies with patent methodological errors. Such studies should be on the contrary, prospective in parallel groups, randomized, double-blinded, using a pertinent, validated and more sensitive criteria of response.

[Contribution of data of efficacy trials to judge the improvement of the medical usefulness of a drug]. / Apports des données des essais d'efficacité pour juger de l'amélioration du service médical rendu par un médicament.

Data from efficacy trials can provide evidence for the Improvement in Medical Service provided by a drug. A critical analysis of protocols already carried out with a drug enables: a) an evaluation of the limiting characteristics of patients suited to the drug and b) its possible side effects which can be extrapolated to its use in the general population where its use will be much less supervised. An analysis of trial results gives relevant information on the future use and usefulness of the drug.

[Genotoxic and clastogenic effects of doxorubicin]. / Pouvoir génotoxique et clastogène de la doxorubicine.

Doxorubicine is an anthracyclin used widely in medical oncology. The purpose of this investigation was to evaluate the genotoxic and clastogenic effects of this substance through the cytokinesis-block micronucleus assay. This short-term mutagenicity assay is of easy realization and quick interpretation. It has enabled the demonstration of a significant decrease, after exposure of cells to doxorubicin, of the rate of micronucleated cells (average = 10.8 +/- 5.7 micronucleus versus 31.9 +/- 11.5 after exposure, p < 0.0001) and chromosomic aberrations (1 aberration for the control culture versus 17 since the first dose, p < 0.001). At the end of this study, the cytokinesis-block micronucleus assay represents a reliable test to study and evaluate the genotoxic power of some substances.