[The pharmaceutical industry and the adverse effects of the drugs]. / L'industriel du médicament face aux effets indésirables des médicaments.

New drug development is a long, expensive and hazardous process especially regarding the final outcome. During the first non-clinical steps, molecules identified as potential candidates are screened for their toxicological profile, which allows to eliminate some but also to identify possible "target" organs. Then clinical trials are conducted, where tolerance profile knowledge is increased through the development with the detection of the most frequent adverse effects (between 1% and 1 per thousand). At marketing authorization, because of the limited number and of the selectivity of patients enrolled in clinical trials, the drug safety profile is based on the more frequent adverse effects. In Europe, since November 2005, a new regulation - the Risk Management system - has been added to Pharmacovigilance. These are designed to better anticipate and even minimize important identified or potential risks or to better inform on populations not studied during the clinical trials. This concept is based on risk reduction throughout drug's life cycle with specific strategic actions in addition to the product information, in order to optimise the drug benefit/risk ratio. Pharmaceutical companies will therefore invest significantly in post-marketing, allowing proper and safety use of their products. As they played a major role in the clinical development few years ago, they could from now on, be recognised as the key player towards this new paradigm defined as the post-approval development.

[Identification, during development, of a methodology targeted at determining the positioning of new drugs for therapeutic strategies: examples of rheumatoid arthritis and cardiac insufficiency]. / Identification, lors du développement, d'une méthodologie pour déterminer la place des nouveaux médicaments dans les stratégies thérapeutiques: exemples de la polyarthrite rhumatoïde et de l'insuffisance cardiaque.

The Marketing Authorization (MA) granted to a new molecular entity does not allow for proper anticipation of its future positioning within the therapeutic strategy. A specific methodology should be devised as early as during the pre-MA development phase that could result in an initial positioning that should be subjected to further reappraisal with regard to scientific advances, the arrival of new treatments and further developments with this molecule. A methodology is thus proposed, based on early optimisation of the development plan, the granting of subsequent MAs, and reappraisal of the positioning within the strategy, based on analysis of all available data. It should be possible to take into account the economic context, within an agreed system with pre-defined medico-economic criteria. This may in turn raise the issue of the role of the various parties involved in this assessment, as well as how to understand the respective opinions of stakeholders: authorities, sponsors, prescribers and patients, each of whom has a specific view of the definition of the strategic objective that should apply to the disease concerned.

[Difficulties with conducting clinical trials in France]. / Difficultés à la réalisation des essais cliniques en France.

France ranks third among European countries as regards the level of investment in clinical R&D and, overall, accounts for a contributive effort proportional to the size of its population and pharmaceutical market respectively. However, there is a trend for phase II and III studies to become proportionally fewer than in the past, while the number of phase IV studies is increasing. In a growing proportion of the mega-trials, which are instrumental for establishing evidence-based practice, French experts, investigators and, even more seriously, French patients, are insufficiently represented. Though studies in France are initiated relatively fast due to a clear regulatory framework and perform equally well as far as quantitative and qualitative factors are concerned, compared with most European countries involved in clinical research the costs incurred per completed patient are higher than those recorded in the other countries. Academic research shares most of these constraints and suffers from a lack of financial and human resources, while it faces additional delays in implementing studies because of longer administrative processes. Given the stakes in play, specific solutions should be implemented to maintain and further develop French competitiveness in clinical R&D. At the patient level, positive perception and awareness of the usefulness and safety of participating in clinical trials need to be emphasized. Education at the school level and using the lay media should be developed. Intervention of institutional and government officials is much needed. Direct patient recruitment should be developed through advertisement and the Internet, as well as within doctors' offices and through collaboration with patients' organizations. Patient information and consent forms should be made much simpler than those imposed within the framework of global studies because of FDA requirements. The French health system discourages the recruitment of patients by investigators who are not the family doctor or the usual care provider. Thus, motivation and education of general practitioners and hospital doctors may be increased by involving them during the trial design phase and in the publication process. Specific administrative solutions, within private or public institutions, need to be developed for investigators who do not personally wish to receive investigation fees. Because of lack of availability, investigators need to be assisted with study nurse services and site management organizations, particularly within hospitals and clinics, using the model of the Clinical Investigation Centres. Networks of clinical investigation centres and of individual investigators need to be created. Implementing these solutions should lead to better implications for and reputation of French clinical research.

[Assessment of preventable iatrogenic drug therapy: methodology. Round Table No 2 at Giens XIII]. / Evaluation de la iatrogénèse médicamenteuse évitable: méthodologie. Table Ronde No 2 de Giens XIII.

The concept of preventable iatrogenesis has a high priority for the Conference Nationale de Santé. Its implementation could result in the identification of the main relevant actions to be taken to prevent drug related iatrogenesis. Based on a critical analysis of pharmacovigilance experiences, we propose, a scheme to evaluate the degree of avoidability of adverse drug effects. This scheme contains three group of items concerning the drug, the patient and the prescription. It assesses the prescription and the therapeutic approach used for a specific patient within the context of medical knowledge as well as the risk factors presented by the patient.

A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients.

This double-blind, randomised, multicentre study compared the antidepressant efficacy and safety of two doses of milnacipran (100 mg/day and 200 mg/day) and fluoxetine (20 mg/day) in 289 inpatients with endogenous depression. After a placebo washout period of 4-7 days, assessments were performed weekly during the first 4 weeks, and then after 6, 8 and 12 weeks, using the 17-item Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI). HDRS total score was reduced by a mean of 14.8 in the milnacipran 100 mg/day group, 12.9 in the milnacipran 200 mg/day group and 12.1 in the fluoxetine 20 mg/day group. MADRS total score decreased by 17.4, 15.8 and 14.6, respectively. No significant difference could be shown between the three treatment groups for either the HDRS or MADRS total scores. However, the time-by-time change showed a trend in favour of milnacipran 100 mg/day, which was found significantly superior to fluoxetine at day 28 for several converging parameters (MADRS, CGI-3). Overall, efficacy ratings for all parameters were highest for milnacipran 100 mg/day, followed by milnacipran 200 mg/day and fluoxetine 20 mg/day. Side-effect profiles were not significantly different between groups except for a significantly greater frequency of dose-related increase in heart rate > or = 100 bpm in milnacipran recipients and a significantly greater weight loss in fluoxetine recipients.

Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode.

The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor. The aim of this double-blind study was to compare the efficacy and safety of milnacipran (50 mg twice daily) with that of imipramine (50 mg twice daily) in elderly patients with major depressive episode. A total of 219 patients were randomly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine; 72 patients withdrew from the study. At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy. A significantly greater number of side-effects, particularly anticholinergic effects, was observed in the imipramine group. Milnacipran may be preferable to imipramine in elderly depressed patients, as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects, and does not impair cognitive ability.

An international medico-economic survey of 2007 children with recurrent nasopharyngitis and acute otitis media. Preliminary bindings.

The terminology used to describe upper respiratory tract infections (URTIs) in children can be based on the symptomatic picture, the aetiological agents or anatomical features involved, or classical disease descriptions. However, there is a lack of precision in the epidemiology and nosology of nasopharyngitis and acute otitis media (AOM) in children. Moreover, there are differences between European countries in diagnostic and therapeutic measures. The aim of this broad survey was to record all items potentially relating to URTIs in children and, therefore, to refine the classification of nasopharyngitis and AOM, as well as to clearly define their medical and economic consequences as observed in normal medical practice. Specifically, the objectives can be summarised as follows: to define nasopharyngitis as a clear-cut entity and thus provide a standard for clinical trials; to identify different definitions of AOM and compare them with Paradise's algorithm; to establish a profile of patients at risk of recurrences; to assess therapeutic habits; and to determine the cost of illness. The survey involved 328 European physicians (general practitioners, paediatricians, ear, nose and throat specialists), who recorded spontaneous medical visits of 2007 children presenting with a first episode of nasopharyngitis or AOM during November and December 1996. These children were then followed up until April 1997 so that any recurrent episodes could be recorded. A parent questionnaire focusing on burden of illness for the family was also included. Demographic characteristics at inclusion and the first data on the multifactorial correspondence analysis for nasopharyngitis at inclusion are available and have been presented.

Clinical efficacy of milnacipran: placebo-controlled trials.

The clinical efficacy of milnacipran, a selective serotonin and noradrenaline reuptake inhibitor, was reviewed on the basis of three, multicentre, placebo-controlled trials in major depression. A dose-range study showed the superiority of milnacipran at 50 or 100 mg twice a day compared with placebo whereas the effect of 25 mg twice a day was not clearly distinguished from that of placebo. This has been confirmed by other studies where the 50-mg twice-a-day regimen was shown to be significantly more efficacious than placebo on all outcome measures (Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression). The positive results in the individual studies were supported by a meta-analysis of the data from the three studies. A subgroup analysis of hospitalized patients in the meta-analysis showed an advantage for milnacipran, suggesting that milnacipran is effective in more severe depression.

Milnacipran and selective serotonin reuptake inhibitors in major depression.

In drug development the move from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs) involved not only the loss of the direct receptor interactions responsible for the adverse side effects of TCAs, but also the ability to inhibit the reuptake of noradrenaline. Selectivity for the single neurotransmitter, serotonin, may explain why SSRIs tend to be less efficacious than the TCAs, especially in more serious forms of depression. The advent of selective serotonin and noradrenaline reuptake inhibitors (SNRIs) has tended to confirm the idea that an action on both monoamine systems is important for maximal antidepressant efficacy. This paper reviews clinical trials comparing the new SNRI milnacipran with the SSRIs fluoxetine and fluvoxamine. A meta-analysis of the principal trials shows greater response rates (the proportion of patients with a decrease in symptom scores of 50% or more) with milnacipran (50 mg twice a day) than with fluoxetine (20 mg once a day), or fluvoxamine (100 mg twice a day) (milnacipran: 64%; SSRIs: 50%). Remission rates (the proportion of patients with Hamilton Depression Rating Scores of 7 or below) were also higher with milnacipran than with SSRIs (39 versus 28%). In one study, in which 100 mg milnacipran was given once a day in the evening, the higher response rate obtained with fluoxetine appears to be largely attributable to an inappropriate milnacipran dosage regimen. Data from a pharmacovigilance database including all patients participating in clinical trials with milnacipran (n = 5732) showed that, compared with the SSRIs, milnacipran produced fewer gastrointestinal side effects, such as nausea, and less anxiety. Milnacipran was, however, associated with a higher incidence of headache, dry mouth and dysuria. The results of these studies suggest that milnacipran is superior in efficacy to SSRIs and is equally well tolerated. Milnacipran, therefore, appears to offer a therapeutic advantage over the SSRIs.

Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results.

Milnacipran is a novel antidepressant agent which selectively inhibits the reuptake of serotonin and noradrenaline. Seven randomized, double-blind trials with a comparable design have compared the efficacy and tolerability of milnacipran with that of tricyclic antidepressants (TCAs) in patients with major depression. At a dose of 50 mg twice a day, milnacipran therapy is associated with a response rate (50% reduction in Hamilton Depression Rating Scale) of 64%. The rate of response to TCAs in these studies was 67%. In contrast to the TCAs, milnacipran was very well tolerated by the patients. The only adverse event that occurred more frequently in milnacipran-treated patients than in TCA-treated patients was dysuria (2.1% of patients treated with milnacipran). Milnacipran is as effective as TCAs in the treatment of patients with major depression and is better tolerated. Milnacipran's lack of effects on cardiovascular function offers improved safety in cases of overdose.

Rufloxacin once daily versus ciprofloxacin twice daily in the treatment of patients with acute uncomplicated pyelonephritis.

PURPOSE: We compare the bacteriological and clinical efficacy of rufloxacin and ciprofloxacin in patients with acute uncomplicated pyelonephritis. MATERIALS AND METHODS: A total of 110 outpatients was enrolled in a randomized, double-blind multicenter study and treated for 10 days with 200 mg. rufloxacin daily (after a loading dose of 400 mg. on day 1) or 500 mg. ciprofloxacin twice daily. Bacteriological and clinical efficacy was based on the accumulated outcomes assessed at the end of treatment, and at 2 and 4 to 6 weeks. RESULTS: The bacteriological and clinical success rates of rufloxacin and ciprofloxacin were comparable: 55.6% versus 58.8% and 74% versus 71%, respectively (95% confidence interval -28% to +22% and -20% to +25%, respectively). Both study medications were well tolerated. CONCLUSIONS: Rufloxacin once daily is a good alternative in the outpatient treatment of acute uncomplicated pyelonephritis.

Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects.

We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g.kg-1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Madox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 micrograms.l-1 on Day 6 and 104 micrograms.l-1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g.l-1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory ultradian rhythms of mean and low frequencies: a comparative physiological approach.

Recent developments in human rhythmic respiratory pathology lead to this review of the literature for ultradian rhythms of middle and low frequencies, that is having periods longer than the usual respiratory rates, whose periods are seconds or fractions of seconds. Ultradian respiratory movements for respiratory periods (5 less than tau less than 50 min) have been reported in many species of small laboratory animals (mice, rats, guinea-pigs, rabbits, quails). Long-period respiratory rates (20 less than tau less than 90 min) have been found in human fetuses and infants. But they are more difficult to detect in human adults, except during sleep where they have been related to REM and NONREM activities. These respiratory rhythms of middle and low frequencies are supposed to result from dissipative energy structures related to surface-volume relationships, with interlocking chemical clocks, and to be relevant to a basic rest-activity cycle.

Environmental parameters in the experimental evaluation of a respiratory aggression.

Acute nitrogen normobaric hypoxic challenges, resulting in an approximately 50% overall survival, were performed in young adult male and female heterozygous OF1 mice under various environmental conditions. The time required to obtain 50% survival was 20 min for a constant pO2 of 42 Torr, and 151 min when pO2 was progressively lowered by nitrogen flushing from 159 to 16.5 Torr. In LD12:12 synchronized animals, survival was significantly (P less than 0.001) less when hypoxia was performed during the light (L) than during the dark (D) phase. Lowering the ambient temperature from 33.8 to 13.2 degrees C increased the length of the progressive hypoxia necessary to obtain a 50% survival of the mice by 1.7 times, and diminished the final pO2 from 35 to 12 Torr. Grouping and crowding both decreased hypoxic survival. A previous stress (starvation) diminished hypoxic resistance of mice, while a preceding hypoxia, carbon monoxide inhalation, or sodium cyanide injection had the opposite effect. In all instances, OF1 females were more resistant than males. Most of these variations can be related to differences in respiratory exchanges, locomotor activity and aggressiveness, which are dependent upon the various experimental environmental parameters.