Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital.

PURPOSE: The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Médicalisation des Systèmes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. METHODS: The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs. RESULTS: During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4 %) and central (11.3 %) ADRs in PMSI database versus cutaneous (22.4 %) and general (17.5 %) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1 %) in PMSI database versus anti-infectives (38.2 %) in FPVDB. The estimated number of ADRs was 717 [95 % confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6 % (95 % CI 0.4, 0.8). CONCLUSIONS: Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.

Impact of rapid urbanisation and industrialisation on river sediment metal contamination.

This study aimed at evidencing contaminant inputs from a rapidly growing population and the accompanying anthropogenic activities to river sediments. The Fez metropolitan area and its impacts on the Sebou's sediments (the main Moroccan river) were chosen as a case study. The Fez agglomeration is surrounded by the river Fez, receiving the wastewaters of this developing city and then flowing into the Sebou. The sediment cores from the Fez and Sebou Rivers were extracted and analysed for major elements, butyltins and toxic metals. Normalised enrichment factors and geoaccumulation index were calculated. Toxicity risk was assessed by two sets of sediment quality guideline (SQG) indices. A moderate level of contamination by butyltins was observed, with monobutyltin being the dominant species across all sites and depths. The lowest level of metal pollution was identified in the Sebou's sediments in upstream of Fez city, whilst the Fez' sediments were heavily polluted and exhibited bottom-up accumulation trends, which is a clear signature of recent inputs from the untreated wastewaters of Fez city. Consequently, the sediments of Fez and Sebou at the downstream of the confluence were found to be potentially toxic, according to the SQG levels. This finding is concerned with aquatic organisms, as well as to the riverside population, which is certainly exposed to these pollutants through the daily use of water. This study suggests that although Morocco has adopted environmental regulations aiming at restricting pollutant discharges into the natural ecosystems, such regulations are neither well respected by the main polluters nor efficiently enforced by the authorities.

Long-term survey of heavy-metal pollution, biofilm contamination and diatom community structure in the Riou Mort watershed, South-West France.

In a metal-polluted stream in the Riou Mort watershed in SW France, periphytic biofilm was analyzed for diatom cell densities and taxonomic composition, dry weight and metal bio-accumulation (cadmium and zinc). Periphytic diatom communities were affected by the metal but displayed induced tolerance, seen through structural impact (dominance of small, adnate species) as well as morphological abnormalities particularly in the genera Ulnaria and Fragilaria. Species assemblages were characterized by taxa known to occur in metal-polluted environments, and shifts in the community structure expressed seasonal patterns: high numbers of Eolimna minima, Nitzschia palea and Pinnularia parvulissima were recorded in Summer and Autumn, whereas the species Surirella brebissonii, Achnanthidium minutissimum, Navicula lanceolata and Surirella angusta were dominant in Winter and Spring. Commonly used indices such as the Shannon diversity index and Specific Pollution Sensitivity Index reflected the level of pollution and suggest seasonal periodicity, the lowest diversities being observed in Summer.

Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance database.

Nefopam is widely used for the relief of moderate acute pain. Its safety profile remains to be specified. The objective of the study was to review adverse reactions to nefopam spontaneously reported to the French Pharmacovigilance system. All cases of adverse drug reactions (ADRs) associated with nefopam, registered in the French Pharmacovigilance database from January 1, 1995 to December 31, 2004, were reviewed. For each reported ADR, information about patient (age, gender, medical history), drug exposure (suspected and concomitantly used drugs), characteristics of ADRs (imputability score, time of onset, seriousness, outcome) were collected. A total of 114 ADRs with an imputability rated from 'plausible' (I2) to 'likely' (I3) and 'very likely' (I4) was analysed. The most frequent ADRs included 'expected' ADRs such as sweating, nausea, tachycardia, malaise or vomiting; 61 ADRs were 'unexpected. No overdose was reported; 26 ADRs (23%) were considered as 'serious'. Most of them were 'unexpected', including neuropsychiatric (hallucinations, convulsions) or cutaneous (pruritus, erythema, urticaria) ADRs. Six cases of anaphylactic ADRs (two angioedema and four anaphylactic shocks) were reported, all occurring shortly after use of nefopam during the post-operative period. Physicians should be aware of the possible occurrence of some serious ADRs when using nefopam such as convulsions and anaphylactic shocks, especially when the drug is used in special medical conditions, like post-operative periods.

A weighted bootstrap method for the determination of probability density functions of freshwater distribution coefficients (Kds) of Co, Cs, Sr and I radioisotopes.

The objective of the study was to provide global probability density functions (PDFs) representing the uncertainty of distribution coefficients (Kds) in freshwater for radioisotopes of Co, Cs, Sr and I. A comprehensive database containing Kd values referenced in 61 articles was first built and quality scores were affected to each data point according to various criteria (e.g. presentation of data, contact times, pH, solid-to-liquid ratio, expert judgement). A weighted bootstrapping procedure was then set up in order to build PDFs, in such a way that more importance is given to the most relevant data points (i.e. those corresponding to typical natural environments). However, it was also assessed that the relevance and the robustness of the PDFs determined by our procedure depended on the number of Kd values in the database. Owing to the large database, conditional PDFs were also proposed, for site studies where some parametric information is known (e.g. pH, contact time between radionuclides and particles, solid-to-liquid ratio). Such conditional PDFs reduce the uncertainty on the Kd values. These global and conditional PDFs are useful for end-users of dose models because the uncertainty and sensitivity of Kd values are taking into account.

Organic carbon, and major and trace element dynamic and fate in a large river subjected to poorly-regulated urban and industrial pressures (Sebou River, Morocco).

An annual-basis study of the impacts of the anthropogenic inputs from Fez urban area on the water geochemistry of the Sebou and Fez Rivers was conducted mostly focusing on base flow conditions, in addition to the sampling of industrial wastewater characteristic of the various pressures in the studied environment. The measured trace metals dissolved/particulate partitioning was compared to the ones predicted using the WHAM-VII chemical speciation code. The Sebou River, upstream from Fez city, showed a weakly polluted status. Contrarily, high levels of major ions, organic carbon and trace metals were encountered in the Fez River and the Sebou River downstream the Fez inputs, due to the discharge of urban and industrial untreated and hugely polluted wastewaters. Trace metals were especially enriched in particles with levels even exceeding those recorded in surface sediments. The first group of elements (Al, Fe, Mn, Ti, U and V) showed strong inter-relationships, impoverishment in Fez particles/sediments and stable partition coefficient (Kd), linked to their lithogenic origin from Sebou watershed erosion. Conversely, most of the studied trace metals/metalloids, originated from anthropogenic sources, underwent significant changes of Kd and behaved non-conservatively in the Sebou/Fez water mixing. Dissolved/particulate partitioning was correctly assessed by WHAM-VII modeling for Cu, Pb and Zn, depicting significant differences in chemical speciation in the Fez River when compared to that in the Sebou River. The results of this study demonstrated that a lack of compliance in environmental regulations certainly explained this poor status.

Blood pressure and plasma catecholamines in never-treated parkinsonian patients: effect of a selective D1 agonist (CY 208-243).

We found blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), and epinephrine (E) levels in the lying and the standing positions to be similar in never-treated parkinsonian patients (stages 1 and 2) and age-matched controls. CY 208-243, a new centrally active D1 agonist, significantly decreased BP, HR, and NE (but not E) values in the lying position; it elicited orthostatic hypotension and blunted the rise in NE elicited by standing up. These results indicate that the early stages of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and suggest the involvement of central D1-receptors in the control of sympathetic tone.

Relationships between kallikrein secretion, kallikrein excretion and beta-adrenoceptors in kidney cortical slices from neurogenic hypertensive dogs.

1. Sinoaortic denervation (SAD) in dogs is characterized by an increase in blood pressure and heart rate as well as the development of renal morphological lesions similar to those observed in essential hypertension in human subjects. To assess the effect of SAD on the secretion of kallikrein kinin systems (KKS), we studied the in vitro secretion of kallikrein by renal cortical slices of normal and neurogenic hypertensive dogs (1 and 18 months after SAD). The method using renal cortical slices allowed the study of secretion of kallikrein independently of renal perfusion pressure. The number of renal beta-adrenoceptors was measured by [125I]-cyanopindolol binding. 2. SAD was associated with a marked increase in urinary kallikrein excretion at one month and a significant decrease at 18 months when compared with controls. Both changes were statistically significant (P < 0.05). Concurrently, a progressive increase in in vitro kallikrein secretion was observed (+80 +/- 10% and +179 +/- 48%, 1 and 18 months after SAD, respectively). Moreover, the cortical slices obtained from sinoaortic denervated dogs contained more kallikrein than the control cortical slices (+32 +/- 16% and +55 +/- 7%, 1 and 18 months after SAD, respectively). 3. Renal beta-adrenoceptor number significantly (P < 0.05) decreased 18 months after SAD from 18 +/- 2 to 8 +/- 3 fmol mg-1 protein without any change in affinity constant. 4. Although there was no test of association, because the number of renal beta-adrenoceptors decreased whereas kallikrein secretion increased, the present data could suggest a beta-adrenoceptor-mediated inhibition of kallikrein secretion. These results show that although the urinary kallikrein is decreased, the tissue secretory capacities are enhanced. This could suggest a renal compensatory mechanism possibly involved in tissue protection in dogs after SAD, although such a mechanism is not sufficient to reverse hypertension.

A randomised placebo-controlled pilot dose-response study with anisoylated plasminogen streptokinase activator complex in acute coronary artery occlusions.

The aim of this study was to determine the dose-response relationship of anisoylated plasminogen streptokinase activator complex (APSAC) by means of a between group double-blind comparison of the new agent and placebo. 50 patients with symptoms of acute myocardial infarction of less than 6 hours duration and whose coronary artery occlusion had been confirmed by coronary angiography were randomly allocated to 5 treatment groups (15, 20, 25 or 30U of APSAC, or placebo) and treatment was given as an intravenous injection over 2 minutes. Angiography was performed again at 15, 30, 45, 60 and 90 minutes and the films were assessed centrally by 2 independent cardiologists. Six patients were excluded from the angiographic analysis, 4 because their angiograms revealed patent arteries before APSAC was administered, 1 patient was excluded because streptokinase had been infused just after randomisation because of cardiogenic shock and 1 because the angiogram was not available due to problems in the film development. Clinical and laboratory examinations carried out for 72 hours after treatment showed that the drug was well tolerated. The reperfusion rates were as follows: placebo, 0/9; APSAC 15U, 5/8; APSAC 20U, 5/9; APSAC 25U, 6/9; APSAC 30U, 5/9. Reperfusion was achieved in 60% of treated patients but no dose relationship was revealed.

Pressor effect of oral tyramine during treatment with befloxatone, a new reversible monoamine oxidase-A inhibitor, in healthy subjects.

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

Effects of befloxatone, a reversible selective monoamine oxidase-A inhibitor, on psychomotor function and memory in healthy subjects.

Befloxatone is a new reversible and selective monoamine oxidase (MAO-A) inhibitor that has been shown to have antidepressant activity in various animal models. To assess the effects of single oral doses of befloxatone (5, 10, and 20 mg) on psychomotor performance and memory, a randomized, double-blind, five-way, crossover study with both placebo and amitriptyline (50 mg) was carried out in 15 healthy male volunteers. Psychomotor and cognitive functions were evaluated using both objective measures, including Critical Flicker Frequency (CFF), Choice Reaction Time (CRT), Digit Symbol Substitution Test (DSST), and a picture memory test and subjective measures, including Visual Analog Scales (VAS) and Addiction Research Center Inventory (ARCI), before and 2, 4, and 8 hours after administration. Pupil diameter was recorded by videopupillography. Single doses of befloxatone from 5 to 20 mg did not result in any detrimental effects on skilled performance and memory. In contrast, amitriptyline significantly impaired arousal (CFF), speed of reaction (CRT), information processing (DSST) and long-term memory (delayed free recall of pictures) and produced subjective sedation from 2 to 8 hours after administration. At the doses studied amitriptyline induced miosis but befloxatone did not modify pupil diameter. There was no evidence in this study to suggest that befloxatone, at the doses studied, has any sedative or amnesic effects in healthy subjects.

Pharmacodynamics and pharmacokinetics of two dose regimens of befloxatone, a new reversible and selective monoamine oxidase inhibitor, at steady state in healthy volunteers.

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose-related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady-state levels of DHPG.

Levodopa up-regulates platelet alpha 2-adrenoceptors.

Treatment of dogs for 21 days with oral levodopa (100 mg b.i.d.) plus benserazide (25 mg b.i.d.) induced a significant increase in the number of platelet alpha 2-adrenoceptors labelled by [3H] yohimbine with no change in Kd. The rise was maximal at the end of the treatment and remained significant during the month following the cessation of treatment. Plasma catecholamine levels did not vary. Competition experiments showed a low affinity of both dopamine and levodopa for platelet alpha 2-adrenoceptors. These results suggest that levodopa treatment regulates alpha 2-adrenoceptor number in dog platelets.

Clinical pharmacology of befloxatone: a brief review.

Clinical pharmacology studies of befloxatone, a new selective reversible inhibitor of monoamine oxidase-A (MAO-A), have addressed safety, with special emphasis on tyramine interactions, and have also investigated pharmacokinetics (PK) and pharmacodynamics in terms of both MAO-A inhibition (using 3,4-dihydroxyphenylglycol, DHPG, as a pharmacological activity marker) and effects on psychomotor and cognitive function, in young and elderly healthy volunteers. Clinical and laboratory safety data were satisfactory in healthy volunteers given single doses of up to 160 mg or repeated doses of up to 80 mg/day for 7 days. Tyramine interaction studies showed that the expected potentiation of the tyramine pressor effect occurred with a safety margin that was so wide as to make dietary restrictions unnecessary with dosages of up to 20 mg once daily in clinical settings. Absorption was rapid (tmax = 2 h), terminal halflife was about 11 h, and PK parameters increased linearly with the dose. Befloxatone induced a dose-dependent decrease in plasma DHPG levels from 2.5 mg upwards, and a 10-mg dose provided sub-maximal activity (80% DHPG decrease) of 24 h duration. No sedative or stimulant effects were detected using several batteries of psychometric tests. Befloxatone was devoid of deleterious effects on memory in young volunteers, and exhibited the EEG profile of a non-sedative antidepressant. In summary, available clinical pharmacology studies confirm that befloxatone is a safe and potent RIMA with no potential for inducing deleterious CNS effects.

Fertility and outcomes of pregnancy after chemotherapy in a sample of childbearing aged women.

The aim of the study was to review the characteristics and outcomes of pregnancies occurring in women of childbearing age after chemotherapy for malignant disease. Between November 1998 and October 1999, a total of 16 patients who were treated for ovary (three), mole (one), vaginal (one), breast (four), Hodgkin's disease (four), lung (one), melanoma (one) and osteosarcoma (one) carcinoma were identified and retrospectively questioned about their fertility status. All the 16 women included in this study received at least one alkylating agent. Five patients (31%) experienced anomalies of hormonal cycle during and after the treatment. All of them recovered normal cycle without consequence of fertility. Caesarean section was performed in seven of 20 (35%) pregnancies with known outcomes. No obstetrical events were reported. The 16 women had 21 pregnancies resulting in 18 normal infants, one newborn with a minor abnormality (tallus foot), one spontaneous abortion and one lost of follow-up to 6 months of pregnancy. The present survey suggests that cytotoxic drug exposure had no deleterious effects on subsequent pregnancies. A prospective and systemic survey would be the only means able to clarify the actual cancer therapy on reproductive outcome and to investigate the long-term effects in the progeny.

Absence of arterial hypertension despite chronic plasma noradrenaline elevation: evidence for down-regulation of alpha-adrenoceptors. A case report.

A 44 year old-healthy female presented chronic and stable high levels of plasma noradrenaline (NA) without any major change in adrenaline. The diagnosis of phaeochromocytoma was discarded. These increased levels of NA offered an unique opportunity to investigate under in vivo conditions a putative regulation of alpha-adrenoceptors by this endogenous catecholamine. Infusion rates of exogenous NA up to 0.74 micrograms/kg per min were unable to induce any change in blood pressure (or heart rate) in the subject, In contrast, in normotensive controls, an increase in blood pressure (+ 15 mm Hg) was observed with 0.39 micrograms/kg per min. The magnitude of yohimbine-induced increase in plasma NA was similar in the subject and in the controls. Platelet alpha 2-adrenoceptors evaluated by specific [3H]-yohimbine binding showed a significantly lower level in the subject when compared to controls. The results show that a sustained increase in plasma NA is able to induce down-regulation of alpha-adrenoceptors. This down-regulation can explain the lack of arterial hypertension despite the increased sympathetic tone.

A study of the pharmacodynamic interaction between befloxatone and ethanol on performance and mood in healthy volunteers.

The effects of befloxatone (20 mg o.d. for 10 days) alone and in combination with ethanol on psychomotor performance, memory and mood were assessed in a randomized, double-blind, placebo controlled study. On treatment days 6, 8 and 10, subjects received 0.5 and 0.8 g/kg ethanol and ethanol placebo in randomly assigned, balanced orders, 2 h post-drug. Critical fusion frequency, choice reaction time, postural instability, critical tracking and mood were measured 1h before ethanol and 1, 3 and 5 h afterwards. Divided attention, sustained attention and memory (immediate and delayed recall) were also measured in single tests, 2.5-5 h post-ethanol.Ethanol's effects were generally significant when blood alcohol concentrations (BAC) after both doses were the highest; i.e. 0.48-0.67 and 0.96-1.10 mg/ml. Those effects were virtually gone after the subjects' mean BACs fell below 0.40 mg/ml. Befloxatone alone had no significant impairing effect in any test. Neither did it significantly interact with ethanol to cause any greater impairment than the latter alone. It was concluded that befloxatone does not potentiate the sedating and impairing effects of ethanol.

Effects of levodopa and bromocriptine on blood pressure and plasma catecholamines in parkinsonians.

Blood pressure (BP), heart rate (HR), plasma noradrenaline (NA), and adrenaline (A) levels in the lying and standing position were compared in patients with Parkinson's disease (PD) and control subjects. Three groups of PD patients (stage 2 and 3) were investigated: six patients deprived of antiparkinsonian drugs from 48 h, seven levodopa + benserazide-treated patients, and seven bromocriptine-treated patients. BP, HR, NA, and A were similar at rest and in the standing position in controls and in PD patients deprived of antiparkinsonian drugs from 48 h. Chronic treatment with levodopa (+ benserazide) failed to modify BP, HR, NA, and A. Bromocriptine decreased BP, HR, and NA (but not A) at rest. In PD patients treated with levodopa (+ benserazide) or bromocriptine alone, the rise in NA (but not A) elicited by standing up was reduced. These results indicate that (a) stages 2 to 3 of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and (b) dopaminergic drugs blunted the sympathetic response to standing up.