Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review.

PURPOSE: Denosumab (an anti RANKL antibody) is known to be associated with an increased risk for osteonecrosis of the jaw (ONJ). Due to the variety of clinical presentation, many ONJ definitions are used. Evaluation of ONJ's frequency during phase III randomized controlled trials (RCTs) is crucial to assess benefit-risk ratio. We verified that phase III RCTs involving denosumab reported the definition of ONJ used. METHODS: We systematically searched in Central, Medline, Cochrane, and Scopus, until 31 August 2015. We included original phase III RCTs, involving denosumab. Post hoc analysis and trial extension were excluded. Articles that did not mention ONJ in their methods or results were excluded. The primary outcome was the prevalence of a complete definition of ONJ. When no definition was provided, ONJ adjudication process was analyzed. RESULTS: Of 313 articles found, 13 RCTs were included. A definition of ONJ was detailed in two RCTs (15%). For the remaining 11 RCTs, adjudication process was mentioned for nine. In those processes, "blinded," "expert," and "independent" were the most used words. CONCLUSION: Most of the published phase III RCTs involving denosumab did not specify the definition of ONJ used to adjudicate events in the study. Instead of definition, non-scientific and non-reproducible expressions were used. Because the chosen definition could impact the ONJ estimated frequency, it should be mandatory to give the precise definition used in each RCT publication involving denosumab.

Relationship between anticholinergic drug use and one-year outcome among elderly people hospitalised in medical wards via emergency department: the SAFES cohort study.

AIM: To investigate the relationship between anticholinergic drug use and one-year outcome of elderly patients hospitalised via the emergency department. METHODS: Prospective, multicentre, cohort study of patients aged 75 years and older. Comprehensive geriatric evaluation was performed. We included in this analysis all patients for whom data on drug use was available. Anticholinergic drugs were coded using the online database "Thesorimed". One-year mortality and nursing home admission were analysed using a Cox model, with matching on the propensity to use anticholinergic drugs. RESULTS: In total, 1176 subjects were included in this analysis, average age 85±6 years, 65% women. Overall, 144 (12%) were taking at least one anticholinergic drug. Mortality and nursing home admission at one year were respectively 29% and 30% in the anticholinergic group, and 34% and 33% respectively in subjects not taking anticholinergic drugs. No significant relationship was observed between anticholinergic drug use and the main endpoints. CONCLUSION: Although we did not observed any statistically significant relationship between use of anticholinergic drugs and one-year outcome in elderly patients, the long-term use of anticholinergic drugs can have deleterious effects on memory and functional capacity, and therefore requires prescriptions to be reviewed regularly.

Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.

AIMS: To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS: Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS: Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION: This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.

[Development of antidepressant drugs. Experience and prospects]. / Développement des antidépresseurs. Acquis et perspectives.

THE FIRST ROUTES OF RESEARCH: The first antidepressants were developed after the discovery of the existence during depression of a perturbation in the synaptic transmission of the principle monoamines: noradrenalin, serotonin and dopamine. The pharmacological effect of the various molecules developed is mainly on the metabolisation routes of neurotransmitters, but may also concern the different receptors present on synaptic level. THE AWARENESS OF NEW MEDIATORS: The progress in research on antidepressants has widened the scope of the development of such medicinal products to the domain of endocrinology (hypothalamo-pituitary-adrenal axis, progestogen hormones, thyreotropic axis) and studies on neuropeptides (substance P, neuropeptide Y). The complexity of the physiopathological mechanisms of depression hence appears enhanced.

Bromism from daily over intake of bromide salt.

Bromide intoxication today is an infrequent disease, but preparations containing bromide are still available in nonprescription compounds, on the French market. We report a casewith bromide intoxication due to daily over intake (approximately 20 tablets per day; i.e. total elemental bromide intake approximately 6 g/day) of calcium bromo-galactogluconate (Calcibronat) for 1.5 months. A 30-year-old woman with a long history of psychotropic drug abuse was hospitalized in a psychiatric department for neuropsychological manifestations. She presented a seriously disturbed mental status with confusion, disorientation, auditory and visual hallucinations, and loss of short-time memory. A markedly increased serum bromide level of 1717 mg/L (21.5 mEq/L) measured on the first day after her admission confirmed the diagnosis of chronic bromism suspected based on her symptomatology. During her hospitalization, bromide plasma concentrations were measured and monitored using inductively coupled plasma mass spectrometry, a sensitive and very specific method. After withdrawal of the drug, the symptoms improved within 8 days. Serial bromide concentrations gradually declined throughout nearly 2 months of monitoring, until she was discharged from the hospital. We found an elimination half-life of bromide in blood of approximately of 10 days. This case demonstrates that, while today bromism occurs infrequently, it should still be included in the differential diagnosis of neuropsychiatric symptoms.

[Utilization of methylphenidate(Ritalin) in France]. / L'utilisation du méthylphénidate (Ritaline) en France.

Methylphenidate (Ritalin) is the only psychostimulant approved in France and indicated in attention deficit hyperactivity disorder in children over 6 years. It is under restricted prescription and distribution conditions. As such, it requires a hospital initiated prescription from either a neurology, psychiatry or pediatric specialist and it is covered by the "narcotics" schedule. The French Pharmacovigilance database spontaneous adverse drug reactions reporting, since it was approved in 1995, were analyzed. 21 adverse drug reactions were reported. In 16 cases, methylphenidate was suspected. They were generally non-serious, mild side effects and in most cases promptly resolved. These results do not suggest methylphenidate misuse in France or an overuse in between 1300 and 4000 treated children, to date. Until more information is available concerning the long-term effects of methylphenidate, and in order to limit misuse, inappropriate or overuse, the current prescription and dispensing regulation should be maintained in France, and could well be developed in other countries.

Reports of withdrawal syndrome with the use of SSRIs: a case/non-case study in the French Pharmacovigilance database.

The SSRIs can be associated with withdrawal reactions and the objective of this study is to test the existence of an association between reports of withdrawal syndromes with the selective serotonin re-uptake inhibitors in the French spontaneous reports database. All reactions are coded according to the WHO ART dictionary. Cases are reports of reactions of interest (withdrawal syndrome). Non-cases are all reports of reactions other than those being studied. We calculated the odds ratio (OR) as the ratio of the odds of the association of reports of withdrawal syndrome with SSRIs in cases and non-cases. SSRIs are clearly associated with a higher risk of withdrawal syndrome (OR: 5.05, 95% CI: 3.81-6.68) and in particular with venlafaxine and paroxetine (OR: 12.16, 95% CI: 6.17-23.35 and OR: 8.47, 95% CI: 5.63-12.65, respectively). The risk of withdrawal reactions appears to be greater with short half-life drugs such as paroxetine and venlafaxine. The precise mechanisms have not been identified.

Seizure induced by ropivacaine.

OBJECTIVE: To report development of a seizure after administration of ropivacaine. CASE SUMMARY: A 26-year-old woman was scheduled for a cesarean section because of a stagnation of the uterine neck dilatation after 4.5 hours. After peridural administration of 279 mg of ropivacaine (total dose) over five hours, she presented with oculogyric movements and slurred speech that preceded convulsions of the face and of the upper limbs. DISCUSSION: Convulsions are well-known complications of local anesthetics. Ropivacaine, a relatively new agent, is considered safer for the central nervous system. Currently, there are only four published reports that implicate ropivacaine as being associated with convulsions. The likelihood that ropivacaine caused the seizure in our patient was possible based on the Naranjo probability scale. CONCLUSIONS: Clinicians should be aware of the possibility of seizures as an adverse effect of ropivacaine.

[Iatrogenic risk of self-medication by the pregnant patient]. / Risques iatrogènes de l'automédication chez la femme enceinte.

REALITY OF SELF-MEDICATION IN PREGNANCY: Pregnant women use self-medication readily. Such behavior must not be overlooked by physicians and midwives during pregnancy. More epidemiology data would be useful. IATROGENIC RISKS: Drug toxicity, generally related to the advancement of somatic development of the embryo and fetus, can appear at variable stages during pregnancy. Moreover, the pharmacokinetic properties of drugs are different during pregnancy. These facts must be taken into account when assessing the risk of uncontrolled drug use by pregnant women. RECOMMENDATIONS FOR PREGNANT WOMEN: Obstetricians, midwives and primary care physicians caring for pregnant women should explain the risks of self-medication. The specific features of disease during pregnancy should be considered when giving relevant information.

Simultaneous determination of inulin and p-aminohippuric acid (PAH) in human plasma and urine by high-performance liquid chromatography.

Inulin and p-aminohippuric acid (PAH) clearances are used for the estimation of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). A simple and rapid high-performance liquid chromatography (HPLC) method with UV detection is described for the simultaneous determination of inulin and PAH in the same chromatogram in the plasma and urine of humans. Plasma and urine samples were hydrolyzed with perchloric acid (0.7%) in boiling water. The mobile phase consisted of 0.01 M potassium dihydrogenphosphate with 0.02 M tetramethylammonium chloride and o-phosphoric acid (pH 3)-acetonitrile (94:6, v/v), pumped at a rate of 1.2 ml min-1 on a C8 reversed-phase column. Tannic acid was used as the internal standard and UV detection at 285 nm was employed. The calibration curves were linear over the concentration range of 12.5-100 mg l-1 for inulin and 6.25-50 mg l-1 for PAH with determination coefficients greater than 0.997. The method is accurate (bias < 13%) and reproducible (intra- and inter-day relative standard deviation less than 11%), with a limit of quantitation of 12.5 mg l-1 and 6.25 mg l-1 for inulin and PAH, respectively. Analytical recoveries from urine and plasma were ranged from 81 to 108% for both compounds. This fully validated method, which allows the simultaneous determination of inulin and PAH clearances, is simple, rapid (total run time < 10 min) and requires only a 200 microliters plasma or urine sample.

Pyrimethamine-sulfadoxine treatment of congenital toxoplasmosis: follow-up of 78 cases between 1980 and 1997. Reims Toxoplasmosis Group.

UNLABELLED: The purpose of this study was to determine the clinical and immunological outcome of 78 children with congenital toxoplasmosis treated with the pyrimethamine-sulfadoxine combination between 1980 and 1997. METHODS: Children were divided into 3 groups according to the initial duration of treatment (always including folinic acid, 5 mg/week by mouth), as follows: pyrimethamine (1.25 mg/kg every 15 d) + sulfadoxine (25 mg/kg every 15 d) for 12 months (Group 1, 47 children), or for 24 months, with or without prenatal therapy (respectively, Group 2, 19 children, and Group 3, 12 children). RESULTS: Chorioretinitis occurred in 23% of these 78 children. Four children had unilateral blindness, 1 had mild epileptic fits and 1 had psychomotor retardation. The lowest rate of sequelae were in Groups 2 and 3. Immunological rebounds, generally without clinical repercussions, occurred frequently (90% of cases on average) during, or more often after therapy, regardless of the treatment duration. Treatment was always well tolerated. CONCLUSIONS: Our current treatment strategy for congenital toxoplasmosis consists of a 24-month course of pyrimethamine-sulfadoxine (Fansidar) combined with folinic acid (Lederfoline). If the prenatal diagnosis is positive, we also prescribe this treatment to the mother until delivery. This combination offers satisfactory compliance, adequate serum concentrations, and good preventive efficacy.