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Prescription drug abuse is a worldwide healthcare concern. Opioid pain relievers and opioid substitution treatments are the main concern. This paper presents the drug products available or under development that have been specifically formulated to limit drug abuse, i.e., abuse-deterrent and tamper-resistant formulations. Abuse-deterrent formulations are products that include an aversive agent or combinations of opioid agonists and antagonists that will induce withdrawal symptoms when abused via nasal or intravenous routes. Tamper-resistant formulations limit the ability of abusers to alter the pharmaceutical form prior to snorting or injection. These strategies are only part of the global care of drug abuse: medical care and legal frameworks must be closely combined with these pharmaceutical approaches.

Aims No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score ≥4 (six-point scale) 30 to 60 min after dosing was rated as a success. Methods A double-blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg−1 dose range. Results Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg−1 dose was 81% (95% CI: 78.5 to 84%). The time to reach a score ≥4 was longer than expected and the median duration-time at score ≥4 was shorter (15 min) than expected. Conclusions Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg−1 administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.

Resume L'utilisation des fluoroquinolones (FQ) est contre-indiquee chez l'enfant jusqu' a la fin de la periode de croissance. Ces antibiotiques sont neanmoins prescrits chez l'enfant dans des situations ou le benefice attendu parait superieur au risque potentiel. Population et methodes Une enquete retrospective sur la prescription de FQ chez l'enfant portant sur le premier semestre 1993 a ete menee au cours du premier semestre 1994 aupres de 167 chefs de service de pediatrie afin d'estimer la frequence d'utilisation des FQ chez l'enfant et l'importance des effets indesirables observes. Resultats Cent cinquante chefs de service (90 %) ont repondu a l'enquete. Soixante-deux etaient prescripteurs de FQ (41,3 %), 83 ne l'etaient pas (55,3 %), et cinq reponses n'etaient pas informatives (3,4 %). Parmi les 62 prescripteurs de FQ, 17 chefs de service (27 %) ne pouvaient pas denombrer les prescriptions, 45 (73 %) ont rapporte un nombre d'enfants traites compris entre un et 75 pendant la periode d'enquete. Parmi ces 45 chefs de service, 21 n'ont pas pu identifier les enfants ayant recu une FQ. Nous avons obtenu, dans les 24 autres services, un groupe de 104 enfants âges de 9,0 ± 5,0 ans ayant recu 165 cures de FQ, d'une duree de 20 ± 45 jours (1–535 jours), avec un traitement associe pour 80 % des cures. Cinquante enfants (48 %) etaient atteints de mucoviscidose. Le traitement a ete la ciprofloxacine pour 114 cures sur 165 (69 %), a la dose de 25,1 ± 7,0 mg/kg/24 h par voie orale (moyenne ± ecart-type) et de 23,5 ± 11,4 mg/kg/24 h par voie intraveineuse; la pefloxacine pour 23 cures sur 165 (14 %), a la dose de 17,2 ± 3,8 mg/kg/24 h; l'ofloxacine pour 15 cures sur 165 (9 %) a la dose de 21,0 ± 11,9 mg/kg/24 h; la norfloxacine pour 13 cures sur 165 (8 %), a la dose de 25,6 ± 7,5 mg/kg/24 h. Ce traitement a ete administre par voie orale dans 73 % des cures et par voie intraveineuse dans 26 % des cures. Vingt et un effets indesirables ont ete notes chez 17 enfants (16 %), 11 etant atteints de mucoviscidose. Il s'agissait de signes cutanes (photosensibilite, eruption) dans huit cas, de signes articulaires (arthralgie, arthrite) dans sept cas et de signes digestifs (nausee, vomissement) dans trois cas. Conclusion Cette enquete retrospective permet de constater que les FQ sont prescrites chez l'enfant en depit de l'absence d'indications reconnues officiellement et que de nombreux effets indesirables ont ete notes. L'absence d'exhaustivite de l'information recueillie, liee au caractere retrospectif de l'enquete, et la difficulte d'interpretation des effets indesirables due a l'absence de validation et de demarche d'imputation de chaque observation ainsi qu'a l'absence de groupe temoin montrent la necessite d'entreprendre une enquete prospective.

This retrospective analysis was designed to evaluate the inactivation index (I3) method used to adjust the isoniazid dose during long-term administration in a pediatric population. Before starting on antituberculosis therapy, sixty-one children received one 10 mg.kg-1 isoniazid test-dose (D). The isoniazid and acetyl isoniazid concentrations were measured by high-performance liquid chromatography on a plasma sample collected 3 hours (C3h) after administration. The patients were separated into slow and fast acetylator groups according to the metabolic ratio. The dose adjustment method using the I3 is based on the assumption that there is a linear correlation between C3h and D [C3h = (I3 x D) - 0.6] in which the slope is I3 and the Y intercept is equal to -0.6 mg.l-1. I3 was determined from a single plasma concentration determination and used to calculate the dose recommended to obtain a desired C3h equal to 1.5 micrograms.ml-1: recommended dose (mg.kg-1) = (1.5 + 0.6)/I3.I3 was significantly higher in the slow acetylator group (0.55 +/- 0.16) than in the fast one (0.26 +/- 0.13), which leads us to recommend a significantly lower dose in the slow acetylator group (4.2 +/- 1.5 mg.kg-1) than in the fast one (10.3 +/- 4.6 mg.kg-1). The data obtained in a subgroup of 21 patients who had at least three consecutive determinations of C3h after different dosages allowed us to verify that there was a linear correlation between C3h and the dose. The mean slope of the correlation lines in that subgroup was 0.61 +/- 0.25 and the 95% confidence interval of the estimated Y-intercept include the theoretical value of -0.60, which shows that our data are consistent with those previously reported in adults. The percentage of patients with a C3h plasma concentration within the expected range (1.5 +/- 0.5 micrograms.ml-1) was significantly higher (69%) in those whose dose was derived from the calculation than in the others (25%). Within each acetylator group, the range of the recommended dose varied widely, and these results emphasize the usefulness of individual dose adjustment based on the inactivation index method.

Isoniazid acetylation metabolic ratio (MR) was studied in 61 children with tuberculosis after administration of isoniazid. MR was calculated as the molar acetylisoniazid to isoniazid concentration ratio. MR was used as a probe for N-acetyltransferase activity and to determine the acetylation phenotype. MR had a bimodal distribution with an antimode between 0.48 and 0.77. MR and the percentage of fast acetylators increased significantly with age. The cumulative frequency of fast acetylators increased with age, with a plateau reached around 4 years. MR value was checked during treatment in 44 children. All children but one who initially appeared as fast acetylators remained in this group after repeated testing. Among the 30 slow acetylators, 12 became fast acetylators, and 10 showed a variable phenotyping at different ages. A bimodal distribution of the isoniazid acetylation MR was shown in children, with an antimode close to that described in the literature and a maturation of isoniazid acetylation during the first 4 years.

In children, tiaprofenic acid (TA), a non steroidal antiinflammatory drug, propionic-acid derivative, has been proven effective in the treatment of symptoms of tonsillitis and pharyngitis but not yet in the symptomatic treatment of fever. This double-blind, parallel group, placebo (Pl) controlled study was designed in order to demonstrate the antipyretic activity of TA. The co-prescription of other antipyretic medications in children may therefore be avoided. Two groups of children, 29 (TA group) and 26 (Pl group), were included and received either 4.2 +/- 0.5 mg/kg of TA given orally in a single dose or a Pl match. Rectal temperature was recorded just before and 1, 2, 4 and 6 hours after dosing. The maximum temperature decrease was significantly greater in the TA group (-1.3 degrees C +/- 0.7 degree C) than in the Pl group (-0.4 degree C +/- 0.8 degree C). The percentage of children who needed a rescue treatment during the study was 35% (10/29) and 62% (16/26) in the TA and Pl group, respectively. The rescue treatment was composed of a single oral acetaminophen dose in case of fever above 39.5 degrees C or if the temperature decrease was not at least equal to 0.6 degree C four hours after dosing. No major side effect was reported by the parents during the study period. In conclusion, TA at a single mean 4.2 mg/kg oral dose, is an effective antipyretic drug in febrile children. The duration of the antipyretic effect was estimated as at least four hours.

The antiepileptic drug vigabatrin (VGB) is a selective irreversible inhibitor of GABA-transaminase. It is administered as a racemic R(-), S(+) mixture, but the pharmacological activity of vigabatrin resides in the S(+) enantiomer and the R(-) enantiomer is inactive. The pharmacokinetic parameters of the two enantiomers have been studied after administration of a single oral 125 mg dose of the racemate to six neonates. The mean values of Cmax and AUC of the S(+) enantiomer were significantly lower (Cmax: 14.0 +/- 4.3 mg l-1; AUC: 143 +/- 44 mg l-1 h) than those of the R(-) enantiomer (Cmax: 34.1 +/- 9.5 mg l-1; AUC: 231 +/- 88 mg l-1 h), whereas no significant difference in the time to reach Cmax (S(+): 2.1 +/- 1.1 h; R(-): 2.2 +/- 1 h) was observed between the two enantiomers. During chronic administration (125 mg twice daily over 4 days), there was no evidence of accumulation of either enantiomer.

Fluoroquinolones (FQ) are contraindicated in children because of the risk of cartilage damage.A retrospective survey concerning the use of FQ in children during the first 6 months of 1993 was organized in 1994. One hundred and sixty-seven Heads of pediatric departments were questioned.One hundred and fifty (90%) of those surveyed responded: 62 (41.3%) were FQ prescribers, 83 (55.3%) were non prescribers and five (3.4%) were not able to answer. Among the 62 prescribers of FQ, 17 departments (27%) were not able to indicate the number of prescriptions and 45 departments (73%) reported one to 75 prescriptions during the study period. Twenty-one departments out of the 45 were not able to identify the children treated with FQ. We obtained a group of 104 children aged 9.0 +/- 5.0 years (mean +/- standard deviation [SD]), treated with 165 courses of FQ during 20 +/- 45 days (1-535 days) with concomitant treatments for 132/165 courses (80%). Fifty children (48%) were suffering from cystic fibrosis, 37 children (36%) were not, and, in 17, the diagnosis was not determined (16%). The FQ treatment administered either orally (73%) or intravenously (26%) was ciprofloxacin in 69% of the courses with a 25.1 +/- 7.0 mg/kg/day oral dose (mean +/- SD dose), and a 23.5 +/- 11.4 mg/kg/day intravenous dose, pefloxacin in 23 courses/165 (14%) with a 17.2 +/- 3.8 mg/kg/day dose, ofloxacin in 15 courses/165 (9%) with a 21.0 +/- 11.9 mg/kg/day dose, norfloxacin in 13 courses/165 (8%) with a 25.6 +/- 7.5 mg/kg/day dose. Twenty-one adverse events were reported in 17 children (16%) (11 of them with cystic fibrosis). These were cutaneous events (photosensitivity, cutaneous eruption) in eight courses, rheumatologic events (arthralgia, arthritis) in seven courses and gastrointestinal events (nausea, vomiting, diarrhea) in three courses.This survey shows that FQ are prescribed in children although their use is not approved in this age group and that numerous side effects have been recorded. The absence of exhaustive information (due to the retrospective nature of the survey) and the difficulties in interpreting the side effects for which validity and causal assessment have not been worked out according to a standardized method and in the absence of a control group stress the need for a prospective study.

The aim of this study was to assess the prevalence of long-term complications in a large sample of French NIDDM patients. Therefore, 427 NIDDM patients 35-74 years old were recruited in ten centers. Standardized clinical criteria and central reading for retinal and electrocardiographic changes were used to assess the presence of complications. The prevalence rates of complications were 29.7% and 3.3% for background and proliferative retinopathy; 21.8%, 6.1%, and 2.8% for microalbuminuria, proteinuria, and renal insufficiency; 19.9 and 11.7% for asymptomatic and symptomatic pheripheral neuropathy; 8.2% for orthostatic hypotension; 10.1% and 8.4% for angina pectoris and myocardial infarction; and 13.1% and 6.3% for mild and moderate to severe peripheral vascular disease, respectively. In conclusion, prevalence rates in this study were lower than in most studies from other countries.

During the course of a multiple-dose metoclopramide (M) oral treatment, M plasma concentrations were measured just before (Cmin) and 1 hour after the administration (C1h) at steady-state in 5 (3 premature and 2 term) neonates. Mean Cmin was equal to 91.6 +/- 45.5 ng/ml and higher than C1h (87.4 +/- 43.2 ng/ml), but not significantly. A significant negative correlation was found between Cmin plasma concentration and gestational age as well as with postconceptional age, suggesting that the lower the gestational and postconceptional age, the lower the metoclopramide dosage should be.

The antipyretic activity of ibuprofen in the Sparklets form was compared, in an equivalence study, with that of paracetamol in the same formulation. The study was conducted as a double-blind multicenter trial, with random allocation of the treatments. One hundred sixteen children of both sexes, aged 4.1 +/- 2.6 years, with a fever related to an infectious disease and a mean temperature of 39 degrees +/- 0.5 degrees C at the time of inclusion, were treated with single doses of either 10.3 +/- 1.9 mg/kg of ibuprofen or 9.8 +/- 1.9 mg/kg of paracetamol. The subjects' rectal temperature was regularly monitored for 6 hours. The statistical analysis of the results confirmed that ibuprofen and paracetamol are equivalent with respect to the following criteria (1) time elapsed between dosing and the lowest temperature: 3.61 +/- 1.34 hours for ibuprofen and 3.65 +/- 1.47 hours for paracetamol (95% confidence interval [CI] of the difference: -0.48; +0.56); (2) extent of the temperature decrease: 1.65 degrees C +/- 0.80 degrees C for ibuprofen and 1.50 degrees C +/- 0.61 degrees C for paracetamol, (95% CI of the difference: -0.41; +0.11); (3) rate of temperature decrease: 0.52 +/- 0.32 degrees C/hr for ibuprofen and 0.51 degrees C +/- 0.38 degrees C/hr for paracetamol (95% CI of the difference: -0.45; +0.55); (4) duration of temperature below 38.5 degrees C: 3.79 +/- 1.33 hours for ibuprofen and 3.84 +/- 1.22 hours for paracetamol (95% CI of the difference: -0.14; +0.12).

The clinical correlates of advanced retinopathy were determined in a sample of 427 type II diabetic outpatients, aged 35 to 74 years, recruited in eight centers from all parts of France. The presence of retinopathy was assessed by fluorescein angiography with centralized interpretation. Advanced retinopathy (proliferative and/or macular edema) was independently linked with nephropathy, peripheral neuropathy, and insulin therapy. Prevalence of advanced retinopathy was 1.6% in the absence of signs of nephropathy and/or peripheral neuropathy, 10.4% in patients with mild signs, and 17.5% in patients with moderate to severe signs. Overall, 87% of the patients with advanced retinopathy had signs of nephropathy and/or peripheral neuropathy. In conclusion, patients showing signs of nephropathy and/or peripheral neuropathy should be sent in priority to an ophthalmologist. Prospective data are necessary to determine if screening is necessary in patients with no signs of nephropathy or peripheral neuropathy.

1. Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication. 2. This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively. 3. Thirty-one children aged 6 months to 5 years were included and received a 2 mg kg-1 single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half-lives (mean +/- s.d.) were: 7.7 +/- 1.8 h, 21.9 +/- 6.8 h, 44.7 +/- 10.2 h in the "inducer', "other' and "inhibitor' groups respectively. 4. Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3 mg l-1. The mean minimum plasma concentration for the three groups was 2.54 +/- 1.28 mg l-1 at steady state. 5. Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.

Objective: Cytochrome P450 III (CYP III) has previously been demonstrated in vitro in fetal liver. Methods: A study was performed in 7 premature, 13 term neonates and 30 infants to assess whether or not maturation had any influence on CYP IIIA activity in children from birth to 1 year of age. A simple non invasive procedure was used (6 βOHF/FF concentration ratio in a morning spot urine sample). Results: The 6 βOHF/FF ratio was 7.2, 7.9 and 5.0 in premature and term neonates and infants, respectively. CYP IIIA activity is present at birth, with a 6 βOHF/FF ratio comparable to adults. Its activity seemed lower in infants. This might be due to the decrease in CYP IIIA7 activity during maturation after birth, which might be more rapid than the increase in CYP IIIA3/4 activity.

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug. Methods: Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg−1⋅day−1) and 84 (STP 90 mg⋅kg−1⋅day−1) by HPLC. Results: The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l−1. Conclusion: The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l−1. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l−1 and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration.

The prevalence and causes of visual impairment have been estimated in a sample of 423 Type 2 diabetic outpatients, aged 35 to 74 years, recruited in 8 centres from all parts of France. The presence of retinopathy was assessed by fluorescein angiography with centralized interpretation. The presence of cataract and glaucoma was also recorded. Prevalence of blindness was 1.2%. Moderate visual impairment affected 7% of the patients. The major cause of blindness was cataract, explaining 38% of the cases of blindness. Retinopathy was associated to blindness in 2 cases out of 26. More than half of the patients with proliferative retinopathy and the third of those who had macular edema had been treated by photocoagulation. According to the present patient material, retinopathy is a minor cause of visual impairment in Type 2 diabetic patients, cataract remaining the major cause. This reflects the introduction of photocoagulation into ophthalmologic practice.

Eight children (3.84 +/- 1.17 years old) received a single oral 5 mg cetirizine dose (0.32 +/- 0.07 mg.kg-1) as a 10 mg.ml-1 solution, 1.73 (+/- 0.64) hours before a minor surgical intervention (mean duration +/- SD = 0.90 +/- 0.25 h). Seven venous blood samples were collected before administration (t0) and 0.5 h, 1.5 h, 4 h, 8 h, 12 h and 24 h after dosing, and urine samples were collected up to 24 hours after the dose. The mean +/- SD kinetic parameters were: peak plasma level (Cmax) 607 +/- 231 micrograms.l-1 reached in 1.93 +/- 1.39 h (tmax), elimination half-life (t1/2) 5.55 +/- 0.98 h, area under the plasma concentration time curve (AUC0-infinity) 4,772.1 +/- 1,318.4 micrograms.l-1.h, mean residence time (MRT) 8.13 +/- 1.31 h, apparent plasma clearance (Cl/f) 1.27 +/- 0.80 ml.min-1.kg-1, apparent volume of distribution (Vz/f) 0.60 +/- 0.38 l.kg-1. Urinary recovery was 38.4 +/- 9.9% (n = 4) of the dose. Renal clearance was 0.42 +/- 0.10 ml.min-1.kg-1 (n = 6). No influence of age on the cetirizine parameters was evidenced among this group, except for MRT (p0.05) which decreases with age. When compared with results in adults, elimination half-life (t1/2) was twice as short and apparent clearance twice as great. These results suggest that a higher dosage b.i.d. may be required in children.

A representative, random sample of French general practitioners, reported the number of diabetic patients they treated in their practices. The resulting NIDDM prevalence rate for France was 1.71% (SE +/- 0.03), compatible with the rates found in other studies. Prevalence rates for NIDDM were also calculated by region and a multivariate covariance model was used to correlate the prevalence with known risk factors. The three significant factors were: the quantity of wine consumed, the female/male sex ratio of people over 45 years of age, both positively correlated, and the consumption of animal fats, which was negatively correlated with NIDDM prevalence.

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.

The regional prevalence of diabetes, in France, has been studied using data from a nationwide household survey conducted by INSEE and CREDOC, two national demographic statistics institutes, in a representative sample of 7,323 households (21,007 subjects). Each subject reported, on a form, all the drugs bought during the study period. Subjects reporting, at least once, an antidiabetic oral drug were classified as diabetic. Two hundred and sixty six subjects reported having bought one or more oral antidiabetic drugs, leading to an overall prevalence rate of 1.27%. Prevalence rates were calculated by region (range: 0.86% Pays de Loire--2.77% Franche-Comté) and by large administrative areas (ZEAT) (range: 0.90% Nord-Pas-de-Calais--1.92% Est). In both cases, a North-west, South-east gradient appeared, with the lowest rates in the North and West of France. This trend was maintained after standardization according to the age distribution in the regions studied. The rates are similar to other data in the literature, in particular those derived from national drug sales data, but there is no explanation for this inter regional variability, which merits specific surveys.

The aim of this study was to analyse the characteristics and the mortality rate of diabetic patients, in France, between 1970 and 1987, as well as the association between diabetes and other pathologies at death. These results are based on both the underlying and the associated causes of death registered on the death certificate, in contrast to most studies which use only the underlying cause. In 1987, there were 16,790 deaths in France for which diabetes was mentioned on the death certificate (as the underlying cause in 38% of cases). There was a higher mortality in male diabetic subjects then in female, for all ages except over 75 years. Between 1970 and 1987, the mortality decreased for both sexes, except for the oldest age group. The death rate varied greatly between geographical regions. A particularly high mortality occurred in the Nord-Pas-de-Calais, Lorraine and Alsace. Diabetes was significantly associated, at death, with other diseases and pathologies. The most frequent were vascular diseases (ischaemic heart disease, cerebral diseases and hypertension) and diseases of the genitourinary system. It if of note that 5% of the death certificates of these diabetic subjects indicated diabetic coma as a cause of death.

A SEARCH FOR THE APPROPRIATE SEDATIVE DOSE OF RECTAL MIDAZOLAM IN INFANTS DURING CARDIAC CATHETERIZATION: APPLICATION OF A CONTINUAL REASSESSMENT METHOD. 452