Unlicensed and off-label drug use in a Swiss paediatric university hospital.

BACKGROUND: Many medicines used in newborns, infants, children and adolescents are not licensed ("unlicensed") or are prescribed outside the terms of the marketing authorization ("off-label"). Several studies have shown that this is a common practice in various healthcare settings in the USA, Europe and Australia, but data are scarce in Switzerland. OBJECTIVES: The aim of our prospective study was to determine the proportion of unlicensed or off-label prescriptions in paediatric patients. METHODS: This pilot study was conducted prospectively over a six month period in the department of paediatrics of a university hospital. RESULTS: Sixty patients aged from three days to 14 years were included in the study. A total of 483 prescriptions were written for the patients. More than half of all prescriptions (247; 51%) followed the terms of the marketing authorization. 114 (24%) were unlicensed and 122 (25%) off-label. All patients received at least one unlicensed or offlabel medicine. CONCLUSION: The use of unlicensed or off-label medicines to treat children was found to be common. Co-operation between the pharmaceutical industry, national regulatory authorities, clinical researchers, healthcare professionals and parents is required in order to ensure that children do not remain "therapeutic orphans".

Médicaments et allaitement: quelques éléments à considérer avant de les juger incompatibles [Drugs and breastfeeding: some facts to consider before deciding they are incompatible]

Breastfeeding is considered the ideal way of providing young infants with the required nutrients for healthy growth and development. An increase in the prevalence and duration of breastfeeding has been observed over the last years in response to promotion campaigns. When a medicamentous treatment is started, discontinuation of breastfeeding is often proposed, for fear of harmful consequences for the infant. Nevertheless such a decision is not unimportant, and it appears that many drugs can actually be used during breastfeeding without significant risk. An assessment of the real risk incurred by exposed children makes it possible to avoid unnecessary discontinuations of breastfeeding. This article aims to review the facts needed to assess amount of drug exposure to the child and to list the few drugs associated with significant effects on the nursing infant.

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

Expositions médicamenteuses pendant la grossesse: une approche différenciée [Drug exposure during pregnancy: a differentiated approach].

Numerous drug exposures do occur unintentionally at the beginning of pregnancy. On the other hand, pursuing drug treatment may be necessary in women who wish to be pregnant. In these situations risk evaluation has to be done in a precise and differentiated manner, taking into account at the same time the risk for the fetus and maternal health. Teratovigilance services are able to give a thorough information enabling to avoid unwarranted drug arrests or pregnancy terminations. In return, physician's catamnesis about the outcome of the pregnancy exposed to one or several therapeutic agents will increase the bulk of knowledge health professionals and pregnant women have at their disposal.

On-line desorption of dried blood spots coupled to hydrophilic interaction/reversed-phase LC/MS/MS system for the simultaneous analysis of drugs and their polar metabolites.

An assay for the simultaneous analysis of pharmaceutical compounds and their metabolites from micro-whole blood samples (i.e. 5 microL) was developed using an on-line dried blood spot (on-line DBS) device coupled with hydrophilic interaction/reversed-phase (HILIC/RP) LC/MS/MS. Filter paper is directly integrated to the LC device using a homemade inox desorption cell. Without any sample pretreatment, analytes are desorbed from the paper towards an automated system of valves linking a zwitterionic-HILIC column to an RP C18 column. In the same run, the polar fraction is separated by the zwitterionic-HILIC column while the non-polar fraction is eluted on the RP C18. Both fractions are detected by IT-MS operating in full scan mode for the survey scan and in product ion mode for the dependant scan using an ESI source. The procedure was evaluated by the simultaneous qualitative analysis of four probes and their relative phase I and II metabolites spiked in whole blood. In addition, the method was successfully applied to the in vivo monitoring of buprenorphine metabolism after the administration of an intraperitoneal injection of 30 mg/kg on adult female Wistar rat.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

Cibles rétiniennes d'action des médicaments [Retinal drug targets].

Retinal effects of systemically administered drugs are rare due to the hematoretinal barriers that protect the retina from circulating active principles. However, some compounds may have direct or indirect toxic effects on the retina through direct interaction with a specific receptor or due to their accumulation within pigment of uveal cells. In the latter case, toxicity is dose-dependent and may be observed years after cessation of medication, as observed with antimalarial drugs. Anti-infective and anti-inflammatory agents, particularly glucocorticoids, are currently injected peri- or intraocularly. The mechanisms and the exact toxicity of glucocorticoids on the retina remain poorly understood. More recently, anti-VEGF has been specifically developed for the treatment of retinal diseases. However, the long-term blockade of VEGF on normal retinal physiology should be determined taking into account VEGF and VEGF receptors expression in the normal and pathologic retina. Whilst enormous advances are made in the treatment of retinal diseases, basic research is still required to define more accurately the molecular targets of drugs to improve their benefits and reduce their potential side effects.

Types of stereoselectivity in drug metabolism: a heuristic approach.

Stereochemical factors are known to play a significant role in the metabolism of drugs and other xenobiotics. Following Prelog's lead, types of metabolic stereoselectivity can be categorized as (i) substrate stereoselectivity (the differential metabolism of two or more stereoisomeric substrates) and (ii) product stereoselectivity (the differential formation of two or more stereoisomeric metabolites from a single substrate). Combinations of the two categories exist as (iii) substrate-product stereoselectivities, meaning that product stereoselectivity itself is substrate stereoselective. Here, published examples of metabolic stereoselectivities are examined in the light of these concepts. In parallel, a graphical scheme is presented with a view to facilitate learning and help researchers to solve classification problems.

Etude descriptive des médicaments non utilisés collectés dans une officine française de la Région Centre

[...] Cette étude a permis d'évaluer ce que représente le coût des MNU [médicaments non utilisés] à l'officine sur une période donnée. Les résultats ont traduit un gaspdlage certain des ressources de santé. La fin du recyclage humanitaire des médicaments étant décidé par les autorités publiques depuis le 11 janvier 2007, la collecte des MNU à l'officine garde un intérêt dans la protection de l'environnement et la prévention des accidents domestiques. Mais les pharmaciens pourraient participer à la prévention de ces gaspillages par un renforcement des mesures d'informations sur le bon usage des médicaments et par une attention particulière donnée au monitoring et au soutien de l'adhésion thérapeutique des patients ('programmes de soins pharmaceutiques).[Auteure, p. 4]

Current and future trens in the quality control of pharmaceuticals and biopharmaticals : impacts on Cost of Goods Sold (COGS)

[Summary] 2. Roles of quality control in the pharmaceutical and biopharmaceutical industries. - 2.1. Pharmaceutical industry. - 2.2. Biopharmaceutical industry. - 2.3. Policy and regulatory. - 2.3.1. The US Food and Drug Administration (FDA). - 2.3.2. The European Medicine Agency (EMEA). - 2.3.3. The Japanese Ministry of Work, Labor and Welfare (MHLW). - 2.3.4. The Swiss Agency for Therapeutic Products (Swissmedic). - 2.3.5. The International Conference on Harmonization (ICH). - - 3. Types of testing. - 3.1. Microbiological purity tests. - 3.2. Physiochemical tests. - 3.3. Critical to quality steps. - 3.3.1. API starting materials and excipients. - 3.3.2. Intermediates. - 3.3.3. APIs (drug substances) and final drug product. - 3.3.4. Primary and secondary packaging materials fro drug products. - - 4. Manufacturing cost and quality control. - 4.1.1. Pharmaceutical manufacturing cost breakdown. - 4.1.2. Biopharmaceutical manufacturing cost breakdown. - 4.2. Batch failure / rejection / rework / recalls. - - 5. Future trends in the quality control of pharmaceuticals and biopharmaceuticals. - 5.1. Rapid and real time testing. - 5.1.1. Physio-chemicals testing. - 5.1.2. Rapid microbiology methods

Quelle adéquation entre les messages publicitaires sur les médicaments avec les évidences basées sur les preuves de l'EBM et les normes législatives

L'objectif de cette étude est d'évaluer l'adéquation des messages publicitaires sur les médicaments parus en 2007 dans quatre journaux destinés aux professionnels de la santé ("Praxis", "Forum médical suisse", "Bulletin des médecins suisses" et "Revue médicale suisse") avec les évidences basées sur les preuves de l'EBM et des normes législatives ainsi que de vérifier s'ils sont supportés par les références bibliographiques mentionnées. Méthode: les messages publicitaires des cinq grands groupes thérapeutiques (à savoir: anti-ostéoporotiques/arthrosiques, antidépresseurs, antihypertenseurs, AINS et hypolipémiants) sont évalués sur [ces] trois critères. [Auteure, p. 5]

Determinação espectrofotométrica por injeção em fluxo de vitamina B6 (piridoxina) em formulações farmacêuticas

A flow injection (FI) spectrophotometric procedure is proposed for the determination of vitamin B6 (pyridoxine hydrochloride) in pharmaceutical preparations. Powdered samples containing from 2.5 to 4.5 mg, were previously dissolved in 0.1 mol L-1 phosphate buffer solution (pH 7.0) and a volume of 500 muL was injected directly into a carrier stream consisting of this same phosphate buffer solution, flowing at 4.4 mL min-1. The stable blue indophenol dye produced in the oxidation of pyridoxine hydrochloride by potassium hexacyanoferrate(III) and N,N-diethyl-p-phenylenediamine solution was directly measured at 684 nm. Vitamin B6 was determined in five pharmaceutical preparations in the 0.5 to 6.0 mg L-1 concentration range (calibration graph: A= -0.00499 + 0.11963 C; r= 0.9991, where A is the absorbance and C is the vitamin B6 concentration in mg L-1), with a detection limit of 0.02 mg L-1 (3 Sblank/slope). The recovery of this vitamin from three samples ranged from 97.5 to 103.3 %. The analytical frequency was 62 h-1 and r.s.d. were less than 2% for solutions containing 1.0 and 3.0 mg L-1 vitamin B6 (n= 10). The results obtained for the determination of vitamin B6 in commercial formulations were in good agreement with those obtained by a spectrophotometric procedure (r=0.9997) and also with the label values (r= 0.9998).

Determinação espectrofotométrica de vitamina B2 (riboflavina) em formulações farmacêuticas empregando sistema de análises por injeção em fluxo

A flow injection spectrophotometric procedure exploiting merging zones is proposed for determining vitamin B2 (riboflavin) in pharmaceutical preparations. The determination is based on the red-colored complex formation between vitamin B2 and silver(I) which was measured at 520 nm. Vitamin B2 was determined in four pharmaceutical preparations in the 1.0 to 50.0 mg L-1 concentration range, with a detection limit of 0.5 mg L-1. The recovery from three samples ranged from 98.0 to 104.0 %. The analytical frequency was 42 h-1 and r.s.d. were lower than 1% for solutions containing 10.0, 30.0 and 50.0 mg L-1 vitamin B2 (n= 10). The results obtained in commercial formulations using the FIA procedure were in good agreement with those obtained by using a conventional fluorimetric procedure (r=0.9998) and also with the label values (r= 0.9997).

Determinação turbidimétrica de metilbrometo de homatropina em formulações farmacêuticas empregando um sistema de análise por injeção em fluxo

A flow injection turbidimetric procedure exploiting merging zones is proposed for determining homatropine methylbromide (HMB) in pharmaceutical preparations. The determination is based on the precipitation reaction of homatropine methylbromide with AgNO3 solution to form a precipitate, which was measured at 410 nm. The analytical curve was linear in the HMB concentration range from 8.0x10-4 to 1.7x10-3 mol L-1, with a detection limit of 9.5x10-5 mol L-1. The recoveries ranged from 94.9 to 104 %, the sampling frequency was 75 h-1 and relative standard deviations were smaller than 2.0 % for solutions containing 1.2x10-3 and 1.5x10-3 mol L-1 HMB (n=10). The results obtained for commercial formulations using the FIA procedure were in good agreement with those obtained by using a comparative method (r= 0.9983).

Analytical methods for vancomycin determination in biological fluids and in pharmaceuticals

Vancomycin is a glycopeptide antibiotic employed in the treatment of infections caused by certain methicillin-resistant staphylococci. It is indicated also for patients allergic to penicillin or when there is no response to penicillins or cephalosporins. The adequate vancomycin concentration levels in blood serum lies between 5 and 10 mg/L. Higher values are toxic, causing mainly nephrotoxicity and ototoxicity. Various analytical methods are described in the literature: spectrophotometric, immunologic, biologic and chromatographic methods. This paper reviews the main analytical methods for vancomycin determination in biological fluids and in pharmaceutical preparations.