L. Estañ

Drug utilization and off-label drug use among Spanish emergency room paediatric patients

ObjectiveTo describe the use of medicines and to determine the frequency of off-label use in emergency room paediatric patients.Patients and methodsA prospective, observational and descriptive study was carried out in the setting of the paediatric emergency room of a Spanish general hospital. Medicines used by children <14 years prior to their emergency room visit were analysed based on information collected from parents/guardians and relatives for each drug prescription. Off-label use was defined as the utilization of a drug at an indication, dosage, frequency or route of administration that differed from the specifications in the Summary of Product Characteristics or by children outside the authorized age group.ResultsThe patient cohort comprised 462 children, among whom 336 children had been prescribed 667 prescriptions. Of the medicines prescribed, 90% fell into only five 5 Anatomical Therapeutic Chemical Classification System groups. The most frequent active principles were ibuprofen and paracetamol. Of a total of 152 different formulations recorded, no paediatric information was provided for 40 formulations, and one formulation was contraindicated in children. Based on the established criteria, 338 prescriptions were off-label: no paediatric information or contraindication in children were available (82 prescriptions); the drug was used for an indication different from the authorized one (111 prescriptions); drug use was inconsistent with age recommendations (16 prescriptions); drug use was inconsistent with dose/frequency (129 prescriptions). Of the 152 formulations, 107 were occasionally used in an off-label manner.ConclusionsAlthough the mean number of drugs used in children is small, off-label use is frequent. Research efforts should target paediatric studies that allow a rational drug use in children.

Identification of α2-adrenoceptors and non-adrenergic idazoxan binding sites in rabbit colon epithelial cells

alpha 2-Adrenoceptors are possibly involved in the regulation of the hydroelectrolytic flux across the digestive mucosa. As no data are available concerning the existence of these receptors in colon epithelial cells, we aimed to investigate the existence of alpha 2-adrenoceptors in this tissue using tritiated antagonists. [3H]Yohimbine and [3H]rauwolscine were not usable to label colonic alpha 2-adrenoceptors because of their very high level of non-specific binding. In contrast, the methoxy derivative of idazoxan, [3H]RX821002, appeared a convenient radioligand for the purpose. [3H]RX821002 bound with high affinity (KD = 6.2 +/- 0.8 nM) to a single population of non-interacting sites (Bmax = 193 +/- 17 fmol/mg protein). The rank order of potency of catecholamine enantiomers and adrenergic drugs to inhibit [3H]RX821002 binding demonstrated that the labelled sites are alpha 2-adrenoceptors and that 53% of the receptors are in a high-affinity state sensitive to GTP + NaCl. [3H]Idazoxan also bound to colocyte membranes, but inhibition by (-)-adrenaline and various imidazoline compounds indicated that this radioligands labels alpha 2-adrenoceptors and non-adrenergic sites. When experiments were performed under binding conditions impeding the interaction of [3H]idazoxan with the alpha 2-adrenoceptors (i.e. in presence of 10(-4) M (-)-adrenaline), the Bmax of non-adrenergic idazoxan binding sites was 97 +/- 8 fmol/mg protein and the KD was 3.5 +/- 0.5 nM. The sites were pharmacologically characterized with various imidazoline and non-imidazoline drugs. In order to study the putative relationship between alpha 2-adrenoceptors and non-adrenergic idazoxan binding sites, the expression of both kinds of sites was investigated along the crypt-to-surface axis. Crypt cells had a higher number of alpha 2-adrenoceptors than surface cells, whereas the number of non-adrenergic idazoxan binding sites remained constant. The results show that (i) alpha 2-adrenoceptors coexist with non-adrenergic idazoxan binding sites in rabbit colocytes; (ii) the number of alpha 2-adrenoceptors is higher in crypt cells than in surface cells and (iii) alpha 2-adrenoceptors and non-adrenergic binding sites are different and unrelated.

Effect of histamine and histamine analogues on human isolated myometrial strips

1 The effect of histamine and histamine H1 and H2‐receptor agonists on isolated myometrium strips of premenopausal women has been examined. The effect of acetylcholine was also determined. 2 Histamine, 2‐pyridylethylamine, 4‐methylhistamine and acetylcholine, but not dimaprit, produced a concentration‐related contractile response in human isolated myometrial strips. Histamine also produced a further contraction in human isolated myometrial strips precontracted with KCl (55 mm). 3 The contractile response to histamine was antagonized by the histamine H1‐receptor angatonist, clemizole (0.1 μm) but was potentiated by the histamine H2‐receptor antagonist, ranitidine (10 μm). Clemizole (0.1 nm to 10 nm) competitively antagonized the contractile effect of 2‐pyridylethylamine (– log KB = 10.5 ± 0.5). The concentration‐response curve for acetylcholine was displaced to the right by atropine 0.1 μm. 4 Atropine (0.1 μm), propranolol (0.1 μm), prazosin (0.1 μm) and indomethacin (1 μm) failed to modify the contractile response to histamine. 5 In human isolated myometrial strips precontracted with KCl (55 mm), clemizole at 1 μm completely abolished the contractile response to histamine and revealed a concentration‐dependent relaxation. Dimaprit alone and 4‐methylhistamine (in the presence of clemizole), produced concentration‐related relaxation with a magnitude similar to that in response to histamine. The relaxant response to dimaprit was antagonized by ranitidine. 6 It is concluded that human isolated uterine strips possess histamine H1‐ and H2‐receptors: the former mediating contraction and the latter relaxation. The predominant response to histamine in this tissue is contraction.

Medicamentos utilizados en pediatría extrahospitalaria : ¿disponemos de información suficiente?

Objetivo Analizar los medicamentos que reciben los pacientes pediatricos en el ambito extrahospitalario y la informacion disponible sobre los mismos. Pacientes y metodos Estudio transversal, observacional y descriptivo realizado en una muestra de pacientes menores de 14 anos atendidos en urgencias del Servicio de Pediatria del Consorcio Hospital General Universitario de Valencia entre junio 2005 y agosto 2006. Se cuantifican y clasifican los medicamentos utilizados antes de acudir a urgencias y se analiza la informacion sobre su uso que contiene el Vademecum Internacional Medicom y la ficha tecnica. Resultados Se recogio informacion sobre 462 ninos con media de edad de 5,2 anos (intervalo de confianza del 95% [IC 95%]: 4,9-5,6). De ellos, 336 reciben 667 medicamentos (152 distintos) que contienen 864 principios activos (161 diferentes). En el 34,3 % de los casos el uso es por automedicacion. Los menores de 4 anos reciben medicamentos en mayor proporcion que los mayores (80,2 y 67,4%, respectivamente). Los pacientes reciben entre 1 y 7 medicamentos (media 2,0). Los que toman 2 o 3 medicamentos son menores que los que toman uno. Cinco grupos terapeuticos de la Clasificacion anatomico-terapeutico-quimica (ATC) incluyen el 93,1% de los medicamentos (R [aparato respiratorio]: 26,5%; M [aparato locomotor]: 23,8%; N [sistema nervioso central]: 22,8 %;J [antiinfecciosos por via general]: 10,6% y A [aparato digestivo y metabolismo]: 10,0%). Para 40 de los 152 medicamentos no hay informacion pediatrica en las fuentes consultadas. Conclusiones Casi tres cuartas partes de los ninos atendidos en urgencias toman medicamentos antes de acudir a este servicio, en muchos casos por automedicacion. La informacion sobre uso pediatrico de medicamentos es incompleta y presenta incongruencias. Es necesario fomentar la investigacion clinica sobre los efectos del tratamiento farmacologico en los ninos para mejorar la informacion sobre su uso.

Studies of the spontaneous motility and the effect of histamine on isolated myometrial strips of the nonpregnant human uterus: The influence of various uterine abnormalities

We investigated the spontaneous uterine activity of isolated corpus uteri myometrial strips from 30 patients with nonpathologic myometrium, 26 patients with uterine myoma, 23 patients with uterine adenomyosis, and three patients with uterine malignancy. We also investigated the influence of these conditions on the response of the uterus to histamine. The results show the same qualitative cyclic changes of the spontaneous motility of isolated myometrial strips throughout the menstrual cycle in all the abnormalities studied. These changes are characterized by a low amplitude and high frequency of spontaneous contractions in the proliferative phase and lower frequency with higher amplitude of contractions in the secretory phase. The isolated strips from patients with myomas present the highest spontaneous activity in reproductive age and preclimacteric women, but not in menopausal women. Histamine produced concentration-related contractions that are not significantly different in all the myometrial strips studied.

Interacciones farmacológicas de los fármacos antihipertensivos

A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a different one. Hypertensive patients, mainly the more elderly ones, frequently present concomitant diseases that require the administration of several medicines which facilitates the appearance of interactions. The lack of effectiveness of the antihypertensive treatment is a relatively frequent fact that sometimes is due to interactions of antihypertensive drugs with other treatments. It is difficult to determine the incidence of interactions, but it is related to the number of drugs administered simultaneously. Between 37 and 60% of hospital-admissions are treated with potentially dangerous drug associations and up to a 6% of fatal events are due to this circumstance. Among antihypertensive drugs, diuretics and angiotensin converting enzyme inhibitors are less affected by drug-interactions. Lipophilic beta-blockers agents may present some clinical relevant interactions, whereas calcium channel blockers, especially the non-dihydropiridinic ones, are implied in clinically relevant pharmacokinetic interactions. Among the angiotensin receptor blockers there are differences that would have to be considered when they are used in patients who receive other drugs. Although it is impossible for the doctor to remember all the clinical relevant interactions, it is important to bear in mind their existence and the possible mechanisms of production which can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein. Enzymes of the cytochrome P450 system may present polymorphisms that can explain the individual differences in the response to drugs or the appearance of drug-interactions.

Naphazoline intoxication in children.

Inappropriate use or unintentional ingestion of naphazoline, especially in children, can quickly cause severe central nervous system depression and cardiovascular adverse effects [2, 6]. A five-year-old boy arrived at the Emergency Room 90 min after the ingestion of approximately 10 ml of Euboral Oftálmico solution (9.7 g of sodium-tetraborate, 0.1 g of naphazoline-chlorhydrate and 0.2 g of methylparaben for 1 l dilution, for topical use), prepared in a bottle without a label in a 0.02% concentration, which was twice that of the manufacturer’s recommendation. During the physical examination, bradycardia (heart rate 45–50 bpm), hypothermia (35.5°C) and a blood pressure of 100/ 70 mmHg (blood pressure percentile 75th/90th) were observed. Gastric lavage and activated carbon administration were performed. A few minutes later, the patient presented somnolence, sweating, persistence of the bradycardia and hypothermia. Blood pressure and oxygen saturation were normal. At the EKG (electrocardiogram), sinusal bradycardia of 48 bpm was observed and laboratory parameters showed no abnormalities. Blood analysis of standard toxicological drugs was performed with negative results. Infusion therapy was started to force diuresis and the patient was admitted to the hospital in order to monitor vital parameters. Bradycardia lowest value (47 bpm) was observed 3 h after the ingestion. Somnolence and hypothermia (35.2°C) were maximum 7 h after the ingestion and sweating persisted until 12 h later. Blood pressure also returned to normal during this period without treatment; its highest value was 130/80 mmHg (blood pressure percentile >99th/99th) with no subsequent hypotension. The patient was discharged 20 h later. Naphazoline has a narrow therapeutic to toxic window and intoxication may occur at a dose of 0.05 mg/kg body weight [2]. Systemic side effects are observed rarely, despite frequent and uncontrolled use because of partial availability without doctor’s prescription. They can progress potentially up to intoxication with vitally threatening cardiovascular symptoms (arterial hypertension with reflex bradycardia defined as a heart rate under 60 bpm and possible ischaemia of vital functions), pulmonary and central nervous symptoms. The central nervous system effects concern the reduction of vigilance ranging from drowsiness to coma, persisting cardiovascular hypotension and reduced respiration rate up to the Cheyne-Stokes breathing and possible pulmonary edema, hypothermia, mydriasis, hyperhydrosis and transient excitation hyperreflexia [1]. Our patient presented a large number of the symptoms described above, especially those affecting cardiovascular and central nervous systems. Blood analysis of standard toxicological drugs excluded alternative causes of intoxication. Because of rapid absorption, we wonder whether gastric lavage and carbon-activated administration are the suitable Eur J Pediatr (2006) 165:815–816 DOI 10.1007/s00431-006-0185-1

Interacciones medicamentosas. Nuevos aspectos

Se denomina interaccion farmacologica a la modificacion cuantitativa o cualitativa del efecto de un farmaco causada por la administracion simultanea o sucesiva de otro. La polimedicacion facilita la aparicion de interacciones cuyo resultado puede ser una reaccion adversa o la perdida de efecto terapeutico. La incidencia es dificil de determinar, pero se relaciona fundamentalmente con el numero de farmacos administrados conjuntamente al mismo paciente. Aunque es imposible recordar todas las interacciones de interes clinico, conocer su existencia y mecanismos de produccion ayuda a identificarlas y prevenirlas. Las que con mayor frecuencia causan problemas son las de tipo farmacocinetico, sobre todo las relacionadas con el metabolismo a traves del sistema del citocromo P450 o el aclaramiento presistemico por la glucoproteina P u otros transportadores. Las interacciones entre farmacos y zumo de pomelo o hierba de San Juan son cada vez mejor conocidas y deben tenerse en cuenta en la practica diaria.

Influence of hormonal treatment on the response of the rat isolated uterus to histamine and histamine receptor agonists.

The response of the isolated uterus to histamine and histamine agonists was investigated in progesterone- and oestrogen-treated rats. The uterine inhibitory responses to histamine and 4-methylhistamine (a histamine H2 receptor agonist) were similar in KCl-contracted uteri from progesterone- and oestrogen-treated rats. The histamine H1 receptor agonist, 2-pyridyl-ethylamine, produced a relaxant response only in progesterone dominant uterus. This was inhibited by the histamine H1 receptor antagonist. In the rat isolated uterus which was not preconstricted by KCl, neither histamine, 4-methylhistamine, nor 2-pyridyl-ethylamine produced any effect in the presence or absence of ranitidine. Ranitidine competitively antagonized the histamine-relaxant uterine response in oestrogen-treated rats (pA2 = 7.21 (6.83-7.58)), but not in progesterone-treated rats, except in the presence of clemizole (10(-7) M) when the pA2 value of ranitidine against histamine was similar to that obtained in oestrogen-treated rats (pA2 = 6.74 (6.64-6.85)). These results indicate that treatment with ovarian steroids influences responses mediated by the histamine receptors of the isolated rat uterus. Both histamine H2 and H1 receptors contribute to the uterine inhibitory effect of histamine in progesterone-treated rats.

Are the adverse drug reactions of amoxycillin and amoxycillin-clavulanic acid similar?

In an attempt to assess the relative toxicity of amoxycillin and amoxycillin–clavulanic acid, we compared the adverse drug reactions reports collected using the spontaneous reporting system of a Regional Drug Surveillance Centre of Spain for both drugs between November 1986 and December 1992. During the 7‐year period 1986–92, the 247 reports of amoxycillin–clavulanic acid represent twice the number of reports of amoxycillin alone, and the number of reports related with sales received concerning the association were higher than those concerning amoxycillin alone. The adverse effects classified as severe were quantitatively and qualitatively similar for both drugs and gastrointestinal and skin are the most common system–organ affected by both drugs. With amoxycillin–clavulanic acid there is a higher proportion of stomatological reactions reported and a later onset of adverse drug reactions related with oropharyngeal lesions, and the reaction of the resistance mechanism when compared with the other organs and systems affected. The duration of the adverse drug reactions to amoxycillin–clavulanic acid is longer than for amoxycillin alone. In conclusion: (i) the adverse drug reactions profile of both drugs is different; (ii) the higher reporting rate for amoxycillin–clavulanic acid may be due to more recent marketing; and (iii) amoxycillin–clavulanic acid produces proportionately more gastrointestinal and fewer skin adverse reactions than amoxycillin alone.