Elena Rubio

Adverse drug reactions in children reported by means of the yellow card in Spain

OBJECTIVE To analyze the case reports concerning children (14 years or younger) in the Spanish Pharmacovigilance System over a 10-year period (1982-1991). FINDINGS The study of 1419 reports of adverse drug reaction (9.8% of all those received) showed the most commonly involved organs and systems to be the skin, digestive tract, and nervous system (62.8%). The most commonly involved pharmacological groups were antibiotics, respiratory medications, and vaccines (69%). The absolute number of reports is higher in children between 1 and 4 years of age (37.9%). There were more reports among males than in females. Less than 5% of the reports notified directly life-threatening or fatal reactions. CONCLUSIONS Adverse drug reaction are not common in pediatric patients, and most are mild. However, due to limitations of clinical trials in children, pharmacoepidemiological studies may be the only source of information on the benefit-risk profile of drugs received by these patients, and as such require special attention.

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.

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.

Pharmacological investigation into the effects of histamine and histamine analogues on guinea-pig and rat colon in vitro

1 The effects of histamine and specific histamine agonists has been examined on isolated longitudinal colon strips of guinea‐pig and rat. 2 Histamine and 2‐pyridyl‐ethylamine but not 4 methylhistamine produced a concentration‐related contractile response in the guinea‐pig colon. 3 The H1‐antagonist clemizole antagonized competitively the effect of histamine but the H2‐antagonist ranitidine did not modify the dose‐response curve to histamine in the guinea‐pig colon. 4 Atropine, hexamethonium, prazosin and propranolol failed to modify the contractile response to histamine. 5 Tone induced with KCl in guinea‐pig isolated colon was not modified by histamine agonists even in tissues pretreated with clemizole or ranitidine. 6 Histamine and histamine analogues were without effect on the isolated longitudinal strip of the rat colon. 7 It is concluded that histamine produced dose‐dependent contractions of the guinea‐pig colon due to direct activation of H1‐histamine receptors. There is no evidence in favour of the existence of H2‐histamine receptors in this preparation. The lack of effect of histamine agonists in rat colon strip argues against the existence of histamine receptors in this preparation.

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.

The inhibitory effect of histamine on the motility of rat uterus in vivo

The experiments concerned the effects of histamine and its analogs 4-methylhistamine and 2-pyridyl-ethylamine on the spontaneous activity of the estrogenized rat uterus in vivo. These agonists given intravenously inhibited uterine activity. Histamine and 4-methylhistamine, but not 2-pyridyl ethylamine, produced this effect in a dose-dependent manner. The ability of histamine to reduce uterine activity was lowered by pretreatment with reserpine, adrenalectomy or 6-hydroxydopamine. The effect of 4-methylhistamine also was reduced by reserpine or adrenalectomy. The inhibitory effect of 2-(2-pyridyl) ethylamine was completely abolished by reserpine or adrenalectomy. Cimetidine attenuated the residual inhibitory effect of histamine in reserpinized rats. These results suggest that the uterine inhibitory action of histamine and 4-methylhistamine is mediated through catecholamine release and direct stimulation of the H2-receptors. The effect of 2-(2-pyridyl) ethylamine is only mediated by release catecholamine.

Transient ischemic attack secondary to hypertensive crisis related to Panax ginseng

1. Okamoto H, Teramura M, Kamatani N. Myelodysplastic syndrome associated with low-dose methotrexate in rheumatoid arthritis. Ann Pharmacother 2004;38:172-3. DOI 10.1345/aph.1D117 2. Pointud P, Prudat M, Peron JM. Acute leukemia after low dose methotrexate in a patient with rheumatoid arthritis. J Rheumatol 1993;20:1215-6. 3. Rosenthal NS, Farhi DC. Myelodysplastic syndromes and acute myeloid leukemia in connective tissue disease after single-agent chemotherapy. Am J Clin Pathol 1996;106:676-9. 4. Yetgin S, Ozen S, Saatci U, Bakkaloglu A, Besbas N, Kirel B. Myelodysplastic features in juvenile rheumatoid arthritis. Am J Hematol 1997;54: 166-9. 5. Nam E-J, Kang Y-M, Kang H-R, Kim J-H, Rho H-J, Lee M-K, et al. Rheumatoid arthritis associated with myelodysplastic syndrome: a case report. J Korean Med Sci 1999;14:319-22.

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.