Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care.

BACKGROUND: Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. AIMS: To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. METHOD: A multicentre three-arm cluster randomised controlled trial was conducted, with randomisation at general practitioner level (trial registration ISRCTN13024375). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were randomly allocated (1:1:1) to usual care, a structured intervention with follow-up visits (SIF) or a structured intervention with written instructions (SIW). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription claims at 12 months. RESULTS: At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 (15%) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 (95% CI 2.03-4.46, P<0.0001) in the SIW and 3.00 (95% CI 2.04-4.40, P<0.0001) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. CONCLUSIONS: Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits.

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.

[Adverse reactions from angiotensin-converting enzyme inhibitor drugs reported by the yellow card]. / Reacciones adversas por fármacos inhibidores de la enzima conversiva de la angiotensina notificadas por medio de tarjeta amarilla.

BACKGROUND: The aim of the present study was to analyze the adverse reactions (AR) to captopril (CP) and enalapril (EN) reported by voluntary notification by the yellow card (YC) over the first five years of the foundation of the Drug Surveillance Center of the Valencian Community. METHODS: The AR described were classified by organs and systems, evaluating the age and the sex of the patient, the indication for the drug, dosage used, and the level of health care assistance received since notification. Previous knowledge of the reported AR was analyzed, as was the possible relation of causality with the drug and severity of the same. The rates of notification were calculated with respect to the consumption of both drugs, expressed in daily dosage defined (DDD). RESULTS: Two hundred one YC were evaluated, 111 for CP and 90 for EN referring 160 and 133 clinical manifestations, respectively. The rate of notification was 2.51 YC/million DDD for CP and 5.57 for EN. The AR in the respiratory tract were the most frequently reported with cases of dry cough representing 33.7% of the total YC for CP and 33.8% for EN. Cutaneous AR followed for both drugs. Angioedema was reported in 0.09 AR/million DDD for CP and 0.56 for EN. Reactions were most frequently observed in patients over the age of 50 with a predominance of the female sex, being usually slight and with 80% having been notified from primary health care centers. CONCLUSIONS: The high number of reports of cough demonstrate that this is the most frequently observed adverse reaction. The distribution of reactions and the characteristics of the patients with the same coincide with other studies. The low number of yellow cards reporting severe adverse reactions may support the favorable safety profile of this pharmacologic group, or, to the contrary, be a consequence of the under-reporting of adverse reactions.

[Adverse reactions to medications in patients in ambulatory otorhinolaryngology]. / Reacciones adversas a medicamentos en pacientes atendidos en consulta externa de otorrinolaringología.

A 12 months prospective study to detect adverse drug reactions (ADR) was carried out in an ORL outpatients clinic. 52 patients (1.8%) out of 2891 examined suffered one or more ADRs. The incidence was higher in women and in older patients. 94% of the ADRs were mild to moderate and 3 patients suffered irreversible lesions. Reactions were most commonly located in the nervous system (50%) and gastrointestinal tract (21%). The most common drugs involved were cardiovascular (40%) and central nervous system (25%) active drugs. Papers concerning ADRs published from 1976 to 1985 in spanish otorhinolaringologic journals have also been analyzed. 0.88% of 1357 published papers described ADRs. The incidence of ADRs observed in our study is higher than expected from the low number of papers published on this subject.

[Quality of the publication of adverse drug reactions in the letters to the editor section of four Spanish internal medicine and general medicine journals]. / Calidad de la publicación de reacciones adversas a medicamentos en la sección de Cartas al Director de cuatro revistas españolas de medicina interna y medicina general.

OBJECTIVE: To assess the quality and relevance of adverse drug reactions (ADRs) published as Letters to the Editor (LE) in Spanish medical journals. DESIGN: Observational study. PARTICIPANTS: LE on adverse drug reactions published over 5 years (1994-98). SETTING: Four Spanish medical journals (Medicina Clínica, Revista Clínica Española, Atención Primaria and Anales de Medicina Interna). MAIN MEASUREMENTS: Patient characteristics, drugs, ADR, causality algorithm, minimum criteria, and publication relevance. RESULTS: Out of 2244 LE, 204 (9.1%) reported ADRs, which included 235 cases. The therapeutic subgroups most commonly implicated were anticoagulants and antiplatelet drugs, antibiotics, and antineoplastic agents; 20.4% of the drugs were recently marketed. ADRs most commonly involved the nervous system (13.6%), liver (10.2%), skin and appendages (9.8%), general reactions (9.8%), and the digestive system (8.1%). The reactions were moderate in 50.2% of cases and severe/fatal in 34%. The mean causality algorithm value (5.9+/-2.2) was similar among journals. Of the ADRs, 28 (11.9%) were definitive, 182 (77%) possible or probable, and 26 (11.1%) improbable or conditional; 10.2% were unknown. There were no differences in the mean minimum publication criteria (9.5+/-1.2). Publication relevance was 3.2+/-1.6 points, and higher in Medicina Clínica. CONCLUSIONS: ADRs constitute an important part of LE in the journals studied. The causal relationship is acceptable, the documentation quality is high, with few unknown reactions and ADRs to recently marketed drugs. Relevance is generally low, although greater in Medicina Clínica.

Weight gain associated with cinnarizine.

OBJECTIVE: To report four cases of cinnarizine-induced weight gain. DATA SOURCES: Case reports from a local obesity center and review articles. DATA EXTRACTION: Data were abstracted from spontaneous comments made by patients to one of the authors, who was a doctor at the clinic, and reviewed by the remaining authors. DATA SYNTHESIS: We reviewed the cases of four women, aged 50-57 years without endocrine or metabolic pathologies, that showed weight gain associated with the intake of cinnarizine for one to two years. No other drugs usually were administered during the period in which the women gained weight, although in two cases cinnarizine was associated with dihydroergocristine in the same medicine (Clinadil). The mean weight increase was 6.25 kg (range 4-10). The increases do not appear to be related to whether the patients' initial weight was ideal or excessive. The weight gain was always associated with increased appetite and food intake. One patient discontinued cinnarizine treatment and her weight returned to its previous level. CONCLUSIONS: Cinnarizine is a piperazine derivative used in the treatment of vertigo and in the prophylaxis of migraine. In contrast to related drugs, data about cinnarizine are scarce because randomized trials of cinnarizine have been inconclusive. Our observations indicate that cinnarizine may cause weight gain, as observed with other drugs in the same class.

Fluoxetine-associated stomatitis.

OBJECTIVE: To describe two cases of stomatitis related to fluoxetine given for the treatment of depression that were detected in the hospital emergency department. DATA SYNTHESIS: Two women developed stomatitis after the intake of fluoxetine for the treatment of depression. One of the patients had six recurrent episodes of stomatitis without suspecting an association with fluoxetine. No other drugs were administered during these episodes. The second patient was treated concurrently with fluoxetine and bentazepam. In both patients the lesion improved upon discontinuation of fluoxetine, even though the second patient continued to take a different benzodiazepine. DISCUSSION: Stomatitis related to fluoxetine has not been previously reported in clinical trials or in the literature. According to the causal algorithm used by the Spanish Drug Surveillance Schemes, the first case constituted a defined adverse reaction and the second was probable. CONCLUSIONS: Our observations suggest that fluoxetine may be considered as a probable cause of stomatitis. The reporting of isolated cases of adverse drug reactions (ADRs) makes it possible to define the toxicity profile of recently marketed drugs such as selective serotonin-reuptake inhibitors, including fluoxetine. Emphasis is placed on the potential role played by emergency departments in detecting ADRs.

Hypotensive action and alpha-adrenolytic properties of a new dopaminergic agonist, CU 32-085, in the rat.

The effect of an 8-alpha-amino-ergoline-derivative, CU 32-085, recently characterized as a dopamine agonist, was studied on blood pressure and heart rate in normotensive anesthetized rats. The effects of CU 32-085 and bromocriptine on dose-response curves to sympathomimetic agents (adrenaline, noradrenaline, methoxamine and clonidine), intravenously administered, were also studied. CU 32-085 slowed heart rate and lowered blood pressure. The hypotensive effect was antagonized by pretreatment with sulpiride. CU 32-085 and bromocriptine reduced the pressor effect of adrenaline, noradrenaline and methoxamine and the hypotensive action of clonidine. These results suggest that the hypotensive action of CU 32-085, like bromocriptine, is mainly due to an action on dopaminergic receptors. In addition, the data obtained with sympathomimetic agents suggest that CU 32-085 is a compound with mixed alpha 1 and alpha 2 antagonist properties, similar to bromocriptine.

The effects of epinine on arterial blood pressure and regional vascular resistances in anesthetized rats.

1. We carried out experiments in anesthetized rats to study the hemodynamic effects of intravenous injections of epinine. 2. Epinine (1-320 micrograms/kg) produced a biphasic effect on mean arterial blood pressure (n = 30). At doses lower than 40 micrograms/kg, arterial blood pressure decreased (by as much as 21.5 +/- 3.4%), though at higher doses it increased dose dependently (by as much as 73.2 +/- 14.5%). Epinine also produced bradicardia in a dose-dependent manner (by as much as 26.4 +/- 4.9%). Sulpiride (100 micrograms/kg) suppressed the hypotensive effect of epinine but did not change the hypertensive effect. In the presence of prazosin (1,000 micrograms/kg), arterial blood pressure remained significantly decreased at all doses of epinine. Neither sulpiride nor prazosin changed the bradycardic effect of epinine. 3. Prazosin produced a significant decrease in renal vascular resistance. Epinine (5 micrograms/kg) after prazosin reverted the effects of prazosin in renal vascular resistance, without any significant modification in the renal blood flows. However, 20 micrograms/kg epinine increased the renal vascular resistances and, moreover, produced a significant decrease in the blood flows of both kidneys. Neither prazosin nor epinine produced modifications in the intestinal vascular bed. 4. Although epinine possesses significant dopamine and alpha-adrenergic activities that are involved in the biphasic effect of the agent on mean arterial blood pressure in anesthetized rats, in the presence of prazosin, it is not possible to manifest dopaminergic activity involved in the increase in renal or mesenteric blood flow; this may be due to the low tone of the vascular wall induced by the alpha-adrenergic antagonist, though an alpha 2-activity cannot be discarded.

The effects of histamine on the isolated mouse uterus.

1. A study is made of the contractile and relaxant effects, and mechanism of action, of histamine on isolated uterus from mice treated with diethylstilboestrol, employing acetylcholine and adrenaline as contractile and relaxant standard agents. 2. Concentration-response curves for histamine agonists were obtained in the absence and presence of selective histaminergic blocking drugs (clemizole, ranitidine and thioperamide) and indomethacin. A number of experiments were carried out in uterus from reserpinised mice. Concentration-response curves for acetylcholine and adrenaline were also obtained in the absence and presence of their selective antagonist (atropine and propranolol). 3. In isolated oestrogenised mouse uterus, histamine and acetylcholine produced a concentration-related contractile response. When the uterus was precontracted with KCl, histamine at lower doses produced a slight contraction, though in the presence of clemizole it induced concentration-related relaxation, reminiscent of that produced by adrenaline. Atropine and propranolol antagonised the contractile and relaxant effects of acetylcholine and adrenaline, respectively. 4. In isolated uterus from reserpinised mice, histamine and 2-pyridylethylamine, but not 4-methylhistamine, produced a concentration-related contractile response. Ranitidine potentiated the contractile effect of histamine, though clemizole--in the presence of ranitidine--competitively antagonised the contractile effect of histamine (pA2 = 10.50 +/- 0.81). The concentration-relaxant curve of histamine in the presence of clemizole was not modified by ranitidine or indomethacin, but shifted to the right with thioperamide. The same displacement was also observed in the presence of clemizole plus ranitidine. 5. In mouse isolated uterus, histamine mainly produced contraction mediated by histamine H1-receptors, though the existence of histamine H2- or H3-receptors mediating relaxation could not be excluded.

Effects of methoxamine on spontaneous uterine activity and blood flow of the rat uterus 'in vivo'.

The vascular (blood pressure, heart rate and peripheral blood flow) and uterine (spontaneous motility) responses to intravenous methoxamine were studied in anaesthetized rats pre-treated with diethylstilboestrol. Methoxamine produced an increase (0.5-2 mg/kg) or did not modify (0.01 and 3 mg/kg) spontaneous uterine motility. The alpha 1-agonist also induced a hypertensive effect (0.1-3 mg/kg) accompanied by bradycardia at the highest doses, and a decrease in blood flow significantly greater in intestinal than uterine tissues. These effects were abolished by prazosin. The uterine action of methoxamine in vivo appears to result from the balance between myometrial alpha 1-excitatory effect and vascular alpha 1-vasoconstriction which induced uterine inhibition. The oestrogens appear to protect the alpha 1-mediated vasoconstriction.

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

UNLABELLED: 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.