RESUMEN
OBJECTIVE: To review the efficacy and safety of moclobemide in comparison with TCAs (for our purposes, "TCAs" will represent tricyclic and tetracyclic antidepressants, including maprotilin and mianserin) and selective serotonin reuptake inhibitors (SSRIs) in elderly depressed patients. METHODS: The efficacy data reviewed were obtained from the following sources: 1) results of published studies in the elderly; 2) data on patients aged > or = 60 years extracted from all available controlled trials in adults (> or = 18 years) in which moclobemide was compared with TCAs or SSRIs; and 3) the adverse events were extracted for patients aged > or = 60 years from the safety data base of all available comparative short-term studies with moclobemide versus TCAs, SSRIs, or placebo and of long-term studies with moclobemide. RESULTS: The data show that moclobemide is an effective antidepressant in depressed patients aged > or = 60 years. The response rate to moclobemide was 50% to 55% in this population. Moclobemide was more effective than placebo and was of similar efficacy to the TCAs and the more recently introduced SSRIs. The tolerability of moclobemide was rated as "very good" or "good" in almost 90% of these patients, which was better than the tolerability of TCAs and similar to that of SSRIs. Patients without any adverse events were more frequently found in the moclobemide group than in those treated with TCAs (P < 0.01) or SSRIs (P < 0.01). Adverse events of the anticholinergic type were more frequent with TCAs than with moclobemide (P < 0.001), and nausea was found 3 times more frequently with SSRIs than with moclobemide (P < 0.01). CONCLUSIONS: Moclobemide is an effective and well-tolerated antidepressant for the treatment of elderly depressed patients.
Asunto(s)
Antidepresivos/uso terapéutico , Benzamidas/uso terapéutico , Depresión/tratamiento farmacológico , Psiquiatría Geriátrica/métodos , Inhibidores de la Monoaminooxidasa/uso terapéutico , Anciano , Antidepresivos/efectos adversos , Antidepresivos Tricíclicos/efectos adversos , Antidepresivos Tricíclicos/uso terapéutico , Benzamidas/efectos adversos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Cognición/efectos de los fármacos , Intervalos de Confianza , Interacciones Farmacológicas , Humanos , Persona de Mediana Edad , Moclobemida , Inhibidores de la Monoaminooxidasa/efectos adversos , Placebos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.
Asunto(s)
Antidepresivos/farmacocinética , Hidrocarburo de Aril Hidroxilasas , Trastorno Depresivo/enzimología , Enzimas/fisiología , Antidepresivos/efectos adversos , Antidepresivos/uso terapéutico , Ensayos Clínicos como Asunto , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/fisiología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/psicología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Enzimas/genética , Humanos , Hígado/enzimología , Tasa de Depuración Metabólica/fisiología , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/fisiología , Polimorfismo Genético/genéticaRESUMEN
The effects of terfenadine and pseudoephedrine, alone and in combination, have been assessed in a nasal provocation test and in perennial rhinitis. In a double-blind, placebo-controlled cross-over nasal provocation test, twelve men allergic to grass pollen were treated with two daily doses of placebo, terfenadine 60 mg, pseudoephedrine 120 mg, or the combination of the two, for 2 days preceding each test. The allergic reaction threshold, based on rhinorrhoea, sneezing and nasal inspiratory peak flow rate, was raised significantly both by terfenadine and pseudoephedrine, and their effects appeared additive (repeated measures analysis of variance). In a double-blind, randomized clinical study of perennial rhinitis two parallel groups, the efficacy and tolerability of terfenadine and terfenadine-pseudoephedrine were compared in 50 patients. Symptoms and signs in both groups were improved after 14 days of treatment. Differences between groups showed a trend in favour of terfenadine-pseudoephedrine, for swelling of the nasal mucosa (rhinoscopy) they were statistically significant. Both medications were well tolerated overall, although adverse events and reactions were more frequent in the terfenadine-pseudoephedrine group. In conclusion, terfenadine-pseudoephedrine and its constituents taken alone were effective. The combination performed better, but adverse events were somewhat more frequent with the combination than with terfenadine alone.
Asunto(s)
Efedrina/farmacología , Rinitis Alérgica Perenne/tratamiento farmacológico , Terfenadina/farmacología , Adulto , Método Doble Ciego , Sinergismo Farmacológico , Quimioterapia Combinada , Efedrina/administración & dosificación , Efedrina/uso terapéutico , Femenino , Humanos , Masculino , Pruebas de Provocación Nasal , Terfenadina/administración & dosificación , Terfenadina/uso terapéuticoRESUMEN
This double-blind, randomized multicentre study was designed to compare efficacy and tolerability of 120 mg terfenadine taken once daily (in the morning) with the established regimen of 60 mg terfenadine taken twice daily in the treatment of seasonal rhinitis. Two comparable groups, a total of 191 hay fever patients, were treated for 1 week. Symptom severity was assessed by the investigators before and at the end of the treatment (visual analogue scale), and daily by the patient (four-point rating scale). All symptoms improved to a similar degree in both groups. Differences between the two groups were not statistically significant, except for nasal symptoms in three cases as assessed by the visual analogue scale in one centre (better relief in the group given 120 mg terfenadine once daily). Tolerability was good and similar in both groups. The data presented show that in the treatment of hay fever 120 mg terfenadine given once daily is an effective, convenient and well tolerated alternative to the regimen of 60 mg terfenadine given twice daily.
Asunto(s)
Compuestos de Bencidrilo/administración & dosificación , Rinitis Alérgica Estacional/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Tolerancia a Medicamentos , Humanos , Estudios Multicéntricos como Asunto , Pruebas Cutáneas , TerfenadinaRESUMEN
We have assessed the effects of terfenadine on rhinitis symptoms associated with the common cold in 91 patients in a double-blind placebo-controlled study. The patients received three doses of either terfenadine 60 mg (n = 44) or placebo (n = 47) at about 12-h intervals, starting in most patients within 48 h from the onset of symptoms. Because of deviations from the protocol, 28 cases were classified as not eligible for efficacy evaluation, but were nevertheless analysed. Excellent/good or moderate efficacy was reported by 63% of eligible and 59% of all patients who received terfenadine (placebo 40% and 51% respectively, p = 0.049 and 0.113 respectively). 68% of eligible and 52% of all patients indicated that they would take terfenadine again (placebo 23%, for both p = 0.002). Two h after tablet intake mean nasal airflow was increased by 11 l.min-1, SD 8 (placebo -1 l.min-1, SD 6, p = 0.005). Symptoms were improved and rhinoscopy showed reduced swelling and redness of the mucosa and reduced nasal secretion and obstruction (basically unchanged in the placebo group). Therefore, terfenadine seems to act favourably on the acute rhinitis symptoms associated with the common cold. Since terfenadine is devoid of anticholinergic activity, nose symptoms during the initial stage of the common cold may be mediated to an important degree by histamine.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Resfriado Común/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Adulto , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/efectos adversos , Ensayos Clínicos como Asunto , Comportamiento del Consumidor , Método Doble Ciego , Esquema de Medicación , Femenino , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Rinitis/tratamiento farmacológico , Comprimidos , TerfenadinaRESUMEN
This double-blind, randomized multi-centre study was designed to compare efficacy and tolerability of 120 mg terfenadine taken once daily (in the morning) with the established regimen of 60 mg terfenadine taken twice daily in the treatment of seasonal rhinitis. Two comparable groups, a total of 191 hay fever patients, were treated for 1 week. Symptom severity was assessed by the investigators before and at the end of the treatment (visual analogue scale), and daily by the patient (four-point rating scale). All symptoms improved to a similar degree in both groups. Differences between the two groups were not statistically significant, except for nasal symptoms in three cases as assessed by the visual analogue scale in one centre (better relief in the group given 120 mg terfenadine once daily). Tolerability was good and similar in both groups. The data presented show that in the treatment of hay fever 120 mg terfenadine given once daily is an effective, convenient and well tolerated alternative to the regimen of 60 mg terfenadine given twice daily.
Asunto(s)
Compuestos de Bencidrilo/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Rinitis Alérgica Estacional/tratamiento farmacológico , Adulto , Compuestos de Bencidrilo/efectos adversos , Ensayos Clínicos como Asunto , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Polen , Terfenadina , Factores de TiempoRESUMEN
In a survey carried out between January and April 1985 covering all of Switzerland except the Canton of Ticino and including 2524 males and females (49% and 51% respectively) aged 15 to 74 years, the subjects were interviewed regarding pollinosis symptoms during the pollen season of 1984 and in previous years, and questioned about other allergic symptoms. Individuals with pollinosis or with family members suffering from pollinosis received an additional questionnaire. This first extraterritorial survey of Switzerland showed that every tenth Swiss aged 15 or over suffers from hay fever (incidence 9.6%). In addition, 3% had suffered from pollinosis previously. In the 15-24 age group the incidence was 16%. It fell with advancing age and was only 4.2% in the over-60 age group. No statistically significant differences were found between incidences in town (9%) and country (10%) and between the sexes. Hay fever morbidity in individuals with higher education (14.5%) and in certain occupations (student, apprentice - 21%) and among job levels "manager, senior civil servant, senior employee" (13.8%) was higher than in other categories. This representative survey confirmed that in Switzerland hay fever is commoner than in 1926 and 1958. The symptoms of pollen allergy are known: symptoms predominate in May (53%) and June (62%) including rhinitis in 94%, conjunctivitis in 82% and asthma in 24%. In 11% pollen allergy was already manifest in the first four years of life, in 62% before puberty and in 80% before the age of 20.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Rinitis Alérgica Estacional/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Asma/epidemiología , Asma/inmunología , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ocupaciones , Polen/inmunología , Rinitis Alérgica Perenne/epidemiología , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Estacional/inmunología , SuizaRESUMEN
Diazepam was administered to Swiss-Webster mice for 53 days as a mixture of drug in laboratory chow, leading to consumption as high as 1000 mg/kg/day. Low plasma concentrations of diazepam, but very high levels (generally between 5,000 and 10,000 ng/ml) of the active metabolites nordiazepam and oxazepam, were found. Animals appeared healthy throughout drug administration, but some died because of apparent drug-induced aggression. Withdrawal was precipitated by omitting drug from the food. The behavior and physiological state of each animal were observed in detail during treatment and withdrawal phases. Tests that showed stable results in control animals and changes during abstinence were used to measure the withdrawal syndrome. These changes included piloerection, tremor, pelvic elevation and tail elevation, as well as changes in body tone, abdominal tone and pupil size. A composite withdrawal score was plotted against time; this score increased significantly (P less than .01) 1 day after withdrawal and remained significantly elevated for 17 days. This technique provides a quantitative method to study the effect of withdrawal from benzodiazepines in mice.
Asunto(s)
Ansiolíticos , Trastornos Relacionados con Sustancias , Agresión/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Diazepam/efectos adversos , Diazepam/sangre , Ingestión de Alimentos/efectos de los fármacos , Masculino , Ratones , Síndrome de Abstinencia a SustanciasRESUMEN
In this double-blind study forty-seven patients with hay fever were treated for 8 days with either terfenadine 60 mg twice a day, astemizole 10 mg once a day or placebo. On the second day of treatment terfenadine was statistically significantly superior to astemizole and placebo according to the ratings of symptomatology, efficacy and individual symptoms. The median onset of symptom alleviation was 3 hours for terfenadine and 2 days for astemizole. On the eighth day both astemizole and terfenadine were statistically significantly more efficacious than placebo, but no significant differences were found between the two drugs. Both drugs were well tolerated.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Bencimidazoles/farmacología , Rinitis Alérgica Estacional/tratamiento farmacológico , Adulto , Astemizol , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Distribución Aleatoria , Terfenadina , Factores de TiempoRESUMEN
Ten subjects were treated with 30 and 60 mg oral doses of yohimbine hydrochloride or placebo under controlled clinical conditions to determine if such doses would create a "model anxiety state." Some evidence of anxiety was found on various rating scales, especially after the 60 mg dose. However, maximum anxiety produced by this dose of the drug exceeded that which occurred during placebo testing in only 5 of the 10 subjects. The 60 mg dose produced substantial increases in systolic blood pressure and less increase in diastolic blood pressure and pulse rate. It was concluded that yohimbine does not produce a very good model of anxiety.
Asunto(s)
Trastornos de Ansiedad/inducido químicamente , Yohimbina/administración & dosificación , Adulto , Trastornos de Ansiedad/psicología , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Emociones/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad , Placebos , Pulso Arterial/efectos de los fármacos , Yohimbina/farmacologíaRESUMEN
Tolerance to alprazolam-induced neurologic deficits was assessed in mice by a rotarod test. Tolerance was found following a second administration of 2 mg/kg alprazolam 24 h after the first dose and it decayed gradually over a period of several weeks. Brain and plasma concentrations of alprazolam indicated that this tolerance was functional.
Asunto(s)
Benzodiazepinas/toxicidad , Hipnóticos y Sedantes/toxicidad , Sistema Nervioso/fisiopatología , Alprazolam , Animales , Benzodiazepinas/metabolismo , Encéfalo/efectos de los fármacos , Tolerancia a Medicamentos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Sistema Nervioso/efectos de los fármacosRESUMEN
Circadian variations of lorazepam-induced neurologic deficits were tested in mice. The duration of the impairment after administration of 3 mg/kg lorazepam was considerably shorter at 2100 h compared to other times of the day. No significant variations could be found for brain concentrations of drug at recovery and 15 or 30 min after drug administration. Food intake did not seem to account for the circadian pattern observed. It was therefore concluded that chronergy of lorazepam is a result of altered sensitivity of the animal over time rather than to altered pharmacokinetics.
Asunto(s)
Encéfalo/efectos de los fármacos , Ritmo Circadiano , Lorazepam/toxicidad , Animales , Encéfalo/metabolismo , Ingestión de Alimentos , Lorazepam/metabolismo , Masculino , Ratones , Equilibrio Postural/efectos de los fármacosRESUMEN
The interaction between cimetidine and two tricyclic antidepressants was examined in healthy subjects. One tricyclic, imipramine, is primarily metabolized to a demethylated active metabolite, desipramine. The other, nortriptyline, is largely metabolized to a 10-hydroxylated metabolite. It was assumed that pretreatment with cimetidine, because of its inhibition of metabolic pathways of both demethylation and hydroxylation as well as its ability to reduce hepatic extraction of these drugs, would increase bioavailability and decrease clearance of both drugs. Such was the case with imipramine, but the bioavailability of nortriptyline was not increased. Further, the bioavailability of the 10-hydroxy metabolite of nortriptyline was increased rather than decreased. The degree of change in these kinetic variables varied widely between individuals. Thus it is not possible to predict which subjects might develop evidence of toxicity to tricyclics when cimetidine is added to the treatment program. The monitoring of tricyclic plasma concentrations is probably desirable in such circumstances.
Asunto(s)
Cimetidina/metabolismo , Imipramina/metabolismo , Nortriptilina/metabolismo , Adulto , Disponibilidad Biológica , Desipramina/sangre , Interacciones Farmacológicas , Humanos , Cinética , Masculino , Nortriptilina/análogos & derivados , Nortriptilina/sangreRESUMEN
Development of single-dose tolerance to diazepam-induced neurologic deficits was assessed in mice by means of a rotarod test. Diazepam suspended in corn oil was administered orally in doses 5-20 mg/kg. Tolerance was found following a second administration of diazepam 24 h after a first dose. It decayed gradually over 4-5 weeks. Hence tolerance persists considerably longer than measurable amounts of diazepam or its metabolites are likely to be present in mice.
Asunto(s)
Diazepam/farmacología , Enfermedades del Sistema Nervioso/inducido químicamente , Administración Oral , Animales , Ataxia/inducido químicamente , Tolerancia a Medicamentos , Masculino , RatasRESUMEN
Eight healthy men received an oral dose of 0.25 mg/kg diazepam followed 40 min later by an intravenous infusion of 100 ml physiological sodium chloride solution, with or without 4.4 mg/kg theophylline. Psychomotor function was assessed after each blood sampling up to 5 h post-infusion. Thirty min after diazepam psychomotor performance measured by Card Sorting test and Digit Symbol Substitution test was impaired and subjects felt sleepy and could think less clearly (two factors of the Clyde Mood Scale). Theophylline antagonized the diazepam-induced impairment statistically significantly for up to 5 h and subjects felt less tense and less apprehensive (State Anxiety Inventory). Since pharmacokinetic parameters of diazepam seemed not to be different after theophylline, interaction at receptor level can be assumed.
Asunto(s)
Diazepam/antagonistas & inhibidores , Desempeño Psicomotor/efectos de los fármacos , Teofilina/farmacología , Administración Oral , Adulto , Ansiedad/inducido químicamente , Diazepam/metabolismo , Humanos , Infusiones Parenterales , Cinética , Masculino , Persona de Mediana EdadRESUMEN
The objective of this double-blind trial was to assess the effect of diclofensine on geriatric patients with depressive syndromes in comparison to placebo. 40 patients (age 60-75 years) were treated for 3 weeks with a mean daily dose of 57.5 mg diclofensine or placebo. Diclofensine was found effective in 18 (= 90%) cases (placebo 60%) after 2.9 days on an average (placebo, 4.2 days), mostly having a mood elevating effect and in only 2 cases (placebo 1) having a stimulatory effect. The results of the global assessments, the Hamilton depression scale, the d2-test, the block design test and the mood scale (Befindlichkeitsskala) demonstrated a statistically significant superiority of diclofensine over placebo. The critical flicker frequency, on the other hand, was not able to differentiate significantly between the two drugs. The tolerance was considered as very good in all cases. Unwanted effects were observed in 13 patients (= 65%) of the diclofensine group and in 9 patients (= 45%) of the placebo group. They disappeared in most cases within one week after their appearance. According to this trial diclofensine can be described as a well tolerated drug without pronounced anticholinergic side effects, capable of improving depressive states faster and more effectively than placebo.