RESUMEN
BACKGROUND: Although antidepressants are often used for preventing chronic headache, their effectiveness is uncertain. METHODS: We performed a meta-analysis of English-language, randomized placebo-controlled trials of antidepressants as prophylaxis for chronic headache. RESULTS: Thirty-eight trials were included. Because some compared more than one drug with placebo, 44 study arms were combined using a random effects model. Twenty-five studies focused on migraines, 12 on tension headaches, and 1 on both. Nineteen used tricyclic antidepressants, 18 serotonin antagonists, and 7 selective serotonin reuptake inhibitors. Patients receiving antidepressants were twice as likely to report headache improvement (rate ratio [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.4). Because 31% (95% CI: 23% to 40%) more treated patients improved than those receiving placebo, clinicians would need to treat 3.2 patients for 1 patient to improve. The average amount of improvement (standardized mean difference) was 0.94 (95% CI: 0.65 to 1.2), an effect considered large. Treated patients also consumed less analgesic medication (standardized mean difference, -0.7; 95% CI: -0.5 to -0.94). There were no differences in outcomes among the three classes of agents studied or by the type of headache (migraine vs. tension), quality score, length of treatment, or percentage of patients lost to follow-up. Assessment of depression across studies was insufficient to determine if the effects were independent of depression. CONCLUSION: Antidepressants are effective in preventing chronic headaches. Whether this is independent of depression and whether there are differences in efficacy by class of agent needs further study.
Asunto(s)
Antidepresivos/uso terapéutico , Cefalea/prevención & control , Antidepresivos Tricíclicos/uso terapéutico , Enfermedad Crónica , Cefalea/tratamiento farmacológico , Humanos , Evaluación de Resultado en la Atención de Salud , Ensayos Clínicos Controlados Aleatorios como Asunto , Antagonistas de la Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Functional gastrointestinal disorders are common, accounting for up to 50% of gastroenterology referrals, and several randomized controlled trials have evaluated antidepressant therapy for their treatment. METHODS: We performed a meta-analysis of published, English-language, randomized clinical trials on the use of antidepressants for the treatment of patients with functional gastrointestinal disorders. RESULTS: Twelve randomized placebo-controlled trials of antidepressant treatment of functional gastrointestinal disorders were identified. One was excluded for using a combination of a tricyclic and neuroleptic agent. The medications included tricyclic antidepressants (amitriptyline [n = 3], clomipramine [n = 1], desipramine [n = 2], doxepin [n = 1], and trimipramine [n = 2]), and the antiserotonin agent, mianserin (n = 2). In addition, one trial compared two different antidepressants (mianserin and clomipramine) with placebo. Data were abstracted for the dichotomous outcome of symptom improvement in seven studies, and for the continuous variable of pain score in eight studies. The summary odds ratio for improvement with antidepressant therapy was 4.2 (95% confidence interval [CI]: 2.3 to 7.9), and the average standardized mean improvement in pain was equal to 0.9 SD units (95% CI: 0.6 to 1.2 SD units). On average 3.2 patients needed to be treated (95% CI: 2.1 to 6.5 patients) to improve 1 patient's symptom. CONCLUSION: Treatment of functional gastrointestinal disorders with antidepressants appears to be effective. Whether this improvement is independent of an effect of treatment on depression needs further evaluation.
Asunto(s)
Antidepresivos/uso terapéutico , Enfermedades Funcionales del Colon/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Adulto , Anciano , Antidepresivos/efectos adversos , Estreñimiento/tratamiento farmacológico , Depresión/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Dispepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Resultado del TratamientoRESUMEN
BACKGROUND: Fibromyalgia is a common, poorly understood musculoskeletal pain syndrome with limited therapeutic options. OBJECTIVE: To systematically review the efficacy of antidepressants in the treatment of fibromyalgia and examine whether this effect was independent of depression. DESIGN: Meta-analysis of English-language, randomized, placebo-controlled trials. Studies were obtained from searching MEDLINE, EMBASE, and PSYCLIT (1966-1999), the Cochrane Library, unpublished literature, and bibliographies. We performed independent duplicate review of each study for both inclusion and data extraction. MAIN RESULTS: Sixteen randomized, placebo-controlled trials were identified, of which 13 were appropriate for data extraction. There were 3 classes of antidepressants evaluated: tricyclics (9 trials), selective serotonin reuptake inhibitors (3 trials), and S-adenosylmethionine (2 trials). Overall, the quality of the studies was good (mean score 5.6, scale 0-8). The odds ratio for improvement with therapy was 4.2 (95% confidence interval [95% CI], 2.6 to 6.8). The pooled risk difference for these studies was 0.25 (95% CI, 0.16 to 0.34), which calculates to 4 (95% CI, 2.9 to 6.3) individuals needing treatment for 1 patient to experience symptom improvement. When the effect on individual symptoms was combined, antidepressants improved sleep, fatigue, pain, and well-being, but not trigger points. In the 5 studies where there was adequate assessment for an effect independent of depression, only 1 study found a correlation between symptom improvement and depression scores. Outcomes were not affected by class of agent or quality score using meta-regression. CONCLUSION: Antidepressants are efficacious in treating many of the symptoms of fibromyalgia. Patients were more than 4 times as likely to report overall improvement, and reported moderate reductions in individual symptoms, particularly pain. Whether this effect is independent of depression needs further study.
Asunto(s)
Antidepresivos/uso terapéutico , Fibromialgia/tratamiento farmacológico , Adulto , Anciano , Depresión/complicaciones , Femenino , Fibromialgia/clasificación , Fibromialgia/psicología , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the efficacy of antidepressant therapy for unexplained symptoms or symptom syndromes. SEARCH STRATEGIES: We identified original studies through searching MEDLINE, EMBASE, PsycLIT, the Federal Research in Progress database, and The Cochrane Library. We also searched the bibliographies of primary and review articles for additional studies. SELECTION CRITERIA: We excluded trials of patients with neuropathic, oncologic, or degenerative joint pain. Independent duplicate review of 392 articles identified 94 relevant reports of randomized trials involving 6595 patients across 6 symptom syndromes. Independent duplicate assessment was made for inclusion and data abstraction. Meta-analysis was performed on extractable placebo-controlled data. MAIN RESULTS: Of 94 included trials, most studied either tricyclic antidepressants, antiserotonin antidepressants, selective serotonin reuptake inhibitors (SSRIs), or multiple agents for the treatment of the following syndromes: headache (50), fibromyalgia (18), functional gastrointestinal syndromes (13), idiopathic pain (11), tinnitus (2), and chronic fatigue (2). The quality of the studies was fair (mean score = 4.8 on a scale of 0 to 8). A majority of the studies (69%) demonstrated benefit for at least one outcome measure. Symptom improvement typically did not correlate with depression response in the few studies where it was assessed. Meta-analysis of all extractable data showed a substantial benefit from antidepressants: For the dichotomous outcome of improvement, the odds ratio was 3.4 (95% confidence interval [CI], 2.6 - 4.5), and for continuous outcomes, the standardized mean difference was 0.87 (95% CI, 0.59-1.14). The absolute percentage difference in improvement between the antidepressant and placebo arms was 32%, yielding a number needed to treat of 3 to improve one person's symptoms. Meta-regression indicated no differential effect across the classes of antidepressants; however, onbivariate tally tricyclic studies were associated with a greater likelihood of efficacy than SSRI studies (P = .02). CONCLUSIONS: Antidepressants can be effective for various physical symptoms and symptom syndromes. The relation of outcome to depression and the efficacy of SSRIs needs further study.
Asunto(s)
Antidepresivos/uso terapéutico , Enfermedades Funcionales del Colon/tratamiento farmacológico , Fibromialgia/tratamiento farmacológico , Cefalea/tratamiento farmacológico , Dolor/tratamiento farmacológico , Adulto , Antidepresivos Tricíclicos/uso terapéutico , Enfermedad Crónica , Depresión/tratamiento farmacológico , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Serotoninérgicos/uso terapéutico , SíndromeRESUMEN
BACKGROUND: Serologic detection of human immunodeficiency virus (HIV) infection in neonates is complicated by the presence of immune complexes, consisting of passively transferred maternal antibodies and HIV antigens. A new, rapid assay has been designed to disrupt these immune complexes in order to permit the detection of a specific HIV antigen. We evaluated the efficacy of this assay in detecting HIV infection in neonates. METHODS: We measured p24 antigen in blood samples from both infected and uninfected children of HIV-infected mothers. The samples were treated with glycine hydrochloride to dissociate the immune complexes, followed by neutralization with TRIS-hydrochloric acid. A commercial HIV p24 antigen assay was then used, with an optical density greater than 0.120 at a wavelength of 450 nm defined as indicating a positive result. RESULTS: Of eight cord-blood samples from neonates with proved HIV infection, five were positive for immune-complex-dissociated p24 antigen. For two other neonates the first postnatal sample, obtained on days 12 and 18, was positive. There was no follow-up sample for the eighth neonate. Of 22 uninfected neonates, 20 were negative on the cord-blood assay. Two neonates had positive cord-blood samples, but the first postnatal sample was negative. Thus, the tests with early postnatal samples identified the HIV-infection status correctly for all 29 children who could be evaluated. In a separate group of 78 children (median age, 188 weeks), the specificity of the test was 100 percent and the sensitivity 81 percent. CONCLUSIONS: The immune-complex-dissociated HIV p24 antigen assay is a rapid, simple serologic test that may be of value in diagnosing HIV infection in neonates born to HIV-infected women.
Asunto(s)
Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/diagnóstico , Complejo Antígeno-Anticuerpo/análisis , Complejo Antígeno-Anticuerpo/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Sangre Fetal/inmunología , Glicina/farmacología , Infecciones por VIH/congénito , Humanos , Lactante , Recién Nacido , Pruebas SerológicasRESUMEN
We have previously described a series of C-terminally-clipped forms of PRL, the 21-23.5K PRL-like molecules (PLMs). Because we noted estrogen (E2) induction of PLMs and E2 also induces a pituitary glandular kallikrein, we have investigated the possibility that processing of PRL by kallikrein is responsible for the production of the PLMs. Subcellular fractionation of pituitaries from control or E2-treated female rats showed total kallikrein to be concentrated 1- to 4-fold and 6- to 20-fold in the granules (vs. original homogenate) from control and E2-treated animals, respectively. Cleavage of purified PRL by kallikrein resulted in the formation of large quantities of a number of the PLMs. Incubation of secretory granules derived from control or E2-treated animals under the same conditions showed no cleavage of PRL in the absence of a limiting granule membrane and a small production of the PLMs in the presence of a granule membrane. Production in the latter instance was slightly greater in granules derived from E2-treated animals. Addition of purified kallikrein to secretory granules from control or E2-treated animals in the presence or absence of granule membranes, resulted in the additional production of large amounts of only the smallest PLM (PLM 9), indicating a lack of cleavage of the two most C-terminal sites for the enzyme. Increasing the concentration of beta-mercaptoethanol to 0.64 M, to ensure monomerization of the granule PRL, had no effect on endogenous kallikrein activity of the number of products resulting from the addition of exogenous kallikrein to granules. In summary: 1) purified kallikrein can cleave purified PRL to form products which run with the same isoelectric point and mol wt values as the PLMs; 2) kallikrein is present in PRL secretory granules; 3) some PLM production occurs in a membrane-bound secretory granule fraction, but none occurs after removal of the membrane; this intragranular production, like cleavage of purified PRL with purified kallikrein, is dependent on the presence of a detergent and a reducing agent; 4) cleavage of granular PRL by exogenous kallikrein is limited to a single site and the more C-terminal sites are protected; and 5) protection of the C-terminus is not removed by intermolecular and intramolecular disulfide bond reduction. We conclude: 1) that pituitary glandular kallikrein is a strong candidate for the enzyme responsible for the production of the PLMs, and 2) that there is some element of PRL storage, other than intermolecular disulfide bonds, which involves the C-terminus of the molecule.
Asunto(s)
Gránulos Citoplasmáticos/metabolismo , Calicreínas/metabolismo , Fragmentos de Péptidos/metabolismo , Hipófisis/ultraestructura , Prolactina/metabolismo , Animales , Catepsina B/metabolismo , Fraccionamiento Celular , Electroforesis en Gel Bidimensional , Estradiol/farmacología , Femenino , Punto Isoeléctrico , Mercaptoetanol/farmacología , Peso Molecular , Fragmentos de Péptidos/química , Hipófisis/metabolismo , Prolactina/química , Ratas , Ratas Endogámicas , Tripsina/metabolismoRESUMEN
Free cytosolic Ca2+ ([Ca2+]i) has been demonstrated to play a crucial role in the prolactin secretory pathway. It regulates events as apparently diverse as prolactin gene transcription and the fusion of secretory granules with the plasma membrane. It is therefore important to understand the mechanisms which regulate the level of [Ca2+]i. Because prolactin secretory granule membranes have been shown to contain large amounts of Ca2+ and there is evidence that this calcium can be released independently of the granule hormone content, we have investigated the possibility that prolactin secretory granule membranes contain Ca2+ channels. When purified prolactin secretory granules were fused with an artificial phospholipid bilayer, we found a Ca2+ channel with a linear current-voltage relationship (conductance -45 pS) in symmetrical 50 mM CaCl2 solutions. Said channel had an open probability that was weakly dependent on the transmembrane potential, and a very good selectivity for calcium over chloride ions. The channel opened and closed very rapidly, when the majority of events lasting well below 25 ms. This channel could be important for the provision of high [Ca2+]i levels necessary for granule-plasma membrane fusion and could also be involved in the modulation of Ca2+ fluxes across the plasma membrane after the exocytotic release of prolactin.
Asunto(s)
Canales de Calcio/metabolismo , Gránulos Citoplasmáticos/metabolismo , Membrana Dobles de Lípidos/metabolismo , Adenohipófisis/metabolismo , Animales , Electroforesis en Gel Bidimensional , Femenino , Membranas Intracelulares/metabolismo , Fusión de Membrana , Potenciales de la Membrana , Prolactina/metabolismo , Ratas , Ratas EndogámicasRESUMEN
PRL exists within the mammotroph population in a number of different molecular forms. Several of these forms are best described as isoforms, as they have the same mol wt (24 K), but differ in their net charges. In this study we have used in vitro translation assays to ascertain the number of 24 K translation products of normal pituitary messenger RNA (mRNA), and, finding only one, have used both in vitro translation assays and subcellular fractionation to determine the intracellular site of the posttranslational modification of this single translation product. Translation of mRNA from normal pituitary tissue or GH3 cells resulted in the apparent production of a number of pre-PRLs, but in only a single rough microsome-processed form of PRL, 24 K isoform 2. Longer term translation assays utilizing a variety of isotopes failed to show any evidence for rough microsomal posttranslational modification of isoform 2. Subcellular fractionation, using a discontinuous sucrose gradient, however, produced a membrane-bound large secretory granule fraction which, when isolated, contained essentially only isoform 2, and which had the capacity to convert isoform 2 to isoforms 3 and 3' by posttranslational phosphorylation.