RESUMEN
The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and PK083 a "damage-corrective" compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Carbazoles/farmacología , Mutágenos/farmacología , Antineoplásicos/química , Neoplasias de la Mama/genética , Carbazoles/química , Daño del ADN , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Femenino , Histonas/metabolismo , Humanos , Células MCF-7 , Mutágenos/química , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.
Asunto(s)
Glucólisis/efectos de los fármacos , Fosfofructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Trypanosoma/enzimología , Tripanosomiasis Africana/metabolismo , Tripanosomiasis Africana/parasitología , Enfermedad Aguda , Regulación Alostérica/efectos de los fármacos , Animales , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Parásitos/efectos de los fármacos , Fosfofructoquinasas/química , Fosfofructoquinasas/metabolismo , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína , Relación Estructura-Actividad , Trypanosoma/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann-Pick typeâ C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6A -amino-6A -deoxy-ß-cyclodextrin and 3A -amino-3A -deoxy-2A (S),3A (S)-ß-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of ß-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.
Asunto(s)
Antioxidantes/farmacología , Ciclodextrinas/farmacología , Deferasirox/análogos & derivados , Deferasirox/farmacología , Quelantes del Hierro/farmacología , Animales , Antioxidantes/síntesis química , Células CHO , Cricetulus , Ciclodextrinas/síntesis química , Deferasirox/síntesis química , Células Hep G2 , Humanos , Quelantes del Hierro/síntesis química , Multimerización de Proteína/efectos de los fármacos , alfa-Sinucleína/metabolismoRESUMEN
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Asunto(s)
Ciclofilinas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Administración Oral , Antivirales/administración & dosificación , Antivirales/química , Antivirales/farmacocinética , Antivirales/farmacología , Disponibilidad Biológica , Línea Celular , Ciclofilinas/química , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Hepacivirus/efectos de los fármacos , Lactonas/administración & dosificación , Lactonas/química , Lactonas/farmacocinética , Lactonas/farmacología , Modelos Moleculares , Conformación Proteica , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacologíaRESUMEN
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
Asunto(s)
Benzazepinas/síntesis química , Receptor de Hormona Paratiroídea Tipo 1/antagonistas & inhibidores , Animales , Benzazepinas/química , Benzazepinas/farmacología , Unión Competitiva , Línea Celular , Línea Celular Tumoral , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Ratones , Ensayo de Unión Radioligante , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.
Asunto(s)
Ciclofilinas/antagonistas & inhibidores , Células Cultivadas , Cromatografía Liquida , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Enlace de Hidrógeno , Lactonas/química , Lactonas/farmacología , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , TermodinámicaRESUMEN
A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.
Asunto(s)
Benzazepinas/síntesis química , Receptor de Colecistoquinina A/antagonistas & inhibidores , Receptor de Colecistoquinina B/antagonistas & inhibidores , Animales , Benzazepinas/química , Benzazepinas/farmacología , Benzodiazepinas/química , Línea Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Humanos , Ratones , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Receptor de Colecistoquinina A/química , Receptor de Colecistoquinina B/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of high-dose sertraline for patients with obsessive-compulsive disorder (OCD) who failed to respond to standard sertraline acute treatment. METHOD: Sixty-six nonresponders to 16 weeks of sertraline treatment who met DSM-III-R criteria for current OCD were randomly assigned, in a double-blind continuation phase of a multicenter trial, either to continue on 200 mg/day of sertraline or to increase their dose to between 250 and 400 mg/day for 12 additional weeks. Efficacy measures included the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH Global OC Scale), and the Clinical Global Impressions-Severity of Illness and -Improvement (CGI-I) scales. Data were collected from July 26, 1994, to October 26, 1995. RESULTS: The high-dose (250-400 mg/day, mean final dose = 357, SD = 60, N = 30) group showed significantly greater symptom improvement than the 200-mg/day group (N = 36) as measured by the YBOCS (p = .033), NIMH Global OC Scale (p = .003), and CGI-I (p = .011). Responder rates (decrease in YBOCS score of > or = 25% and a CGI-I rating < or = 3) were not significantly different for the 200-mg/day versus the high-dose sertraline group, either on completer analysis, 34% versus 52%, or on endpoint analysis, 33% versus 40%. Both treatments showed similar adverse event rates. CONCLUSION: Greater symptom improvement was seen in the high-dose sertraline group compared to the 200-mg/day dose group during continuation treatment. Both dosages yielded similar safety profiles. Administration of higher than labeled doses of selective serotonin reuptake inhibitors may be a treatment option for certain OCD patients who fail to respond to standard acute treatment.
Asunto(s)
Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/psicología , Placebos , Escalas de Valoración Psiquiátrica , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Sertralina/efectos adversos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Case management, in various forms, is now institutionalized as a core part of policy and programs designed to deliver home- and community-based services to older adults. The case management role, in theory, requires attention to both client and system goals, although in practice the system goals that have received most attention have been gatekeeping and resource allocation. While case managers have been admonished to find and develop resources in the community, this has primarily taken the form of including informal services in individual client care plans. What has been missing is focused attention to the potential of the community as a nurturing environment with the capacity to support older adults and their caregivers. Sustainable care for older adults cannot be achieved by formal service and family support alone. This article proposes the creation of linkages between case managers, who build the service arrangements for older people, and community developers, who are responsible for building community capacity and social capital. It is argued that this linkage is essential for establishing the foundations of a caring community with the capacity to support older people.
Asunto(s)
Manejo de Caso/organización & administración , Planificación en Salud Comunitaria/organización & administración , Servicios de Salud para Ancianos/organización & administración , Atención Domiciliaria de Salud/organización & administración , Anciano , Alberta , Control de Acceso , Humanos , Características de la Residencia , Asignación de Recursos , Planificación Social , Apoyo Social , Servicio SocialRESUMEN
OBJECTIVE: Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated. METHOD: Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25). The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score. A secondary efficacy measure was the Clinical Global Impression (CGI) improvement score; response was defined as a score of 2 or less. RESULTS: Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4. Analysis of covariance of the intent-to-treat group at endpoint (with the last observation carried forward) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline (mean=11.7) and placebo (mean=8.0). Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor (6.7 versus 4.1) and somatic factor (5.0 versus 3.9). The rate of responders, based on CGI improvement and last observation carried forward, was significantly higher for sertraline (63%) than placebo (37%). Sertraline was well tolerated; 8% of patients versus 10% for placebo dropped out because of adverse events. CONCLUSIONS: Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder.
Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/uso terapéutico , Adulto , Trastornos de Ansiedad/psicología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Náusea/inducido químicamente , Placebos , Escalas de Valoración Psiquiátrica , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Sertralina/efectos adversos , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Sudoración/efectos de los fármacos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Imipramina/uso terapéutico , Trastorno de Pánico/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/uso terapéutico , Adulto , Antidepresivos Tricíclicos/efectos adversos , Comorbilidad , Trastorno Depresivo/epidemiología , Método Doble Ciego , Femenino , Humanos , Imipramina/efectos adversos , Masculino , Persona de Mediana Edad , Trastorno de Pánico/epidemiología , Escalas de Valoración Psiquiátrica , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Sertralina/efectos adversos , Resultado del TratamientoRESUMEN
The purpose of this study was to investigate the extent to which audit of palliative care service occurs nationally in Britain and Ireland. The following items were measured: (1) audit tools employed, (2) aspects of services undergoing audit, (3) changes in practice as a result of audit, and (4) obstacles to conducting some aspects of the audit. Audit practices were surveyed by means of a postal questionnaire distributed to managers of all hospice and palliative care services in the United Kingdom and Republic of Ireland. A 10 percent sample of managers (n = 40) who responded were subsequently interviewed to confirm and elaborate on questionnaire responses. The response rate was 60 percent and was highest for hospices at 68 percent. Of the respondents, 73 percent audit their services. Of those who audit their services, 79 percent changed their service as a result. Although physical aspects of care were audited frequently (61 percent), other core aspects of palliative care that rarely were audited included bereavement care (17 percent), training (13 percent), and psychological and spiritual care (12 percent). Managers indicated that some aspects of care were rarely audited because they considered clinical and organizational aspects of palliative care to be more important. They also stated that they did not have enough time, expertise, or adequate measurement tools. Until the neglected features of palliative care are audited, the full effectiveness of the services remains unknown.
Asunto(s)
Hospitales para Enfermos Terminales/normas , Auditoría Médica/métodos , Cuidados Paliativos/normas , Humanos , Irlanda , Auditoría Médica/estadística & datos numéricos , Cuidados Paliativos/métodos , Encuestas y Cuestionarios , Reino UnidoRESUMEN
Even after 30 years of experience, two questions persist about case management practice. Who needs it and does it work? Answers to these questions are neither direct nor simple. This article examines the significance of various contexts (policy, system, community, and organization) to efforts attempting to provide responses to these basic questions. Beyond the question of who needs case management, two additional questions are addressed. Who needs it and who gets it? Clients' qualitative perspectives on case management effectiveness, beyond attempts to measure satisfaction and quality of life, are usually absent. The article concludes with a discussion of whether these are the right questions.
Asunto(s)
Manejo de Caso/normas , Necesidades y Demandas de Servicios de Salud , Satisfacción del Paciente , Evaluación de Programas y Proyectos de Salud , Manejo de Caso/organización & administración , Humanos , Estados UnidosRESUMEN
CEfrag is a new fragment screening technology based on affinity capillary electrophoresis (ACE). Here we report on the development of a mobility shift competition assay using full-length human heat shock protein 90α (Hsp90α), radicicol as the competitor probe ligand, and successful screening of the Selcia fragment library. The CEfrag assay was able to detect weaker affinity (IC(50) >500 µM) fragments than were detected by a fluorescence polarization competition assay using FITC-labeled geldanamycin. The binding site of selected fragments was determined by co-crystallization with recombinant Hsp90α N-terminal domain and X-ray analysis. The results of this study confirm that CEfrag is a sensitive microscale technique enabling detection of fragments binding to the biological target in near-physiological solution.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Descubrimiento de Drogas , Electroforesis Capilar , Ensayo de Cambio de Movilidad Electroforética , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Macrólidos/metabolismo , Adenosina Trifosfatasas/química , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Proteínas HSP90 de Choque Térmico/química , Humanos , Unión Proteica , Estructura Terciaria de Proteína , Bibliotecas de Moléculas PequeñasRESUMEN
BACKGROUND: In posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse. METHODS: 395 adult patients with PTSD were randomized to 12-weeks double-blind treatment with flexible dose sertraline (50-200 mg/d) or placebo. Patients with different index traumas were compared in terms of baseline demographic and clinical characteristics, as well as treatment response. Primary efficacy variables included part 2 of the Clinician Administered PTSD Scale (CAPS-2). RESULTS: Interpersonal trauma and childhood abuse were both more common in females than males, and were associated with early age at time of index trauma and longer duration of PTSD, but not with PTSD symptom severity. Sertraline was significantly more effective than placebo on most primary efficacy variables, irrespective of whether patients had experienced interpersonal trauma or childhood abuse. CONCLUSIONS: These data demonstrate that sertraline is valuable for the treatment of PTSD, irrespective of whether the precipitating trauma involves interpersonal trauma in general, or childhood abuse in particular.
Asunto(s)
Antidepresivos/uso terapéutico , Maltrato a los Niños/psicología , Relaciones Interpersonales , Acontecimientos que Cambian la Vida , Sertralina/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Adulto , Antidepresivos/efectos adversos , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Determinación de la Personalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Sertralina/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate gender differences in the clinical presentation of generalized anxiety disorder (GAD) and response to sertraline treatment. METHODS: Adult outpatients who met DSM-IV criteria for GAD with a minimum Hamilton rating scale for anxiety (HAM-A) total score>or=18 were randomized to 12 weeks of double-blind treatment with flexible doses (50-150 mg) of sertraline (n=182; female, 59%) or placebo (n=188; female, 51%). RESULTS: Clinical presentation of GAD was very similar in men and women in terms of the severity of the HAM-A psychic factor, severity of concomitant depression symptoms, duration of GAD, quality of life and impairment in physical health. Women had an earlier age of onset and higher HAM-A somatic factor scores compared with men. For both men and women, treatment with sertraline resulted in greater change from baseline to endpoint on the HAM-A compared with placebo (adjusted change+/-SE: men:-12.1+/-0.9 vs -8.8+/-0.9; women: -11.4+/-0.8 vs -7.1+/-0.9, p<0.001); the interaction between gender and treatment group was not significant, nor was there a significant difference between the average change from baseline for men compared with women. Similarly, responder rates based upon clinical global impression-improvement (CGI-I) scores at endpoint showed no significant interaction between gender and treatment, nor was there a significant difference in the response rates by gender; however, the response rate of sertraline compared with placebo was significantly different (p<0.0001) (men: 64% vs 40%; women: 62% vs 34%). Similar findings were evident at week 4 assessment and for completers (week 12). Overall, sertraline was well tolerated by both men and women. DISCUSSION: Women and men with GAD showed similar clinical presentations, with the exception that women had an earlier age of onset and reported more somatic anxiety symptoms. Sertraline was an effective and well tolerated treatment for GAD in both men and women.
Asunto(s)
Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/epidemiología , Sertralina/uso terapéutico , Resultado del Tratamiento , Antidepresivos/administración & dosificación , Antidepresivos/antagonistas & inhibidores , Trastornos de Ansiedad/diagnóstico , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Incidencia , Masculino , Sertralina/administración & dosificación , Sertralina/efectos adversos , Factores Sexuales , Factores de TiempoRESUMEN
We have used a site-specific photo-cross-linking approach to identify direct interactions between clathrin adaptor protein (AP)1 complexes and small GTPases of the ADP-ribosylation factor (ARF) family and to explore the specificity of this interaction on immature secretory granule (ISG) membranes. ISG membranes are a well-characterized, highly enriched preparation of membranes that has previously been shown to have the membrane-associated factors for ARF1 recruitment that are not present on artificial liposomes. All three classes of ARF proteins could be recruited to ISG membranes, displaying differential requirements for GTPgammaS. We found that ARF1, ARF5, and ARF6 interacted directly with the beta1-adaptin subunit of AP-1 in the presence of GTPgammaS. Furthermore, we observed a direct interaction between the switch 1 region of ARF1 and the N-terminal trunk domains of gamma- and beta1-adaptin. In addition, both ARF1 and ARF6 but not ARF5 interacted directly with the beta3- and delta-adaptin subunits of AP-3. No interaction was observed between AP-2 and any of the ARF proteins. Our results delineate the specificity and provide evidence of a direct interaction between different ARF proteins and the AP complexes AP-1 and AP-3 on natural ISG membranes and show that residues in the switch 1 region of ARF proteins can selectively bind to the trunk domains of these complexes.
Asunto(s)
Factor 1 de Ribosilacion-ADP/metabolismo , Factores de Ribosilacion-ADP/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Ensamble de Clatrina Monoméricas , Proteínas de Saccharomyces cerevisiae , Factor 1 de Ribosilacion-ADP/química , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/química , Proteínas Adaptadoras del Transporte Vesicular , Animales , Anticuerpos , Proteínas Portadoras/química , Reactivos de Enlaces Cruzados , GTP Fosfohidrolasas/metabolismo , Liposomas , Proteínas de la Membrana/química , Mutagénesis Sitio-Dirigida , Conejos , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
Sleep disturbances (SD) are a core clinical feature of PTSD. The goal of the study was to determine the influence of patient-related characteristics, disorder-related characteristics, and psychiatric comorbidity on the severity of SD in PTSD outpatients (n = 367) who were not recruited for a sleep study. Increased severity of SD paralleled increasing overall PTSD severity. The severity of SD did not differ according to gender, age groups, types of trauma, PTSD chronicity, or psychiatric comorbidity. Results suggest that age, gender, and psychiatric comorbidity have minimal impact on sleep quality in this PTSD sample. The inclusion of PTSD patients who were not specifically seeking treatment for SD reinforces the study findings.
Asunto(s)
Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/psicología , Trastornos por Estrés Postraumático/complicaciones , Trastornos por Estrés Postraumático/psicología , Adolescente , Adulto , Factores de Edad , Comorbilidad , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
The efficacy of sertraline in the treatment of civilian posttraumatic stress disorder (PTSD) has been established by two large placebo-controlled trials. The purpose of the current pilot study was to obtain preliminary evidence of the efficacy of sertraline in military veterans suffering from PTSD. Outpatient Israeli military veterans with a DSM-III-R diagnosis of PTSD were randomized to 10 weeks of double-blind treatment with sertraline (50-200 mg/day; N = 23, 83% male, mean age = 41 years) or placebo (N = 19, 95% male, mean age = 38 years). Efficacy was evaluated by the Clinician-Administered PTSD Scale (CAPS-2) and by Clinical Global Impression Scale-Severity (CGI-S) and -Improvement (CGI-I) ratings. Consensus responder criteria consisted of a 30% or greater reduction in the CAPS-2 total severity score and a CGI-I rating of "much" or "very much" improved. The baseline CAPS-2 total severity score was 94.3 +/- 12.9 for sertraline patients, which is notably higher than that reported for most studies of civilian PTSD. On an intent-to-treat endpoint analysis, sertraline showed a numeric but not statistically significant advantage compared with placebo on the CAPS-2 total severity and symptom cluster scores. In the study completer analysis, the mean CGI-I score was 2.4 +/- 0.3 for sertraline and 3.4 +/- 0.3 for placebo (t = 2.55, df = 30, p = 0.016), CGI-I responder rates were 53% for sertraline and 20% for placebo (chi2 = 3.62, df = 1, p = 0.057), and combined CGI-I and CAPS-2 responder rates (>or=30% reduction in baseline CAPS-2 score) were 41% for sertraline and 20% for placebo (chi2 = 1.39, df = 1, p = 0.238). Sertraline treatment was well tolerated, with a 13% discontinuation rate as a result of adverse events. This pilot study suggests that sertraline may be an effective treatment in patients with predominantly combat-induced PTSD, although the effect size seems to be somewhat smaller than what has been reported in civilian PTSD studies. Adequately powered studies are needed to confirm these results and to assess whether continued treatment maintains or further improves response.
Asunto(s)
Antidepresivos/uso terapéutico , Trastornos de Combate/tratamiento farmacológico , Sertralina/uso terapéutico , Veteranos/psicología , Adulto , Atención Ambulatoria , Antidepresivos/efectos adversos , Trastornos de Combate/diagnóstico , Trastornos de Combate/psicología , Método Doble Ciego , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Inventario de Personalidad , Proyectos Piloto , Sertralina/efectos adversos , Resultado del TratamientoRESUMEN
The purpose of this study was to evaluate the comparative efficacy and tolerability of sertraline and fluoxetine in the treatment of obsessive-compulsive disorder (OCD). Outpatients meeting DSM-IV criteria for OCD, with a Yale-Brown Obsessive-Compulsive (Y-BOCS) total score >or= 17, an NIMH Global Obsessive-Compulsive (NIMH-OC) scale score >or= 7, and a CGI-Severity score >or= 4 were randomized to 24 weeks of double-blind treatment with sertraline (N = 77) or fluoxetine (N = 73). Primary efficacy measures consisted of the Y-BOCS, the NIMH-OC scale, and the CGI-Severity (CGI-S) and Improvement (CGI-I) scales. Equivalent and significant (p < 0.001) improvement was found at week 24 in Y-BOCS and NIMH-OC scale scores for sertraline and fluoxetine. After 12 weeks, 49.2% of patients on sertraline were rated on the CGI-S scale as being mildly ill or not ill compared to 24.6% on fluoxetine (p < 0.01). A Cox analysis found patients on sertraline to have a statistically nonsignificant 42% greater likelihood of achieving a response by week 12 (CGI-I, much or very much improved; 95% CI, 0.85, 2.38; p = 0.18). Sertraline treatment also resulted in a higher proportion of remissions than fluoxetine (defined as a CGI-I Asunto(s)
Fluoxetina/uso terapéutico
, Trastorno Obsesivo Compulsivo/tratamiento farmacológico
, Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
, Sertralina/uso terapéutico
, Adolescente
, Adulto
, Femenino
, Fluoxetina/efectos adversos
, Humanos
, Masculino
, Persona de Mediana Edad
, Trastorno Obsesivo Compulsivo/diagnóstico
, Trastorno Obsesivo Compulsivo/psicología
, Escalas de Valoración Psiquiátrica
, Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos
, Sertralina/efectos adversos
, Resultado del Tratamiento