Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 92
Filtrar
1.
PLoS Biol ; 21(12): e3002249, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38127878

RESUMEN

Despite use of tecovirimat since the beginning of the 2022 outbreak, few data have been published on its antiviral effect in humans. We here predict tecovirimat efficacy using a unique set of data in nonhuman primates (NHPs) and humans. We analyzed tecovirimat antiviral activity on viral kinetics in NHP to characterize its concentration-effect relationship in vivo. Next, we used a pharmacological model developed in healthy volunteers to project its antiviral efficacy in humans. Finally, a viral dynamic model was applied to characterize mpox kinetics in skin lesions from 54 untreated patients, and we used this modeling framework to predict the impact of tecovirimat on viral clearance in skin lesions. At human-recommended doses, tecovirimat could inhibit viral replication from infected cells by more than 90% after 3 to 5 days of drug administration and achieved over 97% efficacy at drug steady state. With an estimated mpox within-host basic reproduction number, R0, equal to 5.6, tecovirimat could therefore shorten the time to viral clearance if given before viral peak. We predicted that initiating treatment at symptom onset, which on average occurred 2 days before viral peak, could reduce the time to viral clearance by about 6 days. Immediate postexposure prophylaxis could not only reduce time to clearance but also lower peak viral load by more than 1.0 log10 copies/mL and shorten the duration of positive viral culture by about 7 to 10 days. These findings support the early administration of tecovirimat against mpox infection, ideally starting from the infection day as a postexposure prophylaxis.


Asunto(s)
Antivirales , Mpox , Animales , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Benzamidas , Isoindoles/efectos adversos
2.
Curr Med Res Opin ; 39(4): 597-603, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36842964

RESUMEN

OBJECTIVE: To examine the early outcomes, associated factors and predictive values of clinical outcomes of different tandospirone doses in patients with a generalized anxiety disorder (GAD). METHODS: This was a posthoc analysis of "a randomized, controlled multicenter clinical trial of the efficacy and safety of different doses of tandospirone on GAD". A total of 274 patients with GAD were included and randomized into the high-dose (tandospirone 60 mg/d) and low-dose (tandospirone 30 mg/d) groups for a 6-week treatment. The Hamilton Anxiety (HAMA), Clinical Global Impression-Severity (CGI-S), Short-Form-12 (SF-12) scales were used for assessment. The trial was registered at clinical trail.gov (NCT01614041). RESULTS: (1) In the first week of treatment, 35.8% of patients in the high-dose group fulfilled the early onset criteria, which was significantly higher than 19.0% found in the low-dose group (p = 0.002). In the second week of treatment, 22.6% of patients in the high-dose group achieved an early response, versus 12.4% in the low-dose group, indicating a significant difference (p = .026). (2) Factors associated with early onset at week 1 included baseline HAMA total score (OR = 0.916, 95%CI 0.882-0.952), age (OR = 0.974, 95%CI 0.950-0.998), drug dose (30 mg vs. 60 mg; OR = 0.298, 95%CI 0.156-0.568) and SF-12 physiological total score (OR = 1.030, 95%CI 1.010-1.050). (3) Early onset was significantly associated with response rate (OR = 18.34, 95%CI 12.10-27.81), remarkable response rate (OR = 27.56, 95%CI 11.65-65.17) and recovery rate (OR = 11.85, 95%CI 4.98-28.18). Group (high dose group vs. low dose group) (χ2 = 8.535, p = .003) and baseline HAMA total score (χ2 = 70.840, p < .001) were independent predictors of onset time. CONCLUSIONS: The early outcomes of high-dose tandospirone in the treatment of GAD are better than those of the low-dose group. Patients with younger age at onset, milder anxiety symptoms and better physiological functions administered high-dose tandospirone showed rapid onset, great early outcomes, high recovery rate and good prognosis. Drug onset time had a good predictive effect on treatment outcome.


Asunto(s)
Trastornos de Ansiedad , Isoindoles , Humanos , Isoindoles/efectos adversos , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico
3.
Sci Rep ; 11(1): 12874, 2021 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-34145371

RESUMEN

In animal models, neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood. Consequently, there is growing concern about the use of general anaesthetics in obstetric and paediatric practice. JM-1232(-) has been developed as a novel intravenous anaesthetic, but the effects of JM-1232(-) on the developing brain are not understood. Here we show that neonatal administration of JM-1232(-) does not lead to detectable behavioural deficits in adulthood, contrarily to other widely-used intravenous anaesthetics. At postnatal day 6 (P6), mice were injected intraperitoneally with a sedative-equivalent dose of JM-1232(-), propofol, or midazolam. Western blot analysis of forebrain extracts using cleaved poly-(adenosine diphosphate-ribose) polymerase antibody showed that JM-1232(-) is accompanied by slight but measurable apoptosis 6 h after administration, but it was relatively small compared to those of propofol and midazolam. Behavioural studies were performed in adulthood, long after the neonatal anaesthesia, to evaluate the long-term effects on cognitive, social, and affective functions. P6 administration to JM-1232(-) was not accompanied by detectable long-term behavioural deficits in adulthood. However, animals receiving propofol or midazolam had impaired social and/or cognitive functions. These data suggest that JM-1232(-) has prospects for use in obstetric and paediatric practice.


Asunto(s)
Anestésicos/administración & dosificación , Conducta Animal/efectos de los fármacos , Isoindoles/administración & dosificación , Piperazinas/administración & dosificación , Factores de Edad , Anestésicos/efectos adversos , Animales , Animales Recién Nacidos , Apoptosis , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Isoindoles/efectos adversos , Memoria/efectos de los fármacos , Ratones , Piperazinas/efectos adversos , Conducta Social
4.
Medicine (Baltimore) ; 99(48): e23357, 2020 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-33235105

RESUMEN

INTRODUCTION: As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients. METHODS: This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100 mg/100 mg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated. RESULTS: The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital. CONCLUSION: Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.


Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Ciclopropanos/uso terapéutico , Isoindoles/uso terapéutico , Lactamas Macrocíclicas/uso terapéutico , Prolina/análogos & derivados , Ritonavir/uso terapéutico , Sulfonamidas/uso terapéutico , Adolescente , Adulto , Anciano , Antivirales/administración & dosificación , Antivirales/efectos adversos , COVID-19/diagnóstico por imagen , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Lactamas Macrocíclicas/administración & dosificación , Lactamas Macrocíclicas/efectos adversos , Masculino , Persona de Mediana Edad , Pandemias , Prolina/administración & dosificación , Prolina/efectos adversos , Prolina/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , SARS-CoV-2 , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Tomografía Computarizada por Rayos X , Adulto Joven
5.
J Am Acad Dermatol ; 82(6): 1314-1320, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32007513

RESUMEN

BACKGROUND: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch. OBJECTIVE: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639). METHODS: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening. RESULTS: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients. LIMITATIONS: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded. CONCLUSION: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population.


Asunto(s)
Isoindoles/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Prurito/tratamiento farmacológico , Psoriasis/complicaciones , Adulto , Diarrea/inducido químicamente , Femenino , Cefalea/inducido químicamente , Humanos , Isoindoles/efectos adversos , Masculino , Persona de Mediana Edad , Nasofaringitis/inducido químicamente , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Prurito/etiología , Índice de Severidad de la Enfermedad
6.
Expert Opin Investig Drugs ; 28(8): 659-666, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31272246

RESUMEN

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK1) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK1 receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.


Asunto(s)
Isoindoles/administración & dosificación , Antagonistas del Receptor de Neuroquinina-1/administración & dosificación , Prurito/tratamiento farmacológico , Animales , Antipruriginosos/administración & dosificación , Antipruriginosos/efectos adversos , Antipruriginosos/farmacología , Enfermedad Crónica , Humanos , Isoindoles/efectos adversos , Isoindoles/farmacología , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Antagonistas del Receptor de Neuroquinina-1/farmacología , Prurito/fisiopatología , Calidad de Vida , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-1/metabolismo
7.
J Psychiatr Res ; 114: 133-140, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31075722

RESUMEN

Vascular depression can respond poorly to antidepressants. This study aimed to explore the efficacy and safety of tandospirone plus escitalopram for treating vascular depression with anxiety. This pilot randomized controlled trial included consecutive inpatients/outpatients with vascular depression/anxiety at the Department of Neurology, Fujian Medical University Union Hospital, China (January 2014 to December 2016). Among 157 patients screened, 100 were randomly divided into the tandospirone + escitalopram (combination therapy) and escitalopram (monotherapy) groups equally, and then followed for 8 weeks. Efficacy was evaluated using the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA), Clinical Global Impression (CGI) and Mini-Mental State examination (MMSE) scales. Adverse events (AEs) were assessed with the Treatment Emergent Symptom Scale (TESS). HAMD and HAMA scores decreased progressively, showing reductions versus baseline at 1, 2, 4 and 8 weeks in both groups (P < 0.001). HAMD and HAMA scores were lower in the tandospirone + escitalopram group than those in the escitalopram group at 1 and 2 weeks (P < 0.001), but not at 4 and 8 weeks. Improvements in CGI scores (severity, improvement and efficacy indexes) were greater in the tandospirone + escitalopram group than that in the escitalopram group at 1 and 2 weeks (P < 0.01), but not at 4 and 8 weeks. The tandospirone + escitalopram group had higher MMSE scores than that in the escitalopram group at 4 and 8 weeks (P < 0.01). All AEs were mild, and the rates were comparable between groups. Augmentation of escitalopram with tandospirone accelerates the onset of anti-depressive and anxiolytic effects and improves cognitive function in patients with vascular depression and anxiety.


Asunto(s)
Antidepresivos/uso terapéutico , Trastornos Cerebrovasculares/tratamiento farmacológico , Citalopram/uso terapéutico , Depresión/tratamiento farmacológico , Isoindoles/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Anciano , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Trastornos Cerebrovasculares/complicaciones , China , Citalopram/administración & dosificación , Citalopram/efectos adversos , Depresión/etiología , Quimioterapia Combinada , Femenino , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Masculino , Proyectos Piloto , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Método Simple Ciego
8.
J Am Acad Dermatol ; 80(5): 1395-1402, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30894279

RESUMEN

BACKGROUND: Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). OBJECTIVE: This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. METHODS: In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. RESULTS: Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P = .02) and -1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. LIMITATIONS: The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. CONCLUSIONS: Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.


Asunto(s)
Isoindoles/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Prurito/tratamiento farmacológico , Adulto , Anciano , Enfermedad Crónica , Diarrea/inducido químicamente , Método Doble Ciego , Fatiga/inducido químicamente , Femenino , Humanos , Isoindoles/efectos adversos , Masculino , Persona de Mediana Edad , Nasofaringitis/inducido químicamente , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Prurigo/complicaciones , Prurito/etiología , Escala Visual Analógica
9.
Clin Neuropharmacol ; 41(6): 216-217, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30204599

RESUMEN

BACKGROUND: Rhabdomyolysis involves the release of intracellular contents secondary to muscle cell injury; it generally presents with muscle pain and weakness. Although several psychotropic agents have been documented as causes of rhabdomyolysis, there are no reports of tandospirone-induced rhabdomyolysis. CASE: We present the case of a 15-year-old Japanese girl who had posttraumatic stress disorder after the Great East Japan Earthquake. She received a dose of 60 mg of tandospirone while taking 10 mg of tandospirone and 400 mg of valproic acid every day. She developed appetite loss, muscle weakness, muscle soreness, and general malaise on day 2, and laboratory data revealed a serum creatine phosphokinase level of 17,770 IU/L that reached a peak of 35,530 IU/L on day 4. Lactate dehydrogenase, aspartate aminotransferase, and alanine transaminase levels were also abnormal. After a fluid infusion was initiated and tandospirone was discontinued, most of her symptoms and abnormal laboratory data resolved within 10 days. CONCLUSION: This case suggests that careless high dosing of partial 5-HT1A receptor agonists is harmful to at-risk patients, such as adolescent patients with poor mental condition.


Asunto(s)
Ansiolíticos/efectos adversos , Isoindoles/efectos adversos , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Rabdomiólisis/inducido químicamente , Adolescente , Alanina Transaminasa/sangre , Ansiolíticos/uso terapéutico , Aspartato Aminotransferasas/sangre , Creatina Quinasa/sangre , Femenino , Humanos , Isoindoles/uso terapéutico , L-Lactato Deshidrogenasa/sangre , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Rabdomiólisis/sangre
10.
Drugs ; 78(13): 1377-1382, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30120738

RESUMEN

Tecovirimat (TPOXX®) is an orthopoxvirus-specific antiviral drug developed by SIGA Technologies in conjunction with the US Department of Health and Human Services' Biomedical Advances Research and Development Authority. It acts by inhibiting the activity of the orthopoxvirus VP37 envelope wrapping protein, thereby preventing the formation of egress-competent enveloped virions, which are essential for dissemination of the virus in the host. In July 2018, oral tecovirimat was approved in the USA for the treatment of human smallpox disease caused by variola virus in adults and paediatric patients weighing ≥ 13 kg. Tecovirimat was approved under the US FDA's Animal Rule, in which marketing approval is based on its efficacy in relevant animal models. An intravenous formulation of tecovirimat is undergoing phase I development for the treatment of smallpox infection. This article summarises the milestones in the development of tecovirimat leading to this first approval for the treatment of human smallpox disease in adults and paediatric patients weighing ≥ 13 kg.


Asunto(s)
Antivirales/uso terapéutico , Benzamidas/uso terapéutico , Isoindoles/uso terapéutico , Viruela/tratamiento farmacológico , Administración Intravenosa , Animales , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Aprobación de Drogas , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Isoindoles/farmacocinética , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration
11.
N Engl J Med ; 379(1): 44-53, 2018 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-29972742

RESUMEN

BACKGROUND: Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed. METHODS: We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers. RESULTS: The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed. CONCLUSIONS: On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .).


Asunto(s)
Antivirales/administración & dosificación , Benzamidas/administración & dosificación , Isoindoles/administración & dosificación , Mpox/tratamiento farmacológico , Infecciones por Poxviridae/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Animales , Antivirales/efectos adversos , Antivirales/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Isoindoles/efectos adversos , Isoindoles/farmacocinética , Macaca fascicularis , Masculino , Persona de Mediana Edad , Mpox/mortalidad , Monkeypox virus , Infecciones por Poxviridae/mortalidad , Conejos , Virus Vaccinia , Adulto Joven
12.
J Psychiatr Res ; 99: 104-110, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29433063

RESUMEN

BACKGROUND: High levels of anxiety symptoms are common in individuals with major depressive disorder (MDD). Adjunctive anxiolytics are widely used in such patients; however, only a few studies have examined the strategy using tandospirone. This study aimed to evaluate the efficacy and safety of adjunctive tandospirone in individuals with MDD and high level of anxiety symptoms. METHODS: A multicenter, randomized, parallel-controlled, open-label study was conducted to evaluate the efficacy and safety of tandospirone coupled with selective serotonin reuptake inhibitors (SSRIs) in patients with MDD and high level of anxiety symptoms. Two hundred and forty-five patients fulfilling the DSM-IV-TR criteria for MDD were randomly assigned to 6 weeks of either SSRIs and tandospirone or SSRIs alone treatment. The efficacy was measured by HAMA total scores, HAMD-17 total scores, and Clinical Global Impressions severity subscale (CGI-S) score. RESULTS: After a 6-week follow-up, two hundred and thirty patients completed this study. Tandospirone coupled with SSRIs significantly improved depressive and anxiety symptoms compared to monotherapy with SSRIs as assessed by HAMD-17 total score (P = 0.003), HAMA total score (P = 0.010), and CGI-S score at week 6 (P = 0.003). The incidence rate of treatment-emergent adverse events (TEAEs) was similar in both groups; the therapy was well-tolerated. CONCLUSIONS: Short-term tandospirone augmentation was effective and well-tolerated in this study. Addition of tandospirone may improve outcomes in MDD patients with high anxiety.


Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Isoindoles/farmacología , Evaluación de Resultado en la Atención de Salud , Piperazinas/farmacología , Pirimidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Ansiolíticos/administración & dosificación , Ansiolíticos/efectos adversos , Ansiedad/etiología , Trastorno Depresivo Mayor/complicaciones , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación
13.
Eur Neuropsychopharmacol ; 28(1): 149-158, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29174529

RESUMEN

Azapirones, which are serotonin1A (5-HT1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: -1.03 (95% confidence interval (CI): -1.91, -0.15), P = 0.02; I2 = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: -0.99, -0.02), P = 0.04; I2 = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I2 = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.


Asunto(s)
Antipsicóticos/uso terapéutico , Buspirona/uso terapéutico , Isoindoles/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Antipsicóticos/efectos adversos , Buspirona/efectos adversos , Quimioterapia Combinada , Humanos , Isoindoles/efectos adversos , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Agonistas del Receptor de Serotonina 5-HT1/efectos adversos
14.
Eur J Cancer ; 61: 94-101, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27156227

RESUMEN

BACKGROUND: Gastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST. PATIENTS AND METHODS: In this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150-220 mg/m(2)) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored. RESULTS: Common onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43-165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d. CONCLUSION: The combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population. Trial registration ID: clinicaltrials.gov: NCT01294202.


Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Mesilato de Imatinib/uso terapéutico , Isoindoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Tumores del Estroma Gastrointestinal/secundario , Humanos , Mesilato de Imatinib/efectos adversos , Inyecciones Intravenosas , Isoindoles/efectos adversos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos
15.
Eur J Nucl Med Mol Imaging ; 43(5): 974-982, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26627081

RESUMEN

PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 × 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I-labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment. CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues.


Asunto(s)
Benzamidas/farmacocinética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagen , Receptores ErbB/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Receptores de Hialuranos/metabolismo , Isoindoles/farmacocinética , Animales , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Carcinoma de Células Escamosas/radioterapia , Línea Celular , Femenino , Fluorodesoxiglucosa F18 , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Radioisótopos de Yodo , Isoindoles/efectos adversos , Isoindoles/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Tomografía de Emisión de Positrones , Radioinmunoterapia , Radiofármacos
16.
BMC Psychiatry ; 15: 271, 2015 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-26521019

RESUMEN

BACKGROUND: Early non-response to antipsychotic treatment in patients with schizophrenia has been shown in multiple studies to predict poor response at short-term trial endpoint. Therefore, strategies to address the challenge of non-improvement early in the course of treatment are needed. A novel trial design was developed to assess the potential utility of antipsychotic dose escalation in patients with an inadequate initial treatment response. This design was embedded in a study intended to assess the efficacy of low dose lurasidone in patients with schizophrenia. The purpose of this report is to describe the background, rationale and design of this study that included a novel method for the assessment of the potential for dose-response in early non-responding patients with schizophrenia. METHODS/DESIGN: In this 6-week, international, multicenter, double-blind trial, eligible adults with acute schizophrenia were randomized to receive fixed doses of lurasidone 20 mg/day, 80 mg/day (active control), or placebo in a 1:2:1 ratio. Patients initially randomized to lurasidone 80 mg/day who did not have a Positive and Negative Syndrome Scale total score improvement ≥ 20% at Week 2 were re-randomized on a 1:1 basis to receive either lurasidone 80 mg/day or lurasidone 160 mg/day for the remainder of the trial. All other groups remained on their initially assigned treatment. The formal primary objective of the study was to evaluate the efficacy of low-dose lurasidone (20 mg/day) compared to placebo; secondary objectives included evaluating the efficacy of lurasidone 80 mg/day versus 160 mg/day in early non-responders, and evaluating the efficacy of lurasidone in all subjects initially randomized to 80 mg/day versus placebo. DISCUSSION: Since a lack of early improvement predicts poor response to short-term antipsychotic treatment in patients with schizophrenia, several treatment strategies have been proposed to enhance treatment outcome in early non-responders. A novel clinical trial design involving a placebo arm and re-randomization of early non-responders to increased or maintained antipsychotic dose was developed. The study design described in this report provides a robust method to assess the value of antipsychotic dose escalation in patients with schizophrenia who demonstrate poor initial treatment response. TRIAL REGISTRATION: ClinicalTrials.gov NCT01821378; initial registration March 22, 2013.


Asunto(s)
Antipsicóticos/administración & dosificación , Clorhidrato de Lurasidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Isoindoles/efectos adversos , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
17.
Oncotarget ; 6(34): 35652-66, 2015 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-26452257

RESUMEN

Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8-24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins.In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.


Asunto(s)
Adenocarcinoma/radioterapia , Benzamidas/administración & dosificación , Carcinoma de Células Escamosas/radioterapia , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoindoles/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Benzamidas/efectos adversos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Isoindoles/efectos adversos , Ratones , Ratones Desnudos , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Ensayos Antitumor por Modelo de Xenoinjerto
18.
PLoS One ; 10(10): e0137305, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26436670

RESUMEN

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/clasificación , Isoindoles/administración & dosificación , Isoindoles/farmacología , Infiltración Neutrófila/efectos de los fármacos , Tioamidas/administración & dosificación , Tioamidas/farmacología , Tionas/administración & dosificación , Tionas/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas tau/química , Administración Oral , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Isoindoles/efectos adversos , Isoindoles/uso terapéutico , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Fenotipo , Multimerización de Proteína/efectos de los fármacos , Estructura Secundaria de Proteína/efectos de los fármacos , Seguridad , Solubilidad , Tioamidas/efectos adversos , Tioamidas/uso terapéutico , Tionas/efectos adversos , Tionas/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
19.
Invest New Drugs ; 33(4): 921-30, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26082332

RESUMEN

Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m(2)/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m(2)/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m(2)/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T½ ~8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.


Asunto(s)
Benzamidas/uso terapéutico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoindoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/farmacología , Esquema de Medicación , Femenino , Proteínas de Choque Térmico HSP27/genética , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de Choque Térmico , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Isoindoles/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Chaperonas Moleculares , Neoplasias/metabolismo , ARN Mensajero/metabolismo
20.
J Clin Psychiatry ; 76(4): 398-405, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25844756

RESUMEN

OBJECTIVE: Mixed (subsyndromal hypomanic) features are prevalent in patients with bipolar depression and are associated with more severe and complex illness, including increased risk for suicide attempts, higher switch to mania during antidepressant therapy, and a higher rate of recurrence. The aim of this post hoc analysis was to evaluate the efficacy and safety of lurasidone in the treatment of patients with bipolar depression presenting with mixed features. METHOD: Patients with a DSM-IV-TR diagnosis of major depressive episode associated with bipolar I disorder, with or without rapid cycling, and with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 and a Young Mania Rating Scale (YMRS) score ≤ 12 were randomly assigned to 6 weeks of double-blind, once-daily treatment with lurasidone 20-60 mg, lurasidone 80-120 mg, or placebo. The presence of mixed features was defined as a YMRS score ≥ 4 at study baseline. Efficacy analyses included change in MADRS total score from baseline to week 6 (the primary outcome in the original study, conducted between April 2009 and February 2012). RESULTS: At baseline, mixed features were present in 56% of patients (lurasidone, n = 182/323; placebo, n = 90/162). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in MADRS scores in the mixed features group (-15.7 vs -10.9; P = .001; week 6; mixed model for repeated measures [MMRM]; effect size, 0.48) and in the group without mixed features (-15.2 vs -10.8; P = .002; week 6; MMRM; effect size, 0.48). Rates of protocol-defined treatment-emergent hypomania or mania were similar for patients with mixed features (lurasidone, 2.2%; placebo, 3.2%) and without mixed features (lurasidone, 3.4%; placebo, 0.0%). CONCLUSIONS: Lurasidone was found in this post hoc analysis to be efficacious in the treatment of patients with bipolar depression who present with mixed features (assessed cross-sectionally at study baseline). No increased risk of treatment-emergent mania was observed in either group. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00868699.


Asunto(s)
Trastorno Bipolar/diagnóstico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/tratamiento farmacológico , Isoindoles/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Trastorno Bipolar/clasificación , Trastorno Bipolar/psicología , Trastorno Depresivo Mayor/clasificación , Trastorno Depresivo Mayor/psicología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Isoindoles/efectos adversos , Clorhidrato de Lurasidona , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Psicometría , Reproducibilidad de los Resultados , Tiazoles/efectos adversos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA