RESUMEN
OBJECTIVE: Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. METHODS: Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. RESULTS: During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; χ2 = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. CONCLUSION: Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania.
Asunto(s)
Bifidobacterium animalis/fisiología , Trastorno Bipolar , Lacticaseibacillus rhamnosus/fisiología , Readmisión del Paciente/estadística & datos numéricos , Probióticos/administración & dosificación , Adulto , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/inmunología , Trastorno Bipolar/terapia , Suplementos Dietéticos , Método Doble Ciego , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Inflamación/inmunología , Inflamación/microbiología , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de SaludRESUMEN
Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.
Asunto(s)
Antivirales/toxicidad , Evaluación Preclínica de Medicamentos , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/efectos de los fármacos , Huésped Inmunocomprometido/efectos de los fármacos , Aciclovir/toxicidad , Animales , Sistema Nervioso Central/efectos de los fármacos , Chlorocebus aethiops , Farmacorresistencia Viral/efectos de los fármacos , Herpes Simple/virología , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Neuronas/efectos de los fármacos , Células Madre Pluripotentes/efectos de los fármacos , Células Vero/efectos de los fármacosRESUMEN
Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED(50) values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc(1) complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc(1) complex, and an M221Q amino acid substitution in the Q(i) site of the protein leads to >100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q(i) site of the T. gondii cytochrome bc(1) complex.
Asunto(s)
Antiprotozoarios/farmacología , Inhibidores Enzimáticos/farmacología , Quinolinas/farmacología , Toxoplasma/crecimiento & desarrollo , Toxoplasmosis/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Complejo III de Transporte de Electrones/antagonistas & inhibidores , Femenino , Humanos , Ratones , Proteínas Protozoarias/antagonistas & inhibidores , Ratas , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Toxoplasma/enzimología , Toxoplasmosis/enzimologíaRESUMEN
New drugs are needed for treatment of Toxoplasma gondii infections. We tested derivatives of principles found in Isatis indigotica for in vitro efficacy against T. gondii infection. Indirubin-3'-oxime analogs showed modest micromolar activity, while tryptanthrin derivatives displayed 50% inhibitory doses in the low nanomolar range. Tryptanthrins have potential as anti-Toxoplasma infection therapeutics.
Asunto(s)
Antiprotozoarios/farmacología , Medicamentos Herbarios Chinos/química , Isatis/química , Quinazolinas/farmacología , Toxoplasma/efectos de los fármacos , Animales , Indoles/química , Indoles/farmacología , Pruebas de Sensibilidad Parasitaria , Quinazolinas/química , Toxoplasma/crecimiento & desarrolloRESUMEN
Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is medically important and distributed worldwide. Currently available medications are limited in terms of efficacy and side effects. We synthesized novel, nonacetal, hydrolytically stable derivatives of artemisinin and showed that they inhibit the replication of Toxoplasma gondii in cell culture.