The Role of Serotonin in Breast Cancer Stem Cells.

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.

Psychotropic drugs upregulate aquaporin-2 via vasopressin-2 receptor/cAMP/protein kinase A signaling in inner medullary collecting duct cells.

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.

Therapeutic effects of sertraline on improvement of Ovariectomy-induced decreased spontaneous activity in mice.

We have already reported that ovariectomized (OVX) rats reduced the spontaneous activity during the dark period due to the decease of serotonin release in the amygdala. In this study, we examined the potential of sertraline, a selective serotonin reuptake inhibitor, on the recovery of less spontaneous activity seen in mice with OVX-induced despair-like behaviors. Female 9-week old ICR mice were underwent either OVX or sham surgery. Sertraline (10 mg/kg/day, s.c.) or saline were started to administer to each group for 8 weeks (6 times/week) from the 8th week after OVX. Each spontaneous activity of mouse was evaluated during the dark period (19:00-07:00) using an infrared sensor. Moreover, mRNA expression levels of tryptophan hydroxylase (TPH) and X-box binding protein 1 (XBP1) were measured in the hippocampus and prefrontal cortex using by a real-time PCR method. We found out that the OVX-induced despair-like behaviors were improved by the continuous administration of sertraline. After treatment of OVX, our real-time PCR data showed that sertraline significantly suppressed the upregulation of XBP1 expression levels in both hippocampus and prefrontal cortex, although this suppression of the downregulation of TPH expression levels was seen in only hippocampus. These results suggest that sertraline improves the decrease in spontaneous activity induced by OVX assessed by the hippocampus suppressing decreased serotonin synthesis in the serotonergic neuron.

Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4 < 100 cells/µl can reduce meningitis and death, yet preemptive fluconazole therapy fails in ∼25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800 mg for 2 weeks, then 400 mg for 10 weeks, then 200 mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100 mg/day doses up to 400 mg/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n = 4 sertraline group; n = 3 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200 mg/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.

Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis.

Liposomes containing phosphatidylserine (PS) has been used for the delivery of drugs into the intramacrophage milieu. Leishmania (L.) infantum parasites live inside macrophages and cause a fatal and neglected viscerotropic disease, with a toxic treatment. Sertraline was studied as a free formulation (SERT) and also entrapped into phosphatidylserine liposomes (LP-SERT) against intracellular amastigotes and in a murine model of visceral leishmaniasis. LP-SERT showed a potent activity against intracellular amastigotes with an EC50 value of 2.5 µM. The in vivo efficacy of SERT demonstrated a therapeutic failure. However, when entrapped into negatively charged liposomes (-58 mV) of 125 nm, it significantly reduced the parasite burden in the mice liver by 89% at 1 mg/kg, reducing the serum levels of the cytokine IL-6 and upregulating the levels of the chemokine MCP-1. Histopathological studies demonstrated the presence of an inflammatory infiltrate with the development of granulomas in the liver, suggesting the resolution of the infection in the treated group. Delivery studies showed fluorescent-labeled LP-SERT in the liver and spleen of mice even after 48 h of administration. This study demonstrates the efficacy of PS liposomes containing sertraline in experimental VL. Considering the urgent need for VL treatments, the repurposing approach of SERT could be a promising alternative.

Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial.

BACKGROUND: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. METHODS: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. INTERPRETATION: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. FUNDING: National Institutes of Health and Medical Research Council, Wellcome Trust.

The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy.

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.

Effect of sertraline in paroxysmal hypertension.

OBJECTIVE: Paroxysmal hypertension or pseudopheochromocytoma is quite a common problem in clinical practice. The optimal treatment for this condition has not been established. This study sought to investigate whether sertraline (a selective serotonin reuptake inhibitor) reduces the symptoms. METHODS: We enrolled 64 patients referred to our department between April 2008 and October 2014 for symptomatic paroxysmal hypertension. Patients received sertraline, 50 mg once daily, in addition to their current medication. The effect of the treatment was assessed during their next clinical visit at least 3 months later. RESULTS: Of the 64 patients, 57 (89%) also had sustained arterial hypertension. Mean office baseline blood pressure (BP) was 147.6/83.8 mmHg and patients used a mean of 3.1 antihypertensive drugs. Five patients did not start using sertraline and three were lost to follow-up. Of the 56 patients who started using sertraline and who came for check up, clinical improvement was observed in 42 (75%) patients - symptoms of paroxysmal hypertension fully subsided in 28 (50%) and were partially reduced in 14 (25%) . Side effects or intolerance leading to discontinuation of treatment occurred in 7 patients (12.5%). Mean office BP in patients using sertraline decreased by 12.8/7.4 mmHg (P<0.001 for both). CONCLUSIONS: Sertraline effectively removed or reduced symptoms of paroxysmal hypertension in the majority of patients who used this treatment.

Introduction: How We Encountered TCTP and Our Purpose in Studying It.

In this brief introduction, we describe our encounter with TCTP. Back in 2000, we discovered TCTP in two quite different ways: first, we looked at protein partners of TSAP6 and one of them was TCTP. Then, in collaboration with Sidney Brenner, we performed a high-throughput differential screening comparing the parental cancer cells with revertants. The results indicated that TCTP was of the most differentially expressed genes. These two approaches were carried out only months apart. They guided our research and led to the discoveries of drugs that inhibit the function of TCTP. Much of the preclinical data on sertraline as an inhibitor of TCTP in cancer were obtained with Judith Karp at Johns Hopkins. This drug is now given in combination with Ara-C to patients in a phase I clinical trial for Acute Myeloid Leukemia. We will here detail how all this happened in our lab while working around one central project: tumor reversion.

Effect of sertraline on complications and survival after hematopoietic stem-cell transplantation, a double-blind, placebo-controlled clinical study.

Previous studies have found a connection between psychiatric problems and post-hematopoietic stem-cell transplantation (HSCT) complications. We sought to evaluate the effect of sertraline on engraftment time, hospitalization period, mortality, and post-transplantation complications in HSCT recipients with depression and/or anxiety. We recruited adults aged 18-60, who were candidates for autologous or allogeneic HSCT with major depression and/or anxiety disorder. They were administered 50 mg of sertraline or placebo daily for the first week, and then 100 mg for the following seven weeks. We documented occurrence and severity of early post-HSCT complications, including infection, mucositis, nausea and vomiting, diarrhea, pain, renal toxicities and liver complications, acute graft-versus-host disease, and veno-occlusive disease, as well as time to engraftment, length of hospitalization and 6-month mortality. Overall, 56 patients participated in the study (sertraline group n = 30, placebo group n = 26). Of the complications, only mortality and readmission up to 6 months post-transplantation were significantly higher in the placebo group compared to sertraline group (P values = 0.040, 0.028, respectively). There were no significant differences for other complications between the groups. Mean engraftment time was significantly lower in the sertraline group (P value = 0.048). This study provides evidence that sertraline positively influences engraftment time, readmission, and mortality after HSCT.

Cost-utility analysis of vortioxetine versus agomelatine, bupropion SR, sertraline and venlafaxine XR after treatment switch in major depressive disorder in Finland.

BACKGROUND: To assess the cost-utility of vortioxetine versus relevant comparators (agomelatine, bupropion SR, sertraline, and venlafaxine XR) in the finnish setting in major depressive disorder (MDD) patients with inadequate response to selective serotonin- /serotonin-norepinephrine reuptake inhibitors. METHODS: A one-year analysis was conducted using a decision tree with a Markov state transition component. The health states were remission, relapse and recovery. A Finnish healthcare payer perspective was adopted. RESULTS: Vortioxetine was less costly and more effective versus all comparators in both direct and societal perspectives. Vortioxetine reduced the average annual direct costs by 4% versus venlafaxine XR and 8% versus sertraline. The greater efficacy associated with vortioxetine was translated into a higher percentage of patients in remission and recovery. The model was most sensitive to changes in remission rates at 8 weeks. CONCLUSION: This cost-utility analysis showed vortioxetine to be a good alternative for MDD patients switching therapy in Finland.

Study protocol: a phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness.

INTRODUCTION: Breathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses. METHODS AND ANALYSIS: A total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0-100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained. ETHICS AND DISSEMINATION: Ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12610000464066.

Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer.

Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.

Análisis de costo-efectividad de escitalopram comparado con paroxetina, sertralina, fluoxetina y venlafaxina como terapia de mantenimiento para pacientes con trastorno de fobia social en Colombia / Cost-effectiveness analysis of escitalopram compared to paroxetine, sertraline, fluoxetine and venlafaxine as maintenance therapy for patients with social phobia disorder in Colombia

Problema de investigación: Describir los costos y la efectividad de escitalopram comparado con paroxetina, sertralina, fluoxetina, y venlafaxina como terapia de mantenimiento en adultos con diagnóstico de trastorno de fobia social en Colombia. Tipo de evaluación económica: Análisis de costo-utilidad. Población objetivo: Adultos colombianos con diagnóstico de trastorno de fobia social. Intervención y comparadores: Intervención: escitalopram, Comparadores: paroxetina, sertralina, fluoxetina, y venlafaxina. Horizonte temporal: 32 semanas. Perspectiva: SGSSS. Tasa de descuento: No aplica. Estructura del modelo: Se estructuró un árbol de decisión, teniendo en cuenta modelos publicados en la literatura. Fuentes de datos de efectividad y seguridad: Reporte de efectividad y seguridad elaborado en diciembre de 2014 en el IETS, Ensayos clínicos aleatorizados. Desenlaces y valoración: AVAC, Tasa de respuesta al medicamento. Costos incluidos: Costo de los medicamentos, Costo de procedimientos, Costo de los eventos adversos. Fuentes de datos de costos: SISMED. Manual tarifario ISS 2001. Resultados del caso base: Para el caso base, paroxetina, sertralina y venlafaxina son dominados por fluoxetina y escitalopram. El costo por AVAC ganado con escitalopram comparado con fluoxetina se estimó en $30.968.662. Todas las alternativas tienen una efectividad esperada muy similar. Análisis de sensibilidad: Los análisis de sensibilidad y el diagrama de tornado mostraron que las variables con mayor impacto sobre las estimaciones de costo-utilidad del escitalopram son la probabilidad de respuesta y las ponderaciones de utilidad. Conclusiones y discusión: Escitalopram parece ofrecer una mejor relación entre costos y efectividad respecto a sus comparadores. No obstante, es necesario tener en cuenta que sertralina, paroxetina y fluoxetina pueden llegar a ser costo-efectivas debido a que variaciones en los parámetros de efectividad y utilidad pueden cambiar la decisión. Venlafaxina obtuvo una peor relación de costos y beneficios comparativos. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo. (AU)

Análisis de costo-efectividad de escitalopram comparado con paroxetina, sertralina y venlafaxina como terapia de mantenimiento para pacientes con trastorno de ansiedad generalizada en Colombia / Cost-effectiveness analysis of escitalopram compared to paroxetine, sertraline and venlafaxine as maintenance therapy for patients with generalized anxiety disorder in Colombia

Problema de investigación: Describir los costos y la efectividad de escitalopram comparado con paroxetina, sertralina y venlafaxina como terapia de mantenimiento en adultos con diagnóstico de trastorno de ansiedad generalizada en Colombia. Tipo de evaluación económica: Análisis de costo-utilidad. Población objetivo: Adultos colombianos con diagnóstico de trastorno de ansiedad generalizada. Intervención y comparadores: Intervención: escitalopram, Comparadores: paroxetina, sertralina y venlafaxina. Horizonte temporal: 32 semanas. Perspectiva: SGSSS. Tasa de descuento: No aplica. Estructura del modelo: Se estructuró un árbol de decisión, teniendo en cuenta modelos publicados en la literatura. Fuentes de datos de efectividad y seguridad: Reporte de efectividad y seguridad elaborado en diciembre de 2014 en el IETS, Ensayos clínicos aleatorizados. Desenlaces y valoración: AVAC, Tasa de respuesta al medicamento, Tasa de recaídas con el medicamento. Costos incluidos: Costo de los medicamentos, Costo de procedimientos, Costo de los eventos adversos. Fuentes de datos de costos: SISMED, Manual tarifario ISS 2001. Resultados del caso base: Para el caso base, escitalopram es la alternativa cost-efectiva con un costo esperado de $39.127.045 respecto a sertralina. La RICE de paroxetina fue superior al umbral de costo-efectividad de 3 veces el PIB per cápita. Venlafaxina fue dominada por todos los demás medicamentos. Se encuentra gran incertidumbre en la decisión y una e fectividad esperada muy similar entre todas las alternativas, por lo que estos resultados deben analizarse con precaución. Análisis de sensibilidad: Los análisis de sensibilidad y el diagrama de tornado mostraron que las variables con mayor impacto sobre las estimaciones de costo-utilidad del escitalopram son la probabilidad de respuesta, ponderaciones de utilidad, las dosis de los medicamentos y el desenlace utilizado. Conclusiones y discusión: Escitalopram parece ofrecer una mejorrelación entre costos y efectividad respecto a sus comparadores. No obstante, es necesario tener en cuenta que sertralina y paroxetina pueden llegar a ser costo-efectivas bajo escenarios plausibles. Venlafaxina obtuvo una peor relación de costos y beneficios comparativos. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo.(AU)

Análisis de costo-efectividad de escitalopram comparado con paroxetina, fluoxetina, sertralina, fluvoxamina y clomipramina como terapia de mantenimiento para pacientes con trastorno obsesivo compulsivo en Colombia / Cost-effectiveness analysis of escitalopram compared to paroxetine, fluoxetine, sertraline, fluvoxamine and clomipramine as maintenance therapy for patients with obsessive-compulsive disorder in Colombia

Problema de investigación: Analizar los costos y la efectividad del escitalopram comparado con paroxetina, sertralina, fluoxetina, fluvoxamina y clomipramina como terapia de mantenimiento de primera línea en pacientes con trastorno obsesivo compulsivo en Colombia. Tipo de evaluación económica: Análisis de costo-efectividad. Población objetivo: Pacientes mayores de 18 años con diagnóstico de trastorno obsesivo compulsivo. Intervención y comparadores: Comparadores: paroxetina, sertralina, fluoxetina, fluvoxamina y clomipramina. Horizonte temporal: 32 semanas. Perspectiva: Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: No aplica. Estructura del modelo: Árbol de decisión. Fuentes de datos de efectividad y seguridad: Reporte de efectividad y seguridad, Ensayos clínicos aleatorios. Desenlaces y valoración: Años de vida ajustados por calidad (AVAC). Costos incluidos: Costo de los medicamentos, Costo de procedimientos, Costo de los eventos adversos. Fuentes de datos de costos: SISMED, Manual tarifario ISS 2001. Resultados del caso base: En el escenario del caso base, fluvoxamina, fluoxetina, paroxetina y clomipramina son dominados por sertralina y escitalopram. El costo por AVAC es $16.084.456 de escitalopram comparado con sertralina. Análisis de sensibilidad: Los análisis de sensibilidad y el diagrama de tornado mostraron que las variables con mayor impacto sobre las estimaciones de costo-efectividad del escitalopram son la probabilidad de respuesta y retiro por eventos adversos del medicamento sertralina. Conclusiones y discusión: Escitalopram parece ofrecer una mejor relación entre costos y efectividad respecto a sus comparadores. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo.(AU)

Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study.

BACKGROUND: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. METHODS: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0·37 colony forming units per mL per day (95% CI -0·41 to -0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1·27, 95% CI 0·69-2·32; p=0·45). INTERPRETATION: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. FUNDING: National Institutes of Health, Grand Challenges Canada.

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport.

Effectiveness of CNS-acting drugs depends on the localization, targeting, and capacity to be transported through the blood-brain barrier (BBB) which can be achieved by designing brain-targeting delivery vectors. Hence, the objective of this study was to screen the formulation and process variables affecting the performance of sertraline (Ser-HCl)-loaded pegylated and glycosylated liposomes. The prepared vectors were characterized for Ser-HCl entrapment, size, surface charge, release behavior, and in vitro transport through the BBB. Furthermore, the compatibility among liposomal components was assessed using SEM, FTIR, and DSC analysis. Through a thorough screening study, enhancement of Ser-HCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between Ser-HCl and the charging agent to determine drug entrapment and leakage. Moreover, results of liposomal transport through mouse brain endothelialpolyoma cells demonstrated greater capacity of the proposed glycosylated liposomes to target the cerebellar due to its higher density of GLUT1 and higher glucose utilization. This transport capacity was confirmed by the inhibiting action of both cytochalasin B and phenobarbital. Using C6 glioma cells model, flow cytometry, time-lapse live cell imaging, and in vivo NIR fluorescence imaging demonstrated that optimized glycosylated liposomes can be transported through the BBB by classical endocytosis, as well as by specific transcytosis. In conclusion, the current study proposed a thorough screening of important formulation and process variabilities affecting brain-targeting liposomes for further scale-up processes.

Transdermal estradiol treatment during breastfeeding: maternal and infant serum concentrations.

We examined estradiol (E2) and estrone (E1) concentrations in breastfeeding mother-infant dyads. The mothers had postpartum depression and were participants in a randomized clinical trial with three treatments (transdermal E2, sertraline, and placebo). Neither infant E1 and E2 concentrations nor infant growth differed across the treatments. Transdermal E2 administration of 50 to 200 mcg/day for breastfeeding women did not affect infant E1 or E2 concentrations or infant growth.

Depression care management for adults older than 60 years in primary care clinics in urban China: a cluster-randomised trial.

BACKGROUND: China's national health policy classifies depression as a chronic disease that should be managed in primary care settings. In some high-income countries use of chronic disease management principles and primary care-based collaborative-care models have improved outcomes for late-life depression; however, this approach has not yet been tested in China. We aimed to assess whether use of a collaborative-care depression care management (DCM) intervention could improve outcomes for Chinese adults with depression aged 60 years and older. METHODS: Between Jan 17, 2011, [corrected] and Nov 30, 2013, we did a cluster-randomised trial in patients from primary care centre clinics in Shangcheng district of Hangzhou city in eastern China. We randomly assigned (1:1) clinics to either DCM (involving training for physicians in use of treatment guidelines, training for primary care nurses to function as care managers, and consultation with psychiatrists as support) or to give enhanced care as usual to all eligible patients aged 60 years and older with major depressive disorder. Clinics were chosen randomly for inclusion from all primary care clinics in the district by computer algorithm and then randomly allocated depression care interventions remotely by computer algorithm. Physicians, study personnel, and patients were not masked to clinic assignment. Our primary outcome was difference in Hamilton Depression Rating Scale (HAMD) score using data for clusters at baseline and 3, 6, and 12 month follow-up in a mixed-effects model of the intention-to-treat population. We originally aimed to analyse outcomes at 24 months, however the difference between groups at 12 months was large and funding was insufficient to continue to 24 months, therefore we decided to end the trial at 12 months. This trial is registered with ClinicalTrials.gov, number NCT01287494. FINDINGS: Of 34 primary care clinics in Shangcheng district, 16 were randomly chosen. We randomly assigned eight clinics to the DCM intervention (164 patients enrolled) and eight primary care clinics to enhanced care as usual (162 patients). There were no major differences in baseline demographic and clinical variables between the groups of patients for each intervention. Over the 12 months, patients in clinics assigned to DCM had a significantly greater reduction in HAMD score than did those in practices assigned to enhanced care as usual (estimated between group difference -6·5 [95% CI -7·1 to -5·9]; Cohen's d 0·8 [95% CI 0·8-0·9]; p<0·0001). The intercluster correlation for change in HAMD total score was 0·07 (95% CI 0·06-0·08). There were no study-related adverse events in either group. INTERPRETATION: Clinical outcomes of Chinese adults older than 60 years who had major depression were improved when their primary care clinic used DCM. Primary care-based collaborative management of depression is promising to address this pressing public health need in China. FUNDING: National Institutes of Health, Program for New Century Excellent Talents in Universities of China, Ministry of Education, China.