Informe diário de evidências COVID-19: busca realizada em 19 de junho de 2020 / COVID-19 daily evidence report: search conducted on June 19, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 9 artigos e 6 protocolos.

Péptidos tímicos (Timosina alfa-1) para el tratamiento de pacientes oncológicos / Thymic peptides (Thymosin alfa-1) for treatment of cancer patients

OBJETIVO: Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer. TECNOLOGÍA EVALUADA: El sistema inmunitario juega un rol fundamental en las propias defensas del organismo contra las células cancerosas. El timo juega un papel central en esta situación y modifica los linfocitos T, una clase de linfocitos. Los estudios de péptidos tímicos hallaron numerosos efectos sobre el sistema inmunitario. Existen dos grupos de péptidos tímicos disponibles para el tratamiento, a saber: los extractos purificados de timo animal (mayormente de terneros) y los péptidos de timo producidos de forma sintética. Se cree que los extractos de timo purificados (pTE, por sus siglas en inglés) y los péptidos tímicos sintéticos (sTP, por sus siglas en inglés) mejoran el sistema inmunitario de los pacientes con cáncer para poder luchar contra el crecimiento de células tumorales y resistir las infecciones por la inmunodepresión inducida por la enfermedad y el tratamiento antineoplásico. METODOLOGÍA: Este estudio incluyó 26 ensayos (2736 pacientes). Veinte ensayos investigaron los Pte (timoestimulina o timosina fracción 5) y seis ensayos investigaron los sTP (timopentina o timosina α1). 4 estudios evaluaron el uso de Timosina alfa-1 en pacientes con cáncer Cheng 2004; Gish 2009; Maio 2010; Schulof 1985. Veintiún ensayos informaron los resultados de la SG, seis los de la SLE, 14 los de la RT, nueve los de los EA y diez los de seguridade de los pTE y los sTP. El agregado de pTE no produjo beneficios en la SG (CR 1,00; IC del 95%: 0,79 a 1,25); la SLE (CR 0,97; IC del 95%: 0,82 a 1,16); ni en la RT (CR 1,07; IC del 95%: 0,92 a 1,25). La heterogeneidad de estos resultados fue de moderada a alta. Para la timosina α1el CR agrupado de la SG fue de 1,21 (IC del 95%: 0,94 a 1,56; p = 0,14), con una baja heterogeneidad; y de 3,37 (IC del 95%: 0,66 a 17,30; p = 0,15) para la SLE, con heterogeneidad moderada. Los pTE redujeron el riesgo de complicaciones infecciosas graves (CR 0,54; IC del 95%: 0,38 a 0,78; p = 0,0008; I2 = 0%). El CR de la neutropenia grave en los pacientes tratados con timoestimulina fue de 0,55 (IC del 95%: 0,25 a 1,23; p = 0,15). La tolerabilidad de los pTE y los sTP fue adecuada. La mayoría de ensayos tenían al menos un riesgo de sesgo moderado. RECOMENDACIONES Y JUICIOS: En general, no se hallaron pruebas de que el agregado de pTE al tratamento antineoplásico reduzca el riesgo de mortalidad o la progresión de la enfermedad, ni que mejore la tasa de respuestas tumorales al tratamiento antineoplásico. Se sugiere no utilizar Timosina alfa-1 como terapia adyuvante en el tratamiento del câncer.

The Effect of Thymosin Alpha 1 on Severe Acute Pancreatitis in Rats / Estudios sobre el efecto de la timosina alfa 1 sobre la pancreatitis aguda grave en ratas

ABSTRACT Objective: To observe the effect of thymosin alpha l (Tα1) on severe acute pancreatitis (SAP) in rats. Methods: Twenty-four adult male Sprague-Dawley rats were randomly divided into three groups (eight in each group): control group (Group A), SAP group (Group B) and Tα1 treatment group (Group C). Animal models of SAP were made by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Rats in Group C were treated with Tα1 (6 mg/kg) via intraperitoneal administration prior to SAP modelling. Eight rats in each group were sacrificed at 12 hours, respectively, after modelling. The serum levels of amylase, tumour necrosis factor-α (TNF-α), interleukin-lβ (IL-lβ and interleukin-6 (IL-6) were detected in each group. The pathological scores of the tissue in the pancreas head were observed by light microscopy. Results: The levels of serum amylase of Group B were 6378 ± 538 U/L, which were significantly higher than those (4587 ± 478 U/L) of Group C (p < 0.05). The levels of serum TNF-α of Group B were 360.32 ± 28.67 pg/mL, which were higher than those (269.99 ± 26.11 pg/mL) of Group C (p < 0.05). The levels of serum IL-lβ of Group B were 435.93 ± 36.00 pg/mL, which were higher than those (312.42 ± 17.89 pg/mL) of Group C (p < 0.05). The levels of serum IL-6 of Group B were 433.90 ± 28.36 pg/mL, which were higher than those (289.98 ± 23.00 pg/mL) of Group C (p < 0.05). The pancreatic pathological scores of Group B were 13.34 ± 2.19, which were higher than those (6.39 ± 1.86) of Group C (p < 0.05). Conclusion: Thymosin alpha 1 could decrease proinflammatory cytokines and reduce pancreas injury and had a protective effect in rats with SAP. This provides a new strategy for the clinical treatment of SAP.

RESUMEN Objetivo: Observar el efecto de la timosina alfa l (Tα1) sobre la pancreatitis aguda grave (PAG) en ratas. Métodos: Veinticuatro ratas Sprague-Dawley adultas machos fueron divididas aleatoriamente en tres grupos (ocho en cada grupo): grupo de control (grupo A), grupo de PAG (grupo B) y grupo de tratamiento con Tα1 (grupo C). Los modelos animales de PAG fueron creados mediante inyección retrógrada de taurocolato de sodio al 5% en el conducto biliopancreático. Las ratas del grupo C se trataron con Tα1 (6 mg/kg) via administración intraperitoneal antes del modelado de PAG. Las ocho ratas en cada grupo fueron sacrificadas a las 12 horas, respectivamente, después del modelado. Los niveles séricos de amilasa, factor-α de necrosis tumoral (TNF-α), interleucina-β (Il-β) e interleucina-6 (IL-6) fueron detectados en cada grupo. Las puntuaciones patológicas del tejido en la cabeza del páncreas fueron observadas mediante microscopía de luz. Resultados: Los niveles de amilasa sérica del grupo B fueron 6378 ± 538 U/L, y resultaron significativamente más altos (p < 0.05) que los niveles 4587 ± 478 U/L del grupo C. Los niveles séricos de TNF-α del grupo B fueron 360.32 ± 28.67 pg/mL, y resultaron ser más altos (p < 0.05) que los 269.99 ± 26.11 pg/mL del grupo C. Los niveles séricos de Il-β del grupo B fueron 435.93 ± 36.00 pg/mL, y fueron más altos (p < 0.05) que los 312.42 ± 17.89 pg/mL) del grupo C. Los niveles de suero IL-6 del grupo B fueron 433.90 ± 28.36 pg/mL, y resultaron ser más altos (p < 0.05) que los 289.98 ± 23.00 pg/mL del grupo C. Las puntuaciones patológicas pancreáticas del grupo B fueron 13.34 ± 2.19, y resultaron ser más altas (p < 0.05) que las puntuaciones 6.39 ± 1.86 del grupo C. Conclusión: La timosina alfa pudo disminuir las citoquinas proinflamatorias y reducir la lesión del páncreas, y tuvo un efecto protector en las ratas con PAG. Esto ofrece una nueva estrategia para el tratamiento clínico de PAG.

Effect of thymosin alpha-1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro.

Thymosin alpha 1 (Tα1) has been shown to have beneficial effects on numerous immune system parameters, but little is known about the effects of Tα1 on patients with gastric carcinoma. The objective of this study was to determine the effect of Tα1 on subpopulations of Th1, Th2, Th17, and regulatory T cells (Tregs) in vitro, and to evaluate its efficacy as an immunoregulatory factor in patients with gastric carcinoma. We compared the effect of Tα1 on the frequency of CD4+ and CD8+ T cells, especially the CD4+CD25+Foxp3+ Tregs in peripheral blood mononuclear cells (PBMCs) from gastric carcinoma patients (N = 35) and healthy donors (N = 22). We also analyzed the changes in the proliferation of PBMCs in response to treatment with Tα1, and examined the production of Th1, Th2, and Th17 cytokines by PBMCs and tumor-infiltrating lymphocytes. The treatment of PBMCs from gastric cancer patients, with Tα1 (50 µg/mL) alone increased the percentage of CD4+CD25+Foxp3+ (suppressive antitumor-specific Tregs) from 1.68 ± 0.697 to 2.19 ± 0.795% (P < 0.05). Our results indicate that Tα1 increases the percentage of Tregs and IL-1ß, TNF-α, and IL-6 in vitro.

Efficacy of triple therapy with thymalfasin, peginterferon alpha-2a, and ribavirin for the treatment of hispanic chronic HCV nonresponders.

BACKGROUND/AIMS: Thymalfasin has shown efficacy in the treatment of chronic HCV infection. The aim of this study was to evaluate the efficacy and tolerability of triple therapy with thymalfasin, peginterferon alpha-2a (PEG-IFN alpha-2a), and ribavirin in Hispanic patients with chronic viral hepatitis C who were nonresponders to prior treatment with interferon alfa (IFN-alpha)/ribavirin. METHODS: In this open-label study, 40 subjects received thymalfasin (1.6 mg twice a week), PEG-IFN alpha-2a (180 microg once a week), and ribavirin (800-1,000 mg/day) for 48 weeks. All patients had positive HCV RNA by PCR analysis, abnormal levels of ALT, compensated hepatic disease, and liver biopsy with chronic damage. RESULTS: Viral response was observed in 52.5% patients at week 12 and 50% at week 24. Of the per protocol group, 52.6% showed an end-of-treatment response at week 48 and 21.1% achieved an SVR at week 72. Among genotype 1 patients, 23.5% achieved an SVR at week 72. A reduction of the dose of PEG IFN alpha-2a and ribavirin was required. Thymalfasin was well tolerated without dose reduction. CONCLUSION: Triple therapy with thymalfasin, PEG IFN alpha-2a, and ribavirin is an effective treatment option for difficult-to-treat HCV patients who are refractory to prior conventional treatment, with adequate tolerability.

Cost-effectiveness of chronic hepatitis C treatment with thymosin alpha-1.

BACKGROUND: More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment. METHODS: We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits. RESULTS: Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon + ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of 1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin 2,277/QALY, peginterferon alone 2,929/QALY, and no treatment 4,204/QALY. Sensitivity analyses confirmed the robustness of the base case. CONCLUSIONS: Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option.

Triple combination of thymalfasin, peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior interferon and ribavirin treatment: 24-week interim results of a pilot study.

Despite steady progress in antiviral treatment for patients with chronic hepatitis C virus (HCV), many patients still have detectable serum HCV RNA levels by the end of interferon-based treatment and are known as virological non-responders. Re-treatment of these patients not responding to previous therapy remains challenging. Studies of the dynamics of the HCV population show a marked decline in new cases since 1996; however, the relative proportion of non-responders is expected to increase over time and, similarly, the number of patients eligible for first-line treatment is expected to decrease. The current standard of care for treatment involves the use of pegylated interferons in combination with ribavirin. However, many difficult-to-treat groups still have low response rates. Newer combinations are being investigated to optimize chances of attaining a sustained response in these groups: one such triple therapy regimen is peginterferon alfa-2a, ribavirin and thymalfasin, which was given to 23 previously non-responder patients. Viral response was 60.8% at week 12 and 47.8% at week 24. These preliminary results encourage further evaluation of this promising combination.

Triple combination of thymalfasin, peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior interferon and ribavirin treatment: 24-week interim results of a pilot study.

Despite steady progress in antiviral treatment for patients with chronic hepatitis C virus(HCV), many patients still have detectable serum HCV RNA levels by the end of interferon-based treatment and are known as virological non-responders. Re-treatment of these patients not responding to previous therapy remains challenging. Studies of the dynamics of the HCV population show a marked decline in new cases since 1996; however, the relative proportion of non-responders is expected to increase over time and, similarly, the number of patients eligible for first-line treatment is expected to decrease. The current standard of care for treatment involves the use of pegylated interferons in combination with ribavirin. However, many difficult-to-treat groups still have low response rates. Newer combinations are being investigated to optimize chances of attaining a sustained response in these groups: one such triple therapy regimen is peginterferon alfa-2a, ribavirin and thymalfasin, which was given to 23 previously non-responder patients. Viral response was 60.8% at week 12 and 47.8% at week 24. These preliminary results encourage further evaluation of this promising combination.

Bone marrow transplantation in DiGeorge syndrome.

A Hispanic infant girl with DiGeorge syndrome underwent successful bone marrow transplantation (BMT) at age 28 1/2 weeks. She had typical facies, a cardiac defect, hypoparathyroidism, severe T and B cell immunodeficiency, and low levels of facteur thymique serique (FTS). In vitro incubation of the peripheral blood lymphocytes with thymosin alpha 1 showed no increase in the number of T cells on two occasions. A fetal thymus for transplantation was not available, and further review of past experience with thymic cells or factors revealed inconsistent and incomplete responses. Because of the patient's worsening clinical and immunologic status, BMT was performed, with her histocompatible brother as donor. The patient has had a good clinical and immunologic response to BMT, with evidence of T cell engraftment, improved B cell function, and increased levels of serum FTS. This experience indicates that minimal thymic influence is necessary for successful BMT and that patients with DiGeorge syndrome with significant T cell deficiency may benefit from this treatment.

Circulating thymulin and thymosin-alpha 1 activity in pediatric acquired immune deficiency syndrome: in vivo and in vitro studies.

Twenty-five children with acquired immune deficiency syndrome (AIDS) or AIDS-related complex had a characteristic pattern of T cell deficiency. Abnormally low plasma thymulin levels preceded the development of peripheral blood T cell abnormalities. In contrast to patients with congenital T cell deficiencies, our patients had elevated serum levels of thymosin-alpha 1. Treatment with thymosin fraction 5 in three children with AIDS resulted in only transient clinical and immunologic improvement.

Elevated thymosin alpha I levels in Brazilian pemphigus foliaceus.

Levels of thymosin alpha I in the sera of 37 patients with Brazilian pemphigus foliaceus (BPF) were measured using a competitive binding radioimmunoassay. The values were compared with 19 patients with other forms of pemphigus, 13 relatives of patients with BPF, 18 patients with other dermatological diseases, and 265 normal controls. We found that 27 (73%) of the patients with BPF had thymosin alpha I serum levels that were at least two standard deviations above the mean for normal individuals. The mean value for patients with BPF was significantly greater than any other groups studied. The thymosin elevation is similar to alterations seen in certain viral diseases and suggests that BPF is aetiopathogenically distinct from the forms of pemphigus.