RESUMEN
BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Disfunción Cognitiva/tratamiento farmacológico , Óxidos S-Cíclicos/uso terapéutico , Tiadiazinas/uso terapéutico , Anciano , Péptidos beta-Amiloides/análisis , Química Encefálica , Disfunción Cognitiva/patología , Óxidos S-Cíclicos/efectos adversos , Progresión de la Enfermedad , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Hipocampo/patología , Humanos , Análisis de Intención de Tratar , Imagen por Resonancia Magnética , Masculino , Tamaño de los Órganos , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones , Síntomas Prodrómicos , Tiadiazinas/efectos adversos , Insuficiencia del TratamientoRESUMEN
We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE-1 inhibitor verubecestat. Brain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic-associated Aß compared with a group of age-matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE-1 inhibition has an impact on synaptic soluble Aß accumulation and neuritic derangement in AD.
Asunto(s)
Enfermedad de Alzheimer , Tiadiazinas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Óxidos S-Cíclicos/uso terapéutico , Humanos , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/patología , Tiadiazinas/uso terapéuticoRESUMEN
BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Óxidos S-Cíclicos/uso terapéutico , Tiadiazinas/uso terapéutico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Química Encefálica/efectos de los fármacos , Cognición/efectos de los fármacos , Óxidos S-Cíclicos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tiadiazinas/efectos adversos , Insuficiencia del TratamientoRESUMEN
In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Encéfalo/diagnóstico por imagen , Óxidos S-Cíclicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Tiadiazinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Imagen de Difusión Tensora , Método Doble Ciego , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
HIGHLIGHTS: 2% taurolidine catheter lock solution without additives is safe and efficient. CRBSI and dysfunction rates compare favorably against other studies in hemodialysis. BACKGROUND: In hemodialysis patients, catheter-related bloodstream infection (CRBSI) and catheter dysfunction are common and cause significant morbidity, mortality, and costs. Catheter lock solutions reduce CRBSI and catheter dysfunction rates, but solutions containing heparin, citrate, or antibiotics are associated with adverse effects. Due to its antimicrobial and antithrombotic properties and benign safety profile, taurolidine is suitable for use in catheter lock solutions. In this study the effectiveness and safety of a catheter lock solution containing 2% taurolidine without citrate or heparin (TauroSept®, Geistlich Pharma AG, Wolhusen, Switzerland) in hemodialysis patients were investigated for the first time. METHODS: Data from 21 patients receiving chronic hemodialysis via tunneled central venous catheters with 2% taurolidine solution as a catheter lock were analyzed in a single-center retrospective study and compared with the existing literature in a review. The primary endpoint was CRBSI rate. Secondary endpoints included catheter dysfunction, treatment, and costs; catheter technical problems, resolution, and costs; and adverse events. Data were compared to outcomes with standard lock solutions in the literature. RESULTS: No CRBSIs occurred during the observation period of 5,639 catheter days. The catheter dysfunction rate was 0.71 per 1,000 catheter days, and the catheter dysfunction treatment costs were CHF (Swiss Franc) 543 per patient. No technical problems or adverse events related to the use of 2% taurolidine-containing catheter lock solution were observed. These results compare favorably with other catheter lock solutions. CONCLUSIONS: A solution containing 2% taurolidine seems suitable as a hemodialysis catheter lock. In a Swiss cohort, it prevented CRBSI, limited catheter dysfunction, and was cost-efficient.
Asunto(s)
Bacteriemia , Infecciones Relacionadas con Catéteres , Catéteres Venosos Centrales , Taurina/análogos & derivados , Tiadiazinas , Bacteriemia/etiología , Bacteriemia/prevención & control , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres Venosos Centrales/efectos adversos , Falla de Equipo , Humanos , Diálisis Renal/instrumentación , Estudios Retrospectivos , Suiza , Taurina/uso terapéutico , Tiadiazinas/uso terapéuticoRESUMEN
Candida auris is an emerging pathogen that can cause virulent central-line-associated bloodstream infections. Catheter salvage through the eradication of biofilms is a desirable therapeutic option. We compared taurolidine and minocycline-EDTA-ethanol (MEE) catheter lock solutions in vitro for the eradication of biofilms of 10 C. auris strains. MEE fully eradicated all C. auris biofilms, while taurolidine lock partially eradicated all of the C. auris biofilms. The superiority was significant for all C. auris strains tested (P = 0.002).
Asunto(s)
Biopelículas/efectos de los fármacos , Candida/efectos de los fármacos , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Ácido Edético/uso terapéutico , Etanol/uso terapéutico , Minociclina/uso terapéutico , Antibacterianos/uso terapéutico , Biopelículas/crecimiento & desarrollo , Candida/crecimiento & desarrollo , Candidiasis/tratamiento farmacológico , Candidiasis/prevención & control , Infecciones Relacionadas con Catéteres/prevención & control , Catéteres Venosos Centrales/efectos adversos , Catéteres Venosos Centrales/microbiología , Humanos , Taurina/análogos & derivados , Taurina/uso terapéutico , Tiadiazinas/uso terapéuticoRESUMEN
OBJECTIVE: To assess the efficacy and safety of Aß-targeting agents for mild to moderate Alzheimer's disease. METHODS: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses. RESULTS: Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aß drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I 2=99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aß clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aß production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aß drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit. DISCUSSION: From current evidence, anti-Aß interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aß clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42019126272.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Acitretina/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ansiedad/inducido químicamente , Azepinas/uso terapéutico , Clioquinol/análogos & derivados , Clioquinol/uso terapéutico , Cobre/uso terapéutico , Óxidos S-Cíclicos/uso terapéutico , Depresión/inducido químicamente , Diarrea/inducido químicamente , Exantema/inducido químicamente , Fatiga/inducido químicamente , Flurbiprofeno/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inositol/uso terapéutico , Pruebas de Estado Mental y Demencia , Diferencia Mínima Clínicamente Importante , Ácido Orótico/uso terapéutico , Oxadiazoles/uso terapéutico , Índice de Severidad de la Enfermedad , Sulfonamidas/uso terapéutico , Síncope/inducido químicamente , Tiadiazinas/uso terapéutico , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Óxidos S-Cíclicos/uso terapéutico , Imidazoles/uso terapéutico , Compuestos de Espiro/uso terapéutico , Tiadiazinas/uso terapéutico , Resultado del Tratamiento , Anciano , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-α and 11ß-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11ß-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11ß-HSD1 activity and expression.
Asunto(s)
Adamantano/análogos & derivados , Antioxidantes/uso terapéutico , Síndromes de Ojo Seco/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Tiadiazinas/uso terapéutico , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Antioxidantes/farmacología , Compuestos de Benzalconio/toxicidad , Conjuntiva/efectos de los fármacos , Conjuntiva/metabolismo , Síndromes de Ojo Seco/etiología , Síndromes de Ojo Seco/prevención & control , Inhibidores Enzimáticos/farmacología , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Tiadiazinas/farmacologíaRESUMEN
Catheter-related infections and dysfunction are the main catheter complications causing morbidity and mortality in hemodialysis patients. However, there are no consistent data for the choice of catheter lock solutions for tunneled hemodialysis lines. In this prospective, multicenter, randomized, controlled trial, two lock regimens using three commercial catheter lock solutions were compared in 106 hemodialysis patients with a newly inserted tunneled central catheter. In the taurolidine group, TauroLock™-Hep500 was used twice per week and TauroLock™-U25,000 once a week. In the citrate group, a four percent citrate solution was used after each dialysis. Both groups were compared regarding catheter-related infections, catheter dysfunction, and costs. Over a period of 15,690 catheter days, six catheter-related infections occurred in six of 52 patients in the taurolidine group, but 18 occurred in 13 of 54 patients in the citrate group, corresponding to 0.67 and 2.7 episodes of catheter-related infections per 1000 catheter days, respectively (Incidence Rate Ratio 0.25, 95% confidence interval, 0.09 to 0.63). Catheter dysfunction rates were significantly lower in the taurolidine group (18.7 vs. 44.3/1000 catheter days) and alteplase rescue significantly more frequent in the citrate group (9.8 vs. 3.8/1000 catheter days). These differences provided significant catheter-related cost savings of 43% in the taurolidine group vs. citrate group when overall expenses per patient and year were compared. Thus, use of taurolidine-based catheter lock solutions containing heparin and urokinase significantly reduced complications related to tunneled hemodialysis catheters when compared to four percent citrate solution and was overall more cost-efficient.
Asunto(s)
Antiinfecciosos/uso terapéutico , Obstrucción del Catéter , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/instrumentación , Catéteres de Permanencia , Catéteres Venosos Centrales , Diálisis Renal , Taurina/análogos & derivados , Tiadiazinas/uso terapéutico , Adulto , Anciano , Antiinfecciosos/efectos adversos , Antiinfecciosos/economía , Anticoagulantes/economía , Anticoagulantes/uso terapéutico , Austria , Obstrucción del Catéter/economía , Obstrucción del Catéter/etiología , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/economía , Infecciones Relacionadas con Catéteres/microbiología , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/economía , Catéteres de Permanencia/efectos adversos , Catéteres de Permanencia/economía , Catéteres Venosos Centrales/efectos adversos , Catéteres Venosos Centrales/economía , Ahorro de Costo , Análisis Costo-Beneficio , Costos de los Medicamentos , Diseño de Equipo , Falla de Equipo , Femenino , Fibrinolíticos/economía , Fibrinolíticos/uso terapéutico , Heparina/economía , Heparina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diálisis Renal/economía , Factores de Riesgo , Taurina/efectos adversos , Taurina/economía , Taurina/uso terapéutico , Tiadiazinas/efectos adversos , Tiadiazinas/economía , Factores de Tiempo , Resultado del Tratamiento , Activador de Plasminógeno de Tipo Uroquinasa/economía , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéuticoRESUMEN
Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. Neutrolin® (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of Neutrolin® use were reported. Two patients experienced occasional transient dysgeusia. Neutrolin®, when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls.
Asunto(s)
Antibacterianos/uso terapéutico , Citrato de Calcio/uso terapéutico , Infecciones Relacionadas con Catéteres , Catéteres Venosos Centrales , Heparina/uso terapéutico , Vigilancia de Productos Comercializados , Diálisis Renal , Taurina/análogos & derivados , Tiadiazinas/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Citrato de Calcio/administración & dosificación , Citrato de Calcio/efectos adversos , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/prevención & control , Combinación de Medicamentos , Alemania/epidemiología , Heparina/administración & dosificación , Heparina/efectos adversos , Humanos , Taurina/administración & dosificación , Taurina/efectos adversos , Taurina/uso terapéutico , Tiadiazinas/administración & dosificación , Tiadiazinas/efectos adversos , Trombosis/tratamiento farmacológico , Trombosis/epidemiología , Trombosis/prevención & controlRESUMEN
The Kv2.1 channel plays an important role in the regulation against pancreatic ß-cell dysfunctions. Therefore, it is regarded as a promising target for drug discovery against type 2 diabetes. In the present study, we found that the small molecule 4-ethoxy-N-{[6-(2-thienyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl]methyl}aniline (ETA), a novel Kv2.1 inhibitor, may be capable of promoting glucose-stimulated insulin secretion and protecting from apoptosis in pancreatic INS-832/13 cells. The assay of ETA on type 2 diabetic mice induced by high-fat diet (HFD)/streptozocin (STZ) confirmed its potency in ameliorating glucose homeostasis. ETA administration reduced fasting blood glucose and glycated haemoglobin levels, improved oral glucose tolerance, and increased serum insulin levels in HFD/STZ mice. Mechanism study demonstrated that ETA protected INS-832/13 cells involving the regulation against protein kinase B and extracellular-regulated protein kinase 1/2 signalling pathways. Our study has confirmed the underlying regulation of Kv2.1 against ß-cell function and also addressed the potential of ETA as a lead compound in the treatment of type 2 diabetes mellitus.
Asunto(s)
Hiperglucemia/tratamiento farmacológico , Hiperglucemia/patología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Shab/antagonistas & inhibidores , Tiadiazinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Hiperglucemia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Bloqueadores de los Canales de Potasio/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Canales de Potasio Shab/metabolismo , Transducción de Señal/efectos de los fármacos , Tiadiazinas/uso terapéuticoRESUMEN
Based on hypotheses concerning the role of stress in acute pancreatitis development, the experimental approach for the decrease stress damage via the use the compound with proven antistress/neuroleptic action was conducted. The study was aimed to discover 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide (compound L-17) therapeutic action in experimental acute pancreatitis. The experimental model used was the ligation model. The trial was carried out on 50 male Wistar rats with average body weight 180-240 g. Histological picture of the pancreas was studied and biochemical and enzyme-immunoassays were carried out on the first and seventh days. The significant reduction in mortality on the background of L-17 compound administration was observed. While levels of all cytokines increased in induced experimental acute pancreatitis groups, the cytokine level rise was decreased when compound L-17 was administered. On the cellular level, the study revealed L-17's ability to prevent granulocytosis and decrease granulocytes infiltration to inflammatory foci. The decrease in inflammatory reaction magnitude and prevention of abscess formation in experimental acute pancreatitis accompanied by sistemic inflamamtion was due to L-17's ability to reduce neutrophilia and neutrophil entry into the injury zone.
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Antidepresivos/farmacología , Pancreatitis/tratamiento farmacológico , Tiadiazinas/farmacología , Enfermedad Aguda , Animales , Antidepresivos/uso terapéutico , Recuento de Células , Citocinas/sangre , Modelos Animales de Enfermedad , Granulocitos/citología , Granulocitos/efectos de los fármacos , Ligadura/efectos adversos , Masculino , Monocitos/citología , Monocitos/efectos de los fármacos , Pancreatitis/sangre , Pancreatitis/inmunología , Pancreatitis/psicología , Ratas , Ratas Wistar , Tiadiazinas/uso terapéuticoRESUMEN
OBJECTIVES: The purpose of this study is to evaluate the activity of two different taurolidine (TAU) gels in comparison with a 0.2% chlorhexidine (CHX) gel on an ex vivo subgingival biofilm. MATERIAL AND METHODS: Subgingival including supragingival biofilm samples from periodontitis patients were cultured for 10 days, before TAU 1% and TAU 3% gels and CHX gel were applied for 10 min and thereafter diluted with nutrient media to 10% for 50 min. One third of the samples were analyzed for bacterial counts, biofilm quantity, and biofilm metabolic activity. In the two other thirds, 90% of the nutrient media were replaced and biofilms were incubated for 23 h. The second third was analyzed in the same way as before. In the third part, patients' microorganisms were added again and incubated for additional 24 h to allow reformation of biofilm before proceeding to analysis. RESULTS: Decrease of bacterial counts in biofilms was highest following application of TAU 3% after 60 min (0.87 log10 cfu, corresponding 86.5%), 24 and 48 h (reformation of biofilms), respectively. All antimicrobials reduced biofilm quantity after 24 h (each p < 0.05) and following reformation of biofilms (each p < 0.01). Metabolic activity in biofilms was decreased at 60 min (each p < 0.05) and at 24 h (each p < 0.01) after application of TAU gels, while the activity of the reformed biofilm was lower after application of all evaluated antimicrobials (each p < 0.01) than in the control group (e.g., without exposure to antimicrobials). CONCLUSION: The antimicrobial activity of taurolidine gels clearly depends on its taurolidine concentration. A high concentrated taurolidine gel is equally active or even superior to 0.2% chlorhexidine gel. However, the activity of antimicrobials is limited in a complex established biofilm and underlines the pivotal role of mechanical biofilm disruption. CLINICAL RELEVANCE: Within their limits, the data suggest that TAU 3% gel might represent a potential alternative to 0.2% chlorhexidine gel.
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Antiinfecciosos Locales/uso terapéutico , Biopelículas/efectos de los fármacos , Clorhexidina/uso terapéutico , Periodontitis/microbiología , Taurina/análogos & derivados , Tiadiazinas/uso terapéutico , Carga Bacteriana , Geles , Humanos , Técnicas In Vitro , Taurina/uso terapéutico , Resultado del TratamientoRESUMEN
This review focuses on the biological action of the compounds from the group of substituted 1,3,4-thiadiazines on stress response and myocardial infarction. The aim of this review is to propose the possible mechanisms of action of 1,3,4-thiadiazines and offer prospectives in the development of new derivatives as therapeutic agents. It is known, that compounds that have biological effects similar to those used as antidepressants can down-regulate the secretion of proinflammatory cytokines, up-regulate the release of anti-inflammatory ones and affect cell recruitment, which allows them to be considered immunomodulators as well. The results of pharmacological evaluation, in silico studies, and in vivo experiments of several compounds from the group of substituted 1,3,4-thiadiazines with antidepressant properties are presented. It is proposed that the cardioprotective effects of substituted 1,3,4-thiadiazines might be explained by the peculiarities of their multi-target action: the ability of the compounds to interact with various types of receptors and transporters of dopaminergic, serotonergic and acetylcholinergic systems and to block the kinase signal pathway PI3K-AKT. The described effects of substituted 1,3,4-thiadiazines suggest that it is necessary to search for a new agents for limiting the peripheral inflammatory/ischemic damage through the entral mechanisms of stress reaction and modifying pro-inflammatory cytokine signaling pathways in the brain.
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Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Tiadiazinas/farmacología , Tiadiazinas/uso terapéutico , Animales , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
INTRODUCTION: Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target ß-amyloid (Aß) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aß drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016. Expert opinion: Drugs in Phase III clinical development for AD include one inhibitor of the ß-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aß monoclonal antibodies (solanezumab, gantenerumab, and aducanumab), an inhibitor of receptor for advanced glycation end products (RAGE) (azeliragon) and the combination of cromolyn sodium and ibuprofen (ALZT-OP1). These drugs are mainly being tested in subjects during early phases of AD or in subjects at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The hope is to intervene in the disease process when it is not too late. However, previous clinical failures with anti-Aß drugs and the lack of fully understanding of the pathophysiological role of Aß in the development of AD, put the new drugs at substantial risk of failure.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos de los fármacos , Diseño de Fármacos , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Óxidos S-Cíclicos/farmacología , Óxidos S-Cíclicos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Tiadiazinas/farmacología , Tiadiazinas/uso terapéuticoRESUMEN
Mortality and morbidity are significantly higher among patients with dialysis catheters, which has been associated with chronic activation of the immune system. We hypothesized that bacteria colonizing the catheter lumen trigger an inflammatory response. We aimed to evaluate the inflammatory profile of hemodialysis patients before and after locking catheters with an antimicrobial lock solution. High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), IL-10, and tumor necrosis factor alpha (TNF-α) were measured in serum, and levels of mRNA gene expression of IL-6, IL-10, and TNF-α were analyzed in peripheral blood mononuclear cells (PBMC). Samples were obtained at baseline and again after 3 months' use of taurolidine-citrate-heparin lock solution (TCHLS) in 31 hemodialysis patients. The rate of catheter-related bloodstream infections (CRBSI) was 1.08 per 1,000 catheter-days in the heparin period and 0.04 in the TCHLS period (P = 0.023). Compared with the baseline data, serum levels of hs-CRP and IL-6 showed median percent reductions of 18.1% and 25.2%, respectively (P < 0.01), without significant changes in TNF-α or IL-10 levels. Regarding cytokine gene expression in PBMC, the median mRNA expression levels of TNF-α and IL-6 decreased by 20% (P < 0.05) and 19.7% (P = 0.01), respectively, without changes in IL-10 expression levels. The use of TCHLS to maintain the catheter lumen sterility significantly reduces the incidence of CRBSI and improves the inflammatory profile in hemodialysis patients with tunneled catheters. Further studies are needed to evaluate the potential beneficial effects on clinical outcomes.
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Infecciones Relacionadas con Catéteres/prevención & control , Catéteres Venosos Centrales/microbiología , Ácido Cítrico/uso terapéutico , Heparina/uso terapéutico , Taurina/análogos & derivados , Tiadiazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Anticoagulantes , Proteína C-Reactiva/análisis , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Interleucina-10/sangre , Interleucina-10/genética , Interleucina-6/sangre , Interleucina-6/genética , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , Diálisis Renal/efectos adversos , Diálisis Renal/métodos , Diálisis Renal/mortalidad , Taurina/uso terapéutico , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: Preliminary evidence from some studies suggests that taurolidine-citrate locks decrease catheter-related bacteremia (CRB), which is a major cause of morbidity and mortality in patients using intravascular catheters. No previous study has sought to summarize existing evidence on the use of taurolidine-citrate locks. A systematic review and meta-analysis were undertaken to determine whether taurolidine-citrate was more effective than heparin in the prevention of CRB. METHODS: The major English (PubMed, EBSCO, Web of Science and OVID) and Chinese (CBM, CNKI, VIP and Wanfang Data) healthcare databases were searched for randomized controlled trials comparing the efficacy and safety of taurolidine-citrate lock solution (TCLS) and heparin lock solution in the prevention of CRB. RESULTS: Three studies involving 236 patients with a total of 34,984 catheter days were included. The use of TCLS significantly decreased the risk of CRB (relative risk = 0.47, 95% CI: 0.25-0.89) and Gram-negative bacterial infection. There was no significant difference in Gram-positive infections and exit-site infections. CONCLUSIONS: Catheter locking with TCLS reduced the risk of CRB and Gram-negative bacterial infection. Adverse events include thrombotic events.
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Antiinfecciosos/uso terapéutico , Anticoagulantes/uso terapéutico , Bacteriemia/prevención & control , Ácido Cítrico/uso terapéutico , Taurina/análogos & derivados , Tiadiazinas/uso terapéutico , Dispositivos de Acceso Vascular/efectos adversos , Bacteriemia/etiología , Femenino , Humanos , Masculino , PubMed , Taurina/uso terapéutico , Dispositivos de Acceso Vascular/microbiologíaRESUMEN
Introduction: Objectives: the prevention of central line-associated bloodstream infections is a critical aspect of care for patients with intestinal failure who are treated with parenteral nutrition. The use of taurolidine in this context is becoming increasingly popular, however there is a lack of standardization in its pediatric application. The objective of this work is to develop a guide to support its prescription. Methodology: the guide is based on a review of the literature and expert opinions from the Intestinal Failure Group of the SEGHNP. It was developed through a survey distributed to all its members, addressing aspects of usual practice with this lock solution. Results: this manuscript presents general recommendations concerning taurolidine indications, commercial presentations, appropriate forms of administration, use in special situations, adverse reactions, and contraindications in the pediatric population Conclusions: taurolidine is emerging as the primary lock solution used to prevent central line-associated bloodstream infections, proving to be safe and effective. This guide aims to optimize and standardize its use in pediatrics.
Introducción: Objetivo: la prevención de las infecciones asociadas a catéter ocupa un papel fundamental en los cuidados del paciente en situación de fracaso intestinal en tratamiento con nutrición parenteral. El empleo del sellado del catéter con taurolidina con ese fin se ha generalizado sin que exista una estandarización sobre su uso en población pediátrica. El objetivo de este trabajo es elaborar una guía clínica que sirva de apoyo en su utilización. Métodos: la guía se basa en una revisión de la literatura y en la opinión de expertos del Grupo de Trabajo de Fracaso Intestinal de la SEGHNP recogida a través de una encuesta realizada a todos sus integrantes sobre aspectos de la práctica habitual con este sellado. Resultados: este manuscrito expone unas recomendaciones en cuanto a las indicaciones, presentaciones comerciales disponibles, forma adecuada de administración, uso en situaciones especiales, reacciones adversas y contraindicaciones de la taurolidina en población pediátrica. Conclusiones: el sellado con taurolidina para la prevención de la infección asociada a catéter venoso central se ha mostrado como un tratamiento eficaz y seguro. La presente guía pretender optimizar y homogeneizar su uso en pediatría.
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Insuficiencia Intestinal , Nutrición Parenteral , Taurina , Tiadiazinas , Humanos , Tiadiazinas/uso terapéutico , Tiadiazinas/efectos adversos , Niño , Taurina/análogos & derivados , Taurina/uso terapéutico , Nutrición Parenteral/normas , Nutrición Parenteral/métodos , Insuficiencia Intestinal/terapia , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/efectos adversos , Antiinfecciosos/uso terapéutico , Lactante , PreescolarRESUMEN
Background: Osteosarcoma is the most common malignant primary bone tumor. The prognosis for patients with disseminated disease remains very poor despite recent advancements in chemotherapy. Moreover, current treatment regimens bear a significant risk of serious side effects. Thus, there is an unmet clinical need for effective therapies with improved safety profiles. Taurolidine is an antibacterial agent that has been shown to induce cell death in different types of cancer cell lines. Methods: In this study, we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma. K7M2 murine osteosarcoma cells were injected, both intramuscular and intraperitoneal, into 60 BALB/c mice on day zero. Animals were then randomized to receive treatment with taurolidine 2% (800 mg/kg), taurolidine 1% (400 mg/kg), or NaCl 0.9% control for seven days by intravenous or intraperitoneal administration. Results: After 35 days, mice were euthanized, and the tumors were harvested for analysis. Eighteen mice were excluded from the analysis due to complications. Body weight was significantly lower in the 2% taurolidine intraperitoneal treatment group from day 9 to 21, consistent with elevated mortality in this group. Intraperitoneal tumor weight was significantly lower in the 1% (p = 0.003) and 2% (p = 0.006) intraperitoneal taurolidine treatment groups compared to the control. No antineoplastic effects were observed on intramuscular tumors or for intravenous administration of taurolidine. There were no significant differences in microvessel density or mitotic rate between treatment groups. Reduced body weight and elevated mortality in the 2% taurolidine intraperitoneal group suggest that the lower 1% dose is preferable. Conclusions: In conclusion, there is no evidence of antiangiogenic activity, and the antitumor effects of taurolidine on osteosarcoma observed in this study are limited. Moreover, its toxic profile grants further evaluation. Given these observations, further research is necessary to refine the use of taurolidine in osteosarcoma treatment.