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1.
Gene ; 722: 144057, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31430519

RESUMEN

OBJECTIVE: Fork head domain-containing transcription factor family (FOX), is comprised of >20 members. Members of FOX family have been implicated in a wide range of physiological and/or diseased conditions. Many of FOX members have been shown to be involved in tumorigenesis and progression. The potential roles in carcinogenesis of FOXN4, a member as one of the vast FOX family, remains relatively unknown. METHOD: Here, we explored the potential involvement of FOXN4 in breast cancer. RESULTS: First, observed that a higher FOXN4 was identified in the normal adjacent breast tissue as compared to that in the breast cancer samples; an increased FOXN4 level was associated with a better prognosis in patients with breast cancer. In addition, ectopically expression of FOXN4 led to the decreased cell proliferation, reduced colony formation and metastatic abilities (EMT, migration and invasion) in breast cancer cell lines. Furthermore, we showed the direct interaction between FOXN4 and TP53 and FOXN4 binding led to the increased activity of TP53. Silencing FOXN4 led to reduced TP53 and increased expression of Dll4, Notch and survivin, providing a link between FOXN4 and Notch signaling. Finally, we used patient-derived xenograft mouse model to demonstrate the tumor inhibitory effects of Notch-inhibitor, PF-3084014. We found that PF-3084014 treatment led to a significantly smaller tumor burden and higher survival ratio in patient-derived xenograft mice as compared to the vehicle. This tumor suppressive effect was accompanied by the increased expression of TP53, FOXN4 and decreased Dll4 and Notch. CONCLUSION: Collectively, our data strongly suggested the tumor suppressive roles of FOXN4 in breast tumorigenesis via the activation of TP53 while suppressing Notch signaling. Future studies are warranted to explore the clinical application of PF-3084104 (Notch inhibitor) for the treatment of breast cancer patients.


Asunto(s)
Neoplasias de la Mama/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Metástasis de la Neoplasia , Pronóstico , Receptores Notch/antagonistas & inhibidores , Receptores Notch/metabolismo , Transducción de Señal , Tetrahidronaftalenos/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Valina/análogos & derivados , Valina/uso terapéutico
2.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-31540372

RESUMEN

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy metabolism, and chronic oxidative stress. Likewise, the blood-brain barrier (BBB) dysfunction is suggested to be a cause and AD consequence. Accordingly, therapeutic targeting of the compromised BBB is a promising disease-modifying approach. We utilized a homozygous triple-transgenic mouse model of AD (3×Tg-AD) to assess the effects of L-norvaline on BBB integrity. We scrutinized the perivascular astrocytes and macrophages by measuring the immunopositive profiles in relation to the presence of ß-amyloid and compare the results with those found in wild-type animals. Typically, 3×Tg-AD mice display astroglia cytoskeletal atrophy, associated with the deposition of ß-amyloid in the endothelia, and declining nitric oxide synthase (NOS) levels. L-norvaline escalated NOS levels, then reduced rates of BBB permeability, amyloid angiopathy, microgliosis, and astrodegeneration, which suggests AD treatment agent efficacy. Moreover, results undergird the roles of astrodegeneration and microgliosis in AD-associated BBB dysfunction and progressive cognitive impairment. L-norvaline self-evidently interferes with AD pathogenesis and presents a potent remedy for angiopathies and neurodegenerative disorders intervention.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Barrera Hematoencefálica/efectos de los fármacos , Valina/análogos & derivados , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Angiopatía Amiloide Cerebral/patología , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Valina/uso terapéutico
3.
J Psychosoc Nurs Ment Health Serv ; 57(5): 11-14, 2019 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31042295

RESUMEN

Tardive dyskinesia (TD), the choreoathetoid movements of fingers, arms, legs, and trunk and irregular stereotypical movements of the mouth, face, and tongue, has been the scourge of antipsychotic medications since the approval of chlorpromazine. TD tends to occur late in treatment and sometimes remains after discontinuation of the antipsychotic medication. With the recent approval of two medications, valbenazine (Ingrezza®) and deutetrabenazine (Austedo®), there are now treatments for this disfiguring consequence of dopamine-blocking medications. The current article distinguishes the movement disorder adverse effects of dopamine antagonists, explains the putative mechanism of action, and describes how best to treat TD with the new vesicular monamine transporter 2 (VMAT2) medications now approved by the U.S. Food and Drug Administration. [Journal of Psychosocial Nursing and Mental Health Services, 57(5), 11-14.].


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Discinesia Tardía/tratamiento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/uso terapéutico , Clorpromazina/uso terapéutico , Humanos , Enfermería Psiquiátrica , Tetrabenazina/farmacología , Tetrabenazina/uso terapéutico , Valina/farmacología , Valina/uso terapéutico
4.
Clin Neuropharmacol ; 42(2): 37-41, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30870235

RESUMEN

OBJECTIVES: The aim of this study was to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine (TBZ), deutetrabenazine (DTBZ), and valbenazine (VBZ) for treatment of hyperkinetic movement disorders. Access and adherence to VMAT2 inhibitors may be limited by insurance and regulatory issues, inexperience with their use by the prescribing physician, lack of efficacy, or side effects. METHODS: We performed a retrospective chart review, supplemented with a questionnaire, of all our patients treated with a VMAT2 inhibitor between January 1, 2017, and August 30, 2018. RESULTS: We identified 135 patients (57.8% male) and 178 prescriptions for VMAT2 inhibitors (TBZ, n = 45 [25.3%]; DTBZ, n = 104 [58.4%]; VBZ, n = 29 [16.3%]). Tourette syndrome/tics was the most common diagnosis (n = 67 [49.6%]) for which VMAT2 inhibitors were prescribed. The VMAT2 inhibitor mean treatment durations (range; SD) and daily dosages (range; SD) were as follows: TBZ (n = 31), 5.1 months (1-19; 3.9) at 48.8 mg (12.5-112.5; 29.6); DTBZ (n = 51), 8.0 months (0.25-16.5; 4.4) at 34.4 mg (6-96; 20.7); and VBZ (n = 20), 6.0 months (0.1-16; 5.6) at 64 mg (40-160; 35.3). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1- to 4-point Likert scale (1 = normal or mildly ill, 4 = severely ill) comparing illness severity before starting and while on treatment (score of 1 in 13.0%-26.7% vs 60.9%-71.9% of patients). Side effects were mild and improved or resolved following dose reduction, drug cessation, or addition of adjunctive medications. CONCLUSIONS: The VMAT2 inhibitors are effective and safe in a range of hyperkinetic movement disorders but are not readily accessible by patients in the United States for indications not approved by the Food and Drug Administration.


Asunto(s)
Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapéutico , Tics/tratamiento farmacológico , Síndrome de Tourette/tratamiento farmacológico , Valina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tetrabenazina/farmacología , Tics/diagnóstico , Síndrome de Tourette/diagnóstico , Valina/farmacología , Valina/uso terapéutico , Adulto Joven
5.
Rheumatology (Oxford) ; 58(Suppl 1): i27-i33, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30806706

RESUMEN

Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Azetidinas/uso terapéutico , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Piperidinas/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Triazoles/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico
6.
J Affect Disord ; 246: 217-223, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30583148

RESUMEN

BACKGROUND: Few studies have assessed the treatment of tardive dyskinesia (TD) in patients with primary mood disorders who are managed with antipsychotics. The effects of once-daily valbenazine on TD were evaluated in adults with a bipolar or depressive disorder. METHODS: Data were pooled from two 6-week double-blind placebo-controlled trials (KINECT 2 and KINECT 3; 114 mood participants) and a long-term blinded extension study (KINECT 3 extension; 77 mood participants) of valbenazine in adults with TD. Efficacy assessments included Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7), Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and Patient Global Impression of Change (PGIC). Safety assessments included treatment-emergent adverse events (TEAEs), Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale. RESULTS: At Week 6, mean improvements in AIMS total score were significantly greater with valbenazine versus placebo (40 mg/day, -3.1 [P < 0.01]; 80 mg/day, -3.5 [P < 0.001]; placebo, -0.9). Significant differences between valbenazine (80 mg/day) and placebo were also found for Week 6 AIMS response (≥50% total score improvement) and CGI-TD response ("much improved" or "very much improved"), but not PGIC response. Sustained improvements in AIMS, CGI-TD, and PGIC were found through 48 weeks. Valbenazine was generally well tolerated, with no unexpected TEAEs, worsening in psychiatric symptoms, or emergence of suicidality. LIMITATIONS: Pooled analyses were conducted post hoc, and neither study was designed to focus solely on mood disorder patients. CONCLUSIONS: In participants with primary mood disorders, once-daily treatment with valbenazine was generally well tolerated and resulted in 6-week and sustained TD improvements.


Asunto(s)
Trastornos del Humor/tratamiento farmacológico , Discinesia Tardía/tratamiento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/complicaciones , Discinesia Tardía/inducido químicamente , Discinesia Tardía/complicaciones , Tetrabenazina/efectos adversos , Tetrabenazina/uso terapéutico , Valina/efectos adversos , Valina/uso terapéutico
7.
Bull Exp Biol Med ; 166(1): 1-6, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30417305

RESUMEN

We studied the participation of DNA-methylation processes in the mechanisms of memory storage and reconsolidation, amnesia induction, and in recovery of the conditioned food aversion memory in edible snails. It was found that daily injections of DNA methyltransferases inhibitor over 3 days combined with a reminder of a conditioned food stimulus did not affect memory storage. The administration of DNA methyltransferase inhibitors did not suppress induction of amnesia caused the NMDA receptor antagonist/reminder. Injections of DNA methyltransferase inhibitors combined with the reminder led to memory recovery in 3 days after amnesia induction. Thus, DNA methyltransferase inhibitors in the same doses did not affect storage and reconsolidation of memory, as well as the mechanisms of amnesia induction. At the same time, injections of inhibitors led to memory recovery, apparently, due to disruption of reactivation and amnesia development.


Asunto(s)
Metilasas de Modificación del ADN/metabolismo , Memoria/efectos de los fármacos , Ftalimidas/farmacología , Triptófano/análogos & derivados , Valina/análogos & derivados , Amnesia/tratamiento farmacológico , Amnesia/enzimología , Amnesia/prevención & control , Animales , Metilasas de Modificación del ADN/antagonistas & inhibidores , Ftalimidas/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Triptófano/farmacología , Triptófano/uso terapéutico , Valina/farmacología , Valina/uso terapéutico
8.
Drugs Aging ; 35(11): 959-971, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30357723

RESUMEN

Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are iatrogenic consequences of antidopaminergic drugs. Both are particularly prevalent among the elderly and those with dementia. However, despite their prevalence, these disorders are often overlooked. Both entities share risk factors, physiopathological mechanisms and, to some degree, therapeutic approaches. Withdrawing the causal agent, reducing the dose or switching to a less potent antidopaminergic drug should be the first therapeutic options. Here we review both entities and emerging therapies including the recently approved drugs deutetrabenazine and valbenazine. We discuss relevant aspects for clinical practice such as new diagnostic techniques and the latest advances in the understanding of DIP and TD.


Asunto(s)
Discinesia Inducida por Medicamentos/terapia , Trastornos Parkinsonianos/inducido químicamente , Discinesia Tardía/inducido químicamente , Anciano , Demencia/tratamiento farmacológico , Humanos , Factores de Riesgo , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico
9.
Neurotherapeutics ; 15(4): 1036-1054, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30288668

RESUMEN

The urea cycle is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (Aß) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase ß-1 (S6K1) pathways promotes inflammation and oxidative stress. In this study, we treated triple-transgenic (3×Tg) mice exhibiting increased S6K1 activity and wild-type (WT) mice with L-norvaline, which inhibits both arginase and S6K1. The acquisition of spatial memory was significantly improved in the treated 3×Tg mice, and the improvement was associated with a substantial reduction in microgliosis. In these mice, increases in the density of dendritic spines and expression levels of neuroplasticity-related proteins were followed by a decline in the levels of Aß toxic oligomeric and fibrillar species in the hippocampus. The findings point to an association of local Aß-driven and immune-mediated responses with altered L-arginine metabolism, and they suggest that arginase and S6K1 inhibition by L-norvaline may delay the progression of AD.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Valina/análogos & derivados , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Arginasa/metabolismo , Proteínas de Unión al Calcio/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/ultraestructura , Trastornos del Conocimiento/patología , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Microglía/patología , Mutación/genética , Neuronas/efectos de los fármacos , Neuronas/patología , Presenilina-1/genética , Valina/uso terapéutico , Proteínas tau/genética
10.
CNS Drugs ; 32(12): 1131-1144, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30306450

RESUMEN

The basal ganglia and dopaminergic pathways play a central role in hyperkinetic movement disorders. Vesicular monoamine transporter 2 (VMAT2) inhibitors, which deplete dopamine at presynaptic striatal nerve terminals, are a class of drugs that have long been used to treat hyperkinetic movement disorders, but have recently gained more attention following their development for specific indications in the United States. At present, there are three commercially available VMAT2 inhibitors: tetrabenazine, deutetrabenazine, and valbenazine. Pharmacokinetics, metabolism, and dosing vary significantly between the three drugs, and likely underlie the more favorable side effect profile of the newer agents (deutetrabenazine and valbenazine). Tetrabenazine and deutetrabenazine have demonstrated safety and efficacy in the treatment of chorea associated with Huntington's disease, including in randomized controlled trials, although direct comparison studies are limited. Both deutetrabenazine and valbenazine have demonstrated safety and efficacy in the treatment of tardive dyskinesia, with multiple double-blind, placebo-controlled trials, whereas tetrabenazine has been studied less rigorously. There have been no blinded, prospective trials with tetrabenazine in Tourette's syndrome (TS); however, double-blind, placebo-controlled trials in TS are ongoing for both deutetrabenazine and valbenazine. Given the favored side effect profile of newer VMAT2 inhibitors, clinicians should be aware of the distinctions between agents and become familiar with differences in their use, especially as there is potential for their utilization to increase across the range of hyperkinetic movement disorders.


Asunto(s)
Antipsicóticos/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Trastornos del Movimiento/tratamiento farmacológico , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Ganglios Basales/patología , Humanos , Trastornos Mentales/patología , Tetrabenazina/análogos & derivados , Tetrabenazina/química , Tetrabenazina/uso terapéutico , Valina/análogos & derivados , Valina/química , Valina/uso terapéutico
12.
Proc Natl Acad Sci U S A ; 115(38): 9616-9621, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30185555

RESUMEN

African trypanosomes cause lethal and neglected tropical diseases, known as sleeping sickness in humans and nagana in animals. Current therapies are limited, but fortunately, promising therapies are in advanced clinical and veterinary development, including acoziborole (AN5568 or SCYX-7158) and AN11736, respectively. These benzoxaboroles will likely be key to the World Health Organization's target of disease control by 2030. Their mode of action was previously unknown. We have developed a high-coverage overexpression library and use it here to explore drug mode of action in Trypanosoma brucei Initially, an inhibitor with a known target was used to select for drug resistance and to test massive parallel library screening and genome-wide mapping; this effectively identified the known target and validated the approach. Subsequently, the overexpression screening approach was used to identify the target of the benzoxaboroles, Cleavage and Polyadenylation Specificity Factor 3 (CPSF3, Tb927.4.1340). We validated the CPSF3 endonuclease as the target, using independent overexpression strains. Knockdown provided genetic validation of CPSF3 as essential, and GFP tagging confirmed the expected nuclear localization. Molecular docking and CRISPR-Cas9-based editing demonstrated how acoziborole can specifically block the active site and mRNA processing by parasite, but not host CPSF3. Thus, our findings provide both genetic and chemical validation for CPSF3 as an important drug target in trypanosomes and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal benzoxaboroles. Understanding the mechanism of action of benzoxaborole-based therapies can assist development of improved therapies, as well as the prediction and monitoring of resistance, if or when it arises.


Asunto(s)
Factor de Especificidad de Desdoblamiento y Poliadenilación/antagonistas & inhibidores , Proteínas Protozoarias/antagonistas & inhibidores , Tripanocidas/farmacología , Trypanosoma brucei brucei/fisiología , Tripanosomiasis Africana/prevención & control , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Sistemas CRISPR-Cas , Núcleo Celular/genética , Núcleo Celular/metabolismo , Factor de Especificidad de Desdoblamiento y Poliadenilación/genética , Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/genética , Técnicas de Silenciamiento del Gen , Biblioteca de Genes , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Simulación del Acoplamiento Molecular , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Procesamiento Postranscripcional del ARN/efectos de los fármacos , ARN Mensajero/metabolismo , ARN Protozoario/metabolismo , Tripanocidas/uso terapéutico , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis Africana/transmisión , Tripanosomiasis Africana/veterinaria , Valina/análogos & derivados , Valina/farmacología , Valina/uso terapéutico
13.
CNS Drugs ; 32(9): 849-861, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30076539

RESUMEN

BACKGROUND: ALZ-801 is an oral, small-molecule inhibitor of beta amyloid (Aß) oligomer formation in clinical development for Alzheimer's disease (AD). ALZ-801 is a prodrug of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. During clinical studies, we discovered that the primary metabolite of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule in the human brain and present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases. OBJECTIVE: The objectives of this research were to (1) identify and confirm the presence of 3-SPA in CSF samples from elderly, drug-naïve patients with memory deficits; (2) quantify the levels of 3-SPA in the CSF of patients with AD from tramiprosate phase III North American (NA) trial; (3) evaluate the in vitro anti-Aß42 oligomer activity of 3-SPA; and (4) characterize the pharmacokinetics and brain-penetration properties of 3-SPA. METHODS: Lumbar CSF samples from 64 drug-naïve patients with cognitive deficits (Mini-Mental State Examination [MMSE] score range 15-30) and six patients with AD treated with tramiprosate 150 mg twice daily in the phase III trial, at week 78, were analyzed. We used liquid chromatography-tandem mass spectrometry to confirm the structural molecular identity of endogenous 3-SPA with a 3-SPA reference standard and ion-mobility spectrometry-mass spectrometry with molecular dynamics to characterize interactions of 3-SPA with Aß42 monomers, and the resultant conformational alterations. Rat studies using oral (30 mg/kg) and intravenous (10 mg/kg) doses were conducted to characterize the pharmacokinetic properties and brain penetration of 3-SPA. RESULTS: We confirmed the presence of 3-SPA in the CSF of drug-naïve patients with cognitive deficits (mean concentration 11.7 ± 4.3 nM). The mean concentration of 3-SPA in patients with AD treated with tramiprosate was 135 ± 51 nM. In vitro studies revealed a multi-ligand interaction of 3-SPA with monomeric Aß42 that inhibits the aggregation of Aß42 into small oligomers. Comparisons of the molecular interactions of tramiprosate and 3-SPA with Aß42 are also presented. Furthermore, in rat preclinical studies, 3-SPA displayed 100% oral bioavailability and 25% brain penetration, indicating that the metabolite is well absorbed and crosses the blood-brain barrier. CONCLUSIONS: We confirmed the endogenous presence of 3-SPA, the major metabolite of tramiprosate, in the CSF of drug-naïve elderly patients with memory deficits due to AD and a variety of other neurodegenerative disorders. The levels of 3-SPA were up to 12.6-fold greater in patients with AD receiving tramiprosate than in drug-naïve patients. In addition, we showed that 3-SPA has potent anti-Aß oligomer activity, inhibiting aggregation of Aß42 into small oligomers with efficacy comparable to that of tramiprosate. 3-SPA displays excellent oral availability and brain penetration in rats, suggesting that the higher CSF concentrations of 3-SPA in the human brain after oral administration of ALZ-801 or tramiprosate (and subsequent conversion to 3-SPA) result from the penetration of the metabolite into the central nervous system. These data suggest that 3-SPA is an endogenous agent with potential activity stabilizing the conformational flexibility of Aß monomers that, in turn, inhibit Aß misfolding and formation of soluble toxic Aß oligomers in humans, thereby preventing the initial pathogenic step in the progression of AD. Clinical improvements observed in patients with AD carrying the ε4 allele of the apolipoprotein E gene in tramiprosate phase III studies may in part be explained by the therapeutic effects of excess levels of the metabolite in the brains of these patients. The potential protective role of 3-SPA in AD pathogenesis, as well as its therapeutic role in AD and other neurodegenerative disorders, warrants further investigation.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Taurina/análogos & derivados , Valina/análogos & derivados , Anciano , Enfermedad de Alzheimer/complicaciones , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Liquida , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/etiología , Simulación por Computador , Vías de Administración de Medicamentos , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Modelos Químicos , Dinámicas no Lineales , Profármacos/química , Profármacos/uso terapéutico , Propionatos/líquido cefalorraquídeo , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Taurina/líquido cefalorraquídeo , Taurina/química , Taurina/uso terapéutico , Valina/química , Valina/uso terapéutico
15.
Ear Nose Throat J ; 97(4-5): E1-E4, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29940684

RESUMEN

We conducted a prospective study to investigate the effectiveness of pharmacologic treatment on alleviating facial paralysis, as well as the anxiety and depression that are associated with it. Our study population was made up of 105 patients-59 men and 46 women, aged 18 to 60 years (mean: 38.2)-who had acute idiopathic peripheral facial paralysis. Before treatment, paralysis was classified as House-Brackmann grade II or III in 44 patients (41.9%) and grade IV to VI in the remaining 61 (58.1%). After treatment, 73 patients (69.5%) improved to grade I, 29 (27.6%) were at grade II or III, and only 3 (2.9%) remained at grade IV or higher. Mean scores on the Beck anxiety inventory, the Beck depression inventory, and the Beck hopelessness scale were 20.30, 19.75, and 7.57, respectively, before treatment and 5.72, 5.68, and 2.85 afterward; the difference in all three measures was statistically significant (p < 0.001). We found no correlation between the degree of facial paralysis and anxiety levels (r = 0.094, p = 0.338) or depression levels (r = 0.181, p = 0.064). Clinicians should consider asking patients with peripheral facial paralysis about their feelings of anxiety, depression, and hopelessness and refer them for a psychiatric consultation if necessary.


Asunto(s)
Antivirales/uso terapéutico , Ansiedad/etiología , Depresión/etiología , Parálisis Facial/psicología , Glucocorticoides/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Aciclovir/análogos & derivados , Aciclovir/uso terapéutico , Adolescente , Adulto , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Parálisis Facial/tratamiento farmacológico , Femenino , Esperanza , Humanos , Lansoprazol/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Valaciclovir , Valina/análogos & derivados , Valina/uso terapéutico , Adulto Joven
17.
Consult Pharm ; 33(4): 188-198, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29609697

RESUMEN

Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide.


Asunto(s)
Aprobación de Drogas , Anciano , Alanina/análogos & derivados , Alanina/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticoagulantes/uso terapéutico , Antiparkinsonianos/uso terapéutico , Benzamidas/uso terapéutico , Bencilaminas/uso terapéutico , Estreñimiento/tratamiento farmacológico , Humanos , Péptidos Natriuréticos/uso terapéutico , Psoriasis/tratamiento farmacológico , Piridinas/uso terapéutico , Discinesia Tardía/tratamiento farmacológico , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico
18.
Consult Pharm ; 33(4): 201-209, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29609698

RESUMEN

OBJECTIVE: To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments. DATA SOURCES: PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data. STUDY SELECTION/DATA EXTRACTION: Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017. DATA SYNTHESIS: This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017. CONCLUSION: TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.


Asunto(s)
Aprobación de Drogas , Discinesia Tardía/tratamiento farmacológico , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Humanos , Guías de Práctica Clínica como Asunto , Discinesia Tardía/fisiopatología , Tetrabenazina/efectos adversos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacología , Tetrabenazina/uso terapéutico , Estados Unidos , United States Food and Drug Administration , Valina/efectos adversos , Valina/análogos & derivados , Valina/farmacología , Valina/uso terapéutico
19.
Acta Oncol ; 57(9): 1216-1224, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29630428

RESUMEN

BACKGROUND: Earlier in vitro studies show that irradiation with an ultra-low dose-rate of 15 mGy/h delivered with [3H]-valine leads to loss of clonogenicity in hypoxic T-47D cells. Here, the aim was to determine if [3H]-valine could be used to deliver low dose-rate irradiation in a colorectal cancer model. METHODS: Clonogenicity was measured in cultured cancer cell line HT29 irradiated with 15 mGy/h combined with intermittent hypoxia. Mice with HT29 xenografts were irradiated by repeated injections of [3H]-valine intravenously. The activity in the tumor tissue was measured by scintillation counting and tumor growth, hypoxic fraction and tritium distribution within tumors were assessed by pimonidazole staining and autoradiography. RESULTS: Ultra-low dose-rate irradiation decreased clonogenicity in hypoxic colorectal cancer cells. In vivo, the tumor growth, hypoxic fraction and weight of the mice were similar between the treated and untreated group. Autoradiography showed no [3H]-valine uptake in hypoxic tumor regions in contrast to aerobic tissue. CONCLUSION: Continuous low-dose-rate irradiation was well tolerated by aerobic tissue. This indicates a potential use of low dose-rate irradiation to target hypoxic tumor cells in combination with high dose-rate irradiation to eradicate the well oxygenated tumor regions. However, [3H]-valine is not the appropriate method to deliver ultra-low dose-rate irradiation in vivo.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Tritio/uso terapéutico , Hipoxia Tumoral/efectos de la radiación , Valina/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Células HT29 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Dosificación Radioterapéutica , Valina/química , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Cochrane Database Syst Rev ; 3: CD000208, 2018 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-29552749

RESUMEN

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere. OBJECTIVES: To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. AUTHORS' CONCLUSIONS: This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.


Asunto(s)
Discinesia Inducida por Medicamentos/terapia , Inhibidores de Captación Adrenérgica/uso terapéutico , Adulto , Ansiolíticos/uso terapéutico , Antipsicóticos/efectos adversos , Dihidroergotoxina/uso terapéutico , Discinesia Inducida por Medicamentos/etiología , Humanos , Hipnosis , Extractos Vegetales , Ensayos Clínicos Controlados Aleatorios como Asunto , Terapia por Relajación , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapéutico , Valina/análogos & derivados , Valina/uso terapéutico
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