RESUMEN
We present a case of a primigravida in her 30s who had a caesarean delivery of dichorionic diamniotic twins at 33 weeks of gestation. Her postpartum course was complicated by a herpes simplex virus (HSV) infection of her nipple, found after her neonates were diagnosed with HSV encephalitis. She was evaluated at her 3-week postpartum visit and reported that her neonates were concurrently admitted to the neonatal intensive care unit with disseminated neonatal HSV-1. The patient and her partner were in a monogamous relationship with no known history of HSV. Physical examination demonstrated a vertical fissure on the face of her right nipple and a small cluster of vesicles on her left hand. PCR swabs of the lesions were positive for HSV-1 at both locations. The patient was started on oral valacyclovir 1000 mg two times per day, topical acyclovir ointment applied 4-6 times per day and mupirocin ointment applied 3 times per day to her breast with resolution of her breast lesions. She was able to continue expressing her breastmilk with the help of a pump and then resumed breastfeeding once her infection was cleared. Her infants recovered after prolonged parenteral antiviral therapy with age-appropriate development at follow-up.
Asunto(s)
Aciclovir , Antivirales , Encefalitis por Herpes Simple , Herpes Simple , Herpesvirus Humano 1 , Pezones , Humanos , Femenino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Recién Nacido , Aciclovir/uso terapéutico , Aciclovir/administración & dosificación , Herpes Simple/diagnóstico , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/aislamiento & purificación , Encefalitis por Herpes Simple/diagnóstico , Encefalitis por Herpes Simple/tratamiento farmacológico , Valaciclovir/uso terapéutico , Valaciclovir/administración & dosificación , Complicaciones Infecciosas del Embarazo/diagnóstico , Adulto , Embarazo , Transmisión Vertical de Enfermedad Infecciosa , Valina/análogos & derivados , Valina/uso terapéutico , Valina/administración & dosificación , Lactancia MaternaRESUMEN
Central administration of valine has been shown to cause hyperphagia in fish. Although mechanistic target of rapamycin (mTOR) is involved in this response, the contributions to feed intake of central and peripheral metabolite changes due to excess valine are unknown. Here, we investigated whether intracerebroventricular injection of valine modulates central and peripheral metabolite profiles and may provide insights into feeding response in fish. Juvenile rainbow trout (Oncorhynchus mykiss) were administered an intracerebroventricular injection of valine (10 µg·µL-1 at 1 µL·100·g-1 body wt), and the metabolite profile in plasma, hypothalamus, and rest of the brain (composing of telencephalon, optic tectum, cerebellum, and medulla oblongata) was carried out by liquid chromatography-mass spectrometry (LC/MS)-based metabolomics. Valine administration led to a spatially distinct metabolite profile at 1 h postinjection in the brain: enrichment of amino acid metabolism and energy production pathways in the rest of the brain but not in hypothalamus. This suggests a role for extrahypothalamic input in the regulation of feed intake. Also, there was enrichment of several amino acids, including tyrosine, proline, valine, phenylalanine, and methionine, in plasma in response to valine. Changes in liver transcript abundance and protein expression reflect an increased metabolic capacity, including energy production from glucose and fatty acids, and a lower protein kinase B (Akt) phosphorylation in the valine group. Altogether, valine intracerebroventricular administration affects central and peripheral metabolism in rainbow trout, and we propose a role for the altered metabolite profile in modulating the feeding response to this branched-chain amino acid.NEW & NOTEWORTHY Valine causes hyperphagia in fish when it is centrally administered; however, the exact mechanisms are far from clear. We tested how intracerebroventricular injection of valine in rainbow trout affected the brain and plasma metabolome. The metabolite changes in response to valine were more evident in the rest of the brain compared with the hypothalamus. Furthermore, we demonstrated for the first time that central valine administration affects peripheral metabolism in rainbow trout.
Asunto(s)
Hipotálamo , Oncorhynchus mykiss , Valina , Animales , Oncorhynchus mykiss/metabolismo , Oncorhynchus mykiss/sangre , Valina/farmacología , Valina/administración & dosificación , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Metaboloma/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Metabolómica , Inyecciones Intraventriculares , Metabolismo Energético/efectos de los fármacosRESUMEN
PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.
Asunto(s)
Discinesia Tardía , Tetrabenazina , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacología , Tetrabenazina/administración & dosificación , Tetrabenazina/efectos adversos , Discinesia Tardía/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Valina/análogos & derivados , Valina/administración & dosificación , Valina/farmacología , Valina/efectos adversos , Anciano , Resultado del Tratamiento , Adulto , Escala de Movimientos Involuntarios Anormales , Antipsicóticos/efectos adversos , Antipsicóticos/administración & dosificaciónRESUMEN
INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.
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Enfermedad de Alzheimer , Profármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Profármacos/farmacocinética , Animales , Péptidos beta-Amiloides/metabolismo , Ciclopropanos/uso terapéutico , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Ciclopropanos/administración & dosificación , Combinación de Medicamentos , Fragmentos de Péptidos , Disponibilidad Biológica , Semivida , Valina/análogos & derivados , Valina/farmacocinética , Valina/administración & dosificación , Taurina/análogos & derivadosRESUMEN
BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.
Asunto(s)
Antivirales , Infecciones por Citomegalovirus , Ganciclovir , Trasplante de Riñón , Receptores de Trasplantes , Valaciclovir , Valganciclovir , Humanos , Valaciclovir/uso terapéutico , Infecciones por Citomegalovirus/prevención & control , Valganciclovir/uso terapéutico , Valganciclovir/administración & dosificación , Trasplante de Riñón/efectos adversos , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Masculino , Femenino , Adulto , Niño , Persona de Mediana Edad , Adolescente , Ganciclovir/análogos & derivados , Ganciclovir/uso terapéutico , Ganciclovir/administración & dosificación , Ganciclovir/efectos adversos , Viremia/prevención & control , Carga Viral , Adulto Joven , Valina/análogos & derivados , Valina/uso terapéutico , Valina/administración & dosificación , Citomegalovirus/inmunología , Citomegalovirus/efectos de los fármacos , Preescolar , Aciclovir/uso terapéutico , Aciclovir/análogos & derivados , Aciclovir/administración & dosificación , Aciclovir/efectos adversos , Anciano , Resultado del Tratamiento , IncidenciaRESUMEN
BACKGROUND: Skin aging can be observed at various levels in the epidermis, dermis, and dermo-epidermal junction. Reducing the cosmetic effects of skin aging in the facial region is a widespread demand due to common aesthetic concerns. Consequently, many injectable products on the market promise antiaging effects and cosmetic improvements. We aimed to evaluate the cosmetic efficacy of a high molecular weight sodium hyaluronate and amino acids mixture for the facial region using morphometric analysis. METHODS: This study evaluates the morphometric effectiveness of an injectable mixture (high molecular weight sodium hyaluronate, glycine, L-Proline, L-leucine, L-lysine HCL, L-valine, and L-alanine collagen active ingredient) on the mid-face and jawline in women aged 30-55. We used morphological measurements and digital image data to assess changes and determine effectiveness. Various computational methods were applied simultaneously with statistical tests for validation. RESULTS: The hydration assessment showed a significant increase on both sides of the face. A noticeable decrease was observed in gonion angle, bitragion breadth, bigonion breadth, and marionette wrinkle scale. These results suggest combining mechanical and chemical stimulation from the injection and its components (hyaluronic and amino acids) effectively enhances skin quality. CONCLUSIONS: The study indicates that the mechanical stimulation of the injection improves skin quality. Combining hyaluronic and amino acids (collagen, elastin, and pro-synthetic) is a safe and effective alternative for antiaging treatments.
Asunto(s)
Aminoácidos , Cara , Ácido Hialurónico , Rejuvenecimiento , Envejecimiento de la Piel , Humanos , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Femenino , Persona de Mediana Edad , Adulto , Aminoácidos/administración & dosificación , Aminoácidos/farmacología , Técnicas Cosméticas , Rellenos Dérmicos/administración & dosificación , Rellenos Dérmicos/química , Prolina/administración & dosificación , Prolina/farmacología , Combinación de Medicamentos , Lisina/administración & dosificación , Valina/administración & dosificación , Valina/farmacología , Colágeno/administración & dosificaciónRESUMEN
The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.3 ± 0.1 mg/mL) and CBD-VHS (11.2 ± 0.2 mg/mL). The globule size for the lead CBD formulations (NE and NMC) ranged between 205 and 270 nm while CBD-VHS-NMC formulation had a particle size of about 78 nm. The sterilized formulations, except for CBD-VHS-NMC at 40 °C, were stable for three months of storage (last time point tested). Release, in terms of CBD, in the in-vitro release/diffusion studies over 18 h, were faster from the CBD-VHS nanomicelles (38 %) compared to that from the CBD nanoemulsion (16 %) and nanomicelles (33 %). Transcorneal permeation studies revealed improvement in CBD permeability and flux with both formulations; however, a greater improvement was observed with the NMC formulation compared to the NE formulation. In conclusion, the nanoformulations prepared could serve as efficient topical ocular drug delivery platforms for CBD and its analog.
Asunto(s)
Administración Oftálmica , Cannabidiol , Córnea , Estabilidad de Medicamentos , Emulsiones , Nanopartículas , Tamaño de la Partícula , Solubilidad , Cannabidiol/administración & dosificación , Cannabidiol/química , Cannabidiol/farmacocinética , Animales , Córnea/metabolismo , Córnea/efectos de los fármacos , Nanopartículas/química , Conejos , Micelas , Valina/análogos & derivados , Valina/química , Valina/administración & dosificación , Valina/farmacocinética , Liberación de Fármacos , Lípidos/química , Excipientes/química , Permeabilidad , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Tensoactivos/química , Soluciones Oftálmicas/administración & dosificaciónRESUMEN
We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).
Asunto(s)
Antivirales/administración & dosificación , Carcinoma Hepatocelular/prevención & control , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Administración Oral , Anciano , Antivirales/efectos adversos , Carbamatos/administración & dosificación , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/virología , Quimioterapia Combinada , Diagnóstico por Imagen de Elasticidad , Femenino , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Humanos , Imidazoles/administración & dosificación , Incidencia , Interferones/administración & dosificación , Isoquinolinas/administración & dosificación , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Estudios Retrospectivos , Ribavirina/administración & dosificación , Seúl , Sulfonamidas/administración & dosificación , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Valina/administración & dosificación , Valina/análogos & derivadosRESUMEN
An 8-week feeding trial was performed to evaluate the effects of dietary leucine (Leu) and valine (Val) levels on growth performance, glycolipid metabolism and immune response in Oreochromis niloticus. Fish (15.23 ± 0.05 g) were randomly fed four diets containing two Leu levels (1.2% and 2.3%) and two Val levels (0.7% and 1.4%) as a 2 × 2 experimental design (LL-LV, LL-HV, HL-LV and HL-HV). Compared with LL-LV group, the growth parameters (final weight, daily growth coefficient (DGC) and growth rate per metabolic body weight (GRMBW)), feed conversion rate (FCR), the activities of intestinal amylase, lipase, creatine kinase (CK) and Na+, K+-ATPase, liver NAD+/NADH ratio, as well as the expression of SIRT1, GK, PK, FBPase, PPARα, CPT IA, ACO and IL10 all increased significantly in the HL-LV group; however, in the high Val group, final weight, DGC, GRMBW, intestinal enzyme activities, as well as the expression of PEPCK, SREBP1, FAS, IL8 and IL10 of the HL-HV group were significantly lower than those of the LL-HV group, while the opposite was true for the remaining indicators. Significant interactions between dietary Leu and Val were observed in final weight, DGC, GRMBW, plasma IL1ß and IL6 levels, intestinal amylase and CK activities, liver NAD+/NADH ratio, as well as the expression of SIRT1, PK, PEPCK, FBPase, SREBP1, FAS, PPARα, CPT IA, ACO, NF-κB1, IL1ß, IL6 and IL10. The highest values of growth parameters, intestinal enzyme activities and expression of SIRT1, FBPase, PPARα, CPT IA and ACO were observed in the HL-LV group, while the opposite was true for the expression of SREBP1, FAS, PPARα, NF-κB1, IL1ß and IL6. Overall, our findings indicated that dietary Leu and Val can effect interactively, and fish fed with diets containing 2.3% Leu with 0.7% Val had the best growth performance and hepatic health status of O. niloticus.
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Alimentación Animal , Glucolípidos/metabolismo , Leucina/administración & dosificación , Tilapia , Valina/administración & dosificación , Amilasas , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Suplementos Dietéticos , Inmunidad , Interleucina-10 , Interleucina-6 , NAD , PPAR alfa/genética , Sirtuina 1 , Tilapia/crecimiento & desarrollo , Tilapia/inmunologíaAsunto(s)
Antipsicóticos/efectos adversos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Discinesia Tardía/tratamiento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Femenino , Humanos , Persona de Mediana Edad , Discinesia Tardía/etiología , Tetrabenazina/administración & dosificación , Tetrabenazina/farmacología , Valina/administración & dosificación , Valina/farmacologíaRESUMEN
This study was conducted to determine the effects of dietary valine (Val) on growth, hemato-biochemical parameters, immunity, enzymatic activities, antioxidant status and expression of target of rapamycin (TOR) and 4E-BP genes in rainbow trout, Oncorhynchus mykiss (1.57 ± 0.03 g; 5.10 ± 0.34 cm). Six isonitrogenous (450 g kg-1) and isoenergetic (20.90 kJ 100 g-1, gross energy) diets were designed to represent varied Val levels (10.5, 13.0, 15.5, 18.0, 20.5 and 23.0 g kg-1 dry diet basis). Growth parameters improved significantly (P < 0.05) with the amelioration of dietary Val level up to 18.0 g kg-1. Highest (P < 0.05) body protein content was noted at 18.0 g kg-1 dietary Val. Significant differences in hematological, intestinal enzymatic activities and antioxidant parameters were noted. However, plasma variables did not show any significant differences except aspartate transaminase and uric acid. Total protein content increased significantly, while the albumin and globulin content did not show any significant (P > 0.05) difference. Moreover expression of TOR mRNA and elF4E-binding protein (4E-BP) was observed higher (P < 0.05) at 18.0 g kg-1 Val. On the basis of results, optimum dietary Val requirement for maximal growth of rainbow trout was determined to be 18.19 g kg-1 of dry diet, corresponding to 40.42 g kg-1 of dietary protein.
Asunto(s)
Inmunidad/efectos de los fármacos , Oncorhynchus mykiss/crecimiento & desarrollo , Oncorhynchus mykiss/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Valina/administración & dosificación , Alimentación Animal , Animales , Antioxidantes/metabolismo , Dieta , Proteínas en la Dieta/administración & dosificación , Suplementos DietéticosRESUMEN
INTRODUCTION: The conventional interferon therapy of hepatitis C virus has been substituted substantially with sofosbuvir and daclatasvir due to constraints in efficacy and tolerability. This study aimed diagnostically to monitor the effectiveness and side effects of direct-acting antivirals in the management of HCV infections. METHODOLOGY: This prospective study was conducted on HCV-infected patients treated with sofosbuvir and daclatasvir. Different serological, biochemical, hematological, and molecular techniques were used for the assessment of patients. Only treatment-naive patients aged ≥ 18 to 75 years received 12 weeks of treatment. The primary endpoint was a sustained virologic response with undetectable HCV RNA in the patients' serum at the end of the treatment. RESULTS: We identified 229 cases of confirmed HCV infections by PCR, 94.3% of which had genotype 3. The study population comprised 66% females and 34% males with a median age of 42.2 ± 10.6 SD. Ninety-three percent of the patients accomplished SVR at week 12. The combined therapy of SOF/DAC achieved the highest efficacy rate (92.6%) among the different HCV genotype 3 patients. A statistically significant relationship was observed between low baseline viral load (p < 0.001; 95% CI = 1.2-3.1) and HCV genotype 3 with minor side effects, including lethargy, headache, nausea, insomnia, diarrhea, and fever. CONCLUSIONS: HCV-infected patients can be treated well with an interferon-free SOF/DAC regimen, tolerated with generally mild adverse effects with a higher SVR.
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Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Pirrolidinas/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adulto , Anciano , Antivirales/efectos adversos , Carbamatos/efectos adversos , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/genética , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Valina/administración & dosificación , Valina/efectos adversosAsunto(s)
Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Desarrollo de Medicamentos , Hepatitis C/prevención & control , Valina/administración & dosificación , Valina/química , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valina/análogos & derivadosRESUMEN
INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.
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Acetilcisteína/administración & dosificación , Arginina/administración & dosificación , Diabetes Mellitus Tipo 2/complicaciones , Tolerancia a Medicamentos , Glutamina/administración & dosificación , Isoleucina/administración & dosificación , Leucina/administración & dosificación , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Valina/administración & dosificación , Administración Oral , Diabetes Mellitus Tipo 2/diagnóstico , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.
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Antivirales/administración & dosificación , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/administración & dosificación , Bencimidazoles/administración & dosificación , Benzofuranos/administración & dosificación , Ciclopropanos/administración & dosificación , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Femenino , Fluorenos/administración & dosificación , Estudios de Seguimiento , Técnicas de Genotipaje , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/virología , Humanos , Imidazoles/administración & dosificación , Lactamas Macrocíclicas/administración & dosificación , Masculino , Persona de Mediana Edad , Prolina/administración & dosificación , Prolina/análogos & derivados , Quinoxalinas/administración & dosificación , ARN Viral/sangre , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uracilo/administración & dosificación , Uracilo/análogos & derivados , Valina/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Sofosbuvir (SOF)/daclatasvir (DCV) is the direct-acting antiviral regimen of choice in many low- and middle-income countries for curative treatment of chronic hepatitis C virus (HCV) infection in adults, but data on the use of DCV in children are lacking. We performed a population pharmacokinetic (PK) analysis to predict DCV exposure in children treated with available adult formulations. METHODS: DCV concentration data from HCV-infected adolescents receiving SOF/DCV [400/60 mg, once daily (OD)] who participated in a PK study in Egypt were used for model development. PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual children weighing 10 to <35 kg receiving 60 or 30 mg OD, and DCV exposures were compared with adults ranges. RESULTS: Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. In these adolescents receiving 60 mg DCV, median (interquartile range) DCV area under the concentration time curve 0 to 24 hours, maximum concentrations, and minimum concentrations were 11,130 (8140-14,690) ng·h/mL, 1030 (790-1220) ng/mL and 130 (110-220) ng/mL, respectively, compared with 10,343 (7661-14,095) ng·h/mL, 1132 (876-1518) ng/mL and 110 (55.7-192) ng/mL predicted in children 10 to <35 kg receiving 30 mg. The proportion of children with DCV exposures above the adult range rapidly increased for children <30 kg using 60 mg OD, similarly for children 10-14 kg using 30 mg. CONCLUSIONS: DCV 30 mg OD was predicted to achieve effective and safe exposures in children 14 to <35 kg, perhaps down to 10 kg. These results should be validated clinically. Low-cost available adult DCV formulations together with approved pediatric doses of SOF would expand global access to HCV treatment for children.
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Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Imidazoles/administración & dosificación , Pirrolidinas/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adolescente , Adulto , Antivirales/farmacocinética , Carbamatos/farmacocinética , Niño , Relación Dosis-Respuesta a Droga , Egipto , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Imidazoles/farmacocinética , Masculino , Pirrolidinas/farmacocinética , Sofosbuvir/farmacocinética , Resultado del Tratamiento , Valina/administración & dosificación , Valina/farmacocinéticaRESUMEN
This study aimed to investigate the efficacy and safety of sofosbuvir-based therapies for the treatment of cirrhosis from hepatitis C virus (HCV) genotype 2 infection. Data of all consecutive HCV genotype 2 cirrhotic patients who started sofosbuvir-based treatments between January 2015 and March 2017 in eight Italian tertiary hospitals were collected retrospectively. Overall, 273 patients (Child A: 94.5%) were enrolled. In the 194 subjects treated with sofosbuvir/ribavirin, median initial ribavirin dosage was 13.9 mg/kg/day, and therapy duration was 16 weeks. Sustained virological response (SVR) rates were 93.8% in intention-to-treat (ITT) and 95.3% in per-protocol (PP) analyses for the 129 treatment-naïve patients, and 96.9% (ITT) and 98.4% (PP) for the 65 treatment-experienced subjects. Adverse events were reported in 142 patients (73.2%), but only 1.5% discontinued treatment. Eighty-eight subjects with treatment-induced anemia (mild: 34.5%, moderate: 7.7%, severe: 3.1%) had to reduce ribavirin dosage, but SVR rates were comparable to the weight-based dose group, both in ITT (95.4% and 94.3%) and PP (97.7% and 95.2%) analyses, respectively. Moreover, ITT and PP SVR rates were similar between shorter (<20 weeks) (94.1% and 96.0%, respectively) and prolonged (≥20 weeks) regimens (95.7% and 96.7%, respectively). SVR rates in the 79 subjects treated with sofosbuvir/daclatasvir (without ribavirin) were similar (ITT: 96.2%; PP: 97.4%, respectively), without de novo/worsening anemia. In conclusion, in a real-life study centered on genotype 2 patients with well-compensated cirrhosis, sofosbuvir-based regimens were associated with good SVR and tolerability rates, regardless of previous antiviral treatments, without a significant impact of on treatment ribavirin dose reductions.
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Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Carbamatos/efectos adversos , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Imidazoles/efectos adversos , Cirrosis Hepática/etiología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Pirrolidinas/efectos adversos , ARN Viral/genética , Estudios Retrospectivos , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Valina/administración & dosificación , Valina/efectos adversosRESUMEN
Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Results: Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. Funding: This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).
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Cirugía Bariátrica/efectos adversos , Gastrectomía/efectos adversos , Metaboloma , Ácido Taurodesoxicólico/metabolismo , Valina/metabolismo , Animales , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ácido Taurodesoxicólico/administración & dosificación , Valina/administración & dosificaciónRESUMEN
Hepatitis C virus genotype 4 (HCV-GT4) is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. A combination of three new direct-acting antivirals ombitasvir, paritaprevir, and ritonavir has been recommended for treatment of HCV-GT4 infection. The current study was aimed to assess the efficacy and safety of this combination plus ribavirin in non-cirrhotic, treatment-naïve and -experienced Egyptians with HCV-GT4 infection in a real-world setting. A total of 255 Egyptians with HCV-GT4 infection were enrolled, including 82 treatment-experienced and 173 treatment-naïve patients. All of them completed 12-week treatment protocol of ombitasvir, paritaprevir and ritonavir as an oral dose combination with ribavirin. Virological response (VR) was measured, as well as the biochemical parameters related to treatment efficacy and adverse events at baseline and after treatment, at 4 (VR4) and 12 (VR12) weeks post-treatment. The results showed that the VR4 rates were 98.8% in both groups, and VR12 rates were 97.7% and 96.3% in treatment-naïve and -experienced patients, respectively, with no significant differences found between the groups concerning VR4 (P=0.9) and VR12 (P=0.3). The most common adverse events were headache and fatigue, which were significantly more common (P=0.001 and 0.003, respectively) in treatment-experienced than in treatment-naïve group. The quadruple regimen was well-tolerated, and the reported adverse events were generally mild to moderate. This real-world setting study confirms that the combination of ombitasvir, paritaprevir, ritonavir, and ribavirin is highly effective in the treatment of HCV- GT4 infection with a good safety and tolerability profile.
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Anilidas/administración & dosificación , Ciclopropanos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Lactamas Macrocíclicas/administración & dosificación , Prolina/análogos & derivados , Ribavirina/administración & dosificación , Ritonavir/administración & dosificación , Sulfonamidas/administración & dosificación , Valina/administración & dosificación , Adulto , Anilidas/efectos adversos , Ciclopropanos/efectos adversos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/patogenicidad , Hepatitis C Crónica/genética , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas/efectos adversos , Masculino , Prolina/administración & dosificación , Prolina/efectos adversos , Ribavirina/efectos adversos , Ritonavir/efectos adversos , Sulfonamidas/efectos adversos , Valina/efectos adversosRESUMEN
Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).