RESUMO
Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors.
Assuntos
Antivirais , Benzimidazóis , Carbamatos , Neoplasias Colorretais , Regulação para Baixo , Fluorenos , Imidazóis , Proteínas Proto-Oncogênicas c-akt , Pirrolidinas , Transdução de Sinais , Neoplasias de Mama Triplo Negativas , Valina , Quinases da Família src , Humanos , Benzimidazóis/farmacologia , Animais , Pirrolidinas/farmacologia , Imidazóis/farmacologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinases da Família src/metabolismo , Fluorenos/farmacologia , Linhagem Celular Tumoral , Antivirais/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Carbamatos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Valina/análogos & derivados , Valina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Transdução de Sinais/efeitos dos fármacos , Células NIH 3T3 , Feminino , Proliferação de Células/efeitos dos fármacos , United States Food and Drug Administration , Aprovação de Drogas , Estados UnidosRESUMO
INTRODUCTION: Protonitazene is an opioid belonging to the 2-benzylbenzimidazole structural class. We describe two cases of opioid toxicity involving the reported inhalation of a delta-9-tetrahydrocannabinol vape product in which protonitazene was detected. CASE REPORTS: Case 1 was a young male found unconscious after the reported use of a delta-9-tetrahydrocannabinol vape. He suffered two subsequent apnoeic episodes requiring bag-valve-mask ventilation before eventual recovery. Only protonitazene was detected in blood at a concentration of 0.74 µg/L. Case 2 was a young male who died shortly after being found unresponsive. The postmortem femoral blood concentrations of protonitazene and delta-9-tetrahydrocannabinol were 0.33 µg/L and 2 µg/L, respectively. Analysis of a pod vaping device found in the decedent's hand and a separate e-liquid bottle labelled as delta-9-tetrahydrocannabinol showed a mixture of protonitazene and delta-9-tetrahydrocannabinol. DISCUSSION: The opioid effects of protonitazene are mediated through ß-arrestin2 and mu opioid receptor signalling pathways. Benzimidazole opioids are lipophilic and, when mixed with a suitable solvent, can be used in a vape device. It is anticipated that naloxone would have provided effective reversal of toxicity in our cases. CONCLUSIONS: Novel routes of opioid administration, like vaping, may appear relatively innocuous in comparison to intravenous administration, but opioids may still be absorbed at high concentrations, resulting in severe opioid toxicity or death.
Assuntos
Dronabinol , Humanos , Masculino , Dronabinol/sangue , Adulto , Analgésicos Opioides/intoxicação , Analgésicos Opioides/sangue , Vaping/efeitos adversos , Austrália , Evolução Fatal , Adulto Jovem , Benzimidazóis/intoxicação , Indazóis/intoxicação , Indazóis/sangue , Valina/análogos & derivadosRESUMO
OBJECTIVES: The aim of this study is to indirectly compare and rank the different drugs that have been studied in randomized clinical trials (RCTs) in patients with tardive dyskinesia (TD) in terms of their efficacy in ameliorating the symptoms of TD and safety. DESIGN: A network meta-analysis and a systematic review were registered prospectively on PROSPERO under the ID: CRD42023407823 and were conducted in accordance with the PRISMA-NMA guidelines. DATA SOURCES: PubMed, Scopus, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Sciences, and Clinicaltrials.gov were searched to identify relevant records. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any parallel randomized blinded controlled clinical trials that studied the use of any medications in treating TD and assessed the symptoms using a functional scale that has been previously validated. DATA EXTRACTION: The standardized mean difference of improvement along with the reported adverse events for each drug was extracted from each trial, and a network meta-analysis was conducted using a random-effects model. RESULTS: One thousand eight hundred seventeen patients in 33 RCTs were included in the analysis. Twenty-three different drugs were compared to placebo in terms of reduction in TD symptoms. Among these, valbenazine 80 mg (SMD = - 1.66, 95%CI = [- 2.55; - 0.78]), valbenazine 40 mg (- 1.00, [- 1.89; - 0.11]), and vitamin E (- 0.77, [- 1.45; - 0.1]) significantly reduced TD symptoms in comparison to placebo, while deutetrabenazine 36 mg (- 1.00, [- 2.12; 0.11]) and reserpine (- 0.54, [- 1.09; 0.02]) did not significantly reduce symptoms. Some serious adverse events were reported for valbenazine and deutetrabenazine, which included mainly psychiatric symptoms such as depression, worsening of schizophrenia, and suicidal ideation, while mild adverse events were reported for other drugs, and their incidence in the treatment arms was comparable to those in the placebo arm. CONCLUSIONS: Valbenazine (80 and 40 mg) and vitamin E demonstrated efficacy in treating tardive dyskinesia. However, the significant side effects of valbenazine should prompt further investigation of alternative treatment modalities.
Assuntos
Discinesia Tardia , Humanos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/análogos & derivados , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos , Valina/análogos & derivadosRESUMO
Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs.
Assuntos
Antivirais , Benzimidazóis , Farmacorresistência Viral , Hepacivirus , Imidazóis , Proteínas não Estruturais Virais , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/antagonistas & inibidores , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Farmacorresistência Viral/efeitos dos fármacos , Benzimidazóis/farmacologia , Imidazóis/farmacologia , Carbamatos/farmacologia , Fluorenos/farmacologia , Sofosbuvir/farmacologia , Pirrolidinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Valina/análogos & derivados , Valina/farmacologia , Genótipo , Replicon/efeitos dos fármacos , Replicon/genética , Sulfonamidas/farmacologia , Benzofuranos/farmacologia , Pirazinas/farmacologia , Benzopiranos , RNA Polimerase Dependente de RNARESUMO
BACKGROUND: The link between diabetes mellitus and chronic hepatitis C infection remains well established. It is estimated that up to one third of chronic hepatitis C patients have type II diabetes mellitus. Hepatitis C virus infection is one of the main global health burdens. Sofosbuvir and Daclatasvir are used as effective antiviral inhibitors of hepatitis C virus. The cardiovascular effects of those drugs are not well studied. We used electrocardiography and echocardiography with global longitudinal strain assessment by speckle tracking to detect their effect on cardiac function. METHODS AND RESULTS: One hundred diabetic patients with hepatitis C infection were included in the study. Abdominal ultrasound and laboratory work up were carried out for all participants. Left ventricular systolic and diastolic function were assessed by 2D-echocardiography and global longitudinal strain, before and 3 months after treatment. Results showed significant decrease in global longitudinal strain 3 months after therapy (-21 ± 4 vs. -18 ± 7; P < 0.001) but other echocardiographic findings showed no significant changes. CONCLUSIONS: Sofosbuvir and Daclatasvir were associated with early left ventricular systolic dysfunction as assessed by global longitudinal strain in diabetic patients. More deterioration in left ventricular systolic function was detected among those with Child-Pough class B. Further long-term follow-up may be required.
Assuntos
Antivirais , Carbamatos , Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Imidazóis , Pirrolidinas , Sofosbuvir , Valina , Disfunção Ventricular Esquerda , Função Ventricular Esquerda , Humanos , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Sofosbuvir/uso terapêutico , Sofosbuvir/efeitos adversos , Valina/análogos & derivados , Valina/uso terapêutico , Pirrolidinas/uso terapêutico , Imidazóis/uso terapêutico , Resultado do Tratamento , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Carbamatos/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/diagnóstico , Fatores de Tempo , Idoso , Eletrocardiografia , AdultoRESUMO
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.
Assuntos
Aciclovir , Antivirais , Encefalite por Herpes Simples , Herpes Simples , Herpesvirus Humano 1 , Mamilos , Humanos , Feminino , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Recém-Nascido , Aciclovir/uso terapêutico , Aciclovir/administração & dosagem , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/isolamento & purificação , Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Valaciclovir/uso terapêutico , Valaciclovir/administração & dosagem , Complicações Infecciosas na Gravidez/diagnóstico , Adulto , Gravidez , Transmissão Vertical de Doenças Infecciosas , Valina/análogos & derivados , Valina/uso terapêutico , Valina/administração & dosagem , Aleitamento MaternoRESUMO
PURPOSE: Valbenazine is commonly used to treat tardive dyskinesia, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate neurological safety signals associated with valbenazine. METHODS: Data was collected in FAERS from the second quarter of 2017 to the fourth quarter of 2023 for data cleaning. Neurological adverse event (AE) signals of valbenazine were mined by calculating reporting odds ratios (ROR), information component (IC) and empirical Bayesian geometric mean (EBGM). The serious and non-serious cases and signals were prioritized using a rating scale. RESULTS: The number of neurological AE reports where the primary suspect (PS) drug was 8981 for valbenazine. Significant AE signals were identified by the preferred term (PT) analysis for valbenazine, including somnolence (ROR 19.69), tremor (ROR 15.17), and tardive dyskinesia (ROR 236.91), among which 18 AEs were identified as new signals. Patient age (p < 0.009) and sex (p = 0.197) might be associated with an increased risk of neurological AE severity. Notably, the association between valbenazine and neurological disorders remained when stratified by sex, age, and reporter type. AE timing analysis was performed for the drug and four moderate clinical priority signals [i.e., somnolence, balance disorder, parkinsonism, and akathisia (priorities 7)], showing the same early failure type profiles. CONCLUSIONS: The increase in neurological safety signals is identified in the post-marketing research of valbenazine. Clinicians need to pay attention to not only common AEs but also be alert to new neurological AE signals when using valbenazine.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Discinesia Tardia , Tetrabenazina , United States Food and Drug Administration , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/efeitos adversos , Estados Unidos , Masculino , Feminino , Pessoa de Meia-Idade , Discinesia Tardia/induzido quimicamente , Adulto , Idoso , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Valina/análogos & derivados , Valina/efeitos adversos , Farmacovigilância , Vigilância de Produtos Comercializados/estatística & dados numéricos , Adulto Jovem , Inibidores da Captação Adrenérgica/efeitos adversos , AdolescenteRESUMO
OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
Assuntos
Artrite Reumatoide , Azetidinas , Teorema de Bayes , Inibidores de Janus Quinases , Metanálise em Rede , Piperidinas , Pirimidinas , Humanos , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Azetidinas/uso terapêutico , Azetidinas/efeitos adversos , Purinas/uso terapêutico , Purinas/efeitos adversos , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Niacinamida/efeitos adversos , Benzamidas/uso terapêutico , Benzamidas/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Triazóis/uso terapêutico , Triazóis/efeitos adversos , Triazóis/administração & dosagem , Adamantano/análogos & derivados , Piridinas , Valina/análogos & derivadosRESUMO
Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.
Assuntos
Monitoramento Biológico , Biomarcadores , Eritrócitos , Exposição Ocupacional , Humanos , Biomarcadores/urina , Biomarcadores/sangue , Eritrócitos/metabolismo , Eritrócitos/efeitos dos fármacos , Modelos Biológicos , Óxido de Etileno/toxicidade , Óxido de Etileno/farmacocinética , Óxido de Etileno/urina , Toxicocinética , Globinas/metabolismo , Valina/análogos & derivados , Valina/farmacocinética , Valina/urina , Valina/sangue , Simulação por ComputadorAssuntos
Antivirais , Infecções por Citomegalovirus , Complicações Infecciosas na Gravidez , Valaciclovir , Humanos , Feminino , Gravidez , Valaciclovir/uso terapêutico , Valaciclovir/administração & dosagem , Infecções por Citomegalovirus/tratamento farmacológico , Antivirais/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Aciclovir/uso terapêutico , Aciclovir/administração & dosagem , Valina/análogos & derivados , Valina/uso terapêutico , Valina/administração & dosagemRESUMO
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.
Assuntos
Discinesia Tardia , Tetrabenazina , Valina , Humanos , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Discinesia Tardia/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Valina/análogos & derivados , Valina/administração & dosagem , Valina/farmacologia , Valina/efeitos adversos , Idoso , Resultado do Tratamento , Adulto , Escala de Movimento Involuntário Anormal , Antipsicóticos/efeitos adversos , Antipsicóticos/administração & dosagemRESUMO
The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.
Assuntos
Antivirais , Crioglobulinemia , Vasculite , Humanos , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/etiologia , Antivirais/uso terapêutico , Masculino , Vasculite/tratamento farmacológico , Vasculite/virologia , Pessoa de Meia-Idade , Feminino , Idoso , Hepacivirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Imidazóis/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Pirrolidinas/uso terapêutico , Fator Ativador de Células B , Interferon-alfa/uso terapêutico , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Hepatite C/complicações , Hepatite C/virologia , Resultado do Tratamento , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , CarbamatosRESUMO
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
Assuntos
Antivirais , Linfócitos T CD8-Positivos , Carbamatos , Hepacivirus , Hepatite C Crônica , Receptor de Morte Celular Programada 1 , Sulfonamidas , Linfócitos T Reguladores , Humanos , Antivirais/uso terapêutico , Masculino , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/genética , Feminino , Pessoa de Meia-Idade , Carbamatos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Hepatite C Crônica/sangue , Ciclopropanos/uso terapêutico , Valina/análogos & derivados , Prolina/análogos & derivados , Anilidas/uso terapêutico , Anilidas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Compostos Macrocíclicos/farmacologia , Idoso , Ritonavir/uso terapêutico , Adulto , Quimioterapia Combinada , Linfócitos T Auxiliares-Indutores/imunologia , Imidazóis , Isoquinolinas , PirrolidinasRESUMO
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.
Assuntos
Doença de Alzheimer , Pró-Fármacos , Doença de Alzheimer/tratamento farmacológico , Humanos , Pró-Fármacos/farmacocinética , Animais , Peptídeos beta-Amiloides/metabolismo , Ciclopropanos/uso terapêutico , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Ciclopropanos/administração & dosagem , Combinação de Medicamentos , Fragmentos de Peptídeos , Disponibilidade Biológica , Meia-Vida , Valina/análogos & derivados , Valina/farmacocinética , Valina/administração & dosagem , Taurina/análogos & derivadosRESUMO
Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure.
Assuntos
Antivirais , Hepacivirus , Hepatite C , Polícia , Humanos , Paquistão/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepacivirus/genética , Hepacivirus/imunologia , Adulto Jovem , Proteínas do Core Viral/sangue , Antígenos da Hepatite C/sangue , Idoso , Adolescente , Projetos Piloto , Programas de Rastreamento/métodos , Anticorpos Anti-Hepatite C/sangue , Carbamatos , Imidazóis , Pirrolidinas , Valina/análogos & derivadosRESUMO
Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.
Assuntos
Agonistas de Receptores de Canabinoides , Halogenação , Indazóis , Indóis , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/síntese química , Relação Estrutura-Atividade , Animais , Indazóis/farmacologia , Indazóis/química , Indazóis/síntese química , Humanos , Indóis/farmacologia , Indóis/química , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/química , Deutério , Camundongos , Valina/análogos & derivadosRESUMO
Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.
Assuntos
Antivirais , Infecções por HIV , Hepatite C Crônica , Valina , Humanos , Masculino , Feminino , Hepatite C Crônica/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Antivirais/farmacocinética , Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Valina/farmacocinética , Valina/análogos & derivados , Sofosbuvir/farmacocinética , Sofosbuvir/uso terapêutico , Ciclopropanos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Alcinos , Tailândia , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Quimioterapia Combinada , BenzimidazóisRESUMO
The knife-cut sign is a distinctive manifestation of herpes simplex virus (HSV) type 1 or HSV type 2 infection that has been described in at least 10 immunocompromised patients. It appears as an extremely painful linear erosion or fissure in an intertriginous area such as the body folds beneath the breast, or within the abdomen, or in the inguinal region. Also, concurrent HSV infection at other mucocutaneous sites, or viscera, or both have been observed. The patients had medical conditions (at least 9 patients) and/or immunosuppressive drug therapy (6 patients). The diagnosis of HSV infection was confirmed by viral culture (8 patients), biopsy (4 patients), direct fluorescence antibody testing (3 patients), immunohistochemistry staining (2 patients), polymerase chain reaction (2 patients), or Western blot serologic assay (1 patient). Knife-cut sign-associated HSV infection is potentially fatal; three patients died. However, clinical improvement or complete healing occurred in the patients who received oral valacyclovir (1 patient), or intravenous acyclovir (2 patients), or intravenous acyclovir followed by foscarnet (1 patient). In summary, HSV infection associated with a positive the knife-cut sign is a potentially fatal variant of HSV infection that occurs in the intertriginous areas of immunocompromised patients and usually requires intravenous antiviral therapy.
Assuntos
Antivirais , Herpes Simples , Herpesvirus Humano 1 , Hospedeiro Imunocomprometido , Humanos , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Pessoa de Meia-Idade , Feminino , Masculino , Antivirais/uso terapêutico , Idoso , Herpesvirus Humano 1/isolamento & purificação , Adulto , Valaciclovir/uso terapêutico , Herpesvirus Humano 2/isolamento & purificação , Aciclovir/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Foscarnet/uso terapêuticoRESUMO
Herpetic geometric glossitis is a unique morphologic variant of HSV (herpes simplex virus) type 1 infection on the dorsum of the tongue that presents as an extremely painful linear central lingual fissure with a branched pattern. in the center of the tongue; there is a branched pattern of fissures that extend bilaterally from the central linear fissure. Herpetic geometric glossitis has been reported in 11 patients; 8 of these individuals were immunocompromised. Medical conditions and immunosuppressive medication treatment (7 patients) or only medical disorders (3 patients) or neither (1 patient) were present. HSV type 1 infection was diagnosed by viral culture in (7 patients), Tzanck preparation (2 patients) or clinically (2 patients). Mucocutaneous HSV infection at non-lingual locations--including the lips, labial mucosa, face and chest--were observed in 5 patients. All patients' symptoms and lesions responded to treatment with oral antiviral therapy: acyclovir (9 patients), famciclovir (1 patient) or valacyclovir (1 patient). The lingual pain and dorsal tongue fissures completely resolved completely within two to 14 days. In summary, herpetic geometric glossitis is a unique HSV type 1 infection, usually in immunocompromised patients, that occurs on the dorsal tongue and responds completely after treatment with orally administered antiviral therapy.
Assuntos
Antivirais , Glossite , Herpes Simples , Herpesvirus Humano 1 , Hospedeiro Imunocomprometido , Humanos , Glossite/tratamento farmacológico , Glossite/virologia , Pessoa de Meia-Idade , Feminino , Masculino , Antivirais/uso terapêutico , Herpes Simples/tratamento farmacológico , Herpes Simples/diagnóstico , Herpesvirus Humano 1/isolamento & purificação , Adulto , Idoso , Aciclovir/uso terapêutico , Valaciclovir/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Famciclovir/uso terapêuticoRESUMO
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.