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1.
Methods Mol Biol ; 2390: 103-112, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731465

RESUMO

The development of vaccines for the treatment of COVID-19 is paving the way for new hope. Despite this, the risk of the virus mutating into a vaccine-resistant variant still persists. As a result, the demand of efficacious drugs to treat COVID-19 is still pertinent. To this end, scientists continue to identify and repurpose marketed drugs for this new disease. Many of these drugs are currently undergoing clinical trials and, so far, only one has been officially approved by FDA. Drug repurposing is a much faster route to the clinic than standard drug development of novel molecules, nevertheless in a pandemic this process is still not fast enough to halt the spread of the virus. Artificial intelligence has already played a large part in hastening the drug discovery process, not only by facilitating the selection of potential drug candidates but also in monitoring the pandemic and enabling faster diagnosis of patients. In this chapter, we focus on the impact and challenges that artificial intelligence has demonstrated thus far with respect to drug repurposing of therapeutics for the treatment of COVID-19.


Assuntos
Antivirais/uso terapêutico , Inteligência Artificial , COVID-19/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , COVID-19/diagnóstico , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Aprendizado de Máquina , Estrutura Molecular , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
2.
Methods Mol Biol ; 2390: 177-190, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731469

RESUMO

We describe an approach to early stage drug discovery that explicitly engages with the complexities of human biology. The combined computational and experimental approach is formulated on a conceptual framework in which network biology is used to bridge between individual molecular entities and the cellular phenotype that emerges when those entities interact in a network. Multiple aspects of early stage discovery are addressed including the data-driven elucidation of biological processes implicated in disease, target identification and validation, phenotypic discovery of active molecules and their mechanism of action, and extraction of genetic target support from human population genetics data. Validation is described via summary of a number of discovery projects and details from a project aimed at COVID-19 disease.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Biologia de Sistemas , Animais , Antivirais/efeitos adversos , COVID-19/diagnóstico , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
3.
J Med Virol ; 94(1): 119-130, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34403141

RESUMO

This study investigates the effect of the nanostructure of squalene in the form of microemulsion on COVID-19 patients. In this blinded clinical trial, a comparison was made between the efficacy of squalene treatment and controls. A total of 30 COVID-19 patients admitted to the emergency department, and the infection ward was equally allocated to case (n = 15) and control (n = 15) groups according to their age and underlying diseases. The baseline characteristics of subjects, including age, gender, time of treatment onset, underlying condition, white blood cells count, and lymphocyte count were similar (p < 0.05). Baseline laboratory tests and computed tomography (CT) scans were performed for the study groups. The treatment group received 5 mg of intravenous squalene twice a day and standard treatment for 6 days, while controls received only standard treatment. After 6 days of treatment, clinical and CT scan changes were evaluated and compared in intervention and control groups. The need for oxygen therapy (p = 0.020), 2 days of no fever (p = 0.025), cough alleviation (p = 0.010), and lung high-resolution computed tomography improvement (p = 0.033) were significantly different between cases and controls within 7 days of admission. No adverse effects were observed in the treatment group. Our data suggest that squalene could be considered as a potential treatment for COVID-19, and further studies are required to confirm the results.


Assuntos
COVID-19/tratamento farmacológico , Esqualeno/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/química , Antivirais/uso terapêutico , Emulsões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óleos Vegetais/química , Esqualeno/administração & dosagem , Esqualeno/efeitos adversos , Esqualeno/química , Resultado do Tratamento
4.
J Infect Chemother ; 28(1): 124-127, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34627706

RESUMO

The aim of this study was to investigate the efficacy and safety of minocycline (MIN) and favipiravir combination therapy in patients with coronavirus disease 2019 (COVID-19) admitted to our hospital in Fukui Prefecture, Japan, in March and April of 2020. In this retrospective study, a favipiravir monotherapy group (Control group, n = 9) was compared with a combined favipiravir plus MIN therapy group (MIN group, n = 12). No severe cases were present. The primary comparative endpoints evaluated were duration of fever, duration of hospitalization, duration from treatment initiation to severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR)-negative results, and changes in cytokine and chemokine production. Median duration from start of treatment to negative PCR test was significantly shorter in the MIN group than in the Control group. Mean rates of cytokine and chemokine reduction were significantly greater for interleukin-6 and interleukin-8 in the MIN group. No difference in adverse event rates were seen between groups, and only minor adverse events were encountered. MIN has been reported to have not only broad antibacterial activity, but also antiviral and anti-inflammatory activity. The present results support the efficacy and safety of MIN plus favipiravir therapy for the treatment of COVID-19.


Assuntos
COVID-19 , Minociclina , Amidas , Antivirais/efeitos adversos , Humanos , Minociclina/efeitos adversos , Pirazinas , Estudos Retrospectivos , SARS-CoV-2 , Resultado do Tratamento
5.
World J Gastroenterol ; 27(40): 6861-6873, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34790011

RESUMO

Chronic viral hepatitis is one of the leading causes of cirrhosis worldwide. Chronic hepatitis B is more common in the Asia-Pacific region due to the larger population and lower screening availability. Hepatitis C predominates in the west due to injection drug abuse. The discovery of (oral) direct-acting antiviral agents (DAAs) has changed the landscape of chronic hepatitis C (CHC) management. Nucleos(t)ide analogs (NUCs) have also changed the approach to the treatment of chronic hepatitis B (CHB). Oral NUCs and DAAs have excellent efficacy and patient acceptance as well as a lower risk of resistance. However, certain populations have no robust data and safety and efficacy of such oral drugs is still evolving. In this review, we provide an overview of the management of CHB and CHC in special populations, such as those with chronic kidney disease, pregnant women, healthcare workers, and those undergoing chemo- or immunosuppressive therapy.


Assuntos
Hepatite B Crônica , Hepatite B , Hepatite C Crônica , Antivirais/efeitos adversos , Feminino , Hepatite B/tratamento farmacológico , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Gravidez , Resultado do Tratamento
6.
Clin Drug Investig ; 41(12): 1075-1086, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34784011

RESUMO

OBJECTIVE: Since May 2018, a 6-year post­marketing surveillance (PMS) has been underway to evaluate the safety and effectiveness of letermovir for cytomegalovirus (CMV) prophylaxis in Japanese patients with allogenic hematopoietic stem-cell transplantation (allo-HSCT). The interim PMS data for 461 patients collected as of March 2021 are reported in this publication. METHODS: The case report forms (CRFs) were drafted in part by the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) using data elements in the Transplant Registry Unified Management Program (TRUMP) and sent to individual HSCT centers to decrease burden of reporting. These CRFs were completed by physicians in the respective HSCT centers and sent to MSD K.K., Tokyo, Japan. RESULTS: Allo-HSCT recipients prescribed with letermovir for CMV prophylaxis were included across 136 centers in Japan between May 2018 and March 2021. Safety and effectiveness were assessed for 460 and 373 patients, respectively. Of the patients in the safety analysis, 13.9 % experienced adverse drug reactions, the most frequent of which were renal impairment (2.2 %) and nausea (1.7 %). Among patients in the effectiveness analysis, the overall CMV antigen positivity rate was 21.2 % at Week 14 and 37.5 % at Week 24 after allo-HSCT. CONCLUSIONS: Interim data from this largest of real-world studies confirm the safety and effectiveness of letermovir for CMV prophylaxis in Japanese allo-HSCT recipients. Given the limited data on Asian patients for letermovir use, this survey will provide valuable information for medical decision-making in routine clinical practice, serving as a vital supplement to the results obtained from clinical trials.


Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Acetatos , Antivirais/efeitos adversos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Japão , Vigilância de Produtos Comercializados , Quinazolinas
7.
J Med Case Rep ; 15(1): 568, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34836557

RESUMO

BACKGROUND: In recent years, numerous studies have reported the development or exacerbation of sarcoidosis due to interferon therapy. However, ocular lesions rarely present as initial symptoms. Herein, we describe a rare case of interferon-α-induced sarcoidosis with uveitis as the initial symptom, and present a review of the relevant literature. CASE PRESENTATION: This case involved a 62-year-old-Japanese woman with a history of a combination treatment of pegylated interferon-α-2a, ribavirin, and simeprevir, after which she developed granulomatous panuveitis. She was subsequently diagnosed with sarcoidosis following histological examination of skin biopsy specimens. In addition to reporting this case, we performed a literature review of 27 cases (24 case reports) of histopathologically diagnosed interferon-α-induced sarcoidosis published between January 2009 and November 2018. CONCLUSIONS: Among the reviewed cases, 23 (85.1%) cases developed skin lesions and 19 (70.1%) had lung lesions. Only three cases (11.1%) had accompanying eye lesions. Interferon-α therapy was discontinued in 16 cases (52.9%), and the majority exhibited improvement after systemic corticosteroid treatment. There are few reported cases of interferon-α-induced sarcoidosis with uveitis as the initial symptom. However, if uveitis develops during or after interferon-α treatment, it might represent an initial symptom of interferon-α-induced sarcoidosis, as observed in the present case.


Assuntos
Pan-Uveíte , Sarcoidose , Uveíte , Antivirais/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Pan-Uveíte/induzido quimicamente , Pan-Uveíte/tratamento farmacológico , Ribavirina/efeitos adversos , Sarcoidose/induzido quimicamente , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Uveíte/induzido quimicamente , Uveíte/diagnóstico
9.
World J Gastroenterol ; 27(36): 6053-6063, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34629819

RESUMO

Hepatitis B virus (HBV) infection is one of the main causes of morbidity and mortality worldwide. Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection, with normal or only slightly raised aminotransferases. Although a conservative approach in children is usually recommended, different therapies exist and different therapeutic approaches are possible. The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma, although these complications are rare in children. Both United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved interferon alfa-2b for children aged 1 year and older, pegylated interferon alfa-2a and lamivudine for children aged 3 years and older, entecavir for use in children aged 2 years and older, and adefovir for use in those 12 years of age and older. Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by US-FDA for treatment in children aged 12 years and older. Finally, EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age. This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.


Assuntos
Hepatite B Crônica , Hepatite B , Neoplasias Hepáticas , Adolescente , Antivirais/efeitos adversos , Criança , Pré-Escolar , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Estados Unidos/epidemiologia
10.
Front Immunol ; 12: 730022, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646269

RESUMO

Pulmonary surfactant is a complex and highly surface-active material. It covers the alveolar epithelium and consists of 90% lipids and 10% proteins. Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse and the mechanical work required to breathe. Moreover, pulmonary surfactant lipids, such as phosphatidylglycerol and phosphatidylinositol, and pulmonary surfactant proteins, such as surfactant protein A and D, participate in the pulmonary host defense and modify immune responses. Emerging data have shown that pulmonary surfactant lipids modulate the inflammatory response and antiviral effects in some respiratory viral infections, and pulmonary surfactant lipids have shown promise for therapeutic applications in some respiratory viral infections. Here, we briefly review the composition, antiviral properties, and potential therapeutic applications of pulmonary surfactant lipids in respiratory viral infections.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Lipídeos/uso terapêutico , Pulmão/efeitos dos fármacos , Surfactantes Pulmonares/uso terapêutico , SARS-CoV-2/patogenicidade , Animais , Antivirais/efeitos adversos , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Lipídeos/efeitos adversos , Pulmão/imunologia , Pulmão/virologia , Surfactantes Pulmonares/efeitos adversos , SARS-CoV-2/imunologia
11.
Trials ; 22(1): 701, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649610

RESUMO

INTRODUCTION: Hepatitis B-related compensated liver cirrhosis is related to a higher risk of hepatocellular carcinoma, and antiviral therapy is the preferred method. As the pathological mechanisms of liver fibrosis are complex, drugs developed for a single target are difficult to be effective in clinical practice, so there are no chemical drugs or biological drugs with clear efficacy available for clinical application at present. Traditional Chinese medicine is a kind of medical science that has been gradually formed during thousands of years and continuously enriched by the people of all ethnic groups in China. Traditional Chinese medicine shows curative effects in the treatment of liver diseases, especially in the field of liver fibrosis prevention and treatment. This study aims to test the integrative medicine (Chinese medicine plus antiviral therapy) effective on lowing hepatocellular carcinoma risk among patients with hepatitis-related compensated liver cirrhosis. METHODS AND ANALYSIS: This is a multi-center randomized controlled trial, and a total of 5 hospitals and 802 patients will be involved in. All the subjects are randomly allocated to the YinQiSanHuang Jiedu decoction (YQSHD) group (n = 401) or the placebo group (n = 401). The YQSHD group receives YQSHD granule with entecavir (ETV), and the placebo group receives YQSHD placebo with ETV. The treatment period will last for 52 weeks, and the follow-up period for 52 ± 2 weeks. The primary outcome measure is the annual incidence of HCC. Outcomes will be assessed at baseline and after treatment. The objective of this trial is "the integrative of YQSHD with ETV reduce the annual incidence of HCC to 1%." ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Committee of Guang'anmen Hospital, China (No.2019-006-KY), and the other centers in the trial will not begin recruiting until the local ethical approval has been obtained. Trial final results will be disseminated via publication. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900021532 . Registered on February 26, 2019.


Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Hepatite B , Neoplasias Hepáticas , Antivirais/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
BMC Pharmacol Toxicol ; 22(1): 61, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674775

RESUMO

BACKGROUND: The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10 years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19. METHODS: We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity. RESULTS: Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties. CONCLUSION: In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.


Assuntos
Antivirais/toxicidade , COVID-19/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Animais , Antivirais/efeitos adversos , Captopril/uso terapêutico , Cardiotoxinas/toxicidade , Catecóis/uso terapêutico , Biologia Computacional , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas/métodos , Humanos , Indometacina/uso terapêutico , Linezolida/uso terapêutico , Fígado/efeitos dos fármacos , Camundongos , Modelos Biológicos , Nitrilas/uso terapêutico , Ratos , Reprodução/efeitos dos fármacos , Software , Ácido Valproico/uso terapêutico
13.
Immunopharmacol Immunotoxicol ; 43(6): 644-650, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34698601

RESUMO

BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread throughout the world. During treatment, we found that the majority of patients had a decrease in hemoglobin (Hb). Interferon-α2b (IFN-α2b) was the primary suspected drug that was related to Hb reduction. Thus, the study aimed to investigate whether IFN-α2b could induce Hb reduction in severe patients with COVID-19 and its potential mechanism. MATERIAL AND METHODS: A total of 50 patients who were admitted to the First Affiliated Hospital of Harbin Medical University with severe COVID-19 infection were enrolled from February 12th to 24th, 2020. The demographics, baseline characteristics, clinical data, and therapeutic regimen were collected retrospectively. The patients were divided into two groups according to the declined use of IFN-α2b on day 14. The Hb levels on admission, day 7, day14, and day 21 were collected and analyzed. The primary endpoint was the level of Hb on day 21. RESULTS: A total of 31 patients in the IFN-stop group and 19 patients in the non-IFN-stop group were reviewed. The age, gender, comorbidities, clinical symptoms, nutritional status, disease severity, complications, and other factors of the patients were compared, no difference was found between the IFN-stop group and the non-IFN-stop group. The Hb levels of all patients significantly decreased on day 7 compared with that on admission (p < .0001). In the IFN-stop group, the Hb level was increased in 7 days after IFN-α2b was stopped (p = .0008), whereas no difference was found between day 14 and day 21 in the non-IFN-stop group (p = .3152). CONCLUSIONS: IFN-α2b was associated with Hb reduction in the treatment of severe patients of COVID-19. Clinicians should be aware of the high incidence of Hb reduction for patients treated by IFN-α2b.


Assuntos
Anemia/induzido quimicamente , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Interferon alfa-2/efeitos adversos , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/diagnóstico , Antivirais/administração & dosagem , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , China , Feminino , Hemoglobinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Interferon alfa-2/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Clin Nephrol ; 96(1): 127-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34643504

RESUMO

INTRODUCTION: Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. CASE PRESENTATION: A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. CONCLUSION: Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.


Assuntos
Transplante de Rim , Nefrite Intersticial , Idoso , Aloenxertos , Antivirais/efeitos adversos , Foscarnet/efeitos adversos , Ganciclovir , Humanos , Rim/fisiologia , Transplante de Rim/efeitos adversos , Masculino
15.
Nat Med ; 27(10): 1725-1734, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34642494

RESUMO

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml-1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Adolescente , Adulto , Antivirais/efeitos adversos , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/efeitos adversos , Placebos , Polietilenoglicóis/química , República da Coreia/epidemiologia , Adulto Jovem
16.
Sci Rep ; 11(1): 19998, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620963

RESUMO

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Assuntos
Antivirais/metabolismo , COVID-19/tratamento farmacológico , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/farmacologia , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacologia , Amidas/efeitos adversos , Amidas/metabolismo , Amidas/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , COVID-19/metabolismo , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Cloroquina/metabolismo , Cloroquina/farmacologia , Desenho de Fármacos , Humanos , Redes e Vias Metabólicas , Simulação de Acoplamento Molecular , Nitrocompostos/efeitos adversos , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Pirazinas/efeitos adversos , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ribavirina/efeitos adversos , Ribavirina/metabolismo , Ribavirina/farmacologia , SARS-CoV-2/metabolismo , Tiazóis/efeitos adversos , Tiazóis/metabolismo , Tiazóis/farmacologia
17.
Clin J Gastroenterol ; 14(6): 1725-1732, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34664197

RESUMO

Although direct-acting antiviral (DAA)-based anti-hepatitis C virus (HCV) therapies are very effective for patients with genotypes 1 and 2, evidence of the efficacy of DAA-based therapy for the special population of patients with genotypes 3-6 is insufficient due to the relatively small number of these subjects in Japan. Human immunodeficiency virus (HIV)/HCV-co-infected patients are recommended to be treated as HCV-mono-infected patients by the latest version of the Japan Society of Hepatology guidelines. However, evidence of efficacy in patients with HIV/HCV genotype 3-6 co-infection is insufficient. Currently, HCV genotypes 3-6 can be treated with two DAA-based therapies, including glecaprevir (GLE)/pibrentasvir (PIB) therapy in Japan. We experienced a relatively rare case of a Japanese hemophilia patient co-infected with HIV/HCV genotype 4a. We evaluated resistance-associated substitutions (RASs) against GLE and PIB before GLE/PIB therapy and found that he had no RASs. He was treated with 12 weeks of GLE/PIB therapy and achieved a sustained virologic response at post-treatment weeks 24. Although the treatment was well tolerated, the patient developed hyper-low-density lipoproteinemia that was probably associated with HCV elimination during the therapy. Additional studies are needed to confirm the efficacy and safety of GLE/PIB therapy for this special population in Japan.


Assuntos
Coinfecção , Infecções por HIV , Hemofilia A , Hepatite C Crônica , Ácidos Aminoisobutíricos , Antivirais/efeitos adversos , Benzimidazóis , Coinfecção/tratamento farmacológico , Ciclopropanos , Genótipo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Japão , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , Sulfonamidas
18.
World J Gastroenterol ; 27(30): 5088-5099, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34497437

RESUMO

BACKGROUND: As a country with a high burden of hepatitis B, China has about 86 million cases of hepatitis B virus infection, ranking the first in the world. Currently, there are about 390000 deaths due to hepatitis B-related complications such as liver cirrhosis and liver cancer every year. Consequently, how to control portal hypertension, improve liver functional reserve, and reduce the incidence of hepatic failure and liver cancer in such patients is the focus of current clinical attention. Previous clinical study in our center suggested that at 24 mo after transjugular intrahepatic portosystemic shunt (TIPS), the liver functional reserve of patients with hepatitis B cirrhosis was better than that of patients with alcohol-induced and immune cirrhosis, which may be related to the effective etiological treatment. AIM: To investigate the clinical efficacy of three first-line antiviral drugs recommended by the guidelines of prevention and treatment for chronic hepatitis B in China (2019) in the treatment of patients with hepatitis B-related cirrhosis who had received a TIPS. METHODS: The clinical data of 137 patients with hepatitis B-related cirrhosis with portal hypertension after receiving TIPS at our centre between March 2016 and December 2020 were analysed retrospectively. According to different anti-viral drugs, the patients were divided into entecavir (ETV) (n = 70), tenofovir alafenamide fumarate (TAF) (n = 32), and tenofovir disoproxil fumarate (TDF) (n = 35) groups. The cumulative incidence of hepatic encephalopathy and hepatocellular carcinoma, survival, and changes in hepatic reserve function and glomerular filtration rate in patients treated with different antiviral drugs within 24 mo after surgery were investigated. RESULTS: At 24 mo after surgery, the Child-Pugh score in the TAF group (6.97 ± 0.86) was lower than that in the TDF (7.49 ± 0.82; t = -2.52, P = 0.014) and ETV groups (7.64 ± 1.17; t = -2.92, P = 0.004). The model for end-stage liver disease score in the TAF group at 24 mo after surgery was 9.72 ± 1.5, which was lower than that in the TDF (10.74 ± 2.33; t = -2.09, P = 0.040) and ETV groups (10.97 ± 2.17; t = -2.93, P = 0.004). At 24 mo after surgery, the estimated glomerular filtration rate (eGFR) in the TAF group (104.41 ± 12.54) was higher than that in the TDF (93.54 ± 8.97) and ETV groups (89.96 ± 9.86) (F = 21.57, P < 0.001). CONCLUSION: At 24 mo after surgery, compared with TDF and ETV, TAF has significant advantages in the improvement of liver functional reserve and eGFR.


Assuntos
Doença Hepática Terminal , Hepatite B , Derivação Portossistêmica Transjugular Intra-Hepática , Antivirais/efeitos adversos , Doença Hepática Terminal/tratamento farmacológico , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
19.
World J Gastroenterol ; 27(31): 5181-5188, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34497443

RESUMO

Hepatitis C virus (HCV) reactivation occurs in 23% of HCV-infected cancer patients receiving chemotherapy. Forty-three percent of the patients with reactivation of HCV during chemotherapy develop a hepatitis flare. Most of the cancer patients with HCV reactivation have an unremarkable clinical course following an HCV-related hepatitis flare during chemotherapy. However, 26%-57% of the cancer patients developing an acute flare of chronic hepatitis C during chemotherapy require unanticipated discontinuation or dose reduction of chemotherapy, which results in deleterious changes in the cancer treatment plan. Although an optimal strategy for HCV screening in cancer patients receiving chemotherapy has not been established, universal pre-chemotherapy HCV testing for patients with hematological malignancies is recommended by current guidelines. All the currently approved direct-acting antivirals (DAAs) can be used in cancer patients, but the use of DAAs during chemotherapy should avoid drug-drug interactions between chemotherapy and antiviral agents. If there are no contraindications or anticipated drug-drug interactions, DAAs treatment can be administered before, during, or after chemotherapy. In conclusion, HCV reactivation occurs in approximately one-fourth of HCV-infected cancer patients receiving chemotherapy. An HCV-related hepatitis flare during chemotherapy may lead to the discontinuation of potentially life-saving chemotherapy. Currently, universal HCV screening is recommended in hematological malignancy patients before chemotherapy, but there is no evidence-based guideline for other cancer patients. DAAs treatment can cure HCV infection and prevent HCV reactivation during chemotherapy.


Assuntos
Hepatite B Crônica , Hepatite C Crônica , Hepatite C , Antivirais/efeitos adversos , Hepacivirus , Hepatite B Crônica/tratamento farmacológico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Exacerbação dos Sintomas , Ativação Viral
20.
Rev Cardiovasc Med ; 22(3): 1063-1072, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34565108

RESUMO

We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32-57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06-0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Meta-analysis evidenced consistency with 4 previous outpatient studies (32,124 patients-Odds ratio 0.31 [0.20-0.47], I2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.


Assuntos
Assistência Ambulatorial , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , COVID-19/tratamento farmacológico , Intervenção Médica Precoce , Hidroxicloroquina/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Azitromicina/efeitos adversos , COVID-19/diagnóstico , COVID-19/mortalidade , Quimioterapia Combinada , Feminino , França , Hospitalização , Humanos , Hidroxicloroquina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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