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3.
Front Immunol ; 13: 899617, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720389

RESUMO

COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed for use as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is different from sera of immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04567810, identifier NCT04567810.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Antivirais , COVID-19/prevenção & controle , Galinhas , Feminino , Humanos , Imunoglobulinas , Ratos , Glicoproteína da Espícula de Coronavírus
4.
Artigo em Inglês | MEDLINE | ID: mdl-34969665

RESUMO

BACKGROUND: Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model. METHODS: This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression. RESULTS: Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN. CONCLUSION: IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation. TRIAL REGISTRATION NUMBER: NCT02442960.


Assuntos
Colite Ulcerativa , Colite , Indigofera , Animais , Colite Ulcerativa/tratamento farmacológico , Citocromo P-450 CYP1A1/uso terapêutico , Humanos , Índigo Carmim/uso terapêutico , Camundongos , Qualidade de Vida , RNA/uso terapêutico
5.
Front Immunol ; 12: 696003, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177963

RESUMO

Antiviral, antibacterial, and antiparasitic drugs and vaccines are essential to maintaining the health of humans and animals. Yet, their production can be slow and expensive, and efficacy lost once pathogens mount resistance. Chicken immunoglobulin Y (IgY) is a highly conserved homolog of human immunoglobulin G (IgG) that has shown benefits and a favorable safety profile, primarily in animal models of human infectious diseases. IgY is fast-acting, easy to produce, and low cost. IgY antibodies can readily be generated in large quantities with minimal environmental harm or infrastructure investment by using egg-laying hens. We summarize a variety of IgY uses, focusing on their potential for the detection, prevention, and treatment of human and animal infections.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Galinhas/imunologia , Imunoensaio , Imunoglobulinas/uso terapêutico , Doenças Parasitárias/tratamento farmacológico , Viroses/tratamento farmacológico , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/imunologia , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Especificidade de Anticorpos , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/imunologia , Infecções Bacterianas/virologia , Humanos , Imunoglobulinas/biossíntese , Imunoglobulinas/imunologia , Doenças Parasitárias/diagnóstico , Doenças Parasitárias/imunologia , Doenças Parasitárias/virologia , Valor Preditivo dos Testes , Viroses/diagnóstico , Viroses/imunologia , Viroses/virologia
6.
J Med Virol ; 93(6): 3752-3760, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33150966

RESUMO

Combination regimens of direct-acting antiviral agents (DAAs) for chronic genotype 1 hepatitis C virus (HCV) infection given for 8 or 12 weeks have high cure rates. Shortened treatment durations that maintain high cure rates may lessen treatment barriers related to affordability and drug adherence. We enrolled 12 treatment-naïve adults with chronic genotype 1 HCV infection without cirrhosis in a single-center, open-label trial to receive 2 weeks of the highly potent and selective non-nucleoside inhibitor (NNI) CDI-31244 concurrent with 6 weeks of sofosbuvir/velpatasvir. The main efficacy endpoints were sustained virologic response at 12 (SVR12) and 24 (SVR24) weeks after treatment completion. In all patients, plasma HCV RNA levels rapidly decreased during the first 2 days of treatment and were below the lower limit of quantification by the end of the 6-week treatment period. Eight of 12 (67%) patients achieved both SVR12 and SVR24. Four patients had virological relapse at Week 10, 4 weeks after end of treatment. The most common adverse event was headache, occurring in five (42%) patients. Pharmacokinetic analysis showed no relevant drug interactions between CDI-31244, sofosbuvir, and velpatasvir. In this pilot study of short-duration combination therapy involving a novel NNI with a fixed-combination DAA, 8 of 12 treatment-naïve patients with chronic genotype 1 HCV infection without cirrhosis achieved virologic cure. Future trials might evaluate whether extending the NNI duration beyond 2 weeks with combination DAAs results in higher cure rates comparable with currently approved longer duration therapy.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , RNA Viral/sangue , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo
7.
Pharmacol Rev ; 64(3): 583-620, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22659328

RESUMO

Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. Advances in understanding the pathobiology over the last 2 decades have led to therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins or analogs) initially directed at reversing the pulmonary vasoconstriction and more recently directed toward reversing endothelial cell dysfunction and smooth muscle cell proliferation. Despite these advances, disease progression is common even with use of combination regimens targeting multiple mechanistic pathways. Overall 5-year survival for PAH has increased significantly from approximately 30% in the 1980s to approximately 60% at present, yet remains abysmal. This review summarizes the mechanisms of action, clinical data, and regulatory histories of approved PAH therapies and describes the latest agents in late-stage clinical development.


Assuntos
Anti-Hipertensivos , Hipertensão Pulmonar/tratamento farmacológico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Descoberta de Drogas , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/metabolismo , Circulação Pulmonar/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
8.
J Urol ; 173(5): 1590-4, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15821499

RESUMO

PURPOSE: Interstitial cystitis is a painful bladder condition of unknown etiology and poorly understood pathophysiology. Current therapies have met with limited success. Vanilloid receptor agonists such as resiniferatoxin (RTX) desensitize C-fibers that transmit pain; it is hypothesized that such drugs will be effective in the treatment of interstitial cystitis and painful bladder syndrome by decreasing the pain that leads to urinary frequency and urgency. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled study was conducted in 163 patients with interstitial cystitis. Participants were randomly assigned to receive a single intravesical dose of 50 ml of either RTX 0.01 microM, 0.05 microM, 0.10 microM, or placebo. Safety and efficacy was evaluated over 12 weeks. The primary efficacy endpoint was the Global Response Assessment, a 7-point scale rating overall change in symptoms of interstitial cystitis after 4 weeks. Secondary efficacy endpoints included reduction in pain, urgency, frequency, nocturia, average void volume, and the O'Leary-Sant Symptom and Problem Indexes. RESULTS: RTX did not improve overall symptoms, pain, urgency, frequency, nocturia, or average void volume during 12 weeks followup. RTX resulted in a dose-dependent increase in the incidence of instillation pain, but was otherwise generally well tolerated. CONCLUSIONS: In the largest prospective, randomized clinical trial reported to date with intravesical vanilloid therapy, single administration of RTX at doses of 0.01 microM to 0.10 microM was not effective in patients with interstitial cystitis.


Assuntos
Cistite Intersticial/tratamento farmacológico , Diterpenos/administração & dosagem , Neurotoxinas/administração & dosagem , Administração Intravesical , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Am J Respir Crit Care Med ; 169(4): 441-7, 2004 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-14630619

RESUMO

Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak VO(2) at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, VO(2) at anaerobic threshold, VE per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak VO(2) compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.


Assuntos
Antagonistas dos Receptores de Endotelina , Hipertensão Pulmonar/tratamento farmacológico , Isoxazóis/uso terapêutico , Tiofenos/uso terapêutico , Adolescente , Adulto , Idoso , Limiar Anaeróbio , Método Duplo-Cego , Teste de Esforço , Tolerância ao Exercício , Feminino , Hemodinâmica , Humanos , Hipertensão Pulmonar/fisiopatologia , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Tiofenos/efeitos adversos
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