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2.
Ann Hematol ; 103(9): 3573-3583, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39145781

RESUMO

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.


Assuntos
Interferon alfa-2 , Interferon-alfa , Polietilenoglicóis , Mielofibrose Primária , Proteínas Recombinantes , Humanos , Mielofibrose Primária/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Método Duplo-Cego , Interferon-alfa/uso terapêutico , Interferon-alfa/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon alfa-2/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Idoso
3.
Expert Opin Pharmacother ; 25(11): 1439-1452, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39106053

RESUMO

INTRODUCTION: The treatment landscape of polycythemia vera (PV) has seen major advancements within the last decade including approval of ruxolitinib in the second line setting after hydroxyurea, ropegylated interferon-α2b, and advanced clinical development of a novel class of agents called hepcidin mimetics. AREAS COVERED: We provide a comprehensive review of the evidence discussing the risk stratification, treatment indications, role and limitations of phlebotomy only approach and pivotal trials covering nuances related to the use of interferon-α (IFN-α), ruxolitinib, hepcidin mimetics, and upcoming investigational agents including HDAC and LSD1 inhibitors. EXPERT OPINION: The research paradigm in PV is slowly shifting from the sole focus on hematocrit control and moving toward disease modification. The discovery of hepcidin mimetics has come as a breakthrough in restoring iron homeostasis, achieving phlebotomy-independence and may lead to improved thrombosis-free survival with stricter hematocrit control. On the other hand, emerging data with IFN- α and ruxolitinib as well as combination of the two agents suggests the potential for achieving molecular remission in a subset of PV patients and long-term follow-up is awaited to validate the correlation of molecular responses with clinically relevant outcomes of progression-free and thrombosis-free survival.


Assuntos
Interferon-alfa , Nitrilas , Flebotomia , Policitemia Vera , Pirazóis , Policitemia Vera/tratamento farmacológico , Humanos , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Pirimidinas/uso terapêutico , Hepcidinas/metabolismo , Interferon alfa-2/uso terapêutico , Hematócrito
4.
BMC Infect Dis ; 24(1): 830, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39148030

RESUMO

BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.


Assuntos
Antivirais , Quimioterapia Combinada , Hepatite B Crônica , Interferon-alfa , Polietilenoglicóis , Proteínas Recombinantes , Tenofovir , Humanos , Tenofovir/uso terapêutico , Tenofovir/administração & dosagem , Tenofovir/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Masculino , Feminino , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Antivirais/administração & dosagem , Criança , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Interferon-alfa/uso terapêutico , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Pré-Escolar , Resultado do Tratamento , Interferon alfa-2/uso terapêutico , Interferon alfa-2/administração & dosagem , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/efeitos dos fármacos , DNA Viral/sangue , Alanina/uso terapêutico , Alanina/análogos & derivados
5.
Front Cell Infect Microbiol ; 14: 1426960, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39176265

RESUMO

Background and aims: Limited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure. Methods: A total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks. Results: At week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p<0.001) and higher HBsAg seroconversion rate (38.10% vs 2.38%,p<0.001). Baseline HBsAg levels (Odds Ratio [OR]: 0.051, 95% Confidence Interval [CI]: 0.003-0.273, P=0.010), HBsAg at week 24 (OR:0.214, 95%CI:0.033-0.616, P=0.022), HBsAg decline at week 24 (OR:4.682, 95%CI: 1.624-30.198, P=0.022) and postpartum flare (OR:21.181, 95%CI:1.872-633.801, P=0.030) were significantly associated with HBsAg loss at week 48 after Peg-IFN alpha-2b therapy. Furthermore, the receiver operating characteristic curve (ROC) showed that the use of baseline HBsAg<182 IU/mL, HBsAg at week24 < 4 IU/mL and HBsAg decline at week24>12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported. Conclusion: Peg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.


Assuntos
Antivirais , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Hepatite B Crônica , Interferon alfa-2 , Interferon-alfa , Polietilenoglicóis , Período Pós-Parto , Proteínas Recombinantes , Humanos , Feminino , Hepatite B Crônica/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adulto , Antígenos E da Hepatite B/sangue , Antivirais/uso terapêutico , Interferon-alfa/uso terapêutico , Estudos Retrospectivos , Interferon alfa-2/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Resultado do Tratamento , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Adulto Jovem , Soroconversão
6.
Braz J Otorhinolaryngol ; 90(5): 101449, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38972285

RESUMO

OBJECTIVES: Exophytic Sinonasal Papilloma (ESP) is a benign tumor of the sinonasal tract. Complete surgical excision by endoscopic surgery is the treatment of choice. However, a high recurrence rate (36% at 5-year follow-up) is associated with this method, which may indicate the presence of microorganisms such as Human Papillomavirus (HPV). It is important to note that the standard treatment for ESP does not include antiviral drugs. In our study, we are testing the effectiveness of an interferon-containing drug in reducing recurrence and postoperative reactions in patients with ESP. METHODS: We included 78 patients aged 23-83 years with a confirmed diagnosis of ESP by rhinoscopy and nasal endoscopy and a positive PCR test for HPV in nasal scrapings. To compare the results, we divided the patients into main and control groups. The main group received recombinant human interferon after surgery, while the control group did not receive the drug. We performed a statistical analysis to compare the proportion of patients without reactive manifestations at different stages of the postoperative period, as well as to compare the proportion of patients with recurrent ESP at certain stages of observation. RESULTS: The introduction of recombinant human interferon accelerated the resolution of postoperative reactions and promoted the healing of the nasal mucosa after surgical removal of the ESP. We also found a statistically significant association between treatment with recombinant interferon and a reduction in the recurrence rate of ESP. CONCLUSION: According to the results of the study, it was found that in the main group of patients who received rhIFN-α2b (recombinant human Interferon alpha 2b) in the postoperative period, the frequency of relapses of ESP and the time of postoperative recovery were significantly lower than in patients in the control group who did not take the drug. LEVEL OF EVIDENCE: Cohort Study.


Assuntos
Interferon alfa-2 , Interferon-alfa , Papiloma , Infecções por Papillomavirus , Humanos , Pessoa de Meia-Idade , Adulto , Idoso , Masculino , Feminino , Interferon alfa-2/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Idoso de 80 Anos ou mais , Adulto Jovem , Interferon-alfa/uso terapêutico , Resultado do Tratamento , Papiloma/tratamento farmacológico , Papiloma/cirurgia , Papiloma/virologia , Neoplasias Nasais/cirurgia , Neoplasias Nasais/tratamento farmacológico , Neoplasias Nasais/virologia , Proteínas Recombinantes/uso terapêutico , Recidiva Local de Neoplasia , Antivirais/uso terapêutico
8.
Int J Hematol ; 120(2): 151-156, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38951434

RESUMO

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis. A phase 2 study reported that ropeginterferon alfa-2b is a well-tolerated and effective treatment for PV in Japanese patients. This post hoc analysis of the phase 2 data further evaluated outcomes in patients at low risk of thrombosis (low-risk PV). Among 20 patients with low-risk PV, 60.0% (12/20) and 85.0% (17/20) achieved < 45% hematocrit by weeks 24 and 52, respectively. The proportion of responders with complete hematologic response (CHR) was 60.0% (12/20) at week 52, and the median time to response was 11.9 months. The mean JAK2 V617F allele burden decreased from 75.8% at baseline to 53.7% at week 52. No patient experienced thrombosis or bleeding episodes. All patients experienced treatment-emergent adverse events (TEAEs) related to ropeginterferon alfa-2b, but no grade ≥ 3 TEAEs or deaths related to ropeginterferon alfa-2b occurred, and no new safety concerns arose. This analysis indicated that ropeginterferon alfa-2b may be an effective treatment option for Japanese patients with low-risk PV.


Assuntos
Interferon alfa-2 , Interferon-alfa , Policitemia Vera , Polietilenoglicóis , Proteínas Recombinantes , Humanos , Policitemia Vera/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Interferon-alfa/uso terapêutico , Interferon-alfa/efeitos adversos , Interferon-alfa/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon alfa-2/administração & dosagem , Interferon alfa-2/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Resultado do Tratamento , Idoso , Janus Quinase 2/genética , Japão , Adulto , Povo Asiático , População do Leste Asiático
9.
Microb Cell Fact ; 23(1): 163, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824527

RESUMO

BACKGROUND: Type I interferons (IFN-I)-a group of cytokines with immunomodulatory, antiproliferative, and antiviral properties-are widely used as therapeutics for various cancers and viral diseases. Since IFNs are proteins, they are highly susceptible to degradation by proteases and by hydrolysis in the strong acid environment of the stomach, and they are therefore administered parenterally. In this study, we examined whether the intestinal bacterium, enteropathogenic Escherichia coli (EPEC), can be exploited for oral delivery of IFN-Is. EPEC survives the harsh conditions of the stomach and, upon reaching the small intestine, expresses a type III secretion system (T3SS) that is used to translocate effector proteins across the bacterial envelope into the eukaryotic host cells. RESULTS: In this study, we developed an attenuated EPEC strain that cannot colonize the host but can secrete functional human IFNα2 variant through the T3SS. We found that this bacteria-secreted IFN exhibited antiproliferative and antiviral activities similar to commercially available IFN. CONCLUSION: These findings present a potential novel approach for the oral delivery of IFN via secreting bacteria.


Assuntos
Escherichia coli Enteropatogênica , Sistemas de Secreção Tipo III , Escherichia coli Enteropatogênica/metabolismo , Humanos , Sistemas de Secreção Tipo III/metabolismo , Interferon-alfa/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo , Interferon alfa-2/metabolismo , Proliferação de Células/efeitos dos fármacos
10.
Antiviral Res ; 228: 105924, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38862076

RESUMO

Human interferon α2 (IFNα2) is a cytokine with broad-spectrum antiviral activity, and its engineered forms are widely used to treat viral infections. However, IFNα2 may trigger proinflammatory responses and underlying side effects during treatment. Trefoil factor 2 (TFF2) is a secreted protein with anti-inflammatory properties. Here, we explored whether coupling IFNα2 to TFF2 in a two-in-one fusion form could combine the beneficial effects of both molecules on viral infections toward a more desirable treatment outcome. We engineered two forms of human IFNα2 and TFF2 fusion proteins, IFNα2-TFF2-Fc (ITF) and TFF2-IFNα2-Fc (TIF), and examined their properties in vitro in comparison to IFNα2 and TFF2 alone. RNA-Seq was further used to explore such comparison on dynamic gene regulation at transriptomic level. These in vitro assessments collectively indicated that TIF largely retained the antiviral activity of IFNα2 while being a weaker inflammation inducer, consistent with the presence of TFF2 activity. We further demonstrated the superiority of TIF over IFNα2 or TFF2 alone in treating influenza infection using a mouse infection model. Together, our study provided evidence supporting that, by possessing antiviral activity conferred by IFNα2 with complementation from TFF2 in suppressing the inflammatory side effects, the fusion proteins, particularly TIF, represent more effective agents against influenza and other respiratory viral infections than IFNα2 or TFF2 alone. It implies that merging two molecules with complementary functions holds potential for developing novel therapeutics against viral infections.


Assuntos
Anti-Inflamatórios , Antivirais , Vírus da Influenza A , Infecções por Orthomyxoviridae , Proteínas Recombinantes de Fusão , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Camundongos , Humanos , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/genética , Infecções por Orthomyxoviridae/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Feminino , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon alfa-2/farmacologia , Camundongos Endogâmicos BALB C , Cães , Modelos Animais de Doenças , Células Madin Darby de Rim Canino
11.
Viruses ; 16(6)2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38932280

RESUMO

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.


Assuntos
Antivirais , Modelos Animais de Doenças , Herpes Genital , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Ceratite Herpética , Animais , Coelhos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Camundongos , Herpes Genital/tratamento farmacológico , Herpes Genital/virologia , Ceratite Herpética/tratamento farmacológico , Ceratite Herpética/virologia , Chlorocebus aethiops , Feminino , Células Vero , Interferon alfa-2/administração & dosagem , Interferon alfa-2/uso terapêutico , Replicação Viral/efeitos dos fármacos , Administração Tópica , Soluções Oftálmicas , Interferon-alfa/administração & dosagem , Humanos
12.
J Dermatolog Treat ; 35(1): 2350231, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38754985

RESUMO

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma.Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF.Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment.Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred.Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.


Assuntos
Interferon alfa-2 , Interferon-alfa , Micose Fungoide , Neoplasias Cutâneas , Humanos , Micose Fungoide/terapia , Micose Fungoide/patologia , Micose Fungoide/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Interferon alfa-2/administração & dosagem , Resultado do Tratamento , Idoso , Injeções Subcutâneas , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Terapia Combinada , Fototerapia/efeitos adversos , Estadiamento de Neoplasias , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos
13.
Eur J Ophthalmol ; 34(5): NP13-NP15, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38780357

RESUMO

PURPOSE: To report an unusual case of ocular surface squamous neoplasia (OSSN) associated with human papilloma virus (HPV)-16 infection with an atypical morphology in a young otherwise healthy patient. CASE DESCRIPTION: A 17 year-old healthy male was referred to our department for evaluation of a corneal infiltrate with anterior stromal neovascularization in the right eye. One year before, the patient underwent an excision of a corneo-conjunctival lesion that was located inferiorly in the same eye. Histopathological analysis had shown moderate and severe dysplasia of the conjunctival epithelium and resulted positive for HPV-16. We performed a diagnostic incisional biopsy of the limbal conjunctiva and of the corneal epithelium for histological examination and molecular testing for HPV and Chlamydia by using polymerase chain reaction (PCR). Histopathologic evaluation demonstrated low-grade dysplasia of conjunctiva. PCR testing of the corneal epithelium was positive for HPV-16, similarly to the first biopsy performed by another centre. The patient was successfully treated with topical interferon alfa-2b (1,000,000 IU/ml) for a total of six months. After the treatment, the corneal infiltrate improved dramatically with regression of neovascularization and improvement of corneal transparency and vision. DISCUSSION: The present report described an atypical presentation of HPV-related OSSN due to its unusual morphology, young age of onset and absence of associated comorbidity. CONCLUSION: Conservative treatment with topical interferon-alpha 2b could be used to treat successfully HPV-16 positive OSSN, with no corneal irregularity or potential loss of vision compared to surgical excision.


Assuntos
Neoplasias da Túnica Conjuntiva , Papillomavirus Humano 16 , Interferon alfa-2 , Infecções por Papillomavirus , Humanos , Masculino , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Adolescente , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 16/genética , Interferon alfa-2/uso terapêutico , Interferon alfa-2/administração & dosagem , Neoplasias da Túnica Conjuntiva/diagnóstico , Neoplasias da Túnica Conjuntiva/virologia , Neoplasias da Túnica Conjuntiva/patologia , Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/virologia , Infecções Oculares Virais/tratamento farmacológico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Reação em Cadeia da Polimerase , DNA Viral/análise , DNA Viral/genética , Biópsia , Neoplasias Oculares/diagnóstico , Neoplasias Oculares/tratamento farmacológico , Neoplasias Oculares/virologia , Neoplasias Oculares/cirurgia
15.
Ann Hematol ; 103(7): 2347-2354, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38771499

RESUMO

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.


Assuntos
Interferon alfa-2 , Interferon-alfa , Policitemia Vera , Polietilenoglicóis , Proteínas Recombinantes , Humanos , Policitemia Vera/tratamento farmacológico , Interferon-alfa/uso terapêutico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Interferon alfa-2/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Idoso , Seleção de Pacientes , Resultado do Tratamento , Adulto , Hidroxiureia/uso terapêutico , Hidroxiureia/administração & dosagem
16.
Bioresour Technol ; 400: 130664, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583672

RESUMO

Synechocystis sp. PCC 6803 (Synechocystis) is a unicellular photosynthetic microorganism that has been used as a model for photo-biochemical research. It comprises a potential cell factory for the generation of valuable bioactive compounds, therapeutic proteins, and possibly biofuels. Fusion constructs of recombinant proteins with the CpcA α-subunit or CpcB ß-subunit of phycocyanin in Synechocystis have enabled true over-expression of several isoprenoid pathway enzymes and biopharmaceutical proteins to levels of 10-20 % of the total cellular protein. The present work employed the human interferon α-2 protein, as a study case of over-expression and downstream processing. It advanced the state of the art in the fusion constructs for protein overexpression technology by developing the bioresource for target protein separation from the fusion construct and isolation in substantially enriched or pure form. The work brings the cyanobacterial cell factory concept closer to meaningful commercial application for the photosynthetic production of useful recombinant proteins.


Assuntos
Proteínas Recombinantes , Synechocystis , Synechocystis/metabolismo , Humanos , Proteínas Recombinantes/metabolismo , Interferon-alfa/metabolismo , Interferon alfa-2 , Biossíntese de Proteínas
17.
J Interferon Cytokine Res ; 44(6): 271-280, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38597374

RESUMO

The recombinant human interferon alpha-2b (IFN-α2b) nasal drop formulation (Nasalferon) was studied as prophylaxis for SARS-CoV-2. Healthy volunteers between 19 and 80 years of age received 0.5 million international units of IFN in one drop (0.05 mL ) in each nostril, twice a day, for 10 consecutive days. The nondetection of SARS-CoV-2 by real-time polymerase chain reaction was the primary outcome variable. Several IFN-α biomarkers, including intranasal gene expression and innate immune effector activity, were increased in participants who received intranasal IFN-α2b. The study included 2,930 international travelers and 5,728 persons who were their close contacts. The subjects were treated with Nasalferon in January 2021, and 9,162 untreated travelers were included as controls. COVID-19 rate in treated subjects was significantly lower than in untreated subjects (0.05% vs. 4.84%). The proportion of travelers with COVID-19 decreased from 60.9% to 2.2% between December 2020 and February 2021. Furthermore, 1,719 tourism workers also received Nasalferon, and no cases of SARS-CoV-2 infection were detected, whereas 39 COVID-19 cases (10.6%) were reported in 367 untreated subjects. The main adverse events associated with the use of intranasal IFN-α2b were nasal congestion, headache, and rhinorrhea. Our prophylactic health interventions study demonstrates that the daily administration of Nasalferon for 10 days decreases the risk of developing COVID-19 in healthy volunteers. [Figure: see text].


Assuntos
Administração Intranasal , COVID-19 , Interferon alfa-2 , SARS-CoV-2 , Humanos , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , COVID-19/prevenção & controle , COVID-19/virologia , Idoso , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacos , Interferon alfa-2/administração & dosagem , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Adulto Jovem , Tratamento Farmacológico da COVID-19 , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
18.
Antiviral Res ; 227: 105876, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38641023

RESUMO

BACKGROUND: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy. AIM: To evaluate the use of serum biomarkers to predict HBeAg loss. METHODS: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated. RESULTS: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm. CONCLUSIONS: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.


Assuntos
Antivirais , Biomarcadores , Antígenos E da Hepatite B , Hepatite B Crônica , Interferon-alfa , Polietilenoglicóis , Proteínas Recombinantes , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antivirais/uso terapêutico , Biomarcadores/sangue , DNA Viral/sangue , Quimioterapia Combinada , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
19.
Int Ophthalmol ; 44(1): 184, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630143

RESUMO

PURPOSE: To analyze the efficacy, safety and cost-effectiveness of adjuvant therapy with 5-fluorouracil (5-FU) compared to interferon α-2b (IFNα-2b) after surgery in ocular surface squamous neoplasia (OSSN). METHODS: Retrospective study that included patients diagnosed with OSSN, who underwent surgical excision followed by adjuvant therapy with IFN α-2b (Group A) or 5-FU (Group B), in a tertial referral hospital. Clinical data collected included: demographics, risk factors, appearance, size and location of the lesions, slit-lamp examination, anterior segment optical coherence tomography, iconography and histological classification of subtypes of OSSN. Costs derived from surgery and adjuvant therapy were noted. Resolution of the lesion, recurrences and adverse events were studied. Cost-effectiveness analysis was performed with the incremental cost-effectiveness index (CEI). RESULTS: 54 cases of 54 patients were included, with a mean age of 74.4 years (range 28-109). 30 were male (55.6%), and predominantly Caucasian (79.6%). The main risk factor was prolonged sun exposure (79.6%). Leukoplakic appearance (48.1%), location in bulbar conjunctiva (48.2%) and T3 (46.3%) stage were the most common clinical features. Histologically, the percentage of CIN I, CIN II, CIN III and SCC were 25.9%, 29.6%, 40.7% and 3.7%, respectively. Complete resolution was obtained in 74.1% and tolerance was overall positive. The cost was significantly higher for IFNα (1025€ ± 130.68€) compared to 5-FU (165.57€ ± 45.85 €) (p 0.001). The CEI was - 247.14€. CONCLUSIONS: Both 5-FU and IFN α-2b are effective and present a good security profile as adjuvant therapies after surgery in OSSN. Although presenting slightly more ocular complications, 5-FU can be considered more cost-effective than IFN α-2b.


Assuntos
Carcinoma de Células Escamosas , Neoplasias da Túnica Conjuntiva , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Análise Custo-Benefício , Centros de Atenção Terciária , Fluoruracila/uso terapêutico , Análise de Custo-Efetividade , Estudos Retrospectivos , Interferon-alfa/uso terapêutico , Interferon alfa-2/uso terapêutico , Túnica Conjuntiva , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/cirurgia
20.
Blood Adv ; 8(10): 2384-2397, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38489234

RESUMO

ABSTRACT: Sézary syndrome (SS) is an aggressive leukemic expansion of skin-derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse because of the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear because of limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides with SS using single-cell transcriptome analysis in parallel with high-throughput T-cell receptor sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sézary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired fragment crystallizable γ-dependent phagocytosis, decreased responsiveness to cytokine stimulation, and limited repertoire of intercellular interactions with Sézary cells. Type I interferon supplementation when combined with a monoclonal antibody targeting the chemokine receptor type 4 (CCR4), unleashed monocyte induced phagocytosis and eradication of Sézary cells in vitro. In turn, coadministration of interferon-α with the US Food and Drug Administration-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells after Sézary cell ablation lacked any immunologic shifts. These findings collectively unveil an auxiliary role for augmenting monocytic activity during mogamulizumab therapy in the treatment of SS and underscore the importance of targeted combination therapy in this disease.


Assuntos
Anticorpos Monoclonais Humanizados , Interferon alfa-2 , Monócitos , Micose Fungoide , Síndrome de Sézary , Síndrome de Sézary/imunologia , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patologia , Síndrome de Sézary/terapia , Micose Fungoide/imunologia , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Análise da Expressão Gênica de Célula Única , Macrófagos/imunologia , Interferon Tipo I/imunologia , Monócitos/imunologia , Inflamação/imunologia , Inflamação/patologia , Interferon alfa-2/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Terapia Combinada , Linfócitos T CD4-Positivos/imunologia
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