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1.
Rinsho Ketsueki ; 62(5): 378-387, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34108318

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease whose main symptom is complement-mediated intravascular hemolysis as a result of the clonal expansion of hematopoietic stem cells having mutations in genes involved in glycosylphosphatidylinositol (GPI) anchor synthesis including PIGA. With the advent of a humanized anti-C5 monoclonal antibody (eculizumab), the inhibitory effect on hemolysis, improvement in its various complicating symptoms, and preventive effect on thrombus formation were observed. In addition, the QOL in patients with PNH was significantly improved. Subsequently, the technology of recycling antibodies (ravulizumab and crovalimab) significantly extended the treatment interval and improved convenience, although the poor improvement of anemia due to extravascular hemolysis has been a major issue in some patients. Several clinical trials using proximal complement inhibitors (C3, factor D, factor B) are being conducted to overcome this critical task. Not only efficacy but also safety and convenience will be evaluated, and the best therapeutic agent will be selected in the near future.


Assuntos
Hemoglobinúria Paroxística , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Qualidade de Vida
2.
Cochrane Database Syst Rev ; 3: CD012862, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33783815

RESUMO

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. The condition is primarily caused by inherited or acquired dysregulation of complement regulatory proteins with ~40% of those affected aged < 18 years. Historically, kidney failure and death were common outcomes, however, improved understanding of the condition has led to discovery of novel therapies. OBJECTIVES: To evaluate the benefits and harms of interventions for aHUS. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies for randomised controlled studies (RCTs) up to 3 September 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. MEDLINE(OVID) 1946 to 27 July 2020 and EMBASE (OVID) 1974 to 27 July 2020 were searched for non-RCTs. SELECTION CRITERIA: All randomised and non-randomised clinical trials comparing an intervention with placebo, an intervention with supportive therapy, or two or more interventions for aHUS were included. Given the rare nature of the condition in question, prospective single-arm studies of any intervention for aHUS were also included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted pre-specified data from eligible studies and evaluated risk of bias using a newly developed tool based on existing Cochrane criteria. As statistical meta-analysis was not appropriate, qualitative analysis of data was then performed. MAIN RESULTS: We included five single-arm studies, all of which evaluated terminal complement inhibition for the treatment of aHUS. Four studies evaluated the short-acting C5 inhibitor eculizumab and one study evaluated the longer-acting C5 inhibitor ravulizumab. All included studies within the review were of non-randomised, single-arm design. Thus, risk of bias is high, and it is challenging to draw firm conclusions from this low-quality evidence. One hundred patients were included within three primary studies evaluating eculizumab, with further data reported from 37 patients in a secondary study. Fifty-eight patients were included in the ravulizumab study. After 26 weeks of eculizumab therapy there were no deaths and a 70% reduction in the number of patients requiring dialysis. Complete thrombotic microangiopathic (TMA) response was observed in 60% of patients at 26 weeks and 65% at two years. After 26 weeks of ravulizumab therapy four patients had died (7%) and complete TMA response was observed in 54% of patients. Substantial improvements were seen in estimated glomerular filtration rate and health-related quality of life in both eculizumab and ravulizumab studies. Serious adverse events occurred in 42% of patients, and meningococcal infection occurred in two patients, both treated with eculizumab. AUTHORS' CONCLUSIONS: When compared with historical data, terminal complement inhibition appears to offer favourable outcomes in patients with aHUS, based upon very low-quality evidence drawn from five single-arm studies. It is unlikely that an RCT will be conducted in aHUS and therefore careful consideration of future single-arm data as well as longer term follow-up data will be required to better understand treatment duration, adverse outcomes and risk of disease recurrence associated with terminal complement inhibition.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Inativadores do Complemento/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome Hemolítico-Urêmica Atípica/mortalidade , Viés , Inativadores do Complemento/efeitos adversos , Taxa de Filtração Glomerular , Humanos , Ensaios Clínicos Controlados não Aleatórios como Assunto , Qualidade de Vida , Microangiopatias Trombóticas/tratamento farmacológico
3.
Int Immunopharmacol ; 95: 107516, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33765610

RESUMO

After the advent of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in the late 2019, the resulting severe and pernicious syndrome (COVID-19) immediately was deployed all around the world. To date, despite relentless efforts to control the disease by drug repurposing, there is no approved specific therapy for COVID-19. Given the role of innate and acquired immune components in the control and elimination of viral infections and inflammatory mutilations during SARS-CoV2 pathogenesis, immunotherapeutic strategies appear to be beneficent. Passive immunotherapies such as convalescent plasma, which has received much attention especially in severe cases, as well as suppressing inflammatory cytokines, interferon administration, inhibition of kinases and complement cascade, virus neutralization with key engineered products, cell-based therapies, immunomodulators and anti-inflammatory drugs are among the key immunotherapeutic approaches to deal with COVID-19, which is discussed in this review. Also, details of leading COVID-19 vaccine candidates as the most potent immunotherapy have been provided. However, despite salient improvements, there is still a lack of completely assured vaccines for universal application. Therefore, adopting proper immunotherapies according to the cytokine pattern and involved immune responses, alongside engineered biologics specially ACE2-Fc to curb SARS-CoV2 infection until achieving a tailored vaccine is probably the best strategy to better manage this pandemic. Therefore, gaining knowledge about the mechanism of action, potential targets, as well as the effectiveness of immune-based approaches to confront COVID-19 in the form of a well-ordered review study is highly momentous.


Assuntos
/imunologia , Imunoterapia/métodos , /uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Inativadores do Complemento/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico
4.
N Engl J Med ; 384(11): 1028-1037, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33730455

RESUMO

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Peptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Inativadores do Complemento/efeitos adversos , Diarreia/induzido quimicamente , Quimioterapia Combinada , Transfusão de Eritrócitos , Hemoglobinas/análise , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/terapia , Humanos , Injeções Subcutâneas/efeitos adversos , Pessoa de Meia-Idade , Peptídeos/efeitos adversos
5.
Lancet Haematol ; 8(5): e344-e354, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33765419

RESUMO

BACKGROUND: The haematological benefit of standard-of-care anti-C5 treatment for haemolytic paroxysmal nocturnal haemoglobinuria is limited by residual intravascular haemolysis or emerging C3-mediated extravascular haemolysis. Therefore, the aim of this phase 2 study was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics, and activity of the new complement factor B inhibitor, iptacopan, in patients with paroxysmal nocturnal haemoglobinuria who have active haemolysis despite anti-C5 therapy. METHODS: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled adult patients (aged 18-80 years) with paroxysmal nocturnal haemoglobinuria who showed signs of active haemolysis despite receiving eculizumab treatment. Patients were enrolled at Federico II University Hospital (Naples, Italy), Hôpital Saint-Louis (Paris, France), and University Hospital Essen (Essen, Germany). For enrolment, patients were required to show lactate dehydrogenase more than 1·5-times the upper limit of normal and a paroxysmal nocturnal haemoglobinuria type 3 erythrocyte or granulocyte clone size of 10% or greater. Patients with bone marrow failure, on systemic steroid or immunosuppressive drugs, or with severe comorbidities were excluded from the study. Iptacopan was given orally as an add-on therapy at a dose of 200 mg twice daily. The primary endpoint was the effect of iptacopan on the reduction of chronic residual intravascular haemolysis measured as change in lactate dehydrogenase from baseline value to week 13. At 13 weeks, patients could opt into a long-term study extension (ongoing), allowing for modifications of standard treatment. This trial is registered at ClinicialTrials.gov, NCT03439839. FINDINGS: Between May 31, 2018, and April 9, 2019, ten patients had twice daily 200 mg iptacopan. Iptacopan resulted in marked reduction of lactate dehydrogenase from baseline versus at week 13 (mean 539 IU/L [SD 263] vs 235 IU/L [44], change from baseline -309·2 IU/L [SD 265·5], 90% CI -473·77 to -144·68, p=0·0081), associated with significant improvement of haemoglobin concentrations (mean 97·7 g/L [SD 10·5] vs 129·5 g/L [18·3] change from baseline 31·9 g/L [14·5], 90% CI 23·42-40·28, p<0·0001). All biomarkers of haemolysis improved on iptacopan treatment. Observed haematological benefits were maintained longer than the 13-week study period, throughout the study extension, including seven patients who stopped concomitant standard-of-care treatment and continued iptacopan as monotherapy. There were no deaths or treatment-related serious adverse events during the study period. Of three non-related serious adverse events, two occurred in the same patient (one during run-in and before exposure to iptacopan). INTERPRETATION: Iptacopan at a chronic dose of 200 mg twice daily was well tolerated without any major drug-related safety findings and shows lactate dehydrogenase reduction and haemoglobin normalisation in most patients with paroxysmal nocturnal haemoglobinuria at week 13 and beyond, even in monotherapy. On the basis of these data, iptacopan will be tested as monotherapy in pivotal trials investigating its haematological benefit in a broader paroxysmal nocturnal haemoglobinuria population. FUNDING: Novartis Institutes for Biomedical Research.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fator B do Complemento/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores/sangue , Fator B do Complemento/metabolismo , Inativadores do Complemento/farmacologia , Quimioterapia Combinada , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Hemoglobinas/análise , Hemólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
6.
Clin Immunol ; 226: 108716, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33774179

RESUMO

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.


Assuntos
/imunologia , Ativação do Complemento/imunologia , Via Alternativa do Complemento/imunologia , Lesão Pulmonar/imunologia , Idoso , Idoso de 80 Anos ou mais , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêutico , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/complicações , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Pessoa de Meia-Idade
7.
Hum Immunol ; 82(4): 264-269, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33632561

RESUMO

The novel Coronavirus SARS-CoV-2 is the viral pathogen responsible for the ongoing global pandemic, COVID-19 (Coronavirus disease 2019). To date, the data recorded indicate 1.62 Mln deaths and 72.8 Mln people infected (WHO situation report Dec 2020). On December 27, the first anti-COVID-19 vaccinations started in Europe. There are no direct antivirals against SARS-CoV-2. Understanding the pathophysiological and inflammatory/immunological processes of SARS-CoV-2 infection is essential to identify new drug therapies. In the most severe COVID-19 cases, an unregulated immunological/inflammatory system results in organ injury that can be fatal to the host in some cases. Pharmacologic approaches to normalize the unregulated inflammatory/immunologic response is an important therapeutic solution. Evidence associates a non-regulation of the "complement system" as one of the causes of generalized inflammation causing multi-organ dysfunction. Serum levels of a complement cascade mediator, factor "C5a", have been found in high concentrations in the blood of COVID-19 patients with severe disease. In this article we discuss the correlation between complement system and COVID-19 infection and pharmacological solutions directed to regulate.


Assuntos
/tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Complemento C3a/antagonistas & inibidores , Complemento C5a/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , /fisiopatologia , Ativação do Complemento/imunologia , Complemento C3a/imunologia , Complemento C5a/imunologia , Humanos , /imunologia
8.
Curr Opin Ophthalmol ; 32(3): 294-300, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630787

RESUMO

PURPOSE OF REVIEW: This review describes therapeutic research programs for geographic atrophy (GA) due to age-related macular degeneration (AMD). We highlight clinical trial data from phase I, II, and III studies. RECENT FINDINGS: There are currently no treatments for GA, a form of advanced AMD that causes significant visual morbidity. Currently, therapeutic candidates are being developed to delay further progression of GA or even attempt to reverse some of the damage. The approaches to therapy range from molecular targets to cell transplantation. Studies of these novel treatment approaches have demonstrated varying degrees of success. The progress in understanding the disease pathophysiology as well as clinical trial data is reviewed. SUMMARY: There are promising new treatments to prevent GA progression as well as some that may reverse the disease course.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Inativadores do Complemento/uso terapêutico , Atrofia Geográfica/terapia , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Progressão da Doença , Humanos
9.
BMC Infect Dis ; 21(1): 137, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526010

RESUMO

BACKGROUND: The use of complement inhibition is well established for complement mediated thrombotic microangiopathy, but its role in secondary forms of thrombotic microangiopathy is debated. We here present a case of thrombotic microangiopathy triggered by Capnocytophaga canimorsus, illustrating the diagnostic difficulties in discriminating between different thrombotic microangiopathies, and the dilemmas regarding how to treat this disease entity. CASE PRESENTATION: A previously healthy 56-year-old woman presented with fever and confusion. She was diagnosed with sepsis from Capnocytophaga canimorsus and thrombotic microangiopathy. Marked activation of both T-cells, endothelium and complement were documented. She was successfully treated with antimicrobial therapy, the complement inhibitor eculizumab and splenectomy. After several weeks, a heterozygote variant in complement factor B was localized, potentially implying the diagnosis of a complement mediated TMA over an isolated infection related TMA. CONCLUSIONS: We discuss the possible interactions between complement activation and other findings in severe infection and argue that complement inhibition proved beneficial to this patient's rapid recovery.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Capnocytophaga/patogenicidade , Ativação do Complemento , Inativadores do Complemento/uso terapêutico , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/tratamento farmacológico , Feminino , Infecções por Bactérias Gram-Negativas , Humanos , Pessoa de Meia-Idade , Noruega/epidemiologia , Sepse/etiologia
10.
Life Sci ; 272: 119245, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33609539

RESUMO

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.


Assuntos
/imunologia , Proteínas do Sistema Complemento/imunologia , /imunologia , Animais , /tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Complemento C3/imunologia , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/patologia
11.
Blood ; 137(4): 443-455, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33507296

RESUMO

Blocking the terminal complement pathway with the C5 inhibitor eculizumab has revolutionized the clinical management of several complement-mediated diseases and has boosted the clinical development of new inhibitors. Data on the C3 inhibitor Compstatin and the C5 inhibitors eculizumab and Coversin reported here demonstrate that C3/C5 convertases function differently from prevailing concepts. Stoichiometric C3 inhibition failed to inhibit C5 activation and lytic activity during strong classical pathway activation, demonstrating a "C3 bypass" activation of C5. We show that, instead of C3b, surface-deposited C4b alone can also recruit and prime C5 for consecutive proteolytic activation. Surface-bound C3b and C4b possess similar affinities for C5. By demonstrating that the fluid phase convertase C3bBb is sufficient to cleave C5 as long as C5 is bound on C3b/C4b-decorated surfaces, we show that surface fixation is necessary only for the C3b/C4b opsonins that prime C5 but not for the catalytic convertase unit C3bBb. Of note, at very high C3b densities, we observed membrane attack complex formation in absence of C5-activating enzymes. This is explained by a conformational activation in which C5 adopts a C5b-like conformation when bound to densely C3b-opsonized surfaces. Stoichiometric C5 inhibitors failed to prevent conformational C5 activation, which explains the clinical phenomenon of residual C5 activity documented for different inhibitors of C5. The new insights into the mechanism of C3/C5 convertases provided here have important implications for the development and therapeutic use of complement inhibitors as well as the interpretation of former clinical and preclinical data.


Assuntos
C3 Convertase da Via Alternativa do Complemento/fisiologia , Complemento C3/antagonistas & inibidores , Complemento C4b/fisiologia , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Via Clássica do Complemento/efeitos dos fármacos , Modelos Imunológicos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Membrana Celular/imunologia , Complemento C5/química , Inativadores do Complemento/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/fisiologia , Resistência a Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Moleculares , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Conformação Proteica
13.
Int J Biol Macromol ; 171: 389-397, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33428960

RESUMO

Zizyphus mauritiana Lam. seeds (ZMS) have been used medicinally as sedative or hypnotic drugs in most of Asian countries. ZMS has significant benefits to the human health. Therefore, we have evaluated immunomodulatory effect of lectin extracted from these ZMSL in both in vitro and in vivo study. Anaphylaxis is a severe life-threatening allergic reaction and Arthus reaction is deposition of immune complex and complement system activation, so we hypothesized that if ZMSL can protect these severe allergic diseases. We have studied the effect of ZMSL on macrophages and Wistar albino rats and confirmed its protective effect against anaphylaxis and Arthus reaction. Results of this study suggest ZMSL have immunostimulatory and antiallergic activity.


Assuntos
Adjuvantes Imunológicos/isolamento & purificação , Antialérgicos/isolamento & purificação , Fatores Imunológicos/isolamento & purificação , Lectinas/isolamento & purificação , Ziziphus/química , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Anafilaxia/prevenção & controle , Animais , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Reação de Arthus/prevenção & controle , Antígenos de Grupos Sanguíneos , Inativadores do Complemento/isolamento & purificação , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Hemaglutinação/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Lectinas/farmacologia , Lectinas/uso terapêutico , Leucócitos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Lisossomos/enzimologia , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Plantas Medicinais/química , Coelhos , Ratos Wistar , Sementes/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
14.
Nat Immunol ; 22(2): 128-139, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398182

RESUMO

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Hipoproteinemia/tratamento farmacológico , Imunidade Inata/efeitos dos fármacos , Enteropatias Perdedoras de Proteínas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Biomarcadores/sangue , Antígenos CD55/deficiência , Antígenos CD55/genética , Complemento C5/metabolismo , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/farmacocinética , Predisposição Genética para Doença , Humanos , Hipoproteinemia/genética , Hipoproteinemia/imunologia , Hipoproteinemia/metabolismo , Mutação , Fenótipo , Enteropatias Perdedoras de Proteínas/genética , Enteropatias Perdedoras de Proteínas/imunologia , Enteropatias Perdedoras de Proteínas/metabolismo , Resultado do Tratamento
15.
Eur Rev Med Pharmacol Sci ; 24(23): 12593-12608, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336780

RESUMO

The coronavirus disease 2019 (COVID-19) is declared as an international emergency in 2020. Its prevalence and fatality rate are rapidly increasing but the medication options are still limited for this perilous disease. The emergent outbreak of COVID-19 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps propagating globally. The present scenario has emphasized the requirement for therapeutic opportunities to relive and overcome this latest pandemic. Despite the fact, the deteriorating developments of COVID-19, there is no drug certified to have considerable effects in the medical treatment for COVID-19 patients. The COVID-19 pandemic requests for the rapid testing of new treatment approaches. Based on the evidence, hydroxychloroquine is the first medicine opted for the treatment of disease. Umifenovir, remdesivir, and fevipiravir are deemed the most hopeful antiviral agent by improving the health of infected patients. The dexamethasone is a first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients. The current review recapitulates the existing evidence of possible therapeutic drugs, peptides, humanized antibodies, convulsant plasma, and vaccination that has revealed potential in fighting COVID-19 infections. Many randomized and controlled clinical trials are taking place to further validate these agent's safety and effectiveness in curing COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , /tratamento farmacológico , /terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antiparasitários/uso terapêutico , Canabinoides/uso terapêutico , Cloroquina/uso terapêutico , Inativadores do Complemento/uso terapêutico , Dexametasona/uso terapêutico , Combinação de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/uso terapêutico , Interferons/uso terapêutico , Ivermectina/uso terapêutico , Lopinavir/uso terapêutico , Pirazinas/uso terapêutico , Ritonavir/uso terapêutico , Teicoplanina/uso terapêutico , Tetraciclinas/uso terapêutico , Tiazóis/uso terapêutico
16.
Front Immunol ; 11: 599417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362783

RESUMO

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.


Assuntos
Complemento C5a/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Nefropatias/tratamento farmacológico , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Nefropatias/imunologia , Nefropatias/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia
17.
Clin Immunol ; 220: 108598, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961333

RESUMO

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Assuntos
Betacoronavirus/patogenicidade , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , /tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Coortes , Ativação do Complemento/efeitos dos fármacos , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/virologia , Pandemias , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , /imunologia , Índice de Gravidade de Doença
18.
PLoS One ; 15(9): e0237497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886668

RESUMO

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Preferência do Paciente , Qualidade de Vida , Adulto Jovem
19.
Am J Case Rep ; 21: e927418, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32917848

RESUMO

BACKGROUND Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. CASE REPORT Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. CONCLUSIONS We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/metabolismo , Infecções por Coronavirus/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Pneumonia Viral/complicações , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Betacoronavirus , Complemento C5/efeitos dos fármacos , Complemento C5/imunologia , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/epidemiologia , Feminino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/imunologia , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Microangiopatias Trombóticas/complicações , Microangiopatias Trombóticas/imunologia
20.
Clin Immunol ; 219: 108555, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771488

RESUMO

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Assuntos
Injúria Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/patogenicidade , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Injúria Renal Aguda/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/virologia , Adulto , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Ativação do Complemento/efeitos dos fármacos , Complemento C4b/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Pandemias , Fragmentos de Peptídeos/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia
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