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AReviewofRussianezrinpeptidetreatmentofacuteviralrespiratorydiseaseandvirusinducedpneumoniaapotentialtreatmentforcovid-19..pdf817.75 KB
AReviewofRussianezrinpeptidetreatmentofacuteviralrespiratorydiseaseandvirusinducedpneumoniaapotentialtreatmentforcovid-19..pdf817.75 KB
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2COVID-19patients display a spectrum of disease severity. About 80% haveAcute Viral Respiratory Disease (AVRI) withfeveraround 38oC,dry cough and amild pneumonia. About 15% have severe disease with lung inflammation leading to Acute Respiratory DistressSyndrome (ARDS): including dyspnoea (shortness of breath), and hypoxia (low blood oxygen). About 5% have critical disease:Acute Lung Injury (ALI)including respiratory failure, shock, multi-organ dysfunctionand in about 0.5%to 2% cases, death.11Human Ezrin, Old-Age and COVID-19 fatalityIn Chinese and Italian cohorts of COVID-19 virus infected people, severe and critical disease was very common in people over 65 years old. In contrast, symptomatic infection in childrenwith COVID-19 virusisrare and mild. In aChineseCDCreport, less than2%of all symptomatic infectionswere in individuals younger than 20 years old. In a small study of 10 childrenin China who did develop symptoms, clinical illness was mild; 80 percent had fever, which resolved within 24 hours, 60%had cough, 40%had sore throat, and none required supplemental oxygen.12There is clearly a human factor related to aging that is interacting with COVID-19 virus.In 2012, it was discovered that human ezrin, a submembrane protein that is involved in cell shape, motility, receptor organisation and cell signalling, specificallybound to the carboxy-terminus of the SARS coronavirus spike protein,using its FERM domain. The coronavirus was dependent on using a specific conformation of human ezrin to fuse with the epithelial cells of the airways and successfully infect them. The fully active conformation of ezrin, restrains coronavirus infection at the cell-entry stage. 13Increased expression of non-functional ezrin is associated with organism age and senescence, which accumulates on the interior surface of the cell membrane. 14In old rats, there is a fourfold increase in membrane associated ezrin in old epithelial cells, compared to young epithelial cells. 15Old mice also have 3defective CD4 T lymphocytes, which display age-related defects in ezrin-mediated cytoskeletal signals16. The failure of Ezrin signalling complexes over time with age, may in part explain the age-related fatality observed with COVID-19 disease.Ezrin Peptide TherapyEzrin peptides mimicking the trigger-hinge region of the alpha-domain of human ezrin, are highly polar molecules, with alternating negative and positive charges, which act locally on epithelial cells and fibroblasts inmucus membranes. The receptors for ezrin peptides are believed to be membrane associated ezrin-protein signalling complexes. Ezrin peptides are thought to have an allosteric effect, which results in changes of the conformation of ezrin into various functional forms. These changes can not only prevent viruses entering cells, but also can activate specific signalling pathways. Ezrin-protein complexes are associated with the regulation of the ras>raf>MEK>ERK and PI3K>PKB>mTOR intracellular signalling pathways, andthey are involved in the control of cytokine and interferon expression. Ezrin peptides also act on fibroblasts to stimulate tissue repair processes. 17Clinical studies in Russia over twenty-five years have shown that ezrin peptides can safely and effectively treat viral infections caused by HIV, HCV, HPV, Herpes Simplex 1 & 2, and the spectrum of viruses that cause Acute Viral Respiratory Infection (AVRI). Clinical trials of ezrin peptide TEKKRRETVEREKE [Gepon], determined that the ezrin-peptides possessanti-viral, immuno-modulatingactivity andanti-inflammatory activity, and could beused for successful prevention and treatment of a wide range of infectious diseases caused by viruses, bacteria, chlamydia, mycoplasmas, and candidafungi. 18192021222324252627282930Generally, clinical studies have demonstrated that ezrin peptides are safe, reduce virally induced inflammation, and lead to faster recovery from Acute Viral Respiratory Infection (AVRI). Ezrin 4peptides have even successfullytreated viral pneumonia by shutting down non-specific inflammation, and symptoms of viral infection, probably by amplifying specific anti-viral responses selected by the immune system. CLINICAL STUDY ONE100patient clinical study into intra-nasal Ezrin-peptide TEKKRRETVEREKE[Gepon] solution, as a treatmentof Acute Viral Respiratory Infection[AVRI], inflammatoryLaryngeal-Tracheal-Bronchitis with Stenosis [LTBS]and Recurrent Croup[RC]IntroductionIn year 2000, V.F. Uchaikin, Member of The Russian Academy of Medical Sciences, organizedapost-registration clinical study offourteen amino-acidsyntheticEzrin-peptide TEKKRRETVEREKE[Gepon], atthe MorozovMoscow Children’s Hospital, in collaboration with The Russian Government Medical University, Moscow.The PrincipalClinical Investigators in the clinical study into the safety and efficacy of Gepon in Recurrent Acute Respiratory Diseases were: Kladova O.V., MD, Doctorof Medical Sciences, Professor, Department of children’s infectious diseases of the Russian State Medical University: Legkova T.P., Head of Moscow Children’s Hospital No18 and Ovchinnikova G.S., Doctor of Children’s Home No 5The objective of the clinical study was to test the efficacy of intra-nasal application of ezrin-peptide TEKKRRETVEREKE [Gepon]31,in treatingofrecurrent Acute Viral Respiratory Infection[AVRI], which results in inflammation,and laryngitis-tracheitis-bronchitis complicated with laryngeal stenosis and/or croup syndrome. 323334The clinical research was approved by aDecision of the Committee on Ethics (Minutes No: 6 of 06 December 2000), and a Decision of the Pharmacology Committee (Minutes No: 14 of 21 December 2000).Permission to conduct clinical trialswasissued by the Department of the Stateforcontrol of quality, efficiency and 5safety of the medical preparations and equipment (No: 183 of 31 January 2001).Assessed Patient Population125 child-patientsbetween the ages of 1 year to 14 years old, sufferingAcute Respiratory Virus Infection [AVRI], Virus Induced Inflammation, Laryngeal-Tracheal-Bronchitis with Stenosis [LTBS] and Recurrent Croup [RC] syndrome,were assessed for the clinical trial.ARVI occurred in 85% of the children.50 children suffered Laryngeal-Tracheal-Bronchitis with Laryngeal Stenosis (LTBS) and 75 children suffered Recurrent Croup(RC). The recurrent croup was caused by a chronic virus-induced non-specific inflammation of the upper respiratory tract.The frequency of recurring croup(RC)in child-patients wasbetween 3 to 35 times per annum. Recurrent croup syndrome was associated with 1stdegree stenosis of the larynx in 54of the RC patients(72%), by 2nddegree stenosis of the larynx in 21of the RC patients(28%).10% of the croup cases had no fever, 60% of the croup cases suffered sub-febrile fever, 30% of the croup cases suffered febrile fever. Theaverageduration of fever was 3-4 days. Bacterial complications were observed in 15%,including sore throats, acute otitis media, eustachyitis, and pneumonia.Half of the child-patientswere under treatment in hospital,and half were treated as out-patients at home.Immune Statusof Assessed Patient PopulationThe 125 children of theassessed patient populationwere offered immune status analysis, which was then compared to the average status of healthy children.Generally, a profound non-specificinflammatory response was being induced and maintainedby the viral infection. In contrast, specific anti-viral immunity had beendisrupted. Blood sampleswere assessedby flow-cytometry using monoclonal antibody markers:CD3, CD4, CD8, CD16, CD20, 6CD1b, CD25, CD38, CD54, CD71, CD95, and HLA-DR,to determinethe distribution oflymphocyte sub-populations. In addition, co-expression of [CD4+, CD8+], [CD8, DR] and [CD16+, CD8+]was also measured. The ex vivo phagocytic activities of blood monocytes and neutrophils versus Staphylococcus Aureus were alsodetermined. The levels of inflammatory cytokinesIL-1, IL-6, IL-8 and TNFwere analysed.The functional activity of Th1 and Th2 cellswere assessed andthe level of expression of the interleukins IL-2 and IL-4 were measured. Interferon status of the children was assessed by the functional 1988 Yershov method and by expression of Interferon-gamma.The concentrations of serum IgA IgE, IgG and IgM immunoglobulins were also analysed.The viral respiratory infection had induced a marked imbalance in T cell and B cell immunity, and also significantly impaired the normal functionality of blood monocytes, neutrophils and lymphocytes. For example, lymphocyte adhesion and apoptosis were4x to5x above normal levels. The most consistent differencesbetweenthe assessedchild-patients and healthy children, were the largesignificantincreasesinthe concentrations ofinflammatory cytokines: IL-1, IL-6, IL-8 and TNFIL-6 was significantly elevated 2.1x in vivoand 9x in vitro, and hugely elevated 26x when induced in vitro. IL-8 and TNFalso showed a similar pattern of massive elevation.(Table 1)In the Assessed Patient Population,levels of T cell activatingIL-2 and IL-4,were significantly increased.The level of IL-2 in vivowas increased 24x, in vitrospontaneous production of IL-2 was increased 12x, and in vitroinduced production increased by 5.1x. The level of IL-4 both in vivoand in vitroalso showed similar elevations.The level of mature T-lymphocytes in children was increased by 1.3x over healthy children. Activated [CD71+, CD38+, CDA+, ADD+] lymphocytes were significantly reduced. The assessed patient population hadmarked changes in the immuno-regulatory 7population of cells. The Th1 cell population was 0.63x less than normal, whereas the Th2 cellpopulation was 1.49x more thannormal. There was a significant reduction in the expression of IL-2 Receptors (IL2R+).There was also a significant reduction in the proportion of cytotoxic T cells [CD16+, CD8+, HLA-DR+] and activated [CD8+, HLA-DR+] cells. Macrophage function was disrupted;phagocytosis was reduced 1.6x, phagocytic-index was reduced 1.2x,but absolute-phagocyte-indicator was 1.6x above normal.Neutrophils were significantly increased. Serum IgG and IgE were significantly increased, but IgA was decreased, while IgM stayed normal. Interferon production wasalsodisrupted:interferon-interferon-and interferon-were also significantly reduced.8Table 1.Immunological Status of Assessed Children withAVRI, Virus Induced Inflammation,LTBS and RC,vs healthy childrenLess than healthy children:-, Same as healthy children: n, More than healthy children: +,ImmunologicalVirus Induced ChangeParameterLeucocytes++Lymphocytes-Mature T lymphocytes+Th1Subpopulation--Th2Subpopulation+IRI++Activated CD8+--IL2R+ cells-HLA DR+ cells--NKcells-CD16+CD8+--Mature B lymphocytes++IgG++IgA--IgMnIgE++Neutrophils++Segmented nuclear+Rod-like nuclearn/+Phagocytes-Phagocytic index--Absolute phagocytic index+Production of interferon--IL-1 alpha (in vivo)++IL-1 alpha (in vitro)++IL-2 (in vitro)++IL-2 (in vivo) ++IL-4 (in vitro) ++IL-4 (in vivo) ++IL-6 (in vitro) ++IL-6 (in vivo) ++IL-8 (in vitro) ++IL-8 (in vivo) ++TNF alpha (in vitro) ++TNF alpha (in vivo) ++________________________________________________________________________________________9Criteria for theGeponClinical StudyChild-patientsaged between 1 and 14 years, with a verified diagnosis ofrecurrentrespiratory disease, with 5 or more incidents per annumrecorded in theirmedical documentation,and suffering from Laryngeal-Tracheal-Bronchitis with Stenosis and / or Recurrent Croup, were included in the study.Child-patients were excluded from the study: if the child-patient refused to take part in the clinical trials; if they were below 1 year, or over 14 years of age; they had received any immuno-modulator therapy with the previous 4 months; if otherdiseaseswere present, such asinsulin-dependent diabetes, tuberculosis, chronic kidneyand liver diseases, oncological diseasesor HIV-infection. Patients were also excluded: if theirdoctor’s advice was not followed, ifside effects appearedwhich might require special treatment, and if thechild-patient’sdoctor decided that it was in the interest ofthe child-patientto terminate participation in the Clinical Study.Entry of Child-Patients to the GeponClinical Study.Of the 125 child-patients who had been assessed, 100 were invited to join the clinical study of Gepon. Child-patient’svoluntary participation in the clinical research,was subject to informed written agreement by their parents or guardians. Participation in the clinical research was voluntary,free of charge, and free of incentive payment.Each child-patient wasassessed for: body temperature, skin condition, peripheral lymph nodes, fauces(the arched opening at the back of the mouth leading to the pharynx), and tonsils; function of the lungs, heart,nervoussystem, muscular system and other evaluations.The time elapsed between receiving writtenagreement and the start of theGepontherapy was between 1 and