The use of antiviral drug based on technologically processed antibodies to interferon-γ, CD4 receptor and histamine in the treatment of influenza in adults: results of a multicenter open-label randomized comparative trial with oseltamivir

2021 ◽  
Vol 19 (1) ◽  
pp. 39-57
Author(s):  
K.V. Zhdanov ◽  
◽  
R.F. Khamitov ◽  
V.V. Rafalsky ◽  
M.P. Mikhaylusova ◽  
...  

Objective. A multicenter open-label randomized controlled clinical trial was aimed to compare the efficacy of the study drug (SD) containing technologically processed affinity purified antibodies (high dilutions) to IFN-γ, CD4 receptor and histamine (Ergoferon) with oseltamivir, and evaluate the influence of SD on the antiviral immune response in adults with seasonal influenza. Patients and methods. 184 outpatients aged 18–70 with confirmed influenza of mild/moderate severity were included and randomized into 2 groups (in a 1:1 ratio). Patients received SD (Group 1, n = 92) or oseltamivir (Group 2, n = 92), according to the instructions for medical use for 5 days. As the primary endpoint, the percentage of patients with recovery/improvement was assessed (according to the data of the patient's diary on days 2–7 and according to the clinical examination on days 3 and 7). Additionally, the duration and severity of influenza symptoms, the percentage of patients with virus elimination (according to RT-PCR of nasopharyngeal samples), the percentage of patients with complications, the percentage of patients prescribed antipyretic drugs, the change in concentration of T cell (IL-2, IL-18, IFN-γ) and B cell antigen-specific (IL-4, IL-16) immune response regulators in serum, the leukocyte phenotypes on days 1, 3 and 7 were evaluated. Statistical analysis was performed using a “Non-Inferiority” design (or no less efficiency/safety). Intention-to-Treat (ITT) analysis data are presented. Results. According to patients’ self-assessment, 53.3% of patients in Group 1 recovered/improved on the 6th day in the morning and 65.2% – in the evening (vs. 53.3% and 57.6% in Group 2, respectively). There were 73.9% recovered/ improved patients on the 7th day in the morning (vs. 67.4% in Group 2). A generalized analysis showed that the treatment results in both groups were comparable (p < 0.0001). According to objective medical examination, 79.3% of patients in the SD group and 74.0% of patients in the Оseltamivir group recovered/improved on the 7th day (p < 0.0001). The antiviral efficacy of SD was not inferior to oseltamivir, which was confirmed by comparable periods of virus elimination, duration and severity of fever and other influenza symptoms. A moderate activating effect of SD on the immune system was evaluated. A significant, compared to oseltamivir, increase in the concentration of IL-2 and IL-4 on the 3rd day of treatment (p = 0.03 and p = 0.04 vs. the oseltamivir group), and IFN-γ on the 3rd and the 7th days (p = 0.012 and p < 0.0001, respectively, vs. the oseltamivir group). No stimulating effect of SD on the growth and differentiation of immune cells was found. Conclusion. SD is effective and safe in the treatment of patients with influenza. The therapeutic and antiviral efficacy of SD is comparable to that of oseltamivir. The antiviral activity of SD affects the interferon system and the concentration of the cytokines IL-2 and IL-4, regulators of the T and B cell immune response. At the same time, there is no significant stimulation of interferon production with further development of hyporeactivity. Key words: influenza, oseltamivir, therapy, cytokines, Еrgoferon

2015 ◽  
Vol 6 (1) ◽  
pp. 10-17
Author(s):  
Abeer Ibrahim ◽  
Ali Zedan ◽  
Alia M. A. Attia

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the commonest pathological type of gastrointestinal lymphoma and its management was changed from surgery to combined chemoimmunotherapy in the last decade; however, this strategy is questionable, especially if rituximab is not available. Methods: Seventy-nine files were reviewed retrospectively. We divided the patients into two groups; group 1 included 37 patients who underwent surgery followed by chemotherapy and group 2 included 42 patients who received chemotherapy. The indication of surgery was mainly due to obstruction/perforation. We compared the outcomes of PFS and OS between the two groups and according to primary anatomical site. Results: We found that the outcomes for the surgery group before chemotherapy was superior to chemotherapy alone in terms of DFS, p = 0.012 and OS p = 0.037. But in the anatomical subgroups analysis, it did not show any significant difference in primary gastric lymphoma (PGL) regarding DFS and OS, p = 0.706, p = 0.858, respectively; On the contrary, we found significant improvement in PFS and OS, p = 0.032, p = 0.025, respectively, in primary intestinal lymphoma (PIL) favouring the use of the surgical approach. Conclusion Surgery is still an important strategy in the case of DLBCL in PIL intestinal lymphoma; however, in the case of PGL, the use of chemotherapy even without rituximab achieves similar results. Our conclusions are limited by the small numbers of the study


Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 326
Author(s):  
Anurag R. Mishra ◽  
Siddappa N. Byrareddy ◽  
Debasis Nayak

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.


2007 ◽  
Vol 14 (10) ◽  
pp. 1334-1341 ◽  
Author(s):  
Yeddula Narayana ◽  
Beenu Joshi ◽  
V. M. Katoch ◽  
Kanhu Charan Mishra ◽  
Kithiganahalli N. Balaji

ABSTRACT The multigene PE and PPE family represents about 10% of the genome of Mycobacterium tuberculosis. Here, we report that three members of the PE family, namely, Rv1169c, Rv0978c, and Rv1818c, elicit a strong, but differential, B-cell humoral response among different clinical categories of tuberculosis patients. The study population (n = 211) was comprised of different clinical groups of both adult and child patients: group 1 (n = 94) patients with pulmonary infection, group 2 (n = 30) patients with relapsed infection, group 3 (n = 31) patients with extrapulmonary infections, and clinically healthy donors (n = 56). Among the PE proteins studied, group 1 adult patient sera reacted to Rv1818c and Rv0978c, while Rv1169c elicited immunoreactivity in group 3 children. However, all three PE antigens studied as well as the 19-kDa antigen did not demonstrate humoral reactivity with sera from group 2 patients with relapsed infection. The current study shows that while responsiveness to all three PE antigens is a good marker for M. tuberculosis infection, a strong response to Rv0978c or to Rv1818c by group 1 adult patients with pulmonary infection or largely restricted reactivity to Rv1169c antigen in child patients with extrapulmonary infections offers the possibility of differential utility in the serodiagnosis of tuberculosis.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2874-2874
Author(s):  
Asad Bashey ◽  
Lin Liu ◽  
Anita Ihasz ◽  
Ewa Carrier ◽  
Januario Castro ◽  
...  

Abstract We have previously reported that intermediate dose cyclophosphamide followed by sequential GM-CSF and G-CSF (iCy/GM/G) provides efficient mobilization for patients undergoing autografting. Furthermore, the predictable time course of mobilization with this regimen obviates the need for weekend leukaphereses (Blood 2003: 957a). Recently, the addition of rituximab to mobilization regimens for B-cell NHL has been shown to be effective at depleting contaminating B-cells from the leukapheresis product. However, the effect of rituximab administered for in-vivo purging, on mobilization and stem cell collection parameters is unclear. We compared leukapheresis (LP) yield parameters, and the time course of stem cell mobilization in 23 consecutive B-cell NHL patients mobilized with iCy/GM/G plus rituximab (group 1) with 27 consecutive B-cell NHL patients mobilized with the same regimen without rituximab (group 2). The iCy/GM/G regimen consisted of cyclophosphamide 1.5g/m2 (d1), GM-CSF 500 mcg/d (d 3–7), G-CSF (d 8 until completion of LP) 600mcg/d for weight ≤80kg, 960 mcg for weight &gt; 80 kg. Rituxan was administered at 375mg/m2 as a single dose on d8. LP was begun on d 11 irrespective of WBC. D1 was usually a Friday in order to avoid weekend LP. Patients underwent up to 20 liter LP for ≤ 5 days (median =3, range 1–5 for both groups) with a target collection of &gt; 5 x 10e6 CD34+ cells/kg. The groups were well matched for median age, gender, number of prior chemotherapy regimens (median=2 for both groups), prior pelvic XRT and histological subtype of B-NHL (p=NS in all cases). The estimated (Kaplan-Meier) cumulative probability of achieving a target collection of 2 x 10e6 CD34+ cells/kg on d 1–5 was 0.43, 0.70, 0.78, 0.84, 0.84 respectively for group 1 and 0.22, 0.69, 0.77, 0.84, 0.84 respectively for group 2. The corresponding probabilites of achieving 5 x 10e6 CD34+ cells/kg on d 1–5 were 0.22, 0.39, 0.57, 0.57, 0.57 (group 1) and 0.11, 0.30, 0.46, 0.59, 0.59 (group 2) (p=NS Log-rank test). Percentage of CD34+ cells in the LP product (LP CD34%) was measured daily. Maximums LP CD34% was seen on LP d1 for both groups with a fall on subsequent days (p=NS between groups 1 and 2). Toxicities experienced were generally mild consisting mostly of bone pain and fevers and were similar in both gropups. No patient required admission for febrile neutropenia. The number of CD34+ cells infused were similar for both groups (median 5.9 vs.5.7 x10e6 CD 34+ cells/kg). Median time to reach ANC &gt; 500/mm3 and platelets &gt; 20,000/mm3 were identical between groups 1 and 2 (d11 and d 10 respectively). These data show that the addition of rituximab administered on d 8 to the iCy/GM/G regimen in patients with B-NHL does not impair the yield of CD34+ cells, or the tolerability of the regimen. Furthermore, the time course of the mobilization and therefore the predictbility of the collection is not compromised. Maximum cumulative yield of CD34+ cells is achieved within 4 days of LP with no patient benefitting from a fifth day of collection. The additional cost and inconvenience of weekend leukapheresis can be avoided in all cases using this regimen.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3246-3246
Author(s):  
Ghislaine Gallez-Hawkins ◽  
Lia Thao ◽  
Simon F. Lacey2 ◽  
Joybelle Martinez ◽  
Anne E. Franck ◽  
...  

Abstract Immunity declines with age as demonstrated by cell-mediated and humoral responses to alloantigens. The susceptibility of these elderly subjects to endogenous virus infection, such as human cytomegalovirus (HCMV) reactivation, is a particular concern during the process of hematopoietic stem cell transplantation (HCT) and immune reconstitution. In this report, the host contribution to stem cell engraftment and differentiation was evaluated by comparing the HCMV immune response in older subjects (&gt; 50 y.o.) to a younger (&lt; 50 y.o.) transplant population. This was a retrospective analysis of a subset of data collected prospectively and with IRB approval for characterization of the CMV immune response of allogeneic transplant patients. Within the dataset, two groups of patients were compared. Group 1 consisted of 10 patients &gt;50 y.o. who had received reduced intensity or non-myeloablative conditioning regimen, and Group 2 consisted of 13 patients &lt;50 y.o., most of whom had received a myeloablative regimen. Because 9 of 10 in Group 1 had had CMV reactivation, Group 2 was selected from the subset of younger patients with known post-transplant CMV infection. CMV infection was defined as either a positive CMV blood culture using shell vial assay or a positive CMV PCR on plasma. Subjects were assessed on days 40, 90, 120, 150, 180, and 360 post-HCT by CMV-specific tetramer-binding assay using CD8 cells, assays for intracellular INF-g response of CD4 and CD8 cells, and a T-cell receptor excision circle (TREC) assay. There were no significant differences observed in the CD4+/IFN-g+ cell responses to CMV antigen nor were the rates of activated CD4+/CD69+/IFN-g+ cells different between the groups. Group 1 was also characterized by a robust CD8+/IFN-g+ response to HLA-specific CMV peptides, and all subjects had ≥ 2cells/μl by day 150 post-HCT. The frequency of CMV tetramer positive cells (≥ 2cells/μl) was 50% in Group 1 by day 90 post-HCT and was not statistically different from Group 2. The T cell renewal in the thymus as measured by the TREC spanned over 0 -- 92 copies/μg of total cellular DNA in Group 1 and from 0 – 129 copies/μg in Group 2 during the first year post-HCT (n.s.). In conclusion, CMV immune reconstitution in older transplant subjects, who undergo a reduced intensity or non-myeloablative regimen, is robust and, in this small sampling, did not differ from that observed in a younger adult group.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
J. BlumL. Forero ◽  
M. K. Heiskala ◽  
N. Meneses ◽  
K. Chandrawansa ◽  
F. Fang ◽  
...  

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Marc Pracht ◽  
Barouyr Baroudjian ◽  
...  

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.


Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 50-59 ◽  
Author(s):  
Gili Hart ◽  
Tamar Avin-Wittenberg ◽  
Idit Shachar

To complete their maturation and participate in the humoral immune response, immature B cells that leave the bone marrow are targeted to specific areas in the spleen, where they differentiate into mature cells. Previously, we showed that immature B cells actively down-regulate their integrin-mediated migration to lymph nodes or to sites of inflammation, enabling their targeting to the spleen for final maturation. This inhibition is mediated by IFN-γ, which is transcribed and secreted at low levels by these immature B cells; IFN-γ expression is extinguished following B-cell maturation. Stimulation of the MHC class I receptor, Ly49D, triggers a signaling cascade that increases transcription of both IL-12 (p40) and IL-18; these, in turn, induce the secretion of IFN-γ. In the present study, we demonstrate that Ly49D-dependent secretion of IL-12 and IL-18 induces IL-15 expression by immature B cells, and that these 3 factors together regulate IFN-γ production that inhibits their ability to home to the lymph nodes or to sites of inflammation. Thus, IL-15 controls immature B-cell homing, resulting in shaping the B-cell repertoire to enable an efficient immune response.


2013 ◽  
Vol 10 (3) ◽  
pp. 30-34
Author(s):  
A P Toptygina ◽  
V A Alioshkin

Background. The aim of the study was to investigate peculiarities of immune responses on the vaccination with Priorix in healthy children and patients with atopic dermatitis. Methods. Thirty five healthy children aged 1-2 years old (Group 1) and 15 children the same age with atopic dermatitis (Group 2) were vaccinated with Priorix. Serum level of IgE was measured by ELISA, and serum concentrations of 7 cytokines: IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were measured by BioPlex technology before vaccination, 7 days, and 30 days after. Serum level of IgE was measured by ELISA. Results. The level of serum IgE relatively decreased or increased on seventh day after vaccination. In a month IgE level returned back. It was found that in group1 51,4% children demonstrated Th1 type response and 48,6% children showed Th2 type response on the vaccination. Similar distribution was obtained in group 2 (53,3% children showed Th1 type response and 46,7% children demonstrated Th2 type). A significant positive correlation was observed between IgE level increasing and Th2 type of immune response. It was shown that 68,6% of children of group 1 and 66,7% of children of group 2 demonstrated after vaccination the superiority of anti-inflammatory IL-10 over pro-inflammatory TNF-α. We suppose that children with atopic dermatitis can be vaccinated with Priorix.


2003 ◽  
Vol 27 (1) ◽  
pp. 134-145
Author(s):  
Ali A.H. Shalash ◽  
Ebtesam G. A. Al-Oubaidi

A total of 50 day - old broiler chicks were divided equally into two groups and treated with Lactobacillus salivarus (L S) as follow Group 1: given 3.2X108 cfu/ ml of LS in crop at day 1 of age. Group 2:Untreated control  The two groups were vaccinated against Newcastle disease vaccine (ND vac) Lasota strain at age 10, 21, and 35 days direct in the crop.  The groups were vaccinated in the crop against Gumboro vaccine (G vac) leukert strain at 5, 14 and 24 day of age.  Haemagglutination inhibition test was used and determine antibodies titer (Abt) of (ND vac) and the agar gel precipitating test to 19, 29 and 39 of the chick's age.  The result showed significant (p < 0.05) increase in Abt most of the weeks in the first group compared with second groups  The performance results showed significant (p < 0.05) increase in the weight, weight gain , feed consumption and feed conversion ratio for chicks treated with LS.  It was concluded that oral administration of Lactobacillus salivarus to day – old chicks has a beneficial effect on immune response to ND vac and G vac and on chick's performance.


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