Isoprinosine
46749191
Combined efficacy of oseltamivir, isoprinosine and ellagic acid in influenza A(H3N2) infected mice.
Influenza pathogenesis comprises a complex cascade of impaired cellular processes resulting from the viral replication and exaggerated immune response accompanied by reactive oxygen species (ROS) burst and oxidative stress, destructing membranous structures and tissues. By classical virological and biochemical methods we compared and evaluated the therapeutic effects of 2.5mg/kg/day of the antiviral drug oseltamivir (OS) 500mg/kg/day of the immune modulator isoprinosine (IP) and 500mg/kg/day of the antioxidant agent ellagic acid (EA) with a focus on their combined activities in influenza H3N2 virus infected mice. The survival, lung pathology and titers, as well as the oxidative stress biomarker thiobarbituric acid reactive substances (TBARS) in the lungs, liver and blood plasma, correlated to the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione reductase (GR) were assessed. We found that the viral inhibitor applied together with the immune modulator and the antioxidant exhibited strong therapeutic effects on the survival of the influenza challenged mice. That effect was mostly pronounced for the triple combination protection index (PI) of 75.2% mean survival time (MST) extended by 5.8 days compared to the PBS control and significant reduction of the lung titers by 1.38 Dlg; 2.3 scores lower lung pathology and 8 times reduction of the accumulated TBARS in the lungs and liver on the 5 th day p.i. The enzymatic assays revealed that this combination demonstrated very good protection against the damaging superoxide radicals (83% efficiency of SOD, in comparison to healthy controls 100% The double combinations of OS with IP and EA also showed protective effects according to the virological analysis PI of 53.1% and 54.5% Ten times higher GR activity was observed when the combination EA+OS and monotherapy of EA were applied (96% in comparison to healthy controls 100% The best antioxidant effect in blood plasma was observed in the EA+IP group 4 times reduction in the TBARS content compared to infected controls but it did not have any efficacy on the survival and lung injury.
Biomedicine pharmacotherapy Biomedecine pharmacotherapie
Elitsa L Pavlova Lora S Simeonova Galina Gegova
24139587
Evaluation of isoprinosine to be repurposed as an adjunct anti tuberculosis chemotherapy.
Isoprinosine (Inos) or immunovir is a synthetic purine derivative with immune modulatory and antiviral properties. The drug shows apparent in vivo enhancement of host immune responses by inducing pro inflammatory cytokines and rapid proliferation of T cell subsets. Strikingly, the cytokines induced by Inos also play crucial roles in providing immune resistance against Mycobacterium tuberculosis (Mtb) Inos has been licensed for several antiviral diseases; however, its efficacy against Mtb has not been tested yet. Since Mtb subverts the host immune system to survive within the host. Therefore, we hypothesized that the immune stimulatory properties of Inos can be explored as an adjunct therapy for the management of tuberculosis. We have also outlined a systematic direction of study to evaluate if Inos could be repurposed for tuberculosis. The in vivo studies for therapeutic evaluation of Inos alone or in combination with the first line anti TB drugs in a suitable TB disease model would provide a clearer picture of its utility as a host directed anti TB drug and may endow us with a new application of an existing drug to combat tuberculosis.
Medical hypotheses
Alok Mishra Shivraj M Yabaji Rikesh K Dubey
210122420
Immunological Activities of Isoprinosine Inhibition on Viral Infections Inhuman
Introduction: Isoprinosine is a combination of inosine used as antiviral drug without effect on viral particle itself, but instead only and acts as on immunostimulant and also acts indirectly by activation of immune cells. Aim of this study was to determine level of interferon alpha (INF a) with parainfluenza viruses HPIV 2, and adenoviruses HAdV 2 replication. Materials and Methods: In the present study, cytotoxic effect of isoprinosine was assessed using A549 cell line exposed to different concentrations of compound (isoprinosine: 50 800mg/mL) for 48 hours. Cytotoxic effect was examined visually using light, inverted microscopy Olympus CK2 under 400x magnification and by the MTT colorimetric assay. The yield reduction assay (YRA) which evaluates the ability of the isoprinosine (50 800 mg/mL) to inhibit virus multiplication in cell cultures, was applied. The cytopathic effect of the virus was evaluated 48 h after infection of A549 cell cultures with viruses by means of light, inverted microscopy. The YRA method was used to determine the 50% end point (IC50) in the presence of Isoprinosine with the controlled one. Results: MTT cytotoxicity assay confirmed microscopic observations. There were no morphological changes, as assessed visually, in cell cultures treated with isoprinosine. After conducting the experiments and analyzing the results we noticed that higher concentrations of isoprinosine strongly inhibited multiplication of all viruses. HPIV 2 and HAdV 2 showed the highest sensitivity to the antiviral activity of isoprinosine as compared with the control, however, increasing concentrations of isoprinosine up to 800 mg /ml slightly enhanced the antiviral activity of 400 mg/ml isoprinosine. Conclusions: Our study was conducted that HAdV 2 and HPIV 2 have the highest sensitivity to the antiviral activity of isoprinosine from all tested viral strains.
Hashim Ali Abdualmeer Al-sherees Sumaya Najim Abedali Al-khateeb Fadhil Hussain Nasir Al-Muhannak
35764439
The effect of Isoprinosine treatment on persistent infection of Balb/c mice infected with murine gammaherpesvirus 68.
We demonstrated the positive effect of Isoprinosine treatment on persistent infection of Balb/c mice with murine gammaherpesvirus 68 (MHV 68) Increased number of leukocytes, increased percentage of neutrophils, elevated levels of virus neutralizing (VN) antibodies, reduced number of atypical lymphocytes and reduced virus titers were detected in the examined organs after a 14 day treatment. The positive effect of Isoprinosine therapy vanished after 120 150 days. After this interval, we demonstrated lower numbers of leukocytes, lower levels of VN antibodies and an increased number of atypical lymphoid monocytes in the Isoprinosine treated group. Immunological parameters correlated with increased titers of virus in all investigated organs. Evidence of immunostimulation was demonstrated by lower incidence of tumor formation (7.5% in the group of MHV infected and Isoprinosine treated mice in comparison to group without Isoprinosine treatment (17.5% The presented results showed that Isoprinosine therapy had a positive impact on persistent infection of mice with MHV 68, but this effect was time limited. The improvement of the investigated parameters lasted for five months only. Our presented results confirmed that each treatment with Isoprinosine should be repeated and must be long term in some chronic infections.
Acta virologica
O Janickova L Ancicova Katarina Briestenska Jela Mistrikova
196531457
Protective Efficacy of Asparagus racemosus root extract and Isoprinosine against Ionizing Radiation induced Clastogenicity and Toxicity in Swiss Albino Mice
Objective: We aimed to evaluate anticlastogenic and radioprotective potential of Asparagus racemosus root extract (ARE) and Isoprinosine (IPR) against electron beam radiation (EBR) induced clastogenicity and toxicity in Swiss albino mice. Methodology: In the pre radiation study, the experimental animals were orally administered ARE 200mg and IPR 400mg/ kg b.wt once daily for 15 consecutive days. The animals exposed to sublethal dose (6Gy) of whole body EBR. Chromosomal aberration analysis and micronucleus assay were carried out in the bone marrow cells of the experimental animals. The various types of aberrations were scored and the micronuclei in Polychromatic Erythrocytes (PCE) and Nomochromatic Erythrocytes (NCE) were recorded. Assessment of Granulocyte Macrophage Colony Stimulating Factor (GM CSF) was performed using mouse GM CSF Picokine ELISA kit. Non specific Alpha esterase activity was determined by simultaneous azo dye coupling method. Dose Reduction Factor (DRF) was calculated to determine the protective role of ARE and IPR against EBR. Result: Treatment of mice with ARE 200 mg/kg b.wt and IPR 400mg/kg b.wt decreased the percentage of the total aberration compared to the irradiated group; significantly reduced (P Conclusion: The present study suggests that the antioxidant potential of ARE and IPR could be of extreme significance in offering radioprotection and may be useful in combating various free radical and reactive oxygen species mediated human pathological conditions. Key words: Asparagus racemosus root extract, Isoprinosine, Electron beam radiation, Clastogenicity, Toxicity.
Sharmila Kameyanda Poonacha Satheesh Kumar Bhandary Bavabeedu Ronald Fernandes Suchetha Kumari Nalilu Vadisha Srinivas Bhat Jayarama Shetty Kolakebail Jerish Mangattu Jose Alex John Peter
201194791
Anti betanodavirus activity of isoprinosine and improved efficacy using carbon nanotubes based drug delivery system
Abstract Viral nervous necrosis (VNN) disease has caused mass mortality in cultured marine and freshwater fish worldwide, resulting in enormous economic losses in the aquaculture industry. The causative agent of VNN is betanodavirus [also known as nervous necrosis virus (NNV) which classified as a member of the Nodaviridae family. NNV mainly infects the central nervous system (CNS) of hosts, which is protected by an elaborate barrier system, limiting the number of drugs reaching the infected sites to tackle the infections. Therefore, it is important to develop alternative drugs and smart delivery technologies for treatment the NNV infection. In the study, the anti NNV activity of an immunomodulatory antiviral drug, isoprinosine, was checked both in vitro and in vivo. Besides, single walled carbon nanotubes (SWCNTs) were used as a carrier to improve the anti NNV activity. Results showed that isoprinosine could effective protect SSN 1 cell from NNV infection, and the percentage of apoptosis was significantly decreased following isoprinosine treatment. Similarly, isoprinosine also showed a strong anti NNV activity in zebrafish, and the IC50 (inhibitory concentration at half maximal activity) values were 86.44 and 52.47 mg/L after exposure to isoprinosine for 3 and 5 days, respectively. The expression levels of IL 1b, IFN g and TNF a were up regulated following isoprinosine treatment, indicating that isoprinosine can improve the immune responses to against NNV infection. A smart delivery system (named as SWCNTs I) based on SWCNTs, bovine serum albumin (BSA) and isoprinosine was constructed and characterized by transmission electron microscope, FTIR spectroscopy and UV vis spectroscopy. SWCNTs I was internalized inside the SSN 1 cells, and showed a systemic distribution in the zebrafish larvae. SWCNTs I has a stronger anti NNV activity than naked isoprinosine, and the mortality of larvae treated with SWCNTs I was 39.3% during 7 days post infection, while that were 96.7% and 58% for the control and naked isoprinosine treatment groups, respectively. Results so far indicated that isoprinosine is a powerful anti NNV drug, and drug delivery with SWCNTs has a potential application value to control fish viral diseases in aquaculture.
Aquaculture
Song Zhu Jia-Da Li Aiguo Huang Ji-Qiu Huang Yong-quan Huang Gaoxue Wang
28560511
Acute and Subacute Toxicity Profile of Asparagus racemosus root extract Isoprinosine and Shatvari Syrup in Swiss Albino Mice B Satheesh
Article history: Received on: 21/10/2016 Accepted on: 24/01/2017 Available online: 30/05/2017 The present study was carried out to evaluate the safety of Asparagus racemosus root ethanol extract, isoprinosine and shatvari syrup by acute ad subacute toxicity studies. Acute and subacute oral toxicity study was conducted according to the guidelines of OECD 425 and 407 respectively. In acute oral toxicity, mice were administered with 2000 mg/ kg body weight of ARE, STR and IPR respectively and were observed continuously for the first 4 h and for the next 24 h and for the following 48 h after administration of the test substances. In the subacute toxicity studies, ARE, STR and IPR were given orally at the dose of 2000 mg/ kg body weight daily for 28 consecutive days. General behavior, adverse effects and mortality were observed throughout the experimental period. Food and water intake, body and organ weight variations, hematological and biochemical parameters, histopathological changes were assessed. No mortality or signs of acute toxicity was observed in the mice at the maximum tolerable dose of 2000 mg/kg body weight. The results did not show any treatment related abnormalities in terms of hematological and biochemical parameters in sub acute toxicity tests. No significant differences in body weight and organ weight between the control and treated groups were observed. Histopathological analysis showed no morphological changes of the vital organs namely liver and kidney between the control and treated groups. These results concluded that ARE, STR and IPR did not cause any mortality and signs of toxicity at maximum tolerable dose of 2000 mg/kg body weight in mice.
Kumar Bhandary K P Sharmila Nalilu Suchetha Kumari Vadisha Srinivas Bhat Ronald Fernandes
59348948
Acute and Subacute Toxicity Profile of Asparagus racemosus root extract, Isoprinosine and Shatvari Syrup in Swiss Albino Mice.
The present study was carried out to evaluate the safety of Asparagus racemosus root ethanol extract, isoprinosine and shatvari syrup by acute ad subacute toxicity studies. Acute and subacute oral toxicity study was conducted according to the guidelines of OECD 425 and 407 respectively. In acute oral toxicity, mice were administered with 2000 mg/ kg body weight of ARE, STR and IPR respectively and were observed continuously for the first 4 h and for the next 24 h and for the following 48 h after administration of the test substances. In the subacute toxicity studies, ARE, STR and IPR were given orally at the dose of 2000 mg/ kg body weight daily for 28 days. General behavior, adverse effects and mortality were observed throughout the experimental period. Food and water intake, body and organ weight variations, hematological and biochemical parameters, histopathological changes were assessed. No mortality or signs of acute toxicity was observed in the mice at the maximum tolerable dose of 2000 mg/kg. The results did not show any treatment related abnormalities in terms of hematological and biochemical parameters in sub acute toxicity tests. No significant differences in body weight and organ weight between the control and treated groups were observed. Histopathological analysis showed no morphological changes of the vital organs namely liver and kidney between the control and treated groups. These results concluded that ARE, STR and IPR did not cause any mortality and signs of toxicity at maximum tolerable dose of 2000 mg/kg in mice.
B Satheesh Kumar Bhandary K P Sharmila Nalilu Suchetha Kumari Vadisha Srinivas Bhat Ronald Fernandes
81211568
Radioprotective potential of Asparagus racemosus root extract and isoprinosine against electron beam radiation induced immunosupression and oxidative stress in swiss albino mice
Background: Radiotherapy is an important and the most common treatment modality for human cancers. Cancer radiotherapy is associated with unadorned side effects that results from normal tissue damage which is a major subject of concern. Radiation induces damage to living cells due generation of aqueous free radicals. Therefore, there is a crucial need for the protection of normal cells surrounding the tumor from radiation injury; and hence, the identification of radiation protecting agents is a chief goal for basic radiation biologists and oncologists. Aim: The aim of this present study was to assess the radioprotective potential of Asparagus racemosus root ethanolic extract (ARE) and isoprinosine (IPR) against electron beam radiation (EBR) induced immunosuppression and oxidative stress in Swiss Albino mice. Materials and Methods: Swiss albino mice were used for the assessment of the radioprotective potential of ARE and IPR against EBR induced immunosuppression and oxidative stress. Cytokine estimations, namely, interleukin 2, interferon gamma, and tumor necrosis factor alpha were performed in the liver homogenate using ELISA kits, and bone marrow cellularity was determined in the experimental animals. Results: The results of the present study demonstrated the radioprotective and immunostimulatory efficacy of ARE and IPR against EBR induced cytokine and bone marrow cellularity alterations. Conclusion: The findings of our study demonstrate the potential of ARE and IPR in mitigating radiation induced mortality by offering protection to mice against lethal dose of whole body EBR. The present study also demonstrates that ARE and IPR exert its radioprotection against EBR induced immunosuppression by regulating cytokines.
K P Sharmila B Kumar Bhandary Ronald Fernandes Nalilu Suchetha Kumari Vadisha Srinivas Bhat K Shetty Jerish Mangattu Jose Alex John Peter
28576363
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition characterized by chronic and disabling fatigue and several other symptoms, including pain, sleep disturbance, neurologic and cognitive changes, motor impairment, and altered immune and autonomic responses (13) Experts consider postexertional malaise and memory or concentration problems to be critical components (46) and several diagnostic criteria, including those released by the Institute of Medicine in 2015, require the presence of postexertional malaise (1, 2, 79) There is uncertainty regarding the cause of ME/CFS, whether it is a pathologically discrete syndrome (2, 4) whether ME should be considered a subset of CFS or its own distinct disease (6) and whether symptoms are nonspecific and shared by other disease entities. Some propose that an inciting event initiates an immune response that leads to immune and neuroendocrine dysregulation (10, 11) Viral causes have been studied on the basis of the observation that most patients report a sudden onset of symptoms that were preceded by a febrile illness with enlarged lymph nodes. However, no specific virus or other infectious agent has been identified, and not all patients experience a preceding febrile illness (10) The Centers for Disease Control and Prevention (CDC) reported a 0.3% prevalence of ME/CFS in the United States in 1997, corresponding to more than 1 million adults (12) Through use of different case definitions or different diagnostic methods, the rate may be as high as 3.3% (13, 14) Given the multitude of symptoms that patients with ME/CFS experience, treatment approaches have been broad, including immunologic, pharmacologic, and behavioral treatments and complementary and alternative medicine. No medications for the treatment of ME/CFS have been approved by the U.S Food and Drug Administration (FDA) however, many have been used without review and approval (off label) and some are not approved for any indication in the United States (for example, isoprinosine and rintatolimod) In an FDA survey, patients with ME/CFS identified treatments that fell into 2 broad categories: those intended to treat the cause of the disease and those targeting specific symptoms or perpetuating factors (15) Medications to treat causes include immune modulators, antivirals, and antibiotics. Interventions targeting symptoms include medications to treat specific symptoms, such as pain, fatigue, autonomic dysfunction, and sleep dysfunction, and nondrug therapies, such as yoga, exercise techniques, counseling, pacing strategies, and mental exercises (15) In practice, the clinical management of patients varies widely, and many patients receive a multifaceted approach to treatment. This systematic review is part of a larger report to inform a research agenda for the National Institutes of Health (NIH) 2014 Pathways to Prevention Workshop, an evidence based methodology workshop (16) This review evaluates and summarizes research on the benefits and harms of medical and nonmedical treatments for ME/CFS based on trials enrolling patients meeting criteria for ME, CFS, or both and identifies limitations of current studies and needs for future research in this area. Methods Key questions guiding this review were developed in collaboration with the NIH ME/CFS Working Group following a standard protocol, including input from key informants and a technical expert panel, registration in the PROSPERO database for systematic reviews (17) and posting on an Agency for Healthcare Research and Quality (AHRQ) public Web site. Key questions concern the benefits and harms of therapeutic interventions for adults with ME/CFS, how interventions vary by patient subgroups, and characteristics of patients who respond and do not respond to interventions. A technical report details the methods and includes the analytic framework, search strategies, and additional evidence tables (16) Data Sources and Searches A research librarian searched the following electronic databases to identify relevant articles published between January 1988 (year of first case definition) and September 2014: MEDLINE (Ovid) PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and National Health Sciences Economic Evaluation Database. Searches were supplemented by references identified from additional sources, including trial registries, scientific information packets from manufacturers, reference lists, and experts. Study Selection We included English language trials that enrolled patients aged 18 years or older who met the criteria for ME, CFS, or both according to at least 1 established case definition. Included were randomized, controlled trials of at least 12 weeks' duration that compared medications, complementary and alternative medicine approaches, counseling and behavior therapies, and exercise therapies with no treatment or other types of treatment. For completeness, we separately summarized additional trials of medications that were designed for shorter durations of treatment. Treatment outcomes were patient centered and included function, fatigue, quality of life, involvement in daily activities, and harms. We did not include studies of the results of laboratory tests or studies focusing on individual symptoms, such as pain. Two investigators independently evaluated each study to determine inclusion eligibility. Disagreement was resolved by consensus, with a third investigator making the final decision as needed. Data Extraction and Quality Assessment From the included studies, one investigator extracted study details and a second investigator reviewed them for accuracy and completeness. Investigators rated the quality (risk of bias) of the individual studies and strength of the body of evidence on the basis of established criteria (18) The strength of evidence consisted of 4 major categorieshigh, moderate, low, or insufficientaccording to the design, quantity, size, and quality of studies; consistency across studies; precision of estimates; and directness of effect. A second investigator reviewed ratings, and disagreements were resolved by consensus, with a third investigator making the final decision as needed. Data Synthesis For most treatments, only single trials were available; data were synthesized qualitatively with attention to such factors as patient characteristics and risk of bias. For treatments with more than 2 trials, the appropriateness of statistical meta analysis was determined by considering internal validity of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. The combined effects were estimated by using a random effects model based on the profile likelihood method (19) Combined relative risks were calculated for binary outcomes. For continuous outcomes, the combined weighted mean differences were calculated by using the means and SDs at follow up from each intervention group. The chi square test based on the Q statistic and the I 2 statistic (the proportion of variation in study estimates due to heterogeneity) were used to assess heterogeneity in effects between studies, and sensitivity analyses explored statistical heterogeneity when present. All quantitative analyses were performed by using Stata/IC software, version 13.0 (Stata Corp. Role of the Funding Source The AHRQ funded the review, and a working group convened by the NIH helped develop the review's scope and key questions. Neither had a role in study selection, quality assessment, or synthesis. The investigators are solely responsible for the content. Results Among the 6175 abstracts identified by searches, 35 treatment trials in 45 publications met inclusion criteria (Appendix Figure) These included 9 trials of medications (2028) 7 of complementary and alternative medicine (2935) 14 of counseling or behavioral therapies (8, 3648) 7 of exercise (23, 4854) and 4 comparing or combining different therapies (23, 40, 48, 53) (Appendix Table 1) Most trials met criteria for fair quality (24 trials) or poor quality (5 trials) Trials enrolled predominantly middle aged women from ME/CFS specialty clinics; used CFS case definitions, primarily the 1994 CDC (3) or Oxford criteria (56) to determine participant eligibility; had small sample sizes (27 trials had <100 participants) and were conducted in the United States and Western Europe (16) Outcomes varied across trials and included 20 unique measures as well as various Likert scales developed for individual studies. Even when trials used the same outcome, measures and thresholds were often defined differently, thereby limiting comparisons and statistical meta analysis. In general, harms were rarely reported. Appendix Figure. Summary of evidence search and selection. CAM complementary and alternative medicine; CBT cognitive behavioral therapy. Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the Cochrane Database of Systematic Reviews. Identified from such sources as reference lists, hand searches, and suggestions by experts. Studies that provided data and contributed to the body of evidence were considered "included." Studies may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment. Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71) Appendix Table 1. Summary of Trials of Therapies Major limitations of trials included enrollment of fewer than 20 participants in a study group (8, 20, 25, 2830) dissimilar groups at baseline (31, 43, 5
Annals of Internal Medicine
Megan E Smith Elizabeth M Haney Marian S McDonagh Miranda Pappas Monica Daeges Ngoc Wasson Rongwei Rochelle Fu Heidi D Nelson