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Saturday, March 21, 2020 8:51:10 AM
For those who would like to know a little more about the solid science that STRONGLY supports the efficacy of our drug in treating lung disease, especially the advanced form of lung disease called "Acute Respiratory Distress Syndrome" or ARDS caused by viral illness in the lungs (e.g. coronavirus)....
Below is an exerpt from the recently published paper in 2019 in mSystems journal which describes how the scientists found Ifenprodil as the big hit in decreasing mortality (aka death) and decreasing the ARDS caused by severe viral illness.
Here is a short list, broken down into lay terms so you can understand. If you don't, just let me know and I will explain further. But remember, it is these scientific results that are the reason we feel that Algernon has hit the jackpot and is sitting on a multi-billion dollar drug.
All of my key points here are directly related to the highlighted/bolded text below in the quoted which I took directly from the journal article. If you want a copy of the journal article, just send me your email.
Key points summarized by medchem:
1. Ifenprodil helps keeps infected cells alive
2. Ifenprodil has low side effects and is safe (low cytotoxicity)
3. Ifenprodil improves survival in the context of severe viral illness
4. Ifenprodil decreases (ameliorates) acute lung injury which leads to ARDS (which prevents death)
5. Ifenprodil decreased the lung edema (fluid) caused by the ARDS (aka it decreased the factor that is responsible for ARDS killing so many patients)
6. Ifenprodil deceased the number of white blood cells (neutrophils), natural killer cells, and t-cells (these are the parts of the immune system that attack the lungs with ARDS). Decreasing these decreases INFLAMMATION and gives the lungs a chance to heal.
7. Ifenprodil decreased the cytokine storm (it decreased ten of the most harmful cytokines, which are basically the cause for "inflammation"..)
8. Ifenprodil signficantly decreases the immune response to lung injury
9. NMDA is the receptor that Ifenprodil targets, and it blocks it. NMDA overstimulaiton can cause lung injury. Ifenprodil blocks that.
10. The authors findings indirectly suggest that this will also decrease inflammation from pulmonary fibrosis!
Selection of candidate drugs and screening in H5N1-infected A549 cells.By searching the DrugBank database, we identified 146 drug target genes (372 drugcandidates) among 1,137 host genes that altered cell viability by more than 20% in theRNAi screen after H5N1 virus infection. We further evaluated the prophylactic and therapeutic effects of 104 commercially available drugs (with 65 validated target genes)by examining their ameliorative effects in a cell viability assay in H5N1-infected A549 cells (Fig. S3A and B and Table S2) and found 28 drugs that significantly enhanced cell viability with low cytotoxicity (Fig. 2Aand Fig. S3C; Table S3). Drug candidates that ameliorated ALI and improved survival rates in H5N1-infected mice.Among the 28 drugs with which we observed a significant recovery of cell viability following H5N1 infection, 8 were glucocorticoids, which, at low doses, areused in conventional treatments against influenza virus-induced ALI (18,19). Therefore,we focused on the other 20 nonhormonal drug candidates and tested the top 10nonhormonal drug candidates that enhanced the viability of H5N1-infected A549 cellsagainst ALI in C57BL/6 mice infected with H5N1 (Fig. S4A; see also Table S3). Thefollowing 8 of those 10 drugs significantly decreased the number of infiltrating cells inmouse lung tissues: glyburide (no. 15), bupivacaine (no. 31), ifenprodil (no. 42), 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) (no. 47), flavopiridol (no. 67), diazoxide(no. 97), diflunisal (no. 101), and vemurafenib (no. 104) (Fig. 2B,C, andE). The following4of those 8 drugs significantly reduced lung injury scores in animals: ifenprodil, AEBSF,flavopiridol, and diazoxide (Fig. 2BandD; see also Fig. S4B). Both ifenprodil treatmentandflavopiridol treatment ameliorated lung edema by decreasing the wet-to-dry-weight ratio in H5N1-infected mice with induced ALI (Fig. 2F; see also Fig. S4C and D).We measured the impact of these 2 drugs on major subsets of leukocytes during theresponse to H5N1 virus infection and found that ifenprodil or flavopiridol significantly decreased the levels of neutrophils, natural killer (NK) cells, and T cells in H5N1virus-infected mouse lung tissues (Fig. S5). Notably, both ifenprodil treatment andflavopiridol treatment significantly increased the survival rate of H5N1 virus-infectedmice (Fig. 2G). The weight loss of mice administered ifenprodil or flavopiridol wasrecoveredat the second week after H5N1 virus infection (Fig. S4E). Taken together,these results indicate that 8 of the top 10 nonhormonal drugs can ameliorate ALI inH5N1-infected mice, with ifenprodil and flavopiridol being the most effective.Ifenprodil and flavopiridol attenuated H5N1-induced cytokine storm in mice.RNA sequencing (RNA-Seq) analysis of the lung tissue showed that ifenprodil andflavopiridol alleviated cytokine storm in H5N1-infected mice (Fig. 3AandB; see alsoFig.S6A and B). We obtained blood samples from H5N1-infected mice and performedmultiplex analyses to measure the levels of 23 cytokines/chemokines in plasma frommice administered ifenprodil or flavopiridol. Overall, ifenprodil treatment and flavopiri-dol treatment significantly decreased the measured levels of 8 and 12 cytokines/chemokines, respectively, in the plasma of H5N1-infected mice (Fig. 3C). The other sixdrugsdecreased the mRNA levels of several cytokines and cytokine receptors in mouseblood (Fig. S6C to H). Our results suggest that these drugs, especially ifenprodil andflavopiridol, can attenuate the excessive inflammation caused by H5N1 virus.Ifenprodil-targeted NMDA receptor genes and flavopiridol-targeted cyclin-dependent kinase 4 (CDK4) genes are linked to lung injury.Ifenprodil is a selectiveN-methyl-D-aspartate (NMDA) receptor antagonist (20) and has been clinically used totreatneuronal injury and neurological disorders induced by overstimulation of theNMDA receptor (21). Our RNAi screening data revealed that knockdown of the NMDAreceptorgene (GRIN2B) could alter the viability of H5N1-infected cells (Table S1). Weobtained RNA sequencing data from lung tissues of H5N1-infected mice treated withifenprodil and analyzed biological processes and pathways influenced by ifenprodilcompared to vehicle control mice. We found that ifenprodil influenced the immune response and neurophysiological processes in the mouse lung (Fig. 4A). Nine of the top10pathways of the ifenprodil treatment group were linked to the immune response(Fig. 4C). Dozens of genes in most of the top 10 pathways were reported to be relatedtolung diseases as well as to traditional neuropathic indications of ifenprodil (Fig. 4C;seealso Table S4 in the supplemental material). Although previous reports indicatedthat NMDA receptors are expressed in lung tissues, that NMDA receptor signaling islinked to inflammation, and that overstimulation of the NMDA receptor can trigger lunginjury (22,23), our study revealed for the first time that ifenprodil is effective in avianinfluenzaA H5N1 virus infection and lung injury.Flavopiridol is an inhibitor of cyclin-dependent kinases (CDKs) (including CDK1,CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, and CDK9) and has been investigated for thetreatment of several types of cancers, including leukemia, liver cancer, and renal cancer,in clinical phase 2 trials (24–26). Previous research found that CDK4 inhibition resultedinthe improvement of lung injury by blocking leukocyte adhesion and migration andthat flavopiridol inhibited avian influenza H7N9 virus replication in A549 cells but thatits efficiencyin vivocould not be confirmed (27). Our RNAi screening results showedthatthe viability of H5N1 virus-infected cells was increased due to CDK4 gene knock-down (Table S1). Using RNA sequencing data for biological process and pathwayanalysis, we found that flavopiridol treatment could alter the immune response as wellas cell development and differentiation in H5N1 virus-infected mouse lung tissues(Fig. 4B). Among the top 10 pathways of the flavopiridol treatment group, 5 are relatedtothe immune response of lung disease and 2 are involved in cancer (Fig. 4D). Wefoundthat dozens of genes in most of the top 10 pathways were linked to lung diseasesas well as to the known antineoplastic function of flavopiridol (Fig. 4D; see alsoTableS4). Our study revealed for the first time that flavopiridol is effective in lung injury
We identifiedthe neurological drug ifenprodil and the anticancer drug flavopiridol as potential noveleffective remedies for avian influenza A H5N1 virus-infected lung injury.The mechanisms by which ifenprodil and flavopiridol ameliorate lung injury andimprove the survival of H5N1-infected mice may operate via an influence on the hostimmune response. Previous studies reported that limiting the infiltration of leukocytes such as NK cells and neutrophils could alleviate influenza A virus-induced ALI (29,30).Wefound that both ifenprodil and flavopiridol significantly decreased the number ofinfiltrating cells in H5N1-infected mouse lung tissues. In addition, hypercytokinemiawas reported in the blood samples of patients with lethal avian influenza A virusinfection, and plasma cytokine and chemokine levels were linked to disease fataloutcomes (31,32). In our study, both ifenprodil and flavopiridol alleviated cytokinestorm,as they significantly decreased the RNA and protein levels of some cytokines andchemokines in lung tissues and blood samples from mice with H5N1 virus infection. Inaddition, we obtained H5N1-infected mouse lung tissues for RNA sequencing andconducted bioinformatic analysis, which showed that the genes influenced by ifen-prodil or flavopiridol administration were highly clustered in GO functional terms andpathways related to the immune response. From these collective results, we speculatedthat the impact of ifenprodil and flavopiridol on the immune response contributes tothe amelioration of H5N1-induced ALI and to improvement in mouse survival. However,the efficacy of ifenprodil and flavopiridol for the treatment of H5N1-induced ALI alsoneeds clinical evaluation.In our study, we evaluated the efficiency in H5N1-infected A549 cells of only 104commercially available drugs from 372 drug candidates identified using our genome-wide RNAi screening method; the efficiencies of the rest of the 268 drugs need to befurther tested. Furthermore, we examined the efficiencies of only 10 of the 28invitro-effective drugs in an animal model; the rest of the drug candidates also need tobe testedin vivo.Our report provides an economical, quick, and highly effective method (comparedwith traditional drug development strategies) for identifying novel remedies againstavian influenza virus-induced lung injury. This approach could be generalized foridentifying other contexts in which drugs can be repurposed.
The study also shows:
Endothelin-1- and TNF-alpha-induced inflammatory response in asthmatic airway fibroblasts - another reason why this will likely work for chronic cough secondary to pulmonary fibrosis
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