scholarly journals A drug candidate for treating adverse reactions caused by pathogenic antibodies inducible by COVID-19 virus and vaccines

2021 ◽  
Author(s):  
Huiru Wang ◽  
Xiancong Wu ◽  
Yuekai Zhang ◽  
Qiuchi Chen ◽  
Lin Dai ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Acid Methyl Ester ◽  
Drug Candidate ◽  
Lung Epithelium ◽  
Acetylneuraminic Acid ◽  
Excellent Safety Profile ◽  
Pathogenic Antibodies ◽  
Epithelium Cells ◽  
Unique Mechanism

In a previous study, we reported that certain anti-spike antibodies of COVID-19 and SARS-CoV viruses can have a pathogenic effect through binding to sick lung epithelium cells and misleading immune responses to attack self-cells. We termed this new pathogenic mechanism Antibody Dependent Auto-Attack (ADAA). This study explores a drug candidate for prevention and treatment of such ADAA-based diseases. The drug candidate is a formulation comprising N-acetylneuraminic acid methyl ester (NANA-Me), an analog of N-acetylneuraminic acid. NANA-Me acts through a unique mechanism of action (MOA) which is repairment of the missing sialic acid on sick lung epithelium cells. This MOA can block the antibody binding to sick cells, which are vulnerable to pathogenic antibodies. Our in vivo data showed that the formulation significantly reduced the sickness and deaths caused by pathogenic anti-spike antibodies. Therefore, the formulation has the potential to prevent and treat the serious conditions caused by pathogenic antibodies during a COVID-19 infection. In addition, the formulation has potential to prevent and treat the adverse reactions of COVID-19 vaccines because the vaccines can induce similar antibodies, including pathogenic antibodies. The formulation will be helpful in increasing the safety of the vaccines without reducing the vaccine efficacy. Compared to existing antiviral drugs, the formulation has a unique MOA of targeting receptors, broad spectrum of indications, excellent safety profile, resistance to mutations, and can be easily produced.

scholarly journals Pathogenic antibodies induced by spike proteins of COVID-19 and SARS-CoV viruses

2021 ◽  
Author(s):  
Huiru Wang ◽  
Qiuchi Chen ◽  
Yue Hu ◽  
Xiancong Wu ◽  
Lin Dai ◽  
...  
Keyword(s):  
Immune Response ◽  
Lung Epithelium ◽  
Highly Pathogenic ◽  
Neonatal Deaths ◽  
Pregnant Females ◽  
Still Births ◽  
Pathogenic Antibodies ◽  
Epithelium Cells ◽  
Pathogenic Infection ◽  
Spike Proteins

Abstract This study, using a virus-free mouse model, explores the pathogenic roles and novel mechanism of action of certain antibodies specific to the spike proteins of highly pathogenic coronaviruses such as the COVID-19 and the SARS-CoV viruses. These pathogenic antibodies, induced during a highly pathogenic infection such as the COVID-19 infection, target and bind to host vulnerable cells or tissues such as damaged lung epithelium cells, initiate a persistent self-attack immune response, and lead to serious conditions including ARDS, cytokine storms, and death. Moreover, the pathogenic antibodies may also be responsible for infection-related autoimmune diseases, including those experienced by COVID-19 long haulers. Furthermore, the pathogenic antibodies can bind to the unmatured fetal tissues and cause abortions, postpartum labors, still births, and neonatal deaths of pregnant females. Novel clinical interventions, through disrupting the binding of these pathogenic antibodies, can be developed to fight the COVID-19 pandemic. In addition, the new concept explored by this study may be applicable to other infectious diseases, such as the highly pathogenic influenza infections.

scholarly journals Pathogenic antibodies induced by spike proteins of COVID-19 and SARS-CoV viruses

2021 ◽  
Author(s):  
Huiru Wang ◽  
Qiuchi Chen ◽  
Yue Hu ◽  
Xiancong Wu ◽  
Lin Dai ◽  
...  
Keyword(s):  
Cytokine Release ◽  
Lung Epithelium ◽  
Highly Pathogenic ◽  
Neonatal Deaths ◽  
Still Births ◽  
Pregnant Mice ◽  
Pathogenic Antibodies ◽  
Epithelium Cells ◽  
Pathogenic Effects ◽  
Spike Proteins

Abstract This study, using a virus-free mouse model, explores the pathogenic roles of certain antibodies specific to the spike proteins of highly pathogenic coronaviruses such as the COVID-19 and the SARS-CoV viruses. Our data showed that these pathogenic antibodies, through a mechanism of Antibody Dependent Auto-Attack (ADAA), target and bind to host vulnerable cells or tissues such as damaged lung epithelium cells, initiate a self-attack immune response, and lead to serious conditions including ARDS, cytokine release, and death. Moreover, the pathogenic antibodies also induced inflammation and hemorrhage of the kidneys, brain, and heart. Furthermore, the pathogenic antibodies can bind to unmatured fetal tissues and cause abortions, postpartum labors, still births, and neonatal deaths of pregnant mice. Novel clinical interventions, through disrupting the host-binding of these pathogenic antibodies, can be developed to fight the COVID-19 pandemic. In addition, the new concept of ADAA explored by this study may be applicable to other infectious diseases, such as the highly pathogenic influenza infections. It should be noted that the majority of anti-spike antibodies are non-pathogenic, as only 2 of 7 monoclonal antibodies tested showed significant pathogenic effects.

Role of in vivo and in vitro Tests in the Diagnosis of Severe Cutaneous Adverse Reactions (SCAR) to Drug

2019 ◽  
Vol 25 (36) ◽  
pp. 3872-3880 ◽  
Author(s):  
Marcel M. Bergmann ◽  
Jean-Christoph Caubet
Keyword(s):  
Adverse Reactions ◽  
Lymphocyte Transformation ◽  
Stevens Johnson Syndrome ◽  
In Vitro Tests ◽  
High Morbidity ◽  
Patch Tests ◽  
Severe Cutaneous Adverse Reactions ◽  
Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) are life-threatening conditions including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Diagnosis of causative underlying drug hypersensitivity (DH) is mandatory due to the high morbidity and mortality upon re-exposure with the incriminated drug. If an underlying DH is suspected, in vivo test, including patch tests (PTs), delayed-reading intradermal tests (IDTs) and in vitro tests can be performed in selected patients for which the suspected culprit drug is mandatory, or in order to find a safe alternative treatment. Positivity of in vivo and in vitro tests in SCAR to drug varies depending on the type of reaction and the incriminated drugs. Due to the severe nature of these reactions, drug provocation test (DPT) is highly contraindicated in patients who experienced SCAR. Thus, sensitivity is based on positive test results in patients with a suggestive clinical history. Patch tests still remain the first-line diagnostic tests in the majority of patients with SCAR, followed, in case of negative results, by delayed-reading IDTs, with the exception of patients with bullous diseases where IDTs are still contra-indicated. In vitro tests have shown promising results in the diagnosis of SCAR to drug. Positivity is particularly high when the lymphocyte transformation test (LTT) is combined with cytokines and cytotoxic markers measurement (cyto-LTT), but this still has to be confirmed with larger studies. Due to the rarity of SCAR, large multi-center collaborative studies are needed to better study the sensitivity and specificity of in vivo and in vitro tests.

Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

2020 ◽  
Vol 26 (36) ◽  
pp. 4675-4684 ◽  
Author(s):  
Shabierjiang Jiapaer ◽  
Takuya Furuta ◽  
Yu Dong ◽  
Tomohiro Kitabayashi ◽  
Hemragul Sabit ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Drug Screening ◽  
Therapeutic Agent ◽  
Gelatin Zymography ◽  
Therapeutic Agents ◽  
Drug Candidate ◽  
Potential Therapeutic Agent ◽  
Sphere Formation ◽  
Improve Patient

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

2019 ◽  
Vol 20 (4) ◽  
pp. 285-292 ◽  
Author(s):  
Abdullah M. Alnuqaydan ◽  
Bilal Rah
Keyword(s):  
Medicinal Plant ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Biological Properties ◽  
In Vivo Model ◽  
Drug Candidate ◽  
Phytochemical Analysis ◽  
Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

In Vitro and In Vivo Investigations into the Carbene Copper Bromide Anticancer Drug Candidate WBC4

2014 ◽  
Vol 11 (7) ◽  
pp. 825-832 ◽  
Author(s):  
Wolfgang Walther ◽  
Iduna Fichtner ◽  
Frauke Hackenberg ◽  
Wojciech Streciwilk ◽  
Matthias Tacke
Keyword(s):  
Anticancer Drug ◽  
Drug Candidate ◽  
Copper Bromide

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

scholarly journals T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab

2021 ◽  
Vol 9 (5) ◽  
pp. e002521
Author(s):  
Sean Hammond ◽  
Anna Olsson-Brown ◽  
Joshua Gardner ◽  
Paul Thomson ◽  
Serat-E Ali ◽  
...  
Keyword(s):  
Contrast Media ◽  
Adverse Reactions ◽  
Stevens Johnson Syndrome ◽  
Iodinated Contrast ◽  
Immune Mediated ◽  
Johnson Syndrome ◽  
Healthy Donors ◽  
Concomitant Medications

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance–elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

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