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2022 ◽  
Vol 15 (1) ◽  
pp. 66
Author(s):  
Jyothi Dhuguru ◽  
Eugene Zviagin ◽  
Rachid Skouta

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3673-3673
Author(s):  
Matilde Y Follo ◽  
Alessia De Stefano ◽  
Sara Mongiorgi ◽  
Valentina Indio ◽  
Annalisa Astolfi ◽  
...  

Abstract Background and Rationale. miRNAs are small non-coding RNAs that regulate gene expression by acting on the epigenetic machinery and are themselves controlled by epigenetic mechanisms. The expression of miRNAs is linked to cancer development and miRNA profiles are studied as new prognostic factors or therapeutic new perspectives (Jiang X et al. Nat Commun 2016). High-risk MDS are now treated with hypomethylating agents, like Azacitidine (AZA), alone or in combination with other drugs, such as Lenalidomide (LEN). Recent data showed that the concurrent acquisition of specific point mutations on PI3KCD, PLCG2 and AKT3 genes is associated with loss of response to AZA+LEN therapy (Follo MY et al. Leukemia 2019). Inositide signalling regulated by Phospholipase C (PLC) and PI3K/AKT is indeed involved in epigenetic processes and in MDS progression to AML, through the regulation of proliferation, differentiation and apoptosis. Patients and Methods. This study included 26 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21 or 8-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR), any hematologic improvement (HI) or marrow CR+HI following IWG response criteria were considered as responders, while patients showing stable disease or disease progression were considered as non-responders. miRNAs expression was assessed using an Affymetrix miRNA 4.0 array on patients' cells extracted at baseline and during the therapy, at the 4th (T4) and 8th (T8) cycle of therapy. Results were then validated by Real-Time PCR and miRNA targets were studied by dual Luciferase assay. Real-Time PCR was also used to examine the expression of PLC genes. Results. All patients included in this study were considered evaluable for response. According to the revised IWG criteria (14), the overall response rate (ORR) was 76.9% (20/26 cases): CR (5/26, 19.2%), PR (1/26, 3.8%), marrow CR (mCR, 2/26, 7.7%), HI (6/26, 23.1%), mCR+HI (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. For our analyses, we considered 10 patients as responders (R, showing response within T4 and maintaining it at T8), 10 losing response (LR, showing response within T4 and losing it at T8) and 6 non-responders (NR, never showing a response). Paired analysis between R and NR patients showed a statistically significant up-regulation of miR-192-5p and miR-21-5p between T0 and T4, as well as a down-regulation of miR-224-5p between T4 and T8, hinting at a relevant role for these miRNAs during AZA+LEN response. Real-Time PCR analyses confirmed the modulation of miR-192-5p and an altered expression of PLC genes during AZA+LEN therapy in all patients' subgroups, as well as an involvement of BCL-2 (possible target of miR-192-5p) that was also proven in vitro by dual Luciferase assays. Furthermore, as miR-192-5p expression seemed to be correlated with response, we performed Kaplan-Meier analyses and found out an association between high levels of miR-192-5p at T4 and OS (p=0.08) or LFS (p=0.04) in our MDS cases. More interestingly, this correlation was stronger (p=0.03) in R, as compared with LR and NR. Conclusions. This study shows that AZA+LEN therapy in MDS affects the expression of miR-192-5p, whose high level at T4 is associated with higher OS and LFS in responder patients. Moreover, we showed that miR-192-5p specifically targets and inhibits BCL-2, hinting at a regulation of MDS proliferation and apoptosis. Additional studies, to be performed in a larger cohort of MDS patients, are needed to confirm these data, as well as better understand the molecular mechanisms and the prognostic relevance of miR-192-5p in AZA+LEN therapy. Disclosures Cavo: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Finelli: Celgene BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy; Novartis: Consultancy, Speakers Bureau.


2021 ◽  
Author(s):  
Yao Li ◽  
Jingyi Huang ◽  
Huanchun Xing ◽  
Zinan Zhang ◽  
Xin Sui ◽  
...  

Abstract Background: Nerve agents (NAs) can irreversibly inhibit acetylcholinesterase (AChE). An effective NA antidote should permeate the blood–brain barrier (BBB) to reactivate the inhibited AChE in brain. There is an urgent requirement for the large-scale evaluation and screening of antidotes. Existing methods for evaluating reactivators in vitro can only examine the reactivation effect of drugs and not brain-target properties. The current Transwell BBB model can only evaluate the drug penetration performance for crossing the barrier, but not the pharmacodynamics. Methods: Highly purified rat brain microvascular endothelial cells (RBMECs) from 2-week-old Sprague Dawley rats were inoculated into the upper chamber of Transwell plates to establish a BBB model. Three key parameters of AChE reactivation were determined by the Ellman method: the minimum detection limit of AChE, the effective dosage of NAs (70% enzyme inhibition rate), and the optimal dosage of reactivators. AChE and NAs were added to the lower pool of Transwell plates to simulate central poisoning, and antidotes of reactivators were added to the upper pool to simulate drug administration. The AChE activity of samples, collected from the lower pool, was measured. A liposomal nanomedicine loaded with the reactivator asoxime chloride (HI-6) was prepared using the extraction method and tested by the model.Results: The obtained RBMECs exhibited a typical monolayer “paving stone” morphology, and tight junctions were expressed among the RBMECs. The concentrations of AChE, sarin, and the reactivator were 0.07 mg/mL, 10–6 v/v, and 0.03 mg/mL, respectively. The reaction rate of the reactivators obtained from the model was significantly lower than that obtained from the non-model group. Furthermore, a nanomedicine loaded with HI-6 was synthesized. The final results and rules obtained from the model were in accordance with those evaluated in vivo. Conclusion: The therapeutic effect of antidotes can be rapidly and accurately evaluated using this model. In addition to small-molecule drugs, nanomedicines can also be evaluated by this method. A liposomal nanomedicine with a high reactivation rate against the nerve agent sarin was discovered.


2021 ◽  

Background: One of the most toxic effects of organophosphorus poisoning (OP) is the paralysis of skeletal muscles. The oximes are a group of available antidotes. This study investigated the effects of different concentrations of paraoxon on the function of skeletal muscle and reversal or prevention of these effects by three different oximes (i.e., pralidoxime, obidoxime, and HI-6). Materials and Methods: This study was conducted based on the chicken biventer cervices (CBC) nerve-muscle preparation and the use of twitch tension recording technique. The twitches of the CBC were evoked by stimulating the motor nerve at 0.1 Hz with pulses of 0.2 msec duration and a voltage greater than that required to produce the maximum response. Moreover, twitches and contractures were recorded isotonically using Grass Biosystems. Results: Paraoxon at 0.1 µM induced a significant increase (more than 100%) in the twitch amplitude, while higher concentrations (0.3 and 1µM) induced partial or total contracture. Therefore, paraoxon at a concentration of 0.1 µ M was used to examine the capability of oximes to prevent or reverse its effects. Pralidoxime, obidoxime, and HI-6 dose-dependently prevented (when it was used as pre-treatment, 20 min before or at the same time of administration of the toxin) and reversed (when it was used as post-treatment, 20 min after the administration of the toxin) the effect of paraoxon. Conclusion: In conclusion, these results revealed that oximes were very useful in the prevention and reversal of the OP toxic effects on the skeletal muscle. Moreover, it was suggested that oximes were more effective when used as pre-treatment. Pralidoxime was more potent than obidoxime and HI-6. The HI-6, which is a newer oxime, was unexpectedly less effective than the other two.


Author(s):  
Jack R. McGuire ◽  
Stephanie M. Bester ◽  
Mark A. Guelta ◽  
Jonah Cheung ◽  
Caroline Langley ◽  
...  
Keyword(s):  

2021 ◽  
Vol 64 (3) ◽  
pp. 145-152
Author(s):  
Jiří Kassa ◽  
Jana Hatlapatková ◽  
Jana Žďárová Karasová ◽  
Vendula Hepnarová ◽  
Filip Caisberger ◽  
...  

Aim: The comparison of neuroprotective and central reactivating effects of the oxime K870 in combination with atropine with the efficacy of standard antidotal treatment in tabun-poisoned rats. Methods: The neuroprotective effects of antidotal treatment were determined in rats poisoned with tabun at a sublethal dose using a functional observational battery 2 h and 24 h after tabun administration, the tabun-induced brain damage was investigated by the histopathological evaluation and central reactivating effects of oximes was evaluated by the determination of acetylcholinesterase activity in the brain using a standard spectrophotometric method. Results: The central reactivating efficacy of a newly developed oxime K870 roughly corresponds to the central reactivating efficacy of pralidoxime while the ability of the oxime HI-6 to reactivate tabun-inhibited acetylcholinesterase in the brain was negligible. The ability of the oxime K870 to decrease tabun-induced acute neurotoxicity was slightly higher than that of pralidoxime and similar to the oxime HI-6. These results roughly correspond to the histopathological evaluation of tabun-induced brain damage. Conclusion: The newly synthesized oxime K870 is not a suitable replacement for commonly used oximes in the antidotal treatment of acute tabun poisonings because its neuroprotective efficacy is only slightly higher or similar compared to studied currently used oximes.


2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A24.1-A24
Author(s):  
SE Church ◽  
J Reeves ◽  
DR Zollinger ◽  
J McKay-Fleisch ◽  
AJ Bahrami ◽  
...  

IntroductionIn colorectal cancer (CRC) there have been many recent advances in immune related biomarkers that are both prognostic and predictive of response to immunotherapy. Microsatellite instability (MSI)/mismatch repair deficiency dMMR is present in 15–20% of CRCs and correlates with increased immunogenic mutations that often augment lymphocyte infiltration into the tumor microenvironment (TME). Additionally, location of tumor infiltrating T cells in two areas of the TME, the tumor center (CT) and invasive margin (IM) has also been shown to be prognostic and predictive of response to immunotherapy. Here we use multiplexed protein and RNA digital spatial profiling to elicit the immune landscape of MSI-MSS characterized CRC tumors.MethodsForty-eight CRC tumors were analyzed for gene expression using the NanoString® nCounter® PanCancer IO 360™ Research Use Only (RUO) Gene Expression Panel and assessed for 48 cell typing and biological signatures, including MMR loss/MSI predictor and the Tumor Inflammation Signature (TIS). A subset of 18 CRC tumors (6 MSI-TIS-hi, 6 MSS-TIS-hi, 6 MSS-TIS-lo) was selected for analysis with the RUO GeoMx™ Digital Spatial Profiler (DSP) using 40 antibodies (human IO protein panel), or 84 RNA probes (human IO RNA panel). Selection of regions of interest (ROIs) in two locations, CT and IM were guided by staining with fluorescent markers (CD45, CD3, pan-CK, DNA). 300–600 µM diameter circle ROIs were selected, and in some cases segmented by pan-CK+/pan-CK-. For 2 immune hot samples contour profiling at the IM into stromal and tumor regions was performed using 1400+ RNA probes with NGS readout.SummaryUsing whole tissue gene expression analysis, we determined the TIS and IO 360 signature scores for 48 CRC tumors using PanCancer IO 360 assay. 18 tumors within this cohort were selected based on TIS status to further dissect the location-dependent immune contexture of the TME. Protein DSP confirmed loss of dMMR markers (MSH2/MLH1) and identified an increased amount of potentially suppressive macrophages (CD163+PD-L1+) in MSI-TIS-hi versus MSS-TIS-hi tumors. Segmentation of ROIs based on tumor versus stroma (pan-CK±) identified samples with high proportions of tumor-invading TILs. Two MSI-TIS-hi profiled using probes against 1400+ mRNA targets confirmed protein results (CD163 in IM) and identified tumor-related signatures corresponding to the inside of the tumor (Cytokeratins, HER2/ERBB2, MET).ConclusionsHere we show the use of novel high-plex spatial profiling to profile location and pathways in the TME of MSI and MSS CRC tumors. These findings elicit unique biology related to the location and signaling of immune cells, which have the potential to unveil targets for therapeutic combinations.Disclosure InformationS.E. Church: A. Employment (full or part-time); Significant; NanoString Technologies. J. Reeves: A. Employment (full or part-time); Significant; NanoString Technologies. D.R. Zollinger: A. Employment (full or part-time); Significant; NanoString Technologies. J. McKay-Fleisch: A. Employment (full or part-time); Significant; NanoString Technologies. A.J. Bahrami: A. Employment (full or part-time); Significant; NanoString Technologies. M. Holpert: A. Employment (full or part-time); Significant; NanoString Technologies. A.M. White: A. Employment (full or part-time); Significant; NanoString Technologies. M.D. Bailey: A. Employment (full or part-time); Significant; NanoString Technologies. C.R. Merritt: A. Employment (full or part-time); Significant; NanoString Technologies. M. Hoang: A. Employment (full or part-time); Significant; NanoString Technologies. S. Warren: A. Employment (full or part-time); Significant; NanoString Technologies. J.M. Beechem: A. Employment (full or part-time); Significant; NanoString Technologies.


ACS Omega ◽  
2020 ◽  
Vol 5 (9) ◽  
pp. 4490-4500 ◽  
Author(s):  
Felipe Rodrigues de Souza ◽  
Danielle Rodrigues Garcia ◽  
Teobaldo Cuya ◽  
André Silva Pimentel ◽  
Arlan da Silva Gonçalves ◽  
...  

2019 ◽  
Vol 23 (5) ◽  
pp. 628-639 ◽  
Author(s):  
Dietrich E. Lorke ◽  
Georg A. Petroianu

Standard therapy of Organophosphorus Compound (OPC) poisoning with oxime-type acetylcholinesterase (AChE) reactivators is unsatisfactory. New bispyridinium oximes have therefore been synthesized. This review summarizes in vitro characteristics of established (pralidoxime, obidoxime, trimedoxime, HI-6) and experimental (K-)oximes, and compares their protective efficacy in vivo, when administered shortly after exposure to Diisopropylfluorophosphate (DFP) and three OPC pesticides (ethyl-paraoxon, methylparaoxon, azinphos-methyl) in the same experimental setting. In addition to reactivating cholinesterase, oximes also inhibit this enzyme; strongest AChE inhibition (IC50 rat blood: 1-9 µM) is observed in vitro for the oximes with a xylene linker (K-107, K-108, K-113). AChE inhibition is weakest for K-27, K-48 and HI-6 (IC50 >500 µM). Intrinsic AChE inhibition of oximes in vitro (IC50, rat) is strongly correlated with their LD50 (rat): oximes with a high IC50 (K-27, K-48, pralidoxime, obidoxime) also show a high LD50, making them relatively non-toxic, whereas oximes K-107, K-108 and K-113 (low IC50 and LD50) are far more toxic. When given in vivo after OP exposure, best protection is conferred by K-27, reducing the relative risk of death to 16-58% of controls, which is significantly superior to pralidoxime in DFP-, ethyl-paraoxon- and methylparaoxon- exposure, and to obidoxime in ethyl-paraoxon- and methyl-paraoxon-exposure. Marked reduction in mortality is also achieved by K-48, K-53, K-74 and K-75, whereas K-107, K-108 and K-113 have no or only a very weak mortality-reducing effect. K-27 is the most promising K-oxime due to its strong reactivation potency, weak cholinesterase inhibition and high LD50, allowing administration in large, very efficacious dosages.


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