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1.
Top Curr Chem (Cham) ; 381(1): 8, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36624333

RESUMO

Photochromic compounds of the spiropyran family have two main isomers capable of inter-switching with UV or visible light. In the current review, we discuss recent advances in the synthesis, investigation of properties, and applications of spiropyran derivatives. Spiropyrans of the indoline series are in focus as the most promising representatives of multi-sensitive spirocyclic compounds, which can be switched by a number of external stimuli, including light, temperature, pH, presence of metal ions, and mechanical stress. Particular attention is paid to the structural features of molecules, their influence on photochromic properties, and the reactions taking place during isomerization, as the understanding of the structure-property relationships will rationalize the synthesis of compounds with predetermined characteristics. The main prospects for applications of spiropyrans in such fields as smart material production, molecular electronics and nanomachinery, sensing of environmental and biological molecules, and photopharmacology are also discussed.


Assuntos
Benzopiranos , Nitrocompostos , Estrutura Molecular , Benzopiranos/química , Nitrocompostos/química , Íons
2.
Ecotoxicol Environ Saf ; 250: 114513, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36610296

RESUMO

Thiamethoxam (TMX) is a systemic neonicotinoid that acts as a partial agonist of the nicotinic acetylcholine receptors (nAChRs). However, target species have shown resistance to formulations based on such neonicotinoids, which can also be expected for non-target insects. This research aimed to study the effects of a formulation based on TMX [Cruiser® 350 FS (CRZ)] on the life traits of Chironomus xanthus filial generation (F1) and compare it with the parental generation (P). Environmentally relevant concentrations of CRZ significantly decreased larvae growth P generation , also slowing and decreasing their emergence. Larvae of the F1 generation were less sensitive than their parents, suggesting that the progeny were able to thrive and perform basic physiological functions better than the parental generation. Our results highlight that insect resistance to neonicotinoids may be associated with the better performance of the filial generation, which is related to the change in affinities of the active ingredient for the sub-units constituting the nAChRs subtypes of F1 organisms, inherited from P organisms that were able to survive and reproduce. Moreover, further studies using biochemical and omics tools should be performed to disentangle the specific changes occurring at the nAChRs throughout insect development.


Assuntos
Chironomidae , Inseticidas , Receptores Nicotínicos , Animais , Inseticidas/farmacologia , Larva , Chironomidae/genética , Tiametoxam/farmacologia , Neonicotinoides/toxicidade , Insetos , Receptores Nicotínicos/genética , Nitrocompostos/toxicidade
3.
J Am Chem Soc ; 145(2): 787-793, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36608280

RESUMO

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent "ene"-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions.


Assuntos
Alcanos , Nitrocompostos , Alcanos/química , Nitrocompostos/química , Alquilação , Catálise
4.
J Hazard Mater ; 446: 130715, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36603418

RESUMO

Neonicotinoids (NEOs) are widely applied in agricultural lands and are widespread in different environments, accelerating threats to ecosystems and human health. A number of in vitro/in vivo studies have reported adverse effects of NEOs on mammalian health, but the link between NEO exposure and toxic effects on human liver remains unclear. We randomly recruited 201 participants and quantified eight commercialized NEOs in bile. High frequency and concentration of detection indicate low degradation of human liver on NEOs. The main NEOs are nitenpyram and dinotefuran, which contribute to about 86% of the total residual levels of eight NEOs, due to the highest solubility in bile and are not degraded easily in liver. In contrast, imidacloprid and thiacloprid are major compounds in human blood, according to previous studies, suggesting that individual NEOs behave differently in blood and bile distribution. There was no statistical difference in NEO residues between cancer and non-cancer participants and among the different participant demographics (e.g., age, gender, and body mass index). The serum hematological parameters -bile acid, total bilirubin, cholesterol and alkaline phosphatase -were positively correlated with individual NEO concentrations, suggesting that NEO exposure affects liver metabolism and even enterohepatic circulation. The study first examined the NEO residues in human bile and provided new insights into their bioavailability and hepatoxicity risk.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Inseticidas , Animais , Humanos , Inseticidas/toxicidade , Inseticidas/análise , Bile/química , Ecossistema , Neonicotinoides/toxicidade , Nitrocompostos , Mamíferos
5.
Chem Biol Interact ; 369: 110288, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36509115

RESUMO

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive impairments. Intrastriatal injection of 3- nitropropionic acid (3NP) was used to induce HD-like symptoms by inhibiting succinate dehydrogenase enzyme (SDH) in the mitochondrial complex II. The adenosine A1 receptor has long been known to have a crucial role in neuroprotection, mainly by blocking Ca2+ influx, which causes inhibition of glutamate (Glu) and a decline in its excitatory effects at the postsynaptic level. To this end, this study investigated the possible involvement of TrKB/PI3K/Akt/CREB/BDNF pathway in mediating protection afforded by the central N6-cyclohexyladenosine (CHA), an adenosine A1 receptor agonist. A single intrastriatal CHA injection (6.25 nM/1 µL); 45min after 3-NP injection, attenuated neuronal death, and improved cognitive and motor deficits caused by 3-NP neurotoxin. This effect was shown to parallel an enhanced activation of PI3K/Akt/CREB/BDNF axis as well as boosting pERK1/2 levels. Moreover, CHA attenuated neuroinflammatory and oxidative stress status via reducing NFκB p65, TNFα and iNOS contents and increasing SOD. Furthermore, immunohistochemical data showed a reduction in the glial fibrillary acidic protein (GFAP) immunoreactivity to a marker for astrocyte and microglia activation following CHA treatment. The results of this study suggest that CHA may have protective effect against HD via modulating oxidative stress, excitotoxic and inflammatory pathways.


Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Corpo Estriado , Adenosina/metabolismo , Nitrocompostos/toxicidade , Fármacos Neuroprotetores/uso terapêutico
6.
Environ Res ; 218: 114953, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36504008

RESUMO

Neonicotinoids (NEOs) are fourth generation pesticides, which emerged after organophosphates, pyrethroids, and carbamates and they are widely used in vegetables, fruits, cotton, rice, and other industrial crops to control insect pests. NEOs are considered ideal substitutes for highly toxic pesticides. Multiple studies have reported NEOs have harmful impacts on non-target biological targets, such as bees, aquatic animals, birds, and mammals. Thus, the remediation of neonicotinoid-sullied environments has gradually become a concern. Microbial degradation is a key natural method for eliminating neonicotinoid insecticides, as biodegradation is an effective, practical, and environmentally friendly strategy for the removal of pesticide residues. To date, several neonicotinoid-degrading strains have been isolated from the environment, including Stenotrophomonas maltophilia, Bacillus thuringiensis, Ensifer meliloti, Pseudomonas stutzeri, Variovorax boronicumulans, and Fusarium sp., and their degradation properties have been investigated. Furthermore, the metabolism and degradation pathways of neonicotinoids have been broadly detailed. Imidacloprid can form 6-chloronicotinic acid via the oxidative cleavage of guanidine residues, and it is then finally converted to non-toxic carbon dioxide. Acetamiprid can also be demethylated to remove cyanoimine (=N-CN) to form a less toxic intermediate metabolite. A few studies have discussed the neonicotinoid toxicity and microbial degradation in contaminated environments. This review is focused on providing an in-depth understanding of neonicotinoid toxicity, microbial degradation, catabolic pathways, and information related to the remediation process of NEOs. Future research directions are also proposed to provide a scientific basis for the risk assessment and removal of these pesticides.


Assuntos
Inseticidas , Praguicidas , Abelhas , Animais , Inseticidas/toxicidade , Inseticidas/análise , Neonicotinoides/toxicidade , Neonicotinoides/análise , Insetos/metabolismo , Nitrocompostos/toxicidade , Nitrocompostos/metabolismo , Produtos Agrícolas/metabolismo , Biodegradação Ambiental , Mamíferos/metabolismo
7.
Environ Res ; 216(Pt 1): 114494, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36209786

RESUMO

The present work demonstrates a facile route for synthesizing the organic nanoparticles (ONPs) and the blue fluorescent Quantum Dots (QDs) based on an organic molecule named (E)-(4-fluorophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene. The synthesis process possesses advantages viz green synthesis, non-toxic degraded products, and amount of organic compound. Initially, the ONPs were prepared using the nanoprecipitation method and were screened for their recognition potential against various pesticides, however, no selectivity has been observed. This motivated us to tune the ONPs into QDs. The QDs were prepared using the hydrothermal method and a color change was observed in the QDs solution under daylight and under a UV lamp. The emission wavelength was observed at 400 nm (λexcitation = 278 nm). The synthesized QDs exhibited selective sensing potential towards imidacloprid via a quenching mechanism. A normalised decrement in the luminescence intensity of QDs was observed on raising the concentration of imidacloprid and a good linear response was noticed over a concentration varies from 1 µM to 100 µM with a regression coefficient of 0.99. The detection limit was estimated to be 4.53 nM and quantification limit was calculated to be and 13.72 nM.


Assuntos
Pontos Quânticos , Pontos Quânticos/química , Neonicotinoides , Nitrocompostos , Luminescência
8.
J Hazard Mater ; 424(Pt A): 127344, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34607030

RESUMO

Machine learning (ML) is a branch of artificial intelligence (AI) that enables the analysis of complex multivariate data. ML has significant potential in risk assessments of non-target insects for modeling the multiple factors affecting insect health, including the adverse effects of agrochemicals. Here, the potential of ML for risk assessments of glyphosate (herbicide; formulation) and imidacloprid (insecticide, neonicotinoid; formulation) on the stingless bee Melipona quadrifasciata was explored. The collective behavior of forager bees was analyzed after in vitro exposure to agrochemicals. ML algorithms were applied to identify the agrochemicals that the bees have been exposed to based on multivariate behavioral features. Changes in the in situ detection of different proteins in the midgut were also studied. Imidacloprid exposure leads to the greatest changes in behavior. The ML algorithms achieved a higher accuracy (up to 91%) in identifying agrochemical contamination. The two agrochemicals altered the detection of cells positive for different proteins, which can be detrimental to midgut physiology. This study provides a holistic assessment of the sublethal effects of glyphosate and imidacloprid on a key pollinator. The procedures used here can be applied in future studies to monitor and predict multiple environmental factors affecting insect health in the field.


Assuntos
Agroquímicos , Inseticidas , Agroquímicos/toxicidade , Animais , Inteligência Artificial , Abelhas , Inseticidas/toxicidade , Aprendizado de Máquina , Eventos de Massa , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade
10.
J Am Chem Soc ; 144(50): 23198-23204, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36509594

RESUMO

Mechanophores are powerful molecular tools used to track bond rupture and characterize mechanical damage in polymers. The majority of mechanophores are known to respond to external stresses, and we report in this study the first precedent of a mechanochemical response to internal, residual stresses that accumulate during polymer vitrification. While internal stress is intrinsic to polymers that can form solids, we demonstrate that it can dramatically affect the mechanochemistry of spiropyran probes and alter their intramolecular isomerization barriers by up to 70 kJ mol-1. This new behavior of spiropyrans (SPs) enables their application for analysis of internal stresses distribution and their mechanochemical characterization on the molecular level. Spectroscopy and imaging based on SP mechanochemistry showed high topological sensitivity and allowed us to discern different levels of internal stress impacting various locations along the polymer chain. The nature of the developed technique allows for wide-field imaging of stress heterogeneities in polymer samples of irregular shapes and dimensions, making it feasible to directly observe molecular-level manifestations of mechanical stresses that accompany the formation of a vast number of solid polymers.


Assuntos
Benzopiranos , Polímeros , Polímeros/química , Benzopiranos/química , Indóis/química , Nitrocompostos/química
11.
Molecules ; 27(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36500585

RESUMO

New salts of photochromic indoline spiropyrans capable of reversibly responding to UV radiation were synthesized to develop light-controlled materials. Photoinduced reactions of the synthesized compounds were studied using absorption and luminescence spectroscopies, and the quantum yields of photoisomerization and other spectral and kinetic characteristics were measured. It was shown that the light sensitivity and photostability of the synthesized compounds are considerably influenced by the length of the spacer between the indole and ammonium nitrogen atoms.


Assuntos
Compostos de Amônio , Benzopiranos , Estrutura Molecular , Nitrocompostos
12.
Bull Environ Contam Toxicol ; 110(1): 5, 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36507940

RESUMO

Agricultural use of neonicotinoid insecticides, neuroactive nitroguanidine compounds, has been detected everywhere in the global, posing significant hazard to nontarget organisms. This work studied the developmental neurotoxicity of zebrafish larvae exposed to imidacloprid (IMI) and thiamethoxam (THM), ranging from 0.05 µg L- 1 to 50 µg L- 1 for 35 days. Transcriptions of genes belonging to the behavior, neurodevelopment and cortisol synthesis in zebrafish larvae were monitored. The qPCR data demonstrated that with exposure time increased, the transcription of behavior related genes was down-regulated in both IMI and THM groups, such as macf1, cdh6 and syt10. Additionally, IMI and THM significantly up-regulated the transcriptions of actha, and down-regulated il1rapl1b and pi4k2a at 35 dpf. Importantly, IMI markedly enhanced the transcripiton of gfap, shha, nkx2.2a and nestin in a time dependent manner. This work provided the foundation for understanding zebrafish larvae's neurotoxicity induced by IMI and THM.


Assuntos
Inseticidas , Peixe-Zebra , Animais , Tiametoxam/toxicidade , Larva , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Inseticidas/toxicidade , Inseticidas/análise
13.
Molecules ; 27(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36500530

RESUMO

Regiochemical aspects and the molecular mechanism of the [3 + 2] cycloaddition between nitrous oxide and conjugated nitroalkenes were evaluated on the basis of the wb97xd/6-311 + G(d) (PCM) computational study. It was found that, independently of the nature of the nitroalkene, all considered processes are realized via polar, single-step mechanisms. All attempts at the localization of hypothetical zwitterionic intermediates were unsuccessful. Additionally, the DFT computational study suggested that, in the course of the reaction, the formation of respective Δ2-4-nitro-4-R1-5-R2-1-oxa-2,3-diazolines was preferred from the kinetic point of view.


Assuntos
Alcenos , Óxido Nitroso , Reação de Cicloadição , Modelos Moleculares , Alcenos/química , Nitrocompostos
14.
Proc Biol Sci ; 289(1987): 20220253, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36382527

RESUMO

The systemic neonicotinoid insecticides are considered as one of the key culprits contributing to ongoing declines in pollinator health and abundance. Bumblebees are among the most important pollinators of temperate zone plants, making their susceptibility to neonicotinoid exposure of great concern. We report that bumblebee (Bombus terrestris) colonies exposed to field-realistic concentrations of the commonly used neonicotinoid Imidacloprid grew slower, consumed less food, and produced fewer workers, males and gynes, but unexpectedly produced larger workers compared to control colonies. Behavioural observations show that queens in pesticide-treated colonies spend more time inactive and less time caring for the brood. We suggest that the observed effects on brood body size are driven by a decreased queen ability to manipulate the larva developmental programme. These findings reveal an intricate and previously unknown effect of insecticides on the social interactions controlling brood development in social insect colonies. Insecticide influences on the social mechanisms regulating larval development are potentially detrimental for bumblebees, in which body size strongly influences both caste differentiation and the division of labour among workers, two organization principles of insect societies.


Assuntos
Inseticidas , Praguicidas , Masculino , Humanos , Abelhas , Animais , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Larva
15.
Org Lett ; 24(45): 8370-8374, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36350067

RESUMO

A highly diastereo- and enantioselective formal [4 + 2] cyclization of α,ß-unsaturated ketoesters with nitroalkenes through a tandem asymmetric Michael addition-intramolecular Henry reaction under dihydroquinine-based phase-transfer catalysis, leading to a one-pot construction of four contiguous stereochemical centers and multiple functional groups with excellent diastereo- and enantioselectivities in high yields, has been developed. The ee values of some products were increased to ∼100% in good yields after one crystallization.


Assuntos
Alcenos , Nitrocompostos , Ciclização , Estereoisomerismo , Alcenos/química , Catálise , Nitrocompostos/química
16.
Molecules ; 27(21)2022 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-36364434

RESUMO

The whitefly, Bemisia tabaci, is the main pest for many field and horticultural crops, causing main and significant problems. The efficiency of imidacloprid insecticide as seed treatment and foliar spray at three rates against the whitefly, B. tabaci, was evaluated in tomato plants under field conditions; in addition, insecticide residues were determined in tomato leaves and fruits. The obtained results revealed that the seedlings produced from treated seeds with imidacloprid were the most effective treatment in decreasing whitefly stages. Reduction percentages of whitefly stages in seedlings produced from treated seeds and sprayed with ½, ¾ and 1 field rates of imidacloprid were more than that produced from untreated seeds. Tomato fruit yield in seedlings produced from treated seeds and sprayed with one recommended rate of imidacloprid was more than that of untreated seeds. The residues of imidacloprid in leaves and fruits in seedlings produced from treated seeds and sprayed with field rate were more than that of untreated seeds; additionally, the residues were higher in leaves than in fruits. The residual level in fruits was less than the maximum residual level (MRL = 1 mg kg-1) of the Codex Alimentarius Commission. The half-life (t ½) was 6.99 and 6.48 days for leaves and fruits of seedlings produced from treated seeds and 5.59 and 4.59 days for untreated seeds. Residues in tomato fruits were less than the MRL, therefore, imidacloprid is considered an unconventional insecticide appropriate for B. tabaci control that could be safe for the environment.


Assuntos
Hemípteros , Inseticidas , Animais , Inseticidas/farmacologia , Imidazóis/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Plântula
17.
Expert Rev Anti Infect Ther ; 20(12): 1615-1622, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36317748

RESUMO

BACKGROUND: This study investigated the clinical outcomes, virological efficacy and safety of nitazoxanide in the treatment of patients with COVID-19. RESEARCH DESIGN AND METHODS: The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before August 23, 2022. Only randomized controlled trials (RCTs) that assessed the usefulness and safety of nitazoxanide in patients with COVID-19 were included. RESULTS: Five RCTs were included. The overall mortality of COVID-19 patients receiving nitazoxanide (study group) was 1.3% (9/670), which was lower than the control group (1.8%, 12/681), but this difference did not reach statistical significance (risk difference [RD], 0.00; 95% CI: -0.01 to 0.01; P =0.97). However, nitazoxanide was associated with a higher virological eradication rate than placebo or standard care (RD, 0.09; 95% CI: 0.01 to 0.17; P = 0.03). Compared with the placebo or standard care, nitazoxanide were associated with a similar risk of any adverse event (RD, -0.02; 95% CI: -0.07 to 0.03; P = 0.44). CONCLUSIONS: Although nitazoxanide can help virological eradication and is also tolerable, it does not provide additional clinical benefits. Based on these evidences, the use of nitazoxanide in the treatment of patients with COVID-19 is not recommended.


Assuntos
Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Nitrocompostos/efeitos adversos , Tiazóis/efeitos adversos
18.
Environ Sci Technol ; 56(23): 17143-17152, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36441562

RESUMO

Studies on neonicotinoid (NEO) exposure in pregnant women and fetuses are scarce, and transplacental transfer of these insecticides is unknown. In this study, parent NEOs (p-NEOs) and their metabolites (m-NEOs) were determined in 95 paired maternal (MS) and cord serum (CS) samples collected in southern China. Imidacloprid was the predominant p-NEO in both CS and MS samples, found at median concentrations of 1.84 and 0.79 ng/mL, respectively, whereas N-desmethyl-acetamiprid was the most abundant m-NEO in CS (median: 0.083 ng/mL) and MS (0.13 ng/mL). The median transplacental transfer efficiencies (TTEs) of p-NEOs and m-NEOs were high, ranging from 0.81 (thiamethoxam, THM) to 1.61 (olefin-imidacloprid, of-IMI), indicating efficient placental transfer of these insecticides. Moreover, transplacental transport of NEOs appears to be passive and structure-dependent: cyanoamidine NEOs such as acetamiprid and thiacloprid had higher TTE values than the nitroguanidine NEOs, namely, clothianidin and THM. Multilinear regression analysis revealed that the concentrations of several NEOs in MS were associated significantly with hematological parameters related to hepatotoxicity and renal toxicity. To our knowledge, this is the first analysis of the occurrence and distribution of NEOs in paired maternal-fetal serum samples.


Assuntos
Inseticidas , Gravidez , Humanos , Feminino , Inseticidas/análise , Placenta/química , Neonicotinoides , Nitrocompostos
19.
Molecules ; 27(22)2022 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36431923

RESUMO

A highly chemoselective conversion of α,ß-disubstituted nitroalkenes to ketones is developed. An acid-compatible iridium catalyst serves as the key to the conversion. At a 2500 S/C ratio, nitroalkenes were readily converted to ketones in up to 72% isolated yields. A new mechanistic mode involving the reduction of nitroalkene to nitrosoalkene and N-alkenyl hydroxylamine is proposed. This conversion is ready to amplify to a gram-scale synthesis. The pH value plays an indispensable role in controlling the chemoselectivity.


Assuntos
Irídio , Cetonas , Humanos , Alcenos , Nitrocompostos , Translocação Genética , Concentração de Íons de Hidrogênio
20.
Int J Med Sci ; 19(11): 1628-1630, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36237984

RESUMO

RRx-001 is a small molecule NLRP3 inflammasome inhibitor with anti-CD47 and antiangiogenic/vascular normalization properties in a Phase 3 clinical trial that has been designated as a drug-device combination by the FDA. In the Phase 1 first-in-man dose escalation clinical trial, where RRx-001 was given by direct intravenous (IV) infusion, the main adverse event was a sterile painful infusion phlebitis (IP). Less pain was experienced when RRx-001 was infused at a slower rate over multiple hours which was impractical on an outpatient basis. In Phase 2, for reasons of convenience and safety, RRx-001 was co-administered with an aliquot of autologous blood from an ex-vivo device called the eLOOP on the premise that RRx-001 binds to hemoglobin on red blood cells (RBCs), making it unavailable to directly interact with venous nociceptors. Phlebitis has the potential to progress to deep venous thrombosis or septic thrombophlebitis or post-thrombotic syndrome in hypercoagulable and immunosuppressed cancer patients. In this 13-week toxicology study of once weekly IV RRx-001 administration to Wistar Han rats followed by a recovery period of 28 days. The main observed toxicity was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis observed in man. Due to this development, direct IV infusion of RRx-001 is relatively contraindicated in favor of co-administration with autologous blood.


Assuntos
Inflamassomos , Flebite , Animais , Azetidinas , Hemoglobinas/metabolismo , Inflamação/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nitrocompostos , Ratos , Ratos Wistar
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