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Neurotoxicology Dec 2019Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. Consumption of these... (Review)
Review
Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. Consumption of these compounds affects several central nervous system functions. Some of the most recognised consequences of organophosphate pesticide exposure in humans include neonatal developmental abnormalities, endocrine disruption, neurodegeneration, neuroinflammation and cancer. In addition, neurobehavioral and emotional deficits following OP exposure have been reported. It would be of great value to discover a therapeutic strategy which produces a protective effect against these neurotoxic compounds. Moreover, a growing body of preclinical data suggests that the microbiota may affect metabolism and neurotoxic outcomes through exposure to OPs. The human gut is colonised by a broad variety of microorganisms. This huge number of bacteria and other microorganisms which survive by colonising the gastrointestinal tract is defined as "gut microbiota". The gut microbiome plays a profound role in metabolic processing, energy production, immune and cognitive development and homeostasis. The effects are not only localized in the gut, but also influence many other organs, such as the brain through the microbiome-gut-brain axis. Therefore, given the gut microbiota's key role in host homeostasis, this microbiota may be altered or modified temporarily by factors such as antibiotics, diet and toxins such as pesticides. The aim of this review is to examine scientific articles concerning the impact of microbiota in OP toxicity. Studies focussed on the possible contribution the microbiota has on variable host pharmacokinetic responses such as absorption and biotransformation of xenobiotics will be evaluated. Microbiome manipulation by antibiotic or probiotic administration and faecal transplantation are experimental approaches recently proposed as treatments for several diseases. Finally, microbiota manipulation as a possible therapeutic strategy in order to reduce OP toxicity will be discussed.
Topics: Animals; Gastrointestinal Microbiome; Humans; Organophosphate Poisoning; Organophosphates
PubMed: 31560873
DOI: 10.1016/j.neuro.2019.09.013 -
Expert Review of Anti-infective Therapy Aug 2021: For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side... (Review)
Review
: For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side effects, past intolerance, and administration inability contribute to the need for novel drug classes in this population.: Herein, we review the pharmacology, clinical efficacy, and safety profile of fostemsavir, a first in its class attachment inhibitor recently FDA approved for use.: Fostemsavir is a well-tolerated oral medication with relatively few drug-drug interactions. Clinical trial data demonstrates virologic and notable immunologic response in conjunction with optimal background therapy in HTE persons living with HIV. Fostemsavir exhibits no cross-resistance with other ARV classes and thus is an important advancement for patients harboring drug-resistant HIV. Further study will be needed to determine outstanding clinical questions such as the role of drug resistance testing and fostemsavir use outside of the HTE population.
Topics: Administration, Oral; Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Organophosphates; Piperazines
PubMed: 33331202
DOI: 10.1080/14787210.2021.1865801 -
Clinical Pharmacokinetics Apr 2022Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The... (Review)
Review
Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.
Topics: Animals; Anti-Bacterial Agents; Humans; Mice; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles
PubMed: 35128625
DOI: 10.1007/s40262-021-01099-7 -
American Journal of Health-system... Nov 2020
Topics: Drug Resistance, Multiple, Viral; HIV Fusion Inhibitors; HIV Infections; Humans; Organophosphates; Piperazines; Tromethamine
PubMed: 32936234
DOI: 10.1093/ajhp/zxaa294 -
Archives of Toxicology May 2022
Topics: Nerve Agents; Organophosphates
PubMed: 35267066
DOI: 10.1007/s00204-022-03273-7 -
Drugs Sep 2020Fostemsavir (Rukobia), a prodrug of the HIV-1 attachment inhibitor temsavir, is a first-in-class treatment for HIV infection being developed by ViiV Healthcare. Based on... (Review)
Review
Fostemsavir (Rukobia), a prodrug of the HIV-1 attachment inhibitor temsavir, is a first-in-class treatment for HIV infection being developed by ViiV Healthcare. Based on the results of the phase III BRIGHTE trial fostemsavir was recently approved in the USA for the treatment of patients with HIV not able to be treated with other therapies. This article summarizes the milestones in the development of fostemsavir leading to this first approval.
Topics: Anti-HIV Agents; Drug Approval; HIV Infections; HIV-1; Humans; Molecular Structure; Organophosphates; Piperazines; Prodrugs; United States
PubMed: 32852743
DOI: 10.1007/s40265-020-01386-w -
Molecules (Basel, Switzerland) Feb 2020Biomimetic molecular design is a promising approach for generating functional biomaterials such as cell membrane mimetic blood-compatible surfaces, mussel-inspired... (Review)
Review
Biomimetic molecular design is a promising approach for generating functional biomaterials such as cell membrane mimetic blood-compatible surfaces, mussel-inspired bioadhesives, and calcium phosphate cements for bone regeneration. Polyphosphoesters (PPEs) are candidate biomimetic polymer biomaterials that are of interest due to their biocompatibility, biodegradability, and structural similarity to nucleic acids. While studies on the synthesis of PPEs began in the 1970s, the scope of their use as biomaterials has increased in the last 20 years. One advantageous property of PPEs is their molecular diversity due to the presence of multivalent phosphorus in their backbones, which allows their physicochemical and biointerfacial properties to be easily controlled to produce the desired molecular platforms for functional biomaterials. Polyphosphodiesters (PPDEs) are analogs of PPEs that have recently attracted interest due to their strong affinity for biominerals. This review describes the fundamental properties of PPDEs and recent research in the field of macromolecular bone therapeutics.
Topics: Animals; Biocompatible Materials; Biomimetic Materials; Bone Regeneration; Calcification, Physiologic; Cell Differentiation; Esters; Humans; Materials Testing; Nanoparticles; Organophosphates; Osteoblasts
PubMed: 32050545
DOI: 10.3390/molecules25030758 -
Environment International Jan 2020The present study reports one of the few cases in which organophosphate (OP) and pyrethroid (PYR) pesticide human exposure is evaluated in family contexts by the...
The present study reports one of the few cases in which organophosphate (OP) and pyrethroid (PYR) pesticide human exposure is evaluated in family contexts by the analysis of mother/child pair samples. Urinary concentrations of 6 organic metabolites of organophosphates and 2 pyrethroids were measured in mothers and their 7-to 8-year-old children (n = 168) in a general population from the central area of Slovenia. The results were adjusted for specific gravity and creatinine. The most abundant OP metabolite in children was 4-nitrophenol (PNP) (median 0.7 ng/ml) and in mothers (0.45 ng/ml), representing parathion exposure. 3-Phenoxibenzoic acid (3-PBA) (0.26 ng/ml), the general metabolite of pyrethroids, and 3,5,6-trichloro-2-pyridinol (TCPY) (0.16 ng/ml; chlorpyriphos) were the second most abundant compounds in children and mothers, respectively. The geometric mean specific gravity adjusted concentrations of OPs and PYRs were statistically significantly higher in children than in their mothers (between 3% and 24% higher), with the exception of TCPY (26% lower). All OP and PYR metabolites found in higher concentration in children showed significant positive correlations with the metabolite concentrations found in the mothers (p < 0.05 and 0.01), involving the fact that higher maternal concentrations were associated with higher children levels. These differential mother-children distributions and significant correlations were observed for the 2 types of pesticides studied, OPs and PYRs, which have different chemical properties. This agreement is consistent with the incorporation of the pesticides because of the general activities developed in the family context, instead of pesticide-dependent specific inputs. Comparison of the estimated daily intakes with the acceptable daily intakes of all detected metabolites revealed no significant risk of adverse health effects from exposure to these pesticides.
Topics: Attention; Child; Environmental Exposure; Female; Humans; Mothers; Organophosphates; Pesticides; Pyrethrins
PubMed: 31706197
DOI: 10.1016/j.envint.2019.105264 -
ChemMedChem Jun 2020Phosphoantigens (pAgs) are small phosphorus-containing molecules that stimulate Vγ9Vδ2 T cells with sub-nanomolar cellular potency. Recent work has revealed that these... (Review)
Review
Phosphoantigens (pAgs) are small phosphorus-containing molecules that stimulate Vγ9Vδ2 T cells with sub-nanomolar cellular potency. Recent work has revealed that these compounds work through binding to the transmembrane immunoglobulin butyrophilin 3A1 (BTN3A1) within its intracellular B30.2 domain. Engagement of BTN3A1 is critical to the formation of an immune synapse between cells that contain pAgs and the Vγ9Vδ2 T cells. This minireview summarizes the structure-activity relationships of pAgs and their implications to the mechanisms of butyrophilin 3 activation leading to Vγ9Vδ2 T cell response.
Topics: Antigens, CD; Binding Sites; Butyrophilins; Humans; Intraepithelial Lymphocytes; Ligands; Molecular Structure; Organophosphates; Protein Binding; Protein Domains; Structure-Activity Relationship
PubMed: 32453919
DOI: 10.1002/cmdc.202000198 -
Chemical Reviews Jun 2020The formation of organophosphate molecules by prebiotic processes relies on nonenzymatic synthesis. Given the centrality of phosphorylated biomolecules in metabolic,... (Review)
Review
The formation of organophosphate molecules by prebiotic processes relies on nonenzymatic synthesis. Given the centrality of phosphorylated biomolecules in metabolic, structural, and replicative processes, it is highly likely that such nonenzymatic synthesis had to occur early in Earth's history. This Review collects and uses thermodynamic data to constrain processes that may have produced organophosphates and evaluates both the plausibility of reactants and the likelihood that environments conducive to phosphorylation were present. The energy required to phosphorylate organics is ∼15 kJ/mol, requiring either very low water activities or reactive inorganic phosphorus compounds. Thermodynamics permits evaluating phosphorylation environments for both plausibility and novelty and shows that several routes would have been available to form these potentially key reagents. Building from phosphate monoesters to diesters may have enabled the synthesis of nucleic acids, perhaps opening a way into the RNA world.
Topics: Evolution, Chemical; Nucleic Acids; Organophosphates; Phosphorylation; Thermodynamics
PubMed: 31736304
DOI: 10.1021/acs.chemrev.9b00492