Review

Authors: Bettina Schmitz, Simona Lattanzi, Kristl Vonck...

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti-seizure medication (ASM), a tetrazole-derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABA receptors at a non-benzodiazepine site. CNB, having a long half-life, is an effective add-on ASM in refractory focal epilepsy with a higher response rate and a higher seizure-freedom rate than is usually seen in regulatory clinical trials. Experience post-licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50 000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

Topics: Humans; Anticonvulsants; Drug Resistant Epilepsy; Epilepsies, Partial; Carbamates; Tetrazoles

PubMed: 37743544
DOI: 10.1002/epi4.12830

Review

Authors: Nonkululeko Landy Mdeni, Abiodun Olagoke Adeniji, Anthony Ifeanyi Okoh...

Pesticides are synthetic compounds that may become environmental contaminants through their use and application. The high productivity achieved in the agricultural industry can be credited to the use and application of pesticides by way of pest and insect control. As much as pesticides have a positive impact on the agricultural industry, some disadvantages come with their application in the environment because they are intentionally toxic, and this is more towards non-target organisms. They are grouped into chlorophenols, organochlorines, synthetic pyrethroid, carbamates, and organophosphorus based on their structure. The symptoms of exposure to carbamate (CM) and organophosphates (OP) are similar, although poisoning from CM is of a shorter duration. The analytical evaluation of carbamate and organophosphate pesticides in human and environmental matrices are reviewed using suitable extraction and analytical methods.

Topics: Carbamates; Environmental Exposure; Environmental Monitoring; Humans; Organophosphorus Compounds; Pesticides

PubMed: 35163876
DOI: 10.3390/molecules27030618

Authors: Chuanyu Yu, Xueyan Liu, Bingxiang Ma...

Butyrylcholinesterase (BuChE) and neuroinflammation have recently emerged as promising therapeutic directions for Alzheimer's disease (AD). Herein, we synthesised 19 novel pyranone-carbamate derivatives and evaluated their activities against cholinesterases and neuroinflammation. The optimal compound exhibited balanced BuChE inhibitory activity (eqBuChE IC = 4.68 nM; huBuChE IC = 9.12 nM) and anti-neuroinflammatory activity (NO inhibition = 28.82% at 10 μM, comparable to hydrocortisone). Enzyme kinetic and docking studies confirmed compound was a mix-type BuChE inhibitor. Additionally, compound displayed favourable drug-likeness properties in silico prediction, and exhibited high BBB permeability in the PAMPA-BBB assay. Compound had good safety in vivo as verified by an acute toxicity assay (LD > 1000 mg/kg). Most importantly, compound effectively mitigated cognitive and memory impairments in the scopolamine-induced mouse model, showing comparable effects to Rivastigmine. Therefore, we envisioned that compound could serve as a promising lead compound for treating AD.

Topics: Mice; Animals; Alzheimer Disease; Butyrylcholinesterase; Carbamates; Neuroinflammatory Diseases; Amyloid beta-Peptides; Cholinesterase Inhibitors; Acetylcholinesterase; Structure-Activity Relationship; Molecular Docking Simulation; Molecular Structure

PubMed: 38362862
DOI: 10.1080/14756366.2024.2313682

Meta-Analysis Review

Authors: Lauren B Ellis, Karen Molina, C Rebecca Robbins...

BACKGROUND

Evidence of the negative impacts of contemporary use insecticides on sperm concentration has increased over the last few decades; however, meta-analyses on this topic are rare.

OBJECTIVES

This investigation assessed the qualitative and quantitative strength of epidemiological evidence regarding adult exposure to two classes of contemporary use insecticides-organophosphates (OPs) and -methyl carbamates (NMCs)-and sperm concentration using robust and reproducible systematic review and meta-analysis methods.

METHODS

Three scientific databases (PubMed, Scopus, and Web of Science), two U.S. government databases (NIOSHTIC-2 and Science.gov), and five nongovernmental organization websites were searched for relevant primary epidemiological studies published in any language through 11 August 2022. Risk of bias and strength of evidence were evaluated according to Navigation Guide systematic review methodology. Bias-adjusted standardized mean difference effect sizes were calculated and pooled using a three-level, multivariate random-effect meta-analysis model with cluster-robust variance estimation.

RESULTS

Across 20 studies, 21 study populations, 42 effect sizes, and 1,774 adult men, the pooled bias-adjusted standardized mean difference in sperm concentration between adult men more- and less-exposed to OP and NMC insecticides was (95% CI: , ; ). Sensitivity and subgroup analyses explored statistical heterogeneity and validated the model robustness. Although the pooled effect estimate was modified by risk of bias, insecticide class, exposure setting, and recruitment setting, it remained negative in direction across all meta-analyses. The body of evidence was rated to be of moderate quality, with sufficient evidence of an association between higher adult OP and NMC insecticide exposure and lower sperm concentration.

DISCUSSION

This comprehensive investigation found sufficient evidence of an association between higher OP and NMC insecticide exposure and lower sperm concentration in adults. Although additional cohort studies can be beneficial to fill data gaps, the strength of evidence warrants reducing exposure to OP and NMC insecticides now to prevent continued male reproductive harm. https://doi.org/10.1289/EHP12678.

Topics: Humans; Male; Adult; Insecticides; Organophosphates; Semen; Carbamates; Spermatozoa

PubMed: 37966213
DOI: 10.1289/EHP12678

Authors: Pedro Diaz-Parga, Joy J Goto, V V Krishnan...

Beta-N-methylamino-L-alanine (BMAA) has been demonstrated to contribute to the onset of the ALS/Parkinsonism-dementia complex (ALS/PDC) and is implicated in the progression of other neurodegenerative diseases. While the role of BMAA in these diseases is still debated, one of the suggested mechanisms involves the activation of excitatory glutamate receptors. In particular, the excitatory effects of BMAA are shown to be dependent on the presence of bicarbonate ions, which in turn forms carbamate adducts in physiological conditions. The formation of carbamate adducts from BMAA and bicarbonate is similar to the formation of carbamate adducts from non-proteinogenic amino acids. Structural, chemical, and biological information related to non-proteinogenic amino acids provide insight into the formation of and possible neurological action of BMAA. This article reviews the carbamate formation of BMAA in the presence of bicarbonate ions, with a particular focus on how the chemical equilibrium of BMAA carbamate adducts may affect the molecular mechanism of its function. Highlights of nuclear magnetic resonance (NMR)-based studies on the equilibrium process between free BMAA and its adducts are presented. The role of divalent metals on the equilibrium process is also explored. The formation and the equilibrium process of carbamate adducts of BMAA may answer questions on their neuroactive potency and provide strong motivation for further investigations into other toxic mechanisms.

Topics: Amino Acids, Diamino; Animals; Biological Transport; Carbamates; Cations, Divalent; Cyanobacteria Toxins; Kinetics; Nuclear Magnetic Resonance, Biomolecular

PubMed: 28921378
DOI: 10.1007/s12640-017-9801-2

Review

Authors: Song Bai, Miaohe Zhang, Shouying Tang...

Benzimidazole fungicides are a class of highly effective, low-toxicity, systemic broad-spectrum fungicides developed in the 1960s and 1970s, based on the fungicidal activity of the benzimidazole ring structure. They exhibit biological activities including anticancer, antibacterial, and antiparasitic effects. Due to their particularly outstanding antibacterial properties, they are widely used in agriculture to prevent and control various plant diseases caused by fungi. The main products of benzimidazole fungicides include benomyl, carbendazim, thiabendazole, albendazole, thiophanate, thiophanate-methyl, fuberidazole, methyl (1-{[(5-cyanopentyl)amino]carbonyl}-1-benzimidazol-2-yl) carbamate, and carbendazim salicylate. This article mainly reviews the physicochemical properties, toxicological properties, disease control efficacy, and pesticide residue and detection technologies of the aforementioned nine benzimidazole fungicides and their main metabolite (2-aminobenzimidazole). On this basis, a brief outlook on the future research directions of benzimidazole fungicides is presented.

Topics: Fungicides, Industrial; Benzimidazoles; Carbamates; Thiophanate; Anti-Bacterial Agents

PubMed: 38542855
DOI: 10.3390/molecules29061218

Review

Authors: Emilio Perucca, Maurizio Taglialatela

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 channels, play a critical role in modulating susceptibility to seizures, and mutations in genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation of Kv7.2 and Kv.7.3 channels has long been considered an attractive target in the search for novel antiseizure medications. Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae. A novel formulation of ezogabine for pediatric use (XEN496) has been recently investigated in children with KCNQ2-related developmental and epileptic encephalopathy, but the trial was terminated prematurely for reasons unrelated to safety. Among novel Kv7.2/3 openers in clinical development, azetukalner has shown dose-dependent efficacy against drug-resistant focal seizures with a good tolerability profile and no evidence of pigmentation-related adverse effects in early clinical studies, and it is now under investigation in phase III trials for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder. Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic differences in the action of Kv7 activators, and from the development of molecules that combine Kv7 activation with other mechanisms of action.

Topics: Humans; Anticonvulsants; Epilepsy; Animals; KCNQ2 Potassium Channel; Phenylenediamines; Carbamates; KCNQ3 Potassium Channel

PubMed: 39853501
DOI: 10.1007/s40263-024-01155-3

Review

Authors: John E Casida, Kathleen A Durkin

The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use - the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10 years ago for several reasons: there have been no major new compounds for 30 years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out.

Topics: Acetylcholinesterase; Animals; Carbamates; Catalytic Domain; Cholinesterase Inhibitors; Drug Resistance; History, 20th Century; History, 21st Century; Humans; Insecta; Insecticides; Models, Molecular; Organophosphorus Compounds; Phylogeny

PubMed: 22926007
DOI: 10.1016/j.cbi.2012.08.002

Authors: Jiming Zhang, Jianqiu Guo, Chunhua Wu...

BACKGROUND

Early-life carbamate exposure during developmental period has been linked with adverse health effects and attracted attention.

METHODS

Three hundred and three children at age of seven were included in the current study. Urinary carbofuranphenol concentrations were measured using gas chromatography-tandem mass spectrometry. Verbal, performance and full-scale intelligence quotients (IQ, IQ, and IQ) were assessed using Wechsler Intelligence Scale for Children-Chinese Revised. Generalized linear models were used to explore the associations between carbofuranphenol levels and IQs. Generalized estimating equations were used to explore long-term health effect and sensitive time window.

RESULTS

Carbofuranphenol was detected in 96.6% of the seven-year-old urinary samples, the geometric mean, median, and inter quartile range of the carbofuranphenol concentrations were 0.67 μg/L, 0.30 μg/L, and 0.09-3.72 μg/L, respectively, which were similar with the level of three-year-old children from the SMBCS cohort. Seven-year-old carbofuranphenol level was negatively associated with IQ [β = -0.044; 95% confidence interval (CI): -0.087, -0.001; p = 0.045]. Three-year-old carbofuranphenol level was negatively associated with IQ (β = -0.100; 95% CI: -0.186, -0.014; p = 0.022) and IQ (β = -0.087; 95% CI: -0.173, -0.001; p = 0.047). Carbamate exposure of maternal and children at both three and seven years old had negative associations with IQ (β = -0.089; 95% CI: -0.171, -0.007; p = 0.034), and IQ (β = -0.064; 95% CI: -0.127, -0.000; p = 0.049) of children at age of seven.

CONCLUSION

Results of the present study verify that children in an agricultural region of China were widely exposed to carbamate pesticides. Carbamate exposure in utero and at three and seven years may adversely impact children's neurodevelopment.

Topics: Carbamates; Child; Child, Preschool; China; Female; Gas Chromatography-Mass Spectrometry; Humans; Intelligence; Intelligence Tests; Pregnancy; Prenatal Exposure Delayed Effects

PubMed: 32919260
DOI: 10.1016/j.envint.2020.106105

Evaluation of paraoxonase I and hemoglobin levels in farmers and agricultural workers in relation to organophosphorus and carbamate levels in their blood and urine samples: A cross sectional study.

Authors: Vinutha Bhat, Pragati Nayak, Shankar Bakkannavar...

Pesticides are chemicals that have become common household products in developing countries. The purpose of pesticides is to manage agricultural work. The majority of pesticides for indoor and agricultural use are carbamate and organophosphorus. Toxicity is caused due to excess and improper use or disposal of these chemical agents. Slow exposure to pesticides causes chronic poisoning whereas rapid exposure causes acute poisoning. The paraoxonase I (PON 1) enzyme has a role in detoxifying some of the oxon derivatives which thereby inhibit acetylcholinesterase and butyrylcholinesterase. This study analyzed farmers who were exposed intermittently to organophosphorus and carbamates pesticides during farming for more than five years. Serum paraoxonase I was evaluated by colorimetry method, and hemoglobin levels were evaluated using portable Fresenius Kabi haemoglobinometer. The study showed that the pesticides were found in the blood and urine samples of farmers and there was an alteration of paraoxonase I and hemoglobin levels in them due to the exposure of pesticides in large quantities over some time. The present study showed around 81% of the participants who were intermittently exposed to pesticides for more than five years were detected with pesticide toxicity. The paraoxonase I level was altered in farmers who were positive for organophosphorus and carbamate pesticides. The hemoglobin level did not show much variation among the farmers exposed to pesticides. This may be due to the lifestyle of the subjects, climatic variations and also their eating habits. The study suggested that there was alteration in the levels of PON1 and hemoglobin in farmers and agricultural workers with positive organophosphorus and carbamates in their blood and urine samples. As our study was done without quantifying the amount of pesticides, further studies can be done by quantifying the pesticide level and comparing it with the paraoxonase I level.

Topics: Humans; Farmers; Cross-Sectional Studies; Acetylcholinesterase; Butyrylcholinesterase; Carbamates; Aryldialkylphosphatase; Pesticides

PubMed: 38449835
DOI: 10.12688/f1000research.131690.2