急性氨基甲酸酯及其与有机磷等混配农药中毒的临床治疗研究

目的 探讨肟类药物对氨基甲酸酯（CB）类农药与有机磷杀虫剂（OP）混配中毒的疗效。方法 对收治的11例急性单纯CB（灭多威）及其与OP等其他农药混配中毒的患者进行临床观察、实验室检查[ 包括全血胆碱酯酶（ChE）活力测定]及治疗。患者入院后彻底清洗污染的皮肤或洗胃,并给予阿托品（At）和肟类药物治疗及对症处理。根据病情轻重,At首剂用量为1－10mg,总用量为6．4－101.0mg;肟类药物除2例用碘解磷定外,其余均给予氯解磷定治疗,用量0．5－30．0g。结果 所有患者治疗后急性胆碱能兴奋或危象的症状和体征逐渐减轻和消失,用肟类药物者未见明显的不良反应,5例中、重度中毒患者在给予氯解磷定治疗后3－24h内肌束震颤消失。绝大多数患者全血ChE活力恢复到正常水平（87％－101％）。全部患者住院2－8d,痊愈出院。结论 急性灭多威与OP混配中毒,可用足量At并谨慎使用肟类ChE复能剂治疗。氯解磷定对急性中、重度OP与CB混配中毒患者出现的烟碱样症状有较好的疗效。     

Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities

In this study, oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone] were prepared as potential anticonvulsant and antimicrobial compounds. The oxime was synthesized by the reaction of ketone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock and subcutaneous metrazole tests in mice and rats according to procedures of the Anticonvulsant Screening Program of National Institutes of Health. Neurotoxicity was determined by the rotorod test in mice and the positional sense test, gait and stance test in rats. In addition to anticonvulsant tests, all compounds were also evaluated against the following microorganisms: S. aureus, E. coli, P. aeruginosa, E. faecalis, C. albicans, C. parapsilosis, and C. krusei using microdilution broth method for possible antibacterial and antifungal activities. Although most of the O-alkyl substituted oxime ethers exhibited both anticonvulsant and antimicrobial activities, the O-arylalkyl substituted compounds were found to be inactive in both screening paradigms.     

Pretreatment with pyridinium oximes improves antidotal therapy against tabun poisoning

Oximes K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] were tested as pretreatment drugs in tabun-poisoned mice followed by treatment with atropine plus K033, K048, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)]. Oxime doses of 25% or 5% of its LD(50) were used for pretreatment 15 min before tabun-poisoning and for treatment 1 min after tabun administration to mice. The best therapeutic effect was obtained when oxime K048 (25% of its LD(50)) was used in both pretreatment and treatment with atropine. This regiment insured survival of all tested animals after the application of 10 LD(50) of tabun. In addition, since butyrylcholinesterase (BChE; EC 3.1.1.8) is considered an endogenous bioscavenger of anticholinesterase compounds and its interactions with oximes could be masked by AChE interactions, we evaluated kinetic parameters for interactions of tested oximes with native and tabun-inhibited human plasma BChE and compared them with results obtained previously for human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Progressive inhibition of BChE by tabun was slightly faster than that of AChE. The reactivation of tabun-inhibited BChE by oximes was very slow, and BChE binding affinity for oximes was lower than AChE's. Therefore, BChE could scavenge tabun prior to AChE inhibition, but fast oxime-assisted reactivation of tabun-inhibited AChE or protection of AChE by oxime against inhibition with tabun would not be obstructed by interaction between BChE and oximes.     

Synthesis and Antineoplastic Activity of O‐Alkylated Derivatives of 7‐Hydroximinoandrost‐5‐ene Steroids

Varied positioning of the hydroximino group on the parental steroid skeleton results in remarkable changes in the antineoplastic activity profile of the compounds. Here, the compound 7‐oximino‐5‐androstene and its O‐alkylated derivatives have been prepared and screened for cytotoxic and aromatase inhibitory activity. The steroidal 7‐oximino ether derivatives exhibited insignificant cytotoxic effects when screened against three cancer cell lines, MCF‐7 (breast), NCl‐H460 (lung), and SF‐268 (CNS) at 100 μM. However, the imidazolyl‐substituted steroidal oxime ethers displayed moderate inhibition of cytochrome P450 aromatase.     

体外氯磷定等对氨基甲酰化乙酰胆碱酯酶（AChE）的影响

目的∶观察２－ＰＡＭ·Ｃｌ、ＬüＨ６、ＴＭＢ４、ＨＩ－６四种肟类药物分别对三种氨基甲酰化酶自动重活化过程的体外作用。方法∶以小鼠红细胞乙酰胆碱酯酶为酶源，吡啶斯的明、毒扁豆碱、灭多威为酶抑制剂，改进微量ＤＴＮＢ法测量胆碱酯酶活力。结果：在高浓度条件下，四种肟类药物对三种氨基甲酰化酶的自动重活化过程几乎都有不同程度的促进作用，而当浓度下降时，这种促进作用逐渐减弱，甚至出现抑制作用；其中双吡啶肟作用优于单吡啶肟，而双吡啶肟两个吡啶环之间的连接基团及肟基数目不同对不同的氨基甲酰化酶的作用效果也不同。结论∶认为氨基甲酸酯类化合物中毒时肟类药物的应用不应绝对禁止。     

Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor

As oxime-based structures are the only causal antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE), the majority of studies on these have been directed towards their synthesis and testing. In this study, experimental bispyridinium oximes K027 and K203, which have shown promising results in the last decade of research, were examined in vivo for their therapeutic and reactivating ability in acute poisoning by the direct AChE-inhibitor dichlorvos (DDVP), used as a dimethyl OP structural model. Additionally, the efficacy of oximes K027 and K203 was compared with the efficacy of four oximes (pralidoxime, trimedoxime, obidoxime and HI-6), already used in efficacy experiments and human medicine. To evaluate therapeutic efficacy, groups of Wistar rats were treated with equitoxic doses of oximes (5% LD₅₀, i.m.) and/or atropine (10 mg/kg, i.m.) immediately after s.c. DDVP challenge (4–6 doses). Using the same antidotal protocol, AChE activity was measured in erythrocytes, diaphragm and brain 60 min after s.c. DDVP exposure (75% LD₅₀). The oxime K027 was the most efficacious in reducing the DDVP induced lethal effect in rats, while the oxime K203 was more efficacious than trimedoxime, pralidoxime and HI-6. Significant reactivation of DDVP inhibited AChE was achieved only with oxime K027 or its combination with atropine in erythocytes and the diaphragm. Moreover, the acute i.m. toxicity of oxime K027 in rats was lower than all other tested oximes. The results of this study support previous studies considering the oxime K027 as a promising experimental oxime structure for further testing against structurally-different OP compounds.     

Severe and prolonged neurologic toxicity following subcutaneous chlorpyrifos self-administration: A case report

Introduction.?Organophosphate poisoning by oral or inhalation routes is characterized by a typical time-course of clinical features. Case presentation.?We report a case of subcutaneous chlorpyrifos self-injection leading to a delayed cholinergic phase, prolonged coma, and severe permanent neurologic injury with electrophysiological patterns suggestive of overlapping intermediate syndrome and distal peripheral neuropathy. Time-course and severity of clinical features were not altered by either atropine or pralidoxime administration. Due to prolonged and severe alteration in consciousness, we used brain multimodal nuclear magnetic imaging and auditory cognitive event-related potentials to assess the patient's potential for awakening. Electrophysiological testing used to monitor muscle weakness showed the coexistence of 20 Hz-decremental responses in proximal muscles and severe denervation in distal muscles. Red blood cell acetylcholinesterase activity progressively normalized on day 60, while plasma butyrylcholinesterase activity remained low until day 100. Chlorpyrifos was detectable in serum until day 30 and urine metabolites for up to three months, supporting the hypothesis of a continuous chlorpyrifos release despite repeated surgical debridement. We suggest that adipose and muscle tissues acted as a chlorpyrifos reservoir. At one-year follow-up, the patient exhibited significant neuromuscular sequelae. Conclusion.?Subcutaneous chlorpyrifos self-injection may result in severe toxicity with prolonged neurologic injury, atypical overlapping electrophysiological patterns, and a poor final outcome.     

Pharmacological actions of HS-6, an oxime, on the neuromuscular junction.

The effect of HS-6 [1-(2-hydroxyiminomethylpyridinium)-1-(3-carboxamidopyridinium)-dimethyl ether] on neuromuscular (NM) transmission was investigated using chick biventer cervicis (CBC), rat diaphragm (RD) and guinea pig ileum longitudinal muscle strip (GPLS) preparations. In the CBC preparation HS-6 did not cause a contraction, whereas it produced a dose-related contraction of the GPLS preparation. HS-6 produced a hemicholinium-like NM blockade in the CBC and RD preparations. This was supported by the fact that HS-6 inhibited choline uptake in erythrocytes. HS-6 inhibited the contractions of various nicotinic agonists in the CBC preparation and augmented the acetycholine contractions. The latter was due to AChE inhibition produced by HS-6.     

Genome-free Viral Capsids as Carriers for Positron Emission Tomography Radiolabels

PURPOSE: We have developed a modular synthetic strategy to append imaging agents to a viral capsid. PROCEDURES: The hollow protein shell of bacteriophage MS2 (mtMS2) was labeled on its inside surface with [18F]fluorobenzaldehyde through a multistep bioconjugation strategy. An aldehyde functional group was first attached to interior tyrosine residues through a diazonium coupling reaction. The aldehyde was further elaborated to an alkoxyamine functional group, which was then condensed with n.c.a. [18F]fluorobenzaldehyde. Biodistribution of the radioactive MS2 conjugates was subsequently evaluated in Sprague-Dawley rats. RESULTS: Relative to fluorobenzaldehyde, fluorine-18-labeled MS2 exhibited prolonged blood circulation time and a significantly altered excretion profile. It was also observed that additional small molecule cargo installed inside the capsids did not alter the biodistribution. CONCLUSIONS: These studies provide further insight into the pharmacokinetic behavior of nanomaterials and serve as a platform for the future development of targeted imaging and therapeutic agents based on mtMS2.