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- The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. [JOURNAL ARTICLE]
- J Med Toxicol 2014 Dec 16.
The anticholinergic toxidrome is well described and relatively common. Despite controversy, studies have shown that physostigmine is relatively safe and effective in reversing this toxidrome. We would expect toxicologists would be liberal in its use. We retrospectively analyzed data in the Toxicology Investigators Consortium (ToxIC) registry, representing data from medical toxicologists in multiple institutions nationwide, searching for patients who exhibited an anticholinergic toxidrome, determining what treatment(s) they received, and classifying the treatments as physostigmine, benzodiazepines, physostigmine and benzodiazepines, antipsychotics, or no definitive treatment. The causal agents of the toxidrome were as reported by the treating toxicologist. Eight hundred fifteen consecutive patients with anticholinergic toxidromes were analyzed. Benzodiazepines alone were given in 28.7 %, 12.4 % were given physostigmine alone, 8.8 % received both physostigmine and benzodiazepines, 2.7 % were given antipsychotics, and 47.4 % were given no definitive treatment. In patients who received only physostigmine, there was a significant difference in the rate of intubation (1.9 vs. 8.4 %, OR 0.21, 95 % CI 0.05-0.87) versus other treatment groups. Physostigmine was given at varying rates based on causative agent with use in agents with mixed or unknown effects (15.1 %) being significantly lower than those with primarily anticholinergic effects (26.6 %) (p < 0.001). Patients with anticholinergic toxicity were more likely to receive benzodiazepines than physostigmine. Those patients who received only physostigmine had a significantly lower rate of intubation. Physostigmine was more likely to be used with agents exerting primarily anticholinergic toxicity than in those agents with multiple actions.
- Stabilities of neutral and basic esters of bendamustine in plasma compared to the parent compound: Kinetic investigations by HPLC. [JOURNAL ARTICLE]
- J Pharm Biomed Anal 2014 Nov 27.:137-143.
Esters of the cytostatic bendamustine (1), previously demonstrated to be much more potent than the parent compound as antiproliferative agents in vitro, were investigated for stability in buffer and plasma, as well as against porcine liver esterase in the presence of different amounts of albumin using a validated RP-HPLC method with fluorescence detection. The hydrolysis of the nitrogen mustard moiety was retarded (for 1: approximately 130 vs. 11min) in the presence of plasma proteins. For the derivatives, both cleavage of ester and nitrogen mustard moieties were analyzed. Enzymatic hydrolysis was very fast in the case of 2-pyrrolidino-, 2-piperidino- and 2-(4-methylpiperazino)-ethyl esters, whereas methyl, ethyl, morpholinoethyl and branched 2-pyrrolidinoethyl esters were considerably more stable (half-lives between 41 and 116min, compared to <5min). Inhibition by physostigmine indicated unspecific cholinesterases to be involved in the rapid ester cleavage. Due to lower protein content and higher enzymatic activity in murine compared to human plasma, reduced stability of all investigated esters in mouse plasma (t½<2min) has to be taken into account with respect to the design of animal studies.
- Attenuation of intestinal ischemic injury and shock by physostigmine. [JOURNAL ARTICLE]
- J Surg Res 2014 Nov 10.
Recently, protection in shock (hemorrhagic or septic) by physostigmine has been demonstrated. Here, we studied the protective effect of intravenous infusion of physostigmine in a rat model of severe intestinal ischemia-reperfusion (I/R) injury and shock.Mesenteric I/R was induced in male Wistar rats by occlusion of the superior mesenteric artery (90 min) and subsequent reperfusion (120 min). Physostigmine (30 or 70 μg/kg) was administered as bolus injection before induction of I/R. One additional group received, subsequent to the bolus of 30-μg/kg physostigmine, a continuous infusion of 60-μg/kg physostigmine till the end of the experiment.Physostigmine at a dose of 70 μg/kg administered before I/R significantly decreased the macroscopically and microscopically visible intestinal damage. In addition to and presumably as a result of this local protective effect, physostigmine prevented shock induced by reperfusion of the ischemically injured intestine. Lower doses (30 μg/kg) or continuous application of physostigmine were less advantageous.Physostigmine is clearly protective in intestinal I/R injury and shock. However, for this purpose, physostigmine has to be applied at a dose (70 μg/kg), that is, approximately double the amount of the presently used clinical dose.
- An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics. [JOURNAL ARTICLE]
- Physiol Behav 2014 Dec 2.
Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions.
- Organophosphate and Carbamate Poisoning. [REVIEW]
- Emerg Med Clin North Am 2015 Feb; 33(1):133-151.
Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management.
- No evidence for role of extracellular choline-acetyltransferase in generation of gamma oscillations in rat hippocampal slices in vitro. [JOURNAL ARTICLE]
- Neuroscience 2015 Jan 22.:459-469.
Acetylcholine (ACh) is well known to induce persistent γ-oscillations in the hippocampus when applied together with physostigmine, an inhibitor of the ACh degrading enzyme acetylcholinesterase (AChE). Here we report that physostigmine alone can also dose-dependently induce γ-oscillations in rat hippocampal slices. We hypothesized that this effect was due to the presence of choline in the extracellular space and that this choline is taken up into cholinergic fibers where it is converted to ACh by the enzyme choline-acetyltransferase (ChAT). Release of ACh from cholinergic fibers in turn may then induce γ-oscillations. We therefore tested the effects of the choline uptake inhibitor hemicholinium-3 (HC-3) on persistent γ-oscillations either induced by physostigmine alone or by co-application of ACh and physostigmine. We found that HC-3 itself did not induce γ-oscillations and also did not prevent physostigmine-induced γ-oscillation while washout of physostigmine and ACh-induced γ-oscillations was accelerated. It was recently reported that ChAT might also be present in the extracellular space (Vijayaraghavan et al., 2013). Here we show that the effect of physostigmine was prevented by the ChAT inhibitor (2-benzoylethyl)-trimethylammonium iodide (BETA) which could indicate extracellular synthesis of ACh. However, when we tested for effects of extracellularly applied acetyl-CoA, a substrate of ChAT for synthesis of ACh, physostigmine-induced γ-oscillations were attenuated. Together, these findings do not support the idea that ACh can be synthesized by an extracellularly located ChAT.
- The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat. [JOURNAL ARTICLE]
- Neuroscience 2014 Nov 13.:260-268.
The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist.
- Screening approach by ultra-high performance liquid chromatography-tandem mass spectrometry for the blood quantification of thirty-four toxic principles of plant origin. Application to forensic toxicology. [JOURNAL ARTICLE]
- J Chromatogr B Analyt Technol Biomed Life Sci 2015 Jan 15.:65-76.
Plant poisonings have left their mark on history and still cause many deaths, whether intentional or accidental. The means to show toxicological evidence of such poisonings should be implemented with great care. This article presents a technique for measuring thirty-nine toxic principles of plant origin in the blood, covering a large amount of toxins from local or exotic plants: α-lobeline, α-solanine, aconitine, ajmaline, atropine, brucine, cephalomannine, colchicine, convallatoxin, cymarine, cytisine, digitoxin, digoxin, emetine, gelsemine, ibogaine, jervine, kavain, lanatoside C, lupanine, mitragynine, neriifolin, oleandrin, ouabain, paclitaxel, physostigmine, pilocarpine, podophyllotoxin, proscillaridin A, reserpine, retrorsine, ricinine, scopolamine, senecionine, sparteine, strophanthidin, strychnine, veratridine and yohimbine. Analysis was carried out using an original ultra-high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Extraction was a standard solid phase extraction performed on Oasis(®) HLB cartridge. Thirty-four of the thirty-nine compounds were put through a validation procedure. The assay was linear in the calibration curve range from 0.5 or 5μg/L to 1000μg/L according to the compounds. The method is sensitive (LOD from 0.1 to 1.6μg/L). The within-day precision of the assay was less than 22.5% at the LLOQ, and the between-day precision was less than 21.5% for 10μg/L for all the compounds included. The assay accuracy was in the range of 87.4 to 119.8% for the LLOQ. The extraction recovery and matrix effect ranged from 30 to 106% and from -30 to 14%, respectively. It has proven useful and effective in several difficult forensic cases.
- Black henbane and its toxicity - a descriptive review. [Journal Article, Review]
- Avicenna J Phytomed 2014 Sep; 4(5):297-311.
Black henbane (BH) or Hyoscyamus niger, has been used as a medicine since last centuries and has been described in all traditional medicines. It applies as a herbal medicine, but may induce intoxication accidentally or intentionally. All part of BH including leaves, seeds and roots contain some alkaloids such as Hyoscyamine, Atropine, Tropane and Scopolamine. BH has pharmacological effects like bronchodilating, antisecretory, urinary bladder relaxant, spasmolytic, hypnotic, hallucinogenic, pupil dilating, sedative and anti-diarrheal properties. Clinical manifestations of acute BH poisoning are very wide which include mydriasis, tachycardia, arrhythmia, agitation, convulsion and coma, dry mouth, thirst, slurred speech, difficulty speaking, dysphagia, warm flushed skin, pyrexia, nausea, vomiting, headache, blurred vision and photophobia, urinary retention, distension of the bladder, drowsiness, hyper reflexia, auditory, visual or tactile hallucinations, confusion, disorientation, delirium, aggressiveness, and combative behavior. The main treatment of BH intoxicated patients is supportive therapies including gastric emptying (not by Ipecac), administration of activated charcoal and benzodiazepines. Health care providers and physicians particularly emergency physicians and clinical toxicologists should know the nature, medical uses, clinical features, diagnosis and management of BH poisoning.
- Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver. [Journal Article]
- FEBS Open Bio 2014.:905-14.
Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.