Physostigmine Reversal of Dysarthria and Delirium After Iatrogenic Atropine Overdose From a Dental Procedure.

BACKGROUND: Sublingual atropine, dosed at 0.4-0.8 mg, is used by dentists as an antisialogogue to facilitate and increase the speed of procedures. Concentrated ophthalmic atropine drops (10 mg/mL) are commonly used off-label for this purpose. These highly concentrated drops may result in medication errors, atropine toxicity, and the antimuscarinic toxidrome. We report a case of a man who suffered acute delirium and dysarthria (from dry mouth) after an iatrogenic overdose from a dental procedure. His symptoms were initially interpreted as a stroke, but they completely resolved with physostigmine. CASE REPORT: A 57-year-old man presented with acute dysarthria and delirium after a dental procedure; 4 hours earlier he was fitted for a temporary replacement of some premolar/molar teeth. He received sublingual atropine to assist in gingival drying for molding of his prosthesis, but a calculation error resulted in the administration of approximately 113 mg. A stroke evaluation was initially planned; however, 2.5 mg of intravenous physostigmine completely reversed his symptoms. His symptoms reoccurred and were successfully treated twice more with physostigmine; the patient was observed overnight with no additional symptoms and safely discharged the next morning. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ophthalmic atropine drops are highly concentrated and may cause an overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine.

Physostigmine-loaded liposomes for extended prophylaxis against nerve agent poisoning.

Pre-administration of physostigmine can prevent poisoning against nerve agent exposure by reversibly binding to cholinesterase. However, its cholinesterase protection-based prophylactic effect can be eliminated rapidly due to short biological half-life. Liposomes are useful for encapsulating hydrophilic drugs like physostigmine, and can be used for sustained release after parenteral injection. Thus, physostigmine liposomes were prepared by the pH-gradient condition-based remote-loading method for subcutaneous injection. In addition, polyethylene glycol (PEG)-lipid was applied to further extend the release of physostigmine and its prophylactic action. In vitro release of physostigmine, pharmacokinetics and duration of prophylactic effect were then evaluated. Physostigmine was dissolved in distilled water and used as a solution group for comparison. The prepared liposomes showed spherical shape and their particle size was around 130 µm. Addition of PEG-lipid in liposomes significantly increased the entrapment efficiency of physostigmine. Both control and PEG liposomes exhibited sustained release pattern compared to the solution. Moreover, the release of PEG liposomes was relatively slower than that of the control liposomes. Pharmacokinetic study in rats revealed that physostigmine liposomes exhibited lower maximum plasma concentration and longer half-life compared to the solution. Plasma cholinesterase inhibition ratio in the liposomal group decreased more gradually compared to the solution. Moreover, PEG liposomes showed higher plasma concentration of physostigmine and cholinesterase inhibition ratio compared to the control liposomes. These results suggest that PEG liposomes have potential to enhance the duration of cholinesterase-protecting effect of physostigmine.

Intraoral stimulation of salivary secretion with the cholinesterase inhibitor physostigmine as a mouth spray: a pilot study in healthy volunteers.

Dry mouth produces a deterioration in oral health and impairs quality of life. There is a need for a novel approach to the pharmacological treatment of dry mouth. With a view to enhancing the cholinergic drive on minor salivary glands, whilst at the same time minimising adverse systemic effects, the cholinesterase inhibitor physostigmine was therefore sprayed, in a fixed volume, onto the oral mucosa of seven healthy subjects. Three concentrations (0.5%, 1% and 2%) were tested. The mean salivary output over time (0-105 min) was higher than that of placebo (p<0.05), as the area under the curve increased by 61%, 91% and 66% at physostigmine 0.5%, 1% and 2%, respectively. Two subjects experienced nausea at the highest physostigmine concentration, thus reflecting systemic effects. Heart rate, blood pressure and respiration were unaffected by the physostigmine treatment.

Excitatory amino acid receptors mediate the orofacial stereotypy elicited by dopaminergic stimulation of the ventrolateral striatum.

The present experiments examined the role of excitatory amino acid receptors in the orofacial stereotypy induced by direct amphetamine microinjection into the ventrolateral striatum. In these experiments, the influence of prior intra-ventrolateral striatum treatment with various excitatory amino acid antagonists on the expression of amphetamine-stimulated oral stereotypy was observed. In all experiments, behavioral observations were conducted in the home cage using a time-sampling procedure. In the first experiment, different groups of rats received bilateral microinfusions of either kynurenic acid, 2-amino-5-phosphonopentanoic acid, 6,7-dinitroquinoxaline or dizocilpine maleate. The excitatory amino acid antagonists were administered immediately prior to bilateral microinfusions of d-amphetamine. Both N-methyl-D-aspartate and non-N-methyl-D-aspartate antagonists dose-dependently attenuated or blocked the expression of dopamine-mediated stereotypy. 2-Amino-5-phosphonopentanoic acid was the most potent of these compounds, totally suppressing stereotypy at a dose of 0.3 micrograms (equivalent to 1.5 nmol). In the second experiment, the same compounds were tested for their ability to suppress physostigmine-induced mouth movements. Cholinergic stimulation of the ventrolateral striatum has previously been shown to elicit non-directed mouth movements, quite distinguishable from stimulus-directed, amphetamine-induced biting. Excitatory amino acid antagonists were administered in the same doses prior to bilateral infusion of physostigmine (2.5 micrograms/0.5 microliters). The expression of physostigmine-induced mouth movements was for the most part not affected by excitatory amino acid antagonists, although dizocilpine maleate slightly reduced this oral behavior. In a third experiment, behavior was observed following infusion of the antagonists alone, using the same doses as in the previous experiments. No behavioral alterations were observed with the exception of a small increase in nonspecific mouth movements induced by kynurenic acid and 2-amino-5-phosphonopentanoic acid. These findings indicate that the expression of dopamine-mediated oral stereotypy, induced by amphetamine stimulation of the ventrolateral striatal region, is highly dependent on activation of striatal excitatory amino acid receptors. In contrast, oral behavior induced by cholinergic stimulation of the ventrolateral region is not mediated by glutamate input. These results are discussed in relation to the synaptic organization of neuronal elements within the striatum. Moreover, the relevance to further understanding of orofacial dyskinesias is noted.

Cholinergic stimulation of the ventrolateral striatum elicits mouth movements in rats: pharmacological and regional specificity.

Cholinomimetic drugs are known to induce changes in perioral behavior in rodents, characterized primarily by "purposeless" chewing movements, but little is known about their central sites of action. Using observational methods, the effects of direct microinfusion of a mixture of physostigmine and acetylcholine (PS/Ach, 0, 0.5, 2.5, 5.0 micrograms of each in 0.5 microliter saline) into the ventrolateral striatum (VLS) were assessed. Cholinergic stimulation of this region produced a dose-dependent induction of mouth movements, characterized by chewing movements, jaw opening and closing, tongue protrusions and jaw tremors. These movements were not directed toward any stimulus. In some rats, cholinergic stimulation of the VLS also induced stereotyped self-biting, although this effect was less prominent and of shorter duration. Induction of mouth movements by cholinergic stimulation of the VLS was blocked by prior administration of atropine, either systemically (50 mg/kg) or directly into the VLS (10 micrograms). Systemic administration of methylatropine (50 mg/kg) did not block the mouth movements. Pretreatment with haloperidol (2.5 micrograms into VLS) had no effect on PS/Ach-induced mouth movements. Infusion of PS/Ach (0, 2.5, 5.0 micrograms) into the dorsolateral or ventromedial striatum did not produce significant changes in oral behavior, although the level of mouth movements was somewhat higher at the medial site. The three sites studied were also differentiated with respect to spontaneous motor behaviors (locomotion and rearing) following direct cholinergic stimulation. These findings are considered as further evidence for the role of the ventrolateral striatum in oral motor behavior.

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.

Acute and long-term effects of thyrotropin releasing hormone on behavior mediated by dopaminergic and cholinergic activities in mice.

Acute and long-term (3 weeks) effects of thyrotropin releasing hormone (TRH) on behavior were investigated in mice. A single injection of TRH produced Straub tail, tremor and salivation, as well as stereotyped responses, such as head bobbing, jaw movement, digging and sniffing. Dose- and time-dependency for the effects of TRH were different depending on each response. A single injection of TRH at a low dose of 2.5 mg/kg SC did not produce stereotypy but this behavior was induced when this dose of TRH was administered in combination with atropine (3 mg/kg IP). In addition, a single low dose of TRH elicited tremor and salivation which were potentiated by physostigmine (0.1 mg/kg IP). A single high dose (20 mg/kg IP) produced marked tremor and salivation which were conversely blocked by atropine. Following daily administration of TRH at a low dose of 2.5 mg/kg SC for 21 days, stereotyped behavior was progressively increased whereas tremor and salivation were decreased. This increase in stereotyped behavior was inhibited by haloperidol (1 mg/kg IP) or physostigmine (0.1 mg/kg IP). When saline was administered instead of TRH for 3 days after long-term administration of TRH, sterotyped behavior was maintained for 2 days but thereafter decreased to some extent. When TRH (1.25 mg/kg SC) was again administered at this stage, there was a marked increase in sterotyped response. These results suggest that TRH induces dopaminergic activation, accompanied by both cholinergic inhibition and cholinergic activation, and that the former is potentiated while the latter is reduced after daily administration of TRH.

Muscarinic and nicotinic effects on yawning and tongue protruding in the rat.

Physostigmine, an anticholinesterase agent, elicited yawning with a marked protrusion of the tongue and teeth chattering. Yawning and chattering were also observed after pilocarpine, a cholinergic agonist predominantly acting upon muscarinic receptors. Apomorphine at low doses (0.1-0.5 mg/kg), which preferentially activates presynaptic dopamine autoreceptors, elicited yawning, whereas at high doses (1-2 mg/kg) it produced stereotypy. Yawning induced by both cholinergic agonists and apomorphine was inhibited by scopolamine, a muscarinic receptor blocking agent, but not by methylscopolamine, a peripheral anticholinergic agent and mecamylamine, a nicotinic receptor blocking agent. Low dose (0.02 mg/kg) of haloperidol, which has been reported to block presynaptic dopamine autoreceptors, inhibited apomorphine-induced yawning but did not affect cholinergic agonist-induced yawning. Physostigmine-elicited tongue protruding was inhibited by mecamylamine. The results imply that yawning behavior is essentially associated with the stimulation of central muscarinic receptors, and that physostigmine also induces tongue protruding by activating the central nicotinic receptors.

Effects of selective central muscarinic blockade on schedule-controlled behavior and on the rate-decreasing effects of physostigmine.

N-(4-diethylamino-2-butynyl)-succinimide, or DKJ-21, is a muscarinic receptor antagonist with a high degree of selectivity for the central nervous system. In the present study of 6 rats maintained under a fixed-interval 50-sec schedule of food reinforcement, atropine and methylatropine reduced responding in a dose dependent manner, while DKJ-21 had little or no effect. Our findings suggest that the suppression caused by atropine and methylatropine may be the result of the dry mouth induced by these agents. Doses of DKJ-21 which had no effect on schedule performance antagonized the rate-lowering effects of physostigmine in all of the animals. Neither atropine nor methylatropine consistently antagonized the inhibitory effects of physostigmine. Some antagonism may be inferred, however, from the findings that response rates were suppressed less by combinations of atropine and physostigmine than by either drug alone.

Cholinergic modulation of oral activity in drug-naive and chronic haloperidol-treated rats.

The cholinergic agonists pilocarpine, physostigmine, oxotremorine, and arecoline were administered IP at various doses to rats. Oral activity was assessed in these animals with a computerized video analysis system that determined the number and form of jaw openings and closings (computer scored movelets "CSMs"). The different cholinergic drugs produced distinctive changes in the number of CSMs at various amplitudes and in the frequency distribution of CSMs as determined by fast fourier analysis. Rats treated for 28 weeks with haloperidol showed a previously described, late onset oral dyskinesia characterized by increases in small amplitude CSMs, decreases in CSM slope, increased energy at the 1-3 Hz range and decreased energy at the 5-7 Hz range. Administration of pilocarpine (1.0 mg/kg) reversed all of these effects, while the anticholinergic drug, scopolamine (0.05 mg/kg), had no effect. These results indicate that different cholinomimetics can uniquely alter oral activity in rats and that symptoms of late onset, neuroleptic-induced oral dyskinesia are modified by a cholinergic agonist.

Physostigmine-induced salivary secretion in the rat.

The purpose of this study was to see if physostigmine, a reversible cholinesterase inhibitor, affects the secretion and composition of saliva of the major salivary glands of the rat. Low doses of physostigmine did not elicit secretion. At higher doses there was significant flow from the parotid and submandibular glands within 5 min; however, no sublingual secretion was observed. The submandibular flow rate was highest for the first 5 min, then declined rapidly. The parotid flow rate initially was one-fifth of the maximum submandibular rate and then gradually decreased. The concentrations of Ca, Na and K of physostigmine-induced parotid saliva, and the Na of submandibular saliva, were similar to those with carbachol stimulation. The Ca and K concentrations of submandibular saliva were significantly higher than with carbachol or parasympathetic stimulation, and resembled those of alpha-adrenergic stimulation. The protein concentrations of physostigmine-evoked saliva from both glands were similar. The amylase activity of physostigmine-evoked parotid saliva was much higher than that of carbachol or parasympathetic stimulation. Physostigmine-evoked secretion was completely blocked by atropine, a cholinergic antagonist, and by reserpine, partially blocked by phentolamine, an alpha-adrenergic antagonist and not affected by surgical sympathectomy. Morphologically, physostigmine resulted in a moderate decrease in the number of acinar, but not ductal, secretory granules of both the parotid and submandibular glands, while the sublingual gland was unaffected. Numerous patches of parotid acini also developed vacuoles or vesicles. These results suggest that physostigmine-induced salivary secretion is mediated primarily by direct effects on cholinergic and alpha-adrenergic receptors.

Loading and localization of Fluo-3 and Fluo-3/AM calcium indicators in sinapis alba root tissue.

Stimulus-induced changes in free cytosolic Ca2+ in different types of plant cells have been monitored with the aid of fluorescent calcium indicator dyes. However, there is no simple and convenient method for introducing these dyes into the plant cell cytoplasm. This paper reports tests of different procedures for loading either free fluorescent dyes or their acetoxymethyl esters (Fluo-3 and Fluo-3/AM, respectively) into Sinapis alba root tissue. Loading of Fluo-3 was pH and temperature dependent. Moreover, in the presence of beta-escin (saponin) in the loading medium very high fluorescent signals in root tissues were observed. The highest signals were recorded when tissue was loaded in a medium containing 0.1% beta-escin, at pH 5.0 and 30 degrees C. Only very weak fluorescence signals were found in mustard roots loaded with Fluo-3/AM. Acidity and temperature of the medium had no significant effect on the process. However, addition of eserine, a cholinesterase inhibitor led to a dramatic increase in fluorescence in the root cells. On the basis of these observations rapid and efficient methods of loading both Fluo-3 and Fluo-3/AM into mustard root tissues are proposed.

Attempts to overcome the anti-fertility effect of intrauterine plastic spirals in the ewe.

PIP: A study was conducted to determine whether the antifertilization of intrauterine devices in ewes could be overcome by the use of hormones or drugs that either stimulate or inhibit uterine motility. 44 parous, western ewes were unilaterally ovariectomized, and a plastic spiral was inserted into the uterine horn opposite the remaining ovary. Spirals were immediately removed from 5 ewes. At the time of mating, 2 weeks to 3 months post surgery, sham-operated and spiral control ewes were injected with saline solution. Ewes with spirals were injected with either estradiol, epinephrine, oxytocin, oxytocin and acetylcholine, or oxytocin, acetylcholine, and physostigmine. Other ewes with spirals were laparotomized, and either the uterus was massaged or the cervical lumen was cleaned. 3 days postmating, 8 ova recovered from 5 sham-operated ewes were all cleaved, with a mean of 90 accessory sperm in the zonae pellucidae. 3 of 12 ova recovered from 8 spiral control ewes were cleaved. Only 1 of 40 ova recovered from 28 treated ewes was cleaved. Accessory sperm were not found in either cleaved or uncleaved ova from any spiral ewe. None of the treatments overcame the antifertilization effect of the spiral.^ieng

Acetylcholinesterase characteristics of termite queen exposed to anticholinesterase compounds.

A regional profile of AChE activity was noted in the Indian termite queen Odontotermes redemanni with the head recording the higher and body the lower range of activity. The enzyme characteristics such as substrate and temperature optima were more or less similar while pH requirement for optimum AChE activity varied from 7.0 to 7.6 In vitro inhibition of head and body AChE was studied using pure and commercial anticholinesterase compounds. Interestingly, the commercial formulations like Metacid-50 and Carbaryl are potent enough at 1 x 10(-8) M to produce 50% in vitro inhibition of AChE of head and body regions within 15 min of preincubation. A 20 min of preincubation (t0.5) was necessary to record 50% in vitro inhibition of AChE with known and pure anticholinesterase compounds such as DFP (3.5 x 10(-10) M) and physostigmine (3.6 x 10(-10) M). It is surmised that (a) the response of the head and body AChE to the commercial formulations of the insecticides may be used as a reliable and sensitive bioindicator of pesticidal contamination of the terrestrial environment and (b) termite control may be successfully done with the application of organophosphate or carbamate compounds.

[Central anticholinergic syndrome during postoperative period]. / Syndrome anticholinergique central en période postopératoire.

The central anticholinergic syndrome (CAS) includes central signs (somnolence, confusion, amnesia, agitation, hallucinations, dysarthria, ataxia, delirium, stupor, coma) and peripheral signs (dry mouth, dry skin, tachycardia, visual disturbances and difficulty in micturition). It occurs when central cholinergic sites are occupied by specific drugs and also as a result of an insufficient release of acetylcholine. The CAS can be caused by atropine sulphate, hyoscine (scopolamine), promethazine, benzodiazepines, opioids, halothane, influrane, ketamine. The incidence of CAS during the postoperative period depends on choice and dose of anaesthetic agents, type of surgery, patient's condition and diagnostic criteria. It is close to 10% following general anaesthesia and 4% following regional anaesthesia with sedation. The differential diagnosis of CAS includes an overdose of anaesthetic drugs or an alteration in pharmacokinetics, altered hydratation, electrolyte or acid-base state, hypoglycaemia, hypoxia, hypercapnia, hypocapnia, hyperthermia, hypothermia, hormonal disorders, neurological damage resulting from surgery, embolism, haemorrhage or trauma. The diagnosis of CAS is often determined by a process of exclusion and not actually made until a positive therapeutic response to physostigmine, a centrally active anticholinesterase agent has taken place.

[Cholinergic mechanisms in the central nervous system of the sipunculoid Physcosoma japonicum]. / O kholinergicheskikh mekhanizmakh v tsentral'noi nervnoi sistems sipunkulidy Phycosoma japonicum

Acetylcholine (ACh) content of the central nervous system in the sipunculid P. japonicum was estimated by application of extracts from the nervous tissue to dental retractor of the sea urchin using ACh solutions with known concentration as a standard. It was shown that the nervous tissue contains 46 (from 41 to 51) microng of ACh (calculated as cation) per 1 g of wet material. In the presence of the nervous homogenate from Physcosoma, 880 micronM of ACh are hydrolyzed by 1 g of wet tissue per 1 hour. The content of ACh and the activity of cholinesterase are comparable with those in the brain of molluscs, arthropods and mammals. Anticholinesterase drugs (physostigmine and neostigmine) evoked spontaneous contractions of the proboscis retractor when applied to the nervous cord and enhanced the response of this muscle to electrical stimulation of this cord. Cholinolytics (arpenal and pentaphen) also caused spontaneous muscle contractions, but prevented the increase in muscular activity in response to electrical stimulation in presence of physotigmine. The data obtained suggest cholinergic nature of the transmission in the central nervous system of sipunculids.