Administration Of Physostigmine Research Articles

THIS ARTICLE HAS BEEN RETRACTED Physostigmine for the prevention of postanaesthetic shivering following general anaesthesia – a placebo‐controlled comparison with nefopam

SummaryPhysostigmine was studied for its efficacy in the prevention of postanaesthetic shivering compared to nefopam and placebo. We studied 89 patients undergoing abdominal and urological surgery. The study was randomised and double‐blind, the patients received physostigmine 2 mg (n = 31), nefopam 10 mg (n = 30) or saline (n = 28). Haemodynamic parameters and temperature were measured at induction of anaesthesia (T0), and 5 min (T1), 15 min (T2), 30 min (T3) and 60 min (T4) after reaching the postanaesthetic care unit (PACU). Significantly less shivering occurred following administration of physostigmine and nefopam (9.7 and 3.3%) compared to placebo (53.6%). The degree of shivering was also significantly reduced following physostigmine and nefopam (p < 0.01). Extubation time, haemodynamic parameters and tympanic temperature were found to be similar in all groups. Aldrete score, duration of PACU stay and postoperative analgesic requirements did not differ between the groups. Only nefopam significantly (p < 0.01) reduced postoperative nausea and vomiting. Physostigmine is a safe alternative to nefopam, significantly reducing the incidence and severity of postanaesthetic shivering without affecting postanaesthetic recovery.

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer's disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of beta-amyloid (Abeta) and behavioral deficits during adulthood are useful for investigating this question. The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Abeta plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9-10 months of age, Tg2576-transgenic [Tg(+)] mice develop Abeta plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(-)] mice. Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Abeta plaque number was quantified. Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Abeta plaques. These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Abeta plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.

Physostigmine Does Not Effect Arousal but Produces Toxicity in an Animal Model of Severeγ-hydroxybutyrate Intoxication

Physostigmine is an acetylcholinesterase inhibitor and can produce fasciculations, seizures, bradycardia, and asystole. gamma-hydroxybutyrate (GHB) increases acetylcholine levels in the central nervous system and can decrease heart rate. Despite this, physostigmine has been proposed as an arousal agent to treat coma from overdoses of GHB. The authors hypothesized that in the setting of severe GHB intoxication, physostigmine would reverse sedation without producing adverse effects such as a decrease in heart rate, seizures, and fasciculations. GHB intoxication was induced in 20 rats by intraperitoneal injection of 700 mg/kg of the GHB precursor gamma-butyrolactone. One hour later, rats were randomly assigned to receive either physostigmine (0.06 mg/kg) intraperitoneally or an equivalent volume of saline. After administration of physostigmine, rats were continuously monitored by a blinded observer for arousal (return of righting reflex), fasciculations, and seizures. Heart rate and respiratory rate were recorded at 0, 5, 15, and 60 minutes after administration of physostigmine. Data were analyzed using repeated-measures analysis of variance and chi-square test. A pretest sample size calculation determined that 10 rats per group would detect a change in arousal from 0% to 50% and a 10% change in heart rate. No rats in either group had arousal within one hour (p = 1.0); however, ten of ten physostigmine-treated rats developed signs of physostigmine toxicity (fasciculations, 7; seizures, 3), while no controls developed signs of physostigmine toxicity (p = 0.00). The authors were unable to detect a decrease in heart rate. Physostigmine did not produce a 50% change in arousal as measured by a return of righting reflex but did produce physostigmine toxicity (fasciculations and seizures) in this rat model of severe GHB intoxication.

Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect

In a companion study (Carnicella et al., 2005), we showed that the muscarinic antagonist atropine, when administered after extensive training during both conditioning and testing, affected neither cued nor contextual fear memories when both of them did not compete for the control of the overt behaviour. In contrast, atropine altered the degraded contingency effect (DCE), that is, the processes by which contextual fear memory competes with the cued one for the control of the conditioned response. Atropine-induced disruption of the DCE was fully reversed by the administration of the anticholinesterase inhibitor physostigmine, which suggests a direct cholinergic implication. The present series of experiments was conducted in order to define more precisely the involvement of the cholinergic system in such an effect. Oxotremorine (0.0, 0.0075, 0.015, or 0.03 mg/kg), pilocarpine (0.0, 0.3, 1, or 3 mg/kg), xanomeline (0.0, 2.5, 5.0, 10.0 or 20.0 mg/kg) and nicotine (0.0, 0.1, 0.2, or 0.4 mg/kg) were tested for reversal of the atropine-induced alteration of the DCE. Oxotremorine and pilocarpine did not reverse the atropine-induced alteration of the DCE. In contrast, xanomeline and nicotine reversed the effect of atropine on the DCE. The present series of experiments reveals complex pharmacological interactions within the cholinergic system when cued and contextual fear memories interact. Results are discussed in this connection and with regard to the relation between the properties of cholinergic agonists and their therapeutic values.

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning

Hippocampus-mediated learning enhances neurogenesis in the adult dentate gyrus (DG), and this process has been suggested to be involved in memory formation. The hippocampus receives abundant cholinergic innervation and acetylcholine (ACh) plays an important role in learning and Alzheimer's disease (AD) pathophysiology. Here, we show that a selective neurotoxic lesion of forebrain cholinergic input with 192 IgG-saporin reduces DG neurogenesis with a concurrent impairment in spatial memory. Conversely, systemic administration of the cholinergic agonist physostigmine increases DG neurogenesis. We find that changes of forebrain ACh levels primarily influence the proliferation and/or the short-term survival rather than the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.

Assessing physostigmine’s contraindication in cyclic antidepressant ingestions

Ingestion of cyclic antidepressant medications or prolongation of the electrocardiographic QRS interval are commonly considered as contraindications to the use of physostigmine as an antidote for antimuscarinic toxicity. This dictum seems to stem from a few well-publicized cases in which administration of physostigmine was temporally associated with the development of asystole. Before the report of these cases, physostigmine was more frequently used and had been considered a first-line antidote for both the neurologic and cardiac toxic effects of cyclic antidepressant overdose. This apparent inconsistency, and a resurgence of interest in physostigmine as an antidote, begs the question of the appropriateness of this drug’s contraindication in all cyclic antidepressant ingestions. Review of the published clinical and experimental evidence provides little support for the clinical utility of using electrocardiographic criteria or the ingestion of cyclic antidepressants as contraindications to the use of physostigmine.

Effect of physostigmine and gastric lavage in a datura stramonium-induced anticholinergic poisoning epidemic

This study examines the impact of the administration of physostigmine and of nasogastric evacuation of Jimsonweed seeds on intensive-care unit (ICU) use and the length of stay in the hospital after Jimsonweed poisoning. Clinical data for this retrospective study were gathered from records of consecutive patients treated for Jimsonweed poisoning from September to November 1997. Descriptive statistics, Fisher’s exact test, and Student t-test were used to analyze important clinical and sociodemographic variables. There were 17 victims of the Jimsonweed ingestion epidemic, all of whom presented with an anticholinergic toxidrome 3 to 9 hours after ingestion. Reported quantities of seed ingestion ranged from a low of 7 seeds to as high as 200 seeds. Altered mentation, manifested by combative behavior, necessitated admission of 13 patients to the ICU. The administration of physostigmine did not reduce admissions to the ICU ( P = 0.54) or reduce length of stay in the hospital ( P = 0.45) compared with the use of benzodiazepines alone. Nasogastric lavage was performed in 14 (82%) and seeds were recovered in 8 (57%) of those lavaged. The successful removal of Jimsonweed seeds did not decrease ICU use rates ( P = 0.68) or shorten length of stay in the hospital compared with not recovering seeds ( P = 0.85). The use of physostigmine and the successful nasogastric lavage of Jimsonweed seeds did not result in decreased intensive-care use or shorter length of stay in the hospital for Jimsonweed-induced anticholinergic toxicity.

Complications of diagnostic physostigmine administration to emergency department patients

Study objectives: Literature exists describing the complications associated with therapeutic physostigmine administration. No series exists detailing strictly diagnostic use. Our objective was to document the complications associated with diagnostic physostigmine administration in emergency department (ED) patients suspected of having antimuscarinic delirium. Methods: Two reviewers blinded to the study purpose performed a retrospective chart review on all adult patients administered physostigmine diagnostically over a 79-month period at a tertiary-care hospital. Twenty percent of charts were reviewed by both abstractors. The data abstracted from the chart included total dose of physostigmine, effect on mental status, any subsequent complications, or any use of atropine. Discharge summaries, toxicology consultations, and urine drug screens were used to determine the cause of the altered mental status. Results: Thirty-nine adult patients were administered varying doses of physostigmine (range 0.5 to 2 mg). The reviewers were able to determine the cause of the altered mental status in 35 patients. The cause was purely antimuscarinic in 19 patients, purely nonantimuscarinic in 10 patients, mixed antimuscarinic and nonantimuscarinic in 2 patients, psychiatric in 4 patients, and unknown in 4 patients. A total of 22 patients had full reversal of delirium, and this group comprised all 19 patients with a purely antimuscarinic cause and 3 patients in whom a cause was never determined. One (2.6%) in 39 patients had a brief convulsion without adverse sequelae. This patient was poisoned with an antimuscarinic drug. No patient had dysrhythmias, had signs of cholinergic excess, or was administered atropine. Conclusion: Diagnostic physostigmine administration was without significant complication when given to ED patients suspected of having antimuscarinic delirium. Although a relatively small series, it contributes to the safety profile of physostigmine. [Ann Emerg Med. 2003;42:14-19.]

The effects of central administration of physostigmine in two models of anxiety

The effects of intracerebroventricular and intraseptal (the medial septum) administration of a prototypical acetylcholinesterase inhibitor (AChE-I), physostigmine, and a classic benzodiazepine midazolam on rat behavior in the open field test of neophobia and in the conditioned fear test (freezing reaction) were examined in rats. In the open field test of neophobia midazolam and physostigmine increased at a limited dose range, rat exploratory activity, after intracerebroventricular injection. Physostigmine produced in addition the hyperlocomotory effect. Following intraseptal injections, only physostigmine selectively prolonged the time spent by animals in the central sector of the open field. In the model of a conditioned fear, both midazolam and physostigmine inhibited rat freezing reaction to the aversively conditioned context after intracerebroventricular, but not after intraseptal, pretrial drug administration. The presented data support the notion about the selective anxiolytic-like effects of some AChE-Is. It appears, therefore, that the calming and sedative effects of AChE-Is observed in patients with Alzheimer's disease may be directly related to their anxiolytic action, independent of an improvement in cognitive functions, which in turn may decrease disorientation-induced distress and anxiety.

Influence of acetylcholine levels on the binding of a SPECT nicotinic acetylcholine receptor ligand [123I]5-I-A-85380.

Although in vitro theory indicates that ligand binding is sensitive to competition with neurotransmitters, only some imaging ligands have shown such competition in vivo. The purpose of this study was to determine whether increases in acetylcholine (ACh) levels induced by an acetylcholinesterase inhibitor, physostigmine, inhibit in vivo binding of [(123)I]5-iodo-3-(2(S)-2-azetidinyl-methoxy) pyridine (5-I-A-85380), a single photon emission computed tomography ligand for the high-affinity type nicotinic ACh receptor (nAChR). Baboons were used for seven studies with a bolus plus constant infusion equilibrium paradigm. After achieving equilibrium at 5 h, physostigmine (0.02 (n = 1), 0.067 (n = 3), and 0.2 (n = 3) mg/kg) was administered intravenously and data were acquired for up to 8 h. To confirm equilibrium conditions, [(123)I]5-I-A-85380 plasma levels were measured in four studies, including all studies with 0.2 mg/kg physostigmine. Prior to physostigmine administration, thalamic activities were stable, with changes of 1.1%/h or less, except in one study with a gradual increase of 4.2%/h. Thalamic activities were decreased by 15% in one study with 0.067 mg/kg and 14-17% in all studies with 0.2 mg/kg physostigmine administration (P = 0.009). In these studies with 0.2 mg/kg physostigmine administration, [(123)I]5-I-A-85380 plasma levels showed a transient or a sustained increase after physostigmine administration that would have increased thalamic activities. These results suggest that elevated ACh levels induced by physostigmine can effectively compete in vivo with [(123)I]5-I-A-85380 binding at nAChRs. However, decreased thalamic activities could have been caused by other mechanisms, including internalization of the receptor with an associated decreased affinity for radioligand.

Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy.

Memory function after olfactory bulbectomy (OBX) was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. OBX mice showed a significant impairment of learning and memory-related behavior on the 7th and 14th day, as measured by passive avoidance task but not elevated plus maze task. The impairment of learning and memory-related behavior on the 14th day was improved by administration of the cholinesterase inhibitor physostigmine (0.1 mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.) or the selective muscarinic M(1) agonist McN-A-343 (10 microg/mouse, i.c.v.). In contrast, administration of the nicotinic agonist lobeline (5-9.8 mg/kg, i.p.) or the selective muscarinic M(2) antagonist methoctramine (2.25-18 microg/mouse, i.c.v.) has no effect on the impairment of learning and memory-related behavior induced by OBX. In addition, we have demonstrated that the intensity of choline acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex, hippocampus and amygdala on the 14th day after OBX. These results suggest that the impairment of learning and memory-related behavior induced by OBX may be caused by degeneration of cholinergic neurons and muscarinic M(1) receptors play an important role in the improvement process.

Complications of Diagnostic Physostigmine Administration to Emergency Department Patients

Complications of Diagnostic Physostigmine Administration to Emergency Department Patients

Prophylaxis against organophosphate poisoning by sustained release of scopolamine and physostigmine.

Protection efficacy of continuous prophylactic administration of physostigmine and scopolamine against sarin-induced toxicity was evaluated previously in guinea pigs. The present study in large animals used Beagle dogs, that serve as an animal model with cholinergic sensitivity similar to that of humans. Pretreatment with physostigmine salicylate and scopolamine hydrochloride at dose rates of 2.5 and 1 microg x kg(-1) x h(-1), respectively, was administered via Alzet mini-osmotic pumps. At the time of exposure, the physostigmine salicylate concentration in plasma was 0.7 ng x ml(-1) and the scopolamine hydrochloride concentration was ca. 0.2 ng x ml(-1), both of which are levels known to be well tolerated in humans. Whole-blood cholinesterase inhibition was 15-20%. This regimen conferred full protection against 2.5 x LD50 i.v. of sarin. Albeit the high-dose exposure, cholinergic toxicity symptoms were mild with no convulsions. About 11-14 min following poisoning the treated animals started to walk and 15-20 min following exposure full recovery was observed and the dogs behaved normally. With higher dose rates of physostigmine salicylate and scopolamine hydrochloride, at plasma concentrations of 2.1 and 0.6 ng x ml(-1), respectively, treated dogs regained normal posture 6-10 min after exposure.

Functional relationship between subfornical organ cholinergic stimulation and cellular activation in the hypothalamus and AV3V region

The subfornical organ (SFO) has been suggested to be important for water intake and secretion of vasopressin (AVP). However, the role of the SFO cholinergic mechanism in the control of body fluid regulation is not clear. This study determined the effects of local cholinergic stimulation in the SFO produced by administration of physostigmine on drinking and cellular excitation in the anterior third ventricle (AV3V) region and in the supraoptic and paraventricular nuclei (SON and PVN). The results showed that injection of physostigmine into the SFO induced water intake and c-fos expression in the AV3V area as well as in the AVP containing neurons in the hypothalamus. Pretreatment of the SFO with mecamylamine, a nicotinic receptor antagonist, had no effect on physostigmine induced behavioral and c-fos responses. The muscarinic receptor blocker atropine, however, abolished both drinking and cellular activation after injection of physostigmine into the SFO. Immunostaining experiments demonstrated positive acetyltransferase (ChAT) in the SFO. Intensive ChAT immunoreactivity was located in the cholinergic fibers in the SFO. Together, the results indicate that SFO cholinergic mechanisms are important in co-operation with the AV3V and hypothalamic neurons in the control of thirst and AVP-mediated body fluid homeostasis.

Acetylcholine Mediates the Estrogen-Induced Increase in NMDA Receptor Binding in CA1 of the Hippocampus and the Associated Improvement in Working Memory

Elevated levels of circulating estrogen in female rats result in increased spine and synapse density and parallel increases in NMDA receptor binding in area CA1 of the hippocampus. Estrogen also influences cholinergic neurochemistry in the basal forebrain and hippocampus. The objectives of the present study were to determine the role of acetylcholine in the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus and to investigate the relationship between increased NMDA receptor binding in CA1 and performance on a task of working memory. In the current experiments, elevating endogenous levels of acetylcholine in ovariectomized rats by 3 d of continuous administration of physostigmine, an acetylcholinesterase inhibitor, increased NMDA receptor binding in CA1 as measured by quantitative autoradiography. This increase was comparable with the increase in NMDA receptor binding induced by injections of estradiol benzoate 72 and 48 hr before death. Additionally, the administration of 5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (BIBN 99), an M2 receptor antagonist, blocked the ability of both estrogen and physostigmine to increase NMDA receptor binding. The regimen of estradiol replacement that was demonstrated to increase NMDA receptor binding in CA1 of ovariectomized rats also improved arm-choice accuracy in a working memory task in an eight-arm radial maze. The estrogen-induced improvement in working memory performance was blocked by BIBN 99, which also blocked the increase in NMDA receptor binding. These results indicate that acetylcholine acts at M2 muscarinic receptors to mediate the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus as well as the associated improvement in working memory.

Reduction of cortical amyloid β levels in guinea pig brain after systemic administration of physostigmine

Overproduction of the peptide amyloid β (Aβ) is thought to be a critical pathogenetic event in Alzheimer's disease (AD). Decreasing Aβ production may therefore slow or halt the progression of AD. In vitro work has indicated that cholinergic muscarinic receptor agonists may reduce cellular production of Aβ. Here we show that systemic administration of physostigmine, an acetylcholinesterase inhibitor, lowers Aβ levels in vivo. Guinea pigs treated for 10 days with s.c. physostigmine had levels of cortical AβN-40 and N-42 which were 57% and 72%, respectively, of those in control animals. Levels of cortical β-amyloid precursor protein were not significantly affected by drug treatment. These results suggest that cholinergic therapy may affect the course of AD by limiting Aβ accumulation.

Physostigmine for Alzheimer's disease.

The main pharmacological approach for the treatment of Alzheimer's disease (AD) has been based on the use of agents potentiating cholinergic transmission, particularly by inhibiting acetylcholinesterase (AChE), the enzyme that destroys acetylcholine after it has been secreted into the synaptic clefts. Physostigmine is an AChE inhibitor originally extracted from calabar beans. It is licensed in many countries as an agent for reversing the effect of drugs and poisons causing the anticholinergic syndrome. Studies conducted more than 20 years ago suggested that physostigmine could improve memory in people with or without dementia. Investigation of this property has been limited by the very short half-life of physostigmine. Various forms of administering the drug have been tried to overcome this problem, most recently a controlled-release (CR) oral formulation, and a skin patch. It has been proposed as a potential drug for the symptomatic treatment of AD. To determine whether there is evidence of beneficial effects for the use of physostigmine in Alzheimer's disease. To assess the incidence and severity of adverse effects. The Cochrane Controlled Trials Register was searched using the following terms: 'physostigmine', 'physostigmine salicylate', 'Synapton' and 'Antilirium' in accordance with the Cochrane Dementia and Cognitive Improvement Group's search strategy. The pharmaceutical company was contacted. All relevant unconfounded, double-blind, randomized, placebo-controlled trials in which physostigmine was administered for more than one day to patients with dementia of Alzheimer type. Trials in which the allocation to the treatment was not randomized, or in which the allocation to the treatment was not concealed were excluded. Data were extracted independently by two reviewers (JMC & JB), pooled where appropriate and possible, and the weighted or standardized mean differences or Peto odds ratios (95% CI) were estimated. Where possible, intention-to-treat analysis was used. Fifteen studies were included using four different methods of administration of physostigmine. Four studies, involving 29 people in total, used intravenous infusion; seven, involving 131 people, used a conventional oral form; four, involving 1456 participants, used a controlled-release oral form, and one study of 181 people used a verum skin patch. There are no usable results from the intravenous infusion trials, and the few results from the conventional oral form showed no benefit of physostigmine compared with placebo. The results from two of the four studies of the controlled-release physostigmine apply only to a group of patients identified as responders in a pre-randomization titration period. The best dose physostigmine (mean 25mg/day) was associated with a 1.75 point improvement on ADAS-Cog score (mean difference -1.75, 95% confidence interval -2.90, -0.60 on an intention-to-treat basis) and a 0.26 point improvement on the CGIC score (treated as a continuous scale) (mean difference -0.26, 95% confidence interval 0.06, 0.46 on an intention-to-treat basis) compared with placebo at 6 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial (22/183 vs 2/183)(OR 5.92, 95% confidence limits 2.59, 13.54) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, flatulence or sweating compared with placebo at 6 weeks. The best dose physostigmine (mean 27mg/day) was associated with a 2.0 point improvement on ADAS-Cog score (mean difference -2.02, 95% confidence interval -3.59, -0.45 on an intention to treat basis) compared with placebo at 12 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial due to adverse events (13/83 vs 5/93)(OR 3.05, 95% confidence limits 1.15, 8.07) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, tremor, asthenia or sweating compared with placebo at 12 weeks. When no attempt was made to identify responders and all relevant patients with Alzheimer's disease were randomized, fixed dose physostigmine (mean 33 mg/day) was associated with a statistically significantly higher number withdrawing (234/358 vs 31/117)(OR 4.82, 95% confidence limits 3.17, 7.33), withdrawing due to adverse events (196/358 vs 10/117) (OR 6.54, 95%confidence limits 4.29, 9.95) and suffering at least one event of nausea, vomiting, diarhoea, anorexia, dizziness, stomach pain, dyspepsia, sweating, asthenia, dyspnoea or abnormal dreaming compared with placebo at 24 weeks. The results from the study of the verum patch physostigmine show that the double dose (delivering mean dose 12mg/day) was associated with statistically significantly higher numbers suffering at least one adverse event of vomiting, nausea or abdominal cramps compared with placebo at 24 weeks, but placebo was associated with statistically significantly greater numbers of gastrointestinal complaints at 24 weeks compared with single-dose physostigmine. The evidence of effectiveness of physostigmine for the symptomatic treatment of Alzheimer's disease is limited. Even in a controlled release formulation designed to overcome the short half-life, physostigmine showed no convincing benefit and adverse effects remained common leading to a high rate of withdrawal.

Reversal of morphine-induced memory impairment in mice by withdrawal in Morris water maze: possible involvement of cholinergic system

The effects of morphine and morphine withdrawal on memory performance were examined in mice by using Morris water maze task. Morphine-induced memory impairment at the doses of 5 and 10 mg/kg recovered after repeated administration. Oxotremorine, a muscarinic receptor agonist, at the dose of 0.1 mg/kg ip, and physostigmine, a cholinesterase inhibitor, at the dose of 0.1 mg/kg ip, significantly antagonized morphine (10 mg/kg sc)-induced memory impairment in mice. Furthermore, repeated naloxone (0.5 mg/kg ip) attenuated scopolamine (0.2 mg/kg ip)-induced memory impairment. By using escalating doses of morphine for 13 days, morphine-induced memory impairment was continuously maintained. When withdrawal was precipitated by naloxone (5 mg/kg ip), or administration of oxotremorine (0.1 and 0.2 mg/kg ip) or physostigmine (0.05 and 0.1 mg/kg ip), the impairment was completely reversed. These results suggest that morphine-induced memory impairment could be partially due to the inhibition of the central cholinergic activity.

Long-term changes in hippocampus and neocortex EEG spectra in response to pharmacological treatments affecting the cholinergic system.

Statistical analysis of EEG spectra averaged over 10-min intervals showed that in rats performing free behavior, peripheral administration of the acetylcholinesterase inhibitor physostigmine induced long-lasting characteristic changes (lasting tens of minutes) in the electrical activity of the dorsal hippocampus (field CAI) and the somatosensory cortex. An increase in the physostigmine dose from 0.05 to 1 mg/kg shifted the peak of the theta rhythm to lower frequencies (3.6-4.9 Hz) without a change in power at this frequency, though there was a decrease in power at 5.7-11.9 Hz. The power of the beta-1 rhythm (13.8-16.4 Hz) was also strongly suppressed. In contrast, the power of the beta-2 rhythm (20.3-26.5 Hz) increased several-fold in a non-linear fashion. Scopolamine suppressed all the changes induced by physostigmine, demonstrating the important role of m-cholinoceptors in changes in EEG spectra. The high dose of physostigmine caused inversion of the power of the beta-2 rhythm: unlike the situation obtaining in controls, the beta-2 power in the hippocampus became significantly greater than that in the neocortex. These data suggest the conclusion that overall significant increases in endogenous acetylcholine levels lead to decreases in the functional activity of the hippocampus and neocortex and that the mechanisms of cholinergic modulation of the theta and beta rhythms are significantly different. It is suggested that conditioned reflex switching, contextual learning, and dissociated sates of memory and consciousness are to a significant extent dependent on long-term changes in the oscillatory activity of the hippocampus and neocortex.

Gamma-hydroxybutyrate overdose and physostigmine: Teaching new tricks to an old drug?

Gamma-hydroxybutyrate was introduced as an anesthetic agent in the 1960s and is still used in some countries, despite recognized disadvantages. More recently, it has emerged as a popular recreational drug. We report 3 cases of gamma-hydroxybutyrate overdose, the effects of which were reversed by the administration of low-dose intravenous physostigmine. The origins of this regimen and the case for physostigmine as a potential antidote are described. [Caldicott DGE, Kuhn M. Gamma-hydroxybutyrate overdose and physostigmine: teaching new tricks to an old drug? Ann Emerg Med. January 2001;37:99-102.]