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At least 19 recordsLinked to original sources
PubMed1996

A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer's disease. Physostigmine Study Group.

OBJECTIVE: A multicenter trial to evaluate the efficacy of controlled-release physostigmine salicylate, a cholinesterase inhibitor, was conducted in 1,111 mild-to-moderate Alzheimer's disease (AD) subjects. DESIGN: During dose titration, subjects received 18, 24, or 30 mg of physostigmine or placebo daily. After a 2-week washout period, 366 subjects with putative improvement were randomized to receive either placebo or their best dose of physostigmine in a 6-week double-blind trial. Nonresponding patients (439) were randomized to receive in a separate double-blind trial either placebo or their highest tolerated dose of physostigmine. The primary efficacy measures included the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS) and a Clinical Global Impression of Change (CGIC). Secondary measures included the Mini-Mental State Examination and two activities-of-daily-living scales. RESULTS: At the end of the 6-week double-blind phase, physostigmine-treated patients scored 1.75 points higher than placebo-treated patients on the ADAS (p = 0.003) and 0.26 points higher on the CGIC (p = 0.012) in the intent-to-treat analysis. There was no significant improvement on the secondary outcome measures. Patients failing to respond to physostigmine during the dose titration phase failed to respond on any of the outcome measures during the double-blind period of re-exposure. Common adverse events included nausea, vomiting, diarrhea, and anorexia. There were no significant changes in liver function tests. CONCLUSION: This study demonstrated statistically significant differences between physostigmine and placebo on both a performance-based cognitive functioning instrument and a clinician's global evaluation. The magnitude of the effect size was small and occurred only in the subset of patients who responded in the initial dose titration study period. Nevertheless, the results suggest that in a subset of patients, physostigmine can induce a degree of cognitive improvement over 6 weeks of treatment.

Aged↗
PubMed2000

Extended-release physostigmine in Alzheimer disease: a multicenter, double-blind, 12-week study with dose enrichment. Physostigmine Study Group.

BACKGROUND: The efficacy of extended-release physostigmine salicylate, an acetylcholinesterase inhibitor, was evaluated in 850 subjects with mild-to-moderate Alzheimer disease (AD) in a multicenter trial. METHODS: Subjects initially entered a dose-enrichment phase in which they received 1 week each of physostigmine salicylate, 24 mg/d and 30 mg/d, and daily placebo. Among the subjects who completed this phase, 35.9% responded to physostigmine treatment, whereas 62.4% were considered nonresponders, and 1.6% could not be evaluated because of missing data. After a 4-week placebo-washout phase, 176 responder subjects were randomized to receive their best dose of physostigmine or placebo in a 12-week double-blind phase. Primary efficacy measures included the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC+), and the Clinical Global Impression of Change (CGIC). RESULTS: In the intent-to-treat analysis of the double-blind phase, physostigmine-treated subjects scored -2.02 points better than placebo-treated subjects on the ADAS-Cog (F1,167 = 6.42 [P = .01]) and 0.33 points higher on the CIBIC+ (F1,150 = 5.68 [P = .02]). No significant improvement was observed on the CGIC or the secondary outcome measures. Nausea and vomiting were experienced by 47.0% of all physostigmine-treated subjects during the double-blind phase. CONCLUSIONS: Physostigmine demonstrated a statistically significant benefit compared with placebo on a clinical global rating of change and an objective test of cognitive function. Given the frequency of gastrointestinal side effects, the role of this agent in clinical use remains to be determined.

Aged↗
PubMedDate not supplied

Correlation between plasma physostigmine concentrations and percentage of acetylcholinesterase inhibition over time after controlled release of physostigmine in volunteer subjects.

Five to six subjects ingested doses of controlled-release physostigmine salicylate tablets (9, 12, and 15 mg) followed by sequential blood drawing for measurement of plasma physostigmine concentrations and percentage of acetylcholinesterase (AChE) inhibition. Both plasma physostigmine concentrations and percentage of AChE inhibition demonstrated dose proportionality to three doses of ingested drug. Plasma physostigmine concentrations correlated with percentage of AChE inhibition across time by dose and across all doses and subjects tested. These data should be helpful to physicians in adjusting physostigmine dosing, enabling them to use the relatively simple and widely available AChE assay to approximate plasma physostigmine concentrations.

Adult↗
PubMed1997

Physostigmine: going ... going ... gone? Two cases of central anticholinergic syndrome following anaesthesia and its treatment with physostigmine.

Two patients presented with very different signs of central anticholinergic syndrome following general anaesthesia for which they had received premedication with hyoscine. Both responded dramatically to 1 mg of intravenous (i.v.) physostigmine, which produced a rapid return to a normal level of consciousness. The aetiology of central anticholinergic syndrome is multi-factorial, but the diagnosis should be considered in all patients who demonstrate abnormal post-anaesthetic awakening. It is recommended that 1 mg of intravenous physostigmine is a safe and effective treatment for central anticholinergic syndrome, and that a supply of this important drug must be kept readily available in the recovery area of the operating theatre department.

Adult↗
PubMed2001

Physostigmine for Alzheimer's disease.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH STRATEGY: 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. SELECTION CRITERIA: 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 COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. REVIEWERS' CONCLUSIONS: 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.

Alzheimer Disease↗
PubMed1989

Characterization of the discriminative stimulus effects of physostigmine in the rat.

Rats were trained to discriminate physostigmine (0.1 mg/kg s.c.) from saline in a two-choice, discrete-trial avoidance paradigm. Stimulus generalization curves for physostigmine were steep; complete generalization with physostigmine occurred only at the 0.1 mg/kg training dose. The muscarinic cholinergic agonists oxotremorine, pilocarpine and arecoline were evaluated for physostigmine-like discriminative effects. Oxotremorine generalized with physostigmine at a dose of 0.1 mg/kg in four of six rats tested; partial generalization was engendered by this dose in the remaining two animals. Complete generalization with physostigmine was produced in only one of six rats treated with pilocarpine. However, pilocarpine (3.0-10 mg/kg) did engender some physostigmine-appropriate responding in all rats tested. Arecoline (1.0 mg/kg) produced primarily saline-appropriate responding in all animals tested. Neostigmine, eseroline and nicotine were tested for physostigmine-like discriminative effects in order to assess the specificity of the physostigmine cue. Eseroline (1.0 mg/kg), an opioid-like derivative of physostigmine, and neostigmine (0.1 mg/kg) engendered saline-appropriate responding. Similarly, nicotine failed to generalize with physostigmine at doses up to 1.0 mg/kg. The discriminative stimulus effects of physostigmine were sensitive to antagonism by atropine. Complete blockade of the stimulus effects of the training dose of physostigmine was produced by 1.0 to 3.0 mg/kg of atropine. In contrast, a 10-fold higher dose of the quaternary antagonist homatropine methylbromide was necessary to block the discriminative effects of physostigmine. The discriminative effects of physostigmine were not blocked or were only partially blocked by mecamylamine at doses up to 10 mg/kg. The results of these experiments suggest that the discriminative stimulus effects of physostigmine are selective and probably centrally mediated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Kinetics of transdermal penetration of an organic ion pair: physostigmine salicylate.

Physostigmine salicylate was delivered from a series of solvents consisting of isopropyl myristate, isopropyl alcohol (IPA), and their mixtures across dermatomed human skin. The apparent steady-state fluxes over the time range of the test, obtained separately for physostigmine and its corresponding salicylate, indicate a consistent trend toward higher values for the salicylate in the series tested. The ratios of salicylate fluxes to physostigmine fluxes ranged from 1.1 to 3.34, the higher ratios being obtained at a volume fraction of IPA exceeding 0.7. Ionization of the ion pair at the pH of the hydrated stratum corneum immediately after its partitioning into the membrane, followed by differential diffusion of the species across the membrane, is consistent with the kinetics of penetration. It is proposed that the apparent volume of distribution of physostigmine is larger than that of salicylate and, hence, a smaller concentration difference across the diffusion barrier exists for physostigmine. This hypothesis can explain the lower flux of physostigmine to conform to Fick's first law of diffusion and the assumption of equal molar transfer to the skin of both species. The hypothesis implies that if steady state appears to have been reached for the faster migrating salicylate over the time range tested then the apparent steady state of physostigmine is not a true one. Increasing the salicylate content in one of the donor solutions by eight times over that of physostigmine decreased the saturation concentration of physostigmine but not in its flux. Increasing the physostigmine content by 6.5 times over that of salicylate in the same donor solution did not change either the flux or the salicylate concentration but decreased the permeability coefficient of physostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMedDate not supplied

The inhibition and protection of cholinesterase by physostigmine and pyridostigmine against Soman poisoning in vivo.

It has been shown that some reversible cholinesterase (ChE) inhibitors as physostigmine and pyridostigmine are prophylactically effective in organophosphate poisoning. The inhibition and protection of ChE against Soman poisoning with the above mentioned drugs was investigated in mice. (1) Physostigmine and pyridostigmine significantly inhibited the ChE in whole blood in vivo and their inhibitory potencies with equitoxic doses were approximately equal (1/5LD50 about 30%; 1/2 LD50 about 45% respectively). Physostigmine also significantly inhibited brain ChE and its potency was slightly weaker than that in blood; but pyridostigmine only slightly inhibited brain ChE (17%) with large dose (1/2 LD50). The extent of inhibition was in parallel with the dosage of the drugs used. (2) Physostigmine had definite protection in the blood and brain ChE against Soman poisoning. The extent of protection was in parallel with the dosage used. The protection of blood ChE by pyridostigmine was weaker than that by physostigmine. There was no protection of brain ChE by pyridostigmine. (3) The inhibitory potency of equitoxic doses of physostigmine and pyridostigmine in the ChE of diaphragm muscle was equal too (1/2 LD50 about 45%), and the protective effect of physostigmine was still greater than that of pyridostigmine in Soman poisoning. (4) The time course of blood ChE inhibition by physostigmine in vivo was of short duration. While 30 minutes after administration of physostigmine, the ChE activity gradually recovered and it returned to normal level after 4 hours. The blood ChE inhibition by pyridostigmine reached a peak level after 2 hours, and the ChE activity slowly increased after 4 hours, but there was 30% of ChE activity still inhibited after 8 hours. Physostigmine and pyridostigmine, the reversible ChE inhibitors with carbamate structure, have definite ChE protection against Soman poisoning. The prophylactic efficacy was obviously correlated with their ChE protective potency. Evaluating physostigmine and pyridostigmine based on their efficacy, toxicity, adverse effects, duration, availability and stability, we recommend that pyridostigmine is the drug of choice in the prophylaxis against nerve gas poisoning.

Animals↗
PubMed1998

Effects of hexamethonium, phenothiazines, propranolol and ephedrine on acetylcholinesterase carbamylation by physostigmine, aldicarb and carbaryl: interaction between the active site and the functionally distinct peripheral sites in acetylcholinesterase.

Physostigmine, aldicarb and carbaryl were potent inhibitors of acetylcholinesterase (AChE). The physostigmine-inhibited AChE fluoresced at 300 nm excitation and 500 nm emission wavelengths, but the aldicarb and carbaryl inhibited enzyme did not. This suggests that the carbamylated active center is not the fluorescing site in AChE. The fluorescence intensity of physostigmine-inhibited AChE decreased with increasing the substrate (acetylthiocholine) concentration, thus indicating that physostigmine binding to the active site is essential for the development of fluorescence. Thus, the physostigmine-inhibited AChE fluoresces due to the binding of trimethylpyrrolo[2,3-b]indol (TMPI) moiety, formed by the hydrolysis of physostigmine, to a peripheral site in AChE. The fluorescence intensity of the physostigmine-inhibited enzyme decreased when the inhibited-enzyme was dialyzed for either 30 min that poorly reactivated the enzyme or 180 min that fully reactivated the enzyme. This suggests that dialysis dissociates the AChE-TMPI complex much faster than it reactivates the carbamylated AChE. Ephedrine, propranolol and phenothiazines including trifluoparazine (TPZ) caused non-competitive inhibition, while hexamethonium caused an uncompetitive inhibition of AChE activity. TPZ, upon binding with AChE, formed a fluorescent TPZ-enzyme complex. The fluorescence intensity of TPZ-AChE complex was effectively decreased by ephedrine, but not by propranolol or hexamethonium. This indicates that TPZ and ephedrine bind to the same site in AChE which is different from the site/or sites to which propranolol or hexamethonium bind. Hexamethonium protected AChE from inhibition by carbamates and decreased the fluorescence intensity of the physostigmine-inhibited AChE. Phenothiazines and ephedrine did not modulate the enzyme inhibition or the fluorescence intensity of the physostigmine-inhibited AChE. Propranolol and TPZ potentiated the enzyme inhibition and increased the fluorescence intensity in the presence of physostigmine. These compounds, however, did not affect the inhibition of AChE by carbaryl or aldicarb. Ephedrine blocked the effects of TPZ, but did not alter the effects of propranolol on physostigmine-inhibited AChE. AChE, therefore, contains multiple peripheral binding sites which, upon binding to specific ligands, transduce differential signals to the active center.

Acetylcholinesterase↗
PubMed1994

Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum.

1. The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [3H]-dopamine. In this preparation, nicotinic cholinoceptor activation evoked [3H]-dopamine release. 2. Antagonist activity was examined by giving a brief nicotine (1 microM) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3-300 microM). Physostigmine, neostigmine and tacrine produced a concentration-dependent blockade. Physostigmine and tacrine were particularly potent (IC50S approx. 10 microM and 1 microM, respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 microM). 3. Nicotinic blockade produced by superfusion with physostigmine (30 microM) was insurmountable when tested against nicotine (0.1-100 microM). 4. Physostigmine (30 microM) also reduced responses to the nicotinic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K+ or (+)-amphetamine. A higher concentration of physostigmine (300 microM) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K+. Tacrine (3 microM) reduced responses to nicotine and to high K+ but did not affect responses to amphetamine. 5. Physostigmine (0.3-300 microM), given as a brief pulse, did not produce a nicotinic agonist-like effect. 6. Physostigmine, neostigmine, tacrine and DFP (all at 30 microM) each produced near-total (> 96%) inhibition of AChE activity. However, DFP at a concentration (60 microM) that produced a degree of AChE inhibition equal to that of physostigmine 30 microM, did not significantly reduce nicotine-induced dopamine release. 7. It thus appears that physostigmine blocks CNS nicotinic receptors in an insurmountable and pharmacologically selective manner, independent of its ability to inhibit acetylcholinesterase. Tacrine reduced nicotinic responses, quite possibly by an indirect mechanism. The possibility of direct or indirect blockade of nicotinic receptor-mediated actions may complicate the interpretation of preclinical studies that have employed physostigmine and tacrine.

Animals↗
PubMed2005

Physostigmine does not effect arousal but produces toxicity in an animal model of severe gamma-hydroxybutyrate intoxication.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Animals↗
PubMed2006

The early toxicology of physostigmine: a tale of beans, great men and egos.

Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.

Animals↗
PubMed2004

Nefiracetam and physostigmine: separate and combined effects on learning in older rabbits.

Physostigmine and nefiracetam were tested alone and in combination in 104 rabbits with a mean age of 28 months conditioned in the 750 ms delay eyeblink classical conditioning procedure. In Experiment 1, five doses of physostigmine (0.0005-0.2 mg/kg) enhanced conditioning. In Experiment 2, combinations of 10 mg/kg nefiracetam and 0.01, 0.1 and 0.2 mg/kg physostigmine improved the rate and magnitude of learning over rabbits treated with vehicle or 10 mg/kg nefiracetam alone. Brain AChE levels were significantly lower than vehicle for all doses of physostigmine and physostigmine plus nefiracetam. Control rabbits tested in the explicitly unpaired condition demonstrated that physostigmine alone and nefiracetam plus physostigmine had no non-associative effects. Physostigmine had a dramatic cognition-enhancing effect in older rabbits, and when nefiracetam was combined with physostigmine at a low dose, the ameliorating effect of physostigmine on learning was improved indicating that drug combinations for cognition enhancement may have therapeutic efficacy.

Acetylcholinesterase↗
PubMed2005

Nicotine pretreatment diminished physostigmine-induced tremor in rats.

The aim of this work was evaluate the effects of acute and chronic nicotine pretreatment in the physostigmine-induced tremor in rats. Wistar male rats (3-4 months) were pretreated acutely with different nicotine doses (0, 0.1, 0.5 or 1.0 mg/kg) 10 min before physostigmine (0 and 0.5 mg/kg) treatment and then the tremor was registered by computerized system for 10 min. In another group, rats were pretreated acutely with 0.1 mg/kg of nicotine, recovered at different times (30 or 70 min), and were registered for physostigmine-induced tremor. Nicotine was also used chronically with equal doses for 8 days and recovered at 2, 7 or 21 days before registration of physostigmine-induced tremor. Tremor spectral analysis was performed for amplitude and frequency quantification. Our data show that the acute and chronic nicotine pretreatments alter physostigmine spectrum profile. Nicotine decreased physostigmine-induced tremor amplitude (p<0.05), without changing its tremor frequency. In acutely pretreated rats, recovery experiments showed return of physostigmine-induced tremor for control levels after 70 min, but after 8 days of chronic nicotine pretreatment recovery was delayed 3 weeks. The data analysis shows that acute or chronic nicotine administration can alleviate the physostigmine-induced tremor. Chronic nicotine pretreatment has a long tremor alleviation effect of physostigmine-induced tremor. Possible mechanisms involving the nicotine effects on the physostigmine-induced tremor are discussed.

Animals↗