[Hypotensive and miotic action of stabilized solutions of physostigmine and physostigmine-pilocarpine (experimental data)].
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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↗
In vitro protection of acetylcholinesterase and butyrylcholinesterase by tetrahydroaminoacridine. Comparison with physostigmine.
The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against the long-lasting inactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) brought about by diisopropylfluorophosphate (DFP) and physostigmine, as well as by neostigmine in the case of AChE only, was evaluated by a dilution technique using Electrophorus electricus AChE and horse serum BuChE as target enzymes. In parallel experiments, the ability of physostigmine itself to protect these enzymes from DFP was evaluated and compared with that of THA. THA pretreatment was seen to prevent in a dose-dependent manner the inhibition of both AChE and BuChE. However, it was appreciably more potent towards AChE than towards BuChE. THA mean EC50 values for protecting AChE against 10, 40 and 100 microM DFP were 0.04, 0.16 and 0.45 microM, respectively; against 1 microM physostigmine the value was 1.8 microM and against 1.2 microM neostigmine it was 3.0 microM. The THA mean EC50 value for protecting BuChE against 3 microM physostigmine was 0.55 microM and the values for protecting against 3, 10 and 40 microM DFP were 1.5, 3 and greater than 10 microM, respectively. The protective action of THA was time independent: recovery of the maximal enzymic activity was immediate upon dilution. Unlike THA, the protective action of physostigmine developed progressively after dilution and was maximal within 3-4 (AChE) or 6-8 hr (BuChE). Under our experimental conditions, 0.3 microM physostigmine protected approximately 70% of AChE from 40 microM DFP and 5 microM physostigmine protected 9 and 47% of BuChE from 40 and 3 microM DFP, respectively. The results of this work suggest that THA exerts its protective action by shielding the active site of AChE and BuChE from the attack of the inactivating agents on account of its higher enzymic affinity, whereas the protective action of physostigmine against DFP takes advantage also of the carbamylation of the enzyme. These results are in line with the hypothesis that protection of AChE is the primary mechanism responsible for the antidotal action of THA against organophosphorus poisoning.
Acetylcholinesterase↗
The effects of physostigmine on cholinesterase activity, storage and release of acetylcholine in the isolated chicken heart.
Total activity of the cholinesterases (ChE) and the concentration and output of acetylcholine (ACh) were measured in isolated chicken hearts. The ACh concentration of the right ventricle was as high as that of the total heart (approximately 7 nmol/g). The ChE activity and its kinetic parameters did not differ from those of other vertebrates. In the absence of physostigmine, stimulation of both vagus nerves (20 Hz, 5 minutes) caused an output of ACh and a decrease in rate (-90% of control) and amplitude (-74%) of the ventricular contraction. Physostigmine (10(-7) M) inhibited the ChE by 87%, caused a small reduction of the ACh concentration (P = .05) and more than doubled the ACh output in response to vagal stimulation. In contrast, 10(-6) M physostigmine increased significantly the ACh concentration by about 40% within 5 minutes; the output was almost 3-fold higher than that in the absence of physostigmine and the ChE was nearly completely inhibited (-96%); the output of ACh in the 5th minute of stimulation was not significantly lower than that in the 1st minute. Physostigmine, in a concentration of 10(-4) M, did not change the ACh content of the heart and was much less effective in elevating the ACh output than was a concentration of physostigmine of 10(-6) M. In conclusion, the high ACh output from isolated chicken hearts evoked by preganglionic nerve stimulation was at least partially due to the pronounced innervation of the avian ventricles. Inhibition of the ChE by 96% failed to cause ganglionic transmission block. The formation of surplus ACh required higher physostigmine concentrations (10(-6) M) than the inhibition of the external ChE (protection of ACh released). High physostigmine concentrations (greater than 10(-6) M) counteracted the formation of surplus ACh.
Acetylcholine↗
The role of GABA and glycine in the physostigmine-induced alterations of spinal cord reflexes.
The purpose of this study was to determine which inhibitory pathway(s) mediate the alterations in the monosynaptic (MSR) and polysynaptic (PSR) reflexes after two different doses of physostigmine. It was found previously that 0.8 mg/kg physostigmine facilitated the MSR and 2.0 mg/kg initially depressed and then facilitated the MSR. Both doses facilitated the PSR. In this study, the animals were pretreated with either strychnine (0.1 mg/kg) or bicuculline (0.5 mg/kg), prior to the administration of either dose of physostigmine. It was found that both strychnine and bicuculline blocked the facilitation produced by the small dose of physostigmine, while bicuculline alone blocked the depression of the MSR produced by the large dose of physostigmine. Strychnine partially blocked the effects of both doses of physostigmine on the PSR, while bicuculline only partially blocked the effects of the small dose of physostigmine. These data suggest that the depression of the MSR was the result of a GABA-mediated pathway, while the facilitation of MSR involved both glycine and GABA.
Animals↗
The physostigmine depolarization potentiating effect of salicylate in frog skeletal muscle.
1) The frog's sartorius muscle was depolarized depending on the degree of concentration 2--4 times more intensely by physostigmine salicylate than by physostigmine sulphate. 2) In normal Ringer's solution, 1 mM physostigmine salicylate decreased the sensitivity of the membrane to potassium depolarization by about 90%. Under similar experimental conditions, physostigmine sulphate and Na salicylate, respectively, decrease the sensitivity of the membrane to potassium depolarization by about 30%. 3) The difference manifested in the depolarizing effect of salicylate and other physostigmine salts (chloride, sulphate, phosphate, formiate, acetate, monochloracetate, benzoate and para-oxy-benzoate) is expressed already at 1 mM concentration (about 10-fold), if the muscle had been equilibrated in chloride-free glucuronate or sulphate milieu. 4) The depolarization develops slowly. It takes 30--60 minutes for the new steady state to develop even in the superficial sartorius fibres. If depolarization has reached its maximum on an average 100 mV, the membrane potential remains unchanged for hours. 5) Depolarization ensues at an unchanged degree in the presence of Na-free (choline) Ringer as well as in the presence of 2X10(-8) g/ml tetrodotoxin; therefore, it is not a Na-dependent process. 6) Under the influence of 1 mM physostigmine salicylate the membrane's resistance to the inward potassium current increased about twofold, while the increase was only 15% to the outward potassium current. It is assumed that the salicylate anion is characteristically capable of potentiating the decreasing effect of physostigmine on potassium permeability, though the role of the metabolic effect of salicylate cannot be excluded.
Animals↗
Physostigmine: effects on cognition and affect in normal subjects.
Physostigmine was given intravenously to a total dose of 3 mg to 13 subjects; a placebo of 0.25 N saline was given intravenously to 10 other subjects; both groups received 1 mg of methscopolamine bromide subcutaneously preceding the intravenous infusions. A "physostigmine syndrome" consisting of decreased speech, slowed thoughts, mild sedation, expressionless faces, nausea, and decreased spontaneous activity was evident following doses of 1.5 to 2.0 mg of physostigmine. The capacity of short-term memory (STM) as measured by digit span tasks was significantly less for the subjects who received physostigmine than for the subjects who received placebo. No difference was observed between the two groups on tasks of consolidation from STM to long-term memory (LTM). Subjects who received physostigmine did not significantly differ from subjects who received placebo in their mood. However, two subjects in the physostigmine group, and no subjects in the saline group became tearful and depressed.
Adult↗
Physostigmine-induced contractures in frog skeletal muscle.
Physostigmine in 15 mM concentration at pH 8.4 produces reversible contractures of up to 0.3 Po tension output in frog's whole toe muscle or in 7-10 fiber bundles of these muscles, At pH 7.2, the 15 mM physostigmine contracture output is only about 0.10 Po. The 15 mM, pH 8.4 contractures are essentially unaffected by lack of external Ca2+, complete depolarization of the fibers, detubulation by glycerol treatment, and 0 degrees C ambient temperature. These results and other evidence indicate that physostigmine produces contracture by directly releasing activator Ca2+ from the sarcoplasmic reticulum (SR). Pretreatment of muscles with 4 mM procaine reduces physostigmine's capacity to produce contracture, evidently by means of a competitive inhibition at SR sites. The above results indicate similarities between physostagmine and caffeine contractures. But the physostigmine action differs in that it is reversible, and, especially, it lacks the ability, strongly characteristic of caffeine, to sensitize a muscle to produce a rapid cooling contracture. The internal action of physostigmine requires that it be permeant, and, since it is a weak base (pKa = 8.2), this property is provided by its uncharged base. But, once internal, where the pH = 6.8, most of the drug will be protonated and it may act on the SR in this form, in contrast with caffeine which, since its pKa is about 1.0, acts on the SR as uncharged base.
Animals↗
A randomized evaluation of the reversal of ketamine by physostigmine.
One hundred and eleven patients undergoing ketamine anaesthesia for therapeutic abortion were studied in a double-blind trial of the reversal of ketamine by physostigmine administered postoperatively. The results demonstrate that physostigmine does not shorten recovery time or reduce the occurrence of ketamine emergence phenomena such as hallucinations, restlessness and dreams. In fact, the recovery course was prolonged in patients given physostigmine immediately upon termination of anaesthesia as compared with controls. By contrast, when physostigmine was given 30 minutes after the last dose of ketamine, the recovery was not prolonged as compared with that of the placebo-treated controls. These findings suggest some synergism between the effects of ketamine and physostigmine and should discourage the use of physostigmine as a ketamine antidote.
Abortion, Therapeutic↗
Central cardiovascular effects of physostigmine in anesthetized cats.
The central cardiovascular effects of a cholinesterase inhibitor, physostigmine, were studied in alpha-chloralose- and urethane-anesthetized cats, to determine the underlying site and mechanism of action. Intravenous injection of physostigmine produced a dose-dependent fall in blood pressure and heart rate. These responses were blocked by intravenous injection of atropine; however, the peripheral antimuscarinic agent, methscopolamine, failed to inhibit the depressor response. In decerebrated cats, physostigmine elicited similar responses in blood pressure and heart rate as in intact animals. In spinal cats, physostigmine failed to evoke any response. Physostigmine significantly reduced sympathetic nervous activity, as measured by renal sympathetic nerve discharges, indicating that the fall in blood pressure was due to a decrease in sympathetic tone. These results demonstrate that physostigmine, which crosses the blood-brain barrier, produces a depressor response through stimulation of muscarinic cholinergic receptors, located in the medullary region and that the effect is mediated by a decrease in sympathetic activity.
Anesthesia↗
The effect of physostigmine on normal human sleep and dreaming.
Physostigmine, an anticholinesterase that increases the action of brain acetylcholine, induces rapid eye movement (REM) sleep in normal humans. In this study we show that man dreams during physostigmine-induced REM sleep. Seventeen normal volunteers were pretreated with methscopolamine and received one intravenous infusion per night of either placebo or physostigmine either ten or 35 minutes after sleep onset. Subjects were awakened at specific times after infusion and interviewed regarding any sleep mentation prior to awakening. Results indicated that dreaming occurred during physostigmine-induced REM periods but that physostigmine did not alter mentation during non-REM sleep. These dreams were similar to spontaneous REM sleep dreams in content, vividness, unusualness, and emotionality.
Adult↗
Effects of physostigmine and lecithin on memory in Alzheimer disease.
Because there is evidence that central cholinergic mechanisms are depleted in dementia, we studied the effects of central cholinergic augmentation on the memory of 5 patients with Alzheimer disease. Patients received placebo, lecithin, physostigmine, or lecithin plus physostigmine in a double-blind study using titrated doses of the acetylcholinesterase inhibitor physostigmine. Memory was evaluated with alternate forms of the selective reminding procedure. Compared with lecithin alone, the combination of physostigmine and lecithin consistently enhanced memory storage and retrieval; physostigmine without lecithin produced no memory facilitation. The strategy of combining a cholinergic agonist and precursor holds promise, although a larger clinical trial is needed.
Aged↗
Physostigmine as an adjuvent to neuroleptanaesthesia in neurosurgical procedures.
The use of physostigmine electively to reverse the effects of droperidal and diazepam has permitted an optimum level of neuroleptanaesthesia in neurosurgical operations where co-operation of the patient is required during part of the procedure. The patient can be put to sleep or readily awakened to be fully co-operative depending on the needs of the surgeon. In this series of seven anaesthetics there were no side effects from the small doses of physostigmine employed. Bradycardia and salivation were not a problem. One child vomited once. Atropine was not necessary. Since a narcotic antagonist is not needed, a reasonable degree of analgesia can be maintained in these patients while they are awake. The latent time for the effect of physostigmine was two to four minutes and the effect of an intravenous dose lasted from 35 to 45 minutes. With physostigmine, these patients wake up gently as though from normal sleep. If neurological assessment is required post-operatively, drowsiness due to drugs can be reversed by giving more physostigmine and the level of consciousness can then be assessed.
Adjuvants, Pharmaceutic↗
Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.
Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.
Acetylcholinesterase↗
Perceptual bisection in rats: the effects of physostigmine, scopolamine and pirenzepine.
The effects of cholinergic drugs on three different perceptual bisection tasks were studied in rats. Physostigmine (0.056-0.56 mg/kg), a reversible anticholinesterase, produced dose-dependent decrements in discriminability (A'), but did not affect the bisection point (BP) in visual duration, auditory duration, and auditory intensity bisection tasks. This finding is consistent with results previously obtained in an auditory duration bisection task with an irreversible anticholinesterase, diisopropyl phosphofluoridate. Scopolamine (0.075-0.422 mg/kg), a muscarinic cholinergic-receptor antagonist, produced dose-dependent decrements in both A' and BP in visual and auditory duration bisection tasks. The behavioral antagonism between physostigmine (0.56 mg/kg) and scopolamine (0.075-0.237 mg/kg) was studied in the visual and auditory duration bisection tasks. The BP was not affected by physostigmine alone or in combination with scopolamine, except at the largest dose of scopolamine, which produced a reliable decrement in the BP. A', however, was equally decreased by physostigmine alone and all combinations of physostigmine and scopolamine. Pirenzepine (1, 3 and 10 mg/kg), a selective high-affinity M1 muscarinic antagonist, had no effect on A' or the BP in the duration bisection tasks, suggesting changes in perception produced by muscarinic antagonists do not involve the M1 receptor subtype. The similar drug effects in different sensory modalities (visual and auditory) and perceptual systems (subjective duration and loudness) suggest that cholinergic drugs may affect perceptual mechanisms responsible for sensory coding, such as the output of a neural generator.
Animals↗
Methacholine and physostigmine airway reactivity in asthmatic and nonasthmatic subjects.
Inhalation challenges using methacholine and physostigmine were performed in 3 human asthmatic and 3 nonallergic normal subjects. Plethysmographic measurements of specific airways conductance (Gaw/Vtg) were used to monitor the response. The dose required to produce a 17% fall in Gaw/Vtg was significantly lower in asthmatic subjects than in normal subjects for both physostigmine (p less than 0.0125) and methacholine (p less than 0.05). Moreover, in all subjects the relative airway sensitivity to methacholine correlated with the relative airway sensitivity to physostigmine. Both methacholine and physostigmine are cholinergic agents. Whereas methacholine acts directly at the end organ cholinergic receptor, physostigmine acts by increasing release and decreasing destruction of endogenous acetycholine at the vagal distal innervation. This suggests that the cholinergic airway hyperreactivity characteristic of asthma is a manifestation of end organ hypersensitivity.
Acetylcholine↗
The use of physostigmine as an antidote in tricyclic anti-depressant intoxication.
The value of physostigmine treatment of unconsciousness due to self-poisoning by tricyclic antidepressant drugs (TAD) was evaluated in 10 patients, and the following conclusions are drawn: 1. A slow i.v. injection of 2 mg of physostigmine produces a clear-cut increase in consciousness within 15 min if a TAD (or other drugs with central anticholingeric potencies) is mainly responsible for the poisoning. This "test dose" can give valuable diagnostic information. 2. Repeated i.v. injections seem of little practical value, since they may be expected to produce a state with rapid shifts in the level of consciousness. 3. If the test dose has a positive effect, immediate i.v. infusion of 4 mg physostigmine/h will maintain a high level of consciousness. Infusion should be stopped every sixth hour for about 30 min to check whether the level of consciousness still falls upon withdrawal of therapy 4. In cases of massive TAD overdosage, i.v. injection of physostigmine may increase the risk of grand mal seizures. 5. No signs of enhanced peripheral cholinergic activity following physostigmine are seen if 30 mg of propantheline is given i.v. every sixth hour. 6. No evidence has been produced that the morality rate in TAD poisoning is lower following physostigmine treatment whan with conventional supportive care. There must be the usual preparedness for cardiac complications.
Adult↗
Physostigmine and anesthetic requirement for halothane in dogs.
To investigate the effect of physostigmine on central nervous system (CNS) depression produced by halothane, control halothan minimum alveolar concentration (MAC) measured over 1 hour in 7 dogs was compared to MAC 30 minutes after each sequential IV dose of 0.04, 0.4, and 4 mg/kg physostigmine. MAC decreased 6.8, 11.1 (p less than 0.05), and 35.9 (p less than 0.01) percent, respectively. Six dogs were observed for an acute increase in halothane requirement in the first 30 minutes after administration of physostigmine. All 6 showed such a response at 1 or more dose levels, beginning within 1 to 5 minutes after administration and lasting 2 to 30 minutes (p less than 0.05). Five other dogs were tested with neostigmine in the same doses and showed respective decreases in MAC of 7.9, 16.6 (p less than 0.01), and 17.5 ( less than 0.01) percent. No dog showed an acute increase in anesthetic requirement. Intravenous atropine 0.5 mg/kg failed to further alter MAC after 4 mg/kg neostigmine. Physostigmine transiently antagonizes halothane anesthesia, presumably by facilitating cholinergic transmission in the CNS; neostigmine does not. After this initial response, both drugs decrease anesthetic requirement. If these data may be extrapolated to patients, they suggest that physostigmine is not an effective antagonist to postoperative somnolence due to halothane.
Animals↗