Physostigmine Salicylate Research Articles

Treatment of acute anticholinergic poisoning with physostigmine

Five cases of acute anticholinergic poisoning presenting to an inner-city emergency department (ED) are discussed. All five patients presented with classic signs and symptoms of anticholinergic toxicity, which included tachycardia, hot, dry and flushed skin, markedly dilated and fixed pupils, and pronounced delirium. The patients were violently agitated, and physical restraint was required. Initial treatment with benzodiazepines did not diminish their combative behavior. Treatment with intravenous physostigmine salicylate resulted in a decrease in agitation within 15 to 20 minutes of therapy. No untoward effects occurred as a result of treatment with physostigmine.

Effects of physostigmine on scopolamine-induced changes in quantitative electroencephalogram and cognitive performance

The effects of physostigmine on scopolamine-induced changes were investigated in a randomized, double-blind cross-over study utilizing quantitative electroencephalogram (qEEG) and cognitive tasks. Ten healthy male volunteers received scopolamine 0·6 mg subcutaneously. After 90 min, single doses of either 0·5, 1·0 and 2·0 mg physostigmine salicylate or placebo were administered subcutaneously in randomized order. qEEG, cognitive function and the visual analogue scale were recorded before and at 1, 2, 3, 4, 6, and 8 h after scopolamine administration; that was 0·5, 1·5, 2·5, 4·5, and 6·5 h after physostigmine administration. Scopolamine produced an increase in delta (1·25–4·50 Hz) and theta power (4·75–6·75 Hz) in qEEG 1 h after administration compared to baseline, while physostigmine decreased the spectral delta power density in qEEG compared to placebo. The maximal effect of physostigmine was seen up to 1·5 h after injection. A dose-dependent reversal of the scopolamine induced decrements in cognitive performance was found 0·5 h after administration of physostigmine. Psychometric tests sensitively discriminated between the doses of physostigmine, and showed dose- and time-dependent effects. The results suggest that physostigmine may reverse the scopolamine-induced changes in both qEEG and cognitive function. This reversal was temporary and of short duration. © 1998 John Wiley & Sons, Ltd.

Cholinergic modulation of cerebral cortical blood flow changes induced by trauma.

These experiments tested the role of cholinergic mechanisms in the changes of cerebral cortical blood flow (CBF) induced by brain trauma. CBF was measured with Iodo-14C-antipyrine autoradiography, in 128 cerebral cortex regions of both hemispheres, distributed in eight coronal slices. The effects of a 6.3-mm diameter craniotomy over the left motor-sensory cortex with no weight drop, and of trauma (drop weight of 20 g from 30 cm height on left motor-sensory cortex through a 6.3 mm circular craniotomy) on CBF were studied at 2 and 24 h after the interventions. A group of control animals that received no intervention was also set up. Animals were treated with the cholinesterase inhibitor physostigmine salicylate (3.3 microg/kg/min i.v. infusion started 60 min before CBF measurements), the cholinergic blocker scopolamine hydrobromide (1 mg/kg i.v. pulse, 18 min before CBF measurements), or with the drugs vehicle (saline). A focus of decreased CBF at the site of impact was observed 2 h after trauma, extending caudally as far as the occipital cortex. CBF on the contralateral cerebral cortex was also decreased. Both phenomena reversed partially at 24 h. This spontaneous recovery of CBF was blocked by scopolamine. Physostigmine reversed the decrease in CBF of the traumatized cortex, partially around the contused area and completely in more distant regions. The cerebral cortex contralateral to the trauma showed significantly higher CBF 24 h after trauma when compared to intact controls or craniotomy that peaked at the area symmetrical to the center of trauma. This phenomenon was also enhanced by physostigmine and completely blocked by scopolamine. These results suggest a prominent role of cholinergic mechanisms in the vascular adjustments that accompany cerebral trauma.

Physostigmine increases aqueous humor production in human eyes

PURPOSEvestigate if part of the progressive reduction of intraocular pressure (IOP), seen when physostigmine is applied on alternate hours, is due to a reduced aqueous flow. METHODSrandomized, open study, one drop of physostigmine salicylate, 8 mg/ml, was instilled at 7 AM in one randomly assigned eye in each of twenty healthy volunteers. Instillations were repeated on alternate hours throughout the day. Each subject's untreated eye served as control. Fluorophotometry of the anterior segment was performed hourly between 7 AM and 8 PM and aqueous flow was calculated. Subsequently, the subjects underwent tonography and tonometry. The change in anterior chamber depth and volume induced by physostigmine was assessed separately. RESULTS. The mean aqueous flow during the day was 25–28% higher in the physostigmine-treated eye than in the control eye. The difference was statistically significant from 9 AM (p < 0.05–p < 0.001). Each dose caused a further increase. The mean outflow facility increased by 0.14 µl/min/mm Hg with 95% confidence interval (CI) 0.09–0.18. Although the increase in outflow facility was small, there was a marked reduction of IOP with a mean difference between treated and untreated eye of 3.2 mm Hg (95% CI: 2.3–4.0). CONCLUSIONS. Repeated administrations of physostigmine increase the aqueous flow and outflow facility. The combined effect is a marked reduction of IOP.

Effects of morphine and physostigmine on the ventilatory response to carbon dioxide.

It has been reported that physostigmine antagonizes morphine-induced respiratory depression, but it is not known whether this is due to a central chemoreceptor effect, an effect on the peripheral chemoreflex loop, or both. We therefore assessed the effect of morphine and physostigmine on the normoxic hypercapnic ventilatory response mediated by the central and peripheral chemoreceptors in ten alpha-chloralose-urethan-anesthetized cats. The breath-by-breath ventilatory responses to stepwise changes in end-tidal CO2 tension were determined before (control), after administration of morphine hydrochloride (0.15 mg.kg-1) and during intravenous infusion of physostigmine salicylate (bolus of 0.05 mg.kg-1 followed by 0.025 mg.kg-1.h-1). Each response was separated into a central and a peripheral chemoreflex characterized by CO2 sensitivity (Sc and Sp), time constant, time delay, and apneic threshold (a single off-set B). Morphine increased B and decreased Sc and Sp (P < 0.01), but not the ratio Sp/Sc. Subsequent infusion of physostigmine decreased B (P < 0.01), without further change of Sp and Sc. Premedication with physostigmine decreased B, Sp and Sc (P < 0.01) vs. control, but not Sp/Sc. Subsequent administration of morphine decreased Sp and Sc further but increased B (P < 0.01), while Sp/Sc remained constant. Because morphine diminishes the Sc and Sp of the chemoreflex loop to the same extent this depressant effect is presumably due to an action on the respiratory integrating centers rather than on the peripheral and central chemoreceptors as such and is not antagonized by physostigmine. We argue that the increase in B may be due to changes in the amount of acetylcholine available in the brain and can be antagonized by physostigmine.

Trial of oral physostigmine in amyotrophic lateral sclerosis

We evaluated a double-blind, placebo-controlled, and double-crossover trial of oral physostigmine salicylate for a 9-month period in 13 of 25 patients with sporadic amyotrophic lateral sclerosis (ALS). A large dropout rate of 48% was secondary to eight deaths and four exclusions attributed to the incapability to swallow the tablets (physostigmine) and capsules (lecithin) or to attend the clinic. Parameters used for assessment of the drug efficacy included body weight, ALS score, Jamar grip strength, forced vital capacity, and maximum voluntary ventilation. It revealed slight benefit in reduced loss of grip strength compared with the pretrial and placebo periods. However, the rates of decline for body weight, ALS score, forced vital capacity, maximum voluntary ventilation, and megascore did not differ significantly between the pretrial, placebo, and physostigmine periods. We therefore concluded that overall no significant alteration in the clinical course was gained by oral physostigmine therapy in the 13 patients with ALS who were included in this study.

Behavioral toxicity of anticholinesterases in primates: Chronic physostigmine and soman interactions

Dose rates for continuous infusion of physostigmine salicylate required to inhibit 30 and 60% of normal serum cholinesterase activity in rhesus monkeys were determined. The effects of continuous physostigmine infusion at these dose rates on the behavioral toxicity of daily repeated low-dose soman were determined not to be deleterious; in fact, they were slightly (and variably) protective.

Ambient temperature effects on thermoregulation and endurance in anticholinesterase-treated rats

In sedentary animals, physostigmine (PH) administration resulted in a decreased core temperature that is ambient temperature (Ta) dependent. PH administration in rats exercising on a treadmill (26°C, 50% rh, 11m/min, 6° incline) decremented endurance and increased rate of rise of core temperature (heating rate, HR). This study was undertaken to examine the effects of Ta on the endurance and thermoregulatory decrements of PH-treated running rats. Adult male rats (510–530g) were given either 0.2ml saline (C) or 100 ug/kg physostigmine salicylate in 0.2 ml saline via tail vein 15 min prior to the start of running to exhaustion at 10, 15, 26, or 30°C. In both C- and PH-treated groups, endurance decreased and HR increased with increasing Ta from 15 to 30°C. At 15 and 26°C the C rats ran significantly (p<.05) longer and had significantly lower HR than the PH rats: C15 = 90±9 min, 0.022±0.006°C/min; C26 = 67±6, 0.051±0.007; PH15 = 57±5, 0.052±0.008; and PH26 = 43±6, 0.092±0.007. At 10 and 30°C there were no significant differences between C and PH-treated rats. A Ta of 30°C was too high for effective cooling in either group, and at 10°C both groups were able to dissipate heat despite the increased metabolic rate of the PH-treated rats. The PH-treated rat model of cholinergic drug effect is useful at a Ta of 15 and 26°C.

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. lonization 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. This result suggests that fixed, structural, negatively charged groups in the membrane compete with the salicylate anion for binding the protonated physostigmine through coulombic attractive forces, thus affecting its diffusion rate. A more hydrated membrane, obtained at high hydrophilic IPA content in the solvent, is expected to favor the formation of physostigmine dication and thus slow its diffusion rate with respect to a less hydrated membrane.

Physostigmine: dose-response effects on endurance and thermoregulation during exercise

We previously reported that the administration of 200 ug/kg of physostigmine (PH) to rats exercising on a treadmill resulted in decrements in both endurance (decreased running time to exhaustion) and thermoregulation. However, it was necessary to determine the dose-response effects of PH administration before PH-treated exercising rats could be used as a model with which to examine the relative anticholinergic potency of drugs. In the present work saline, 50, 100, or 200 ug/kg of physostigmine salicylate (0%, 40%, 50%, and 60% whole blood cholinesterase inhibition) was administered to rats (N = 12/ group) prior to treadmill exercise (26°C, 50% rh, 11 m/min, 6° incline). The saline control group ran for 67 ± 6 min (mean ± SE) with a rate of rise of core temperature of 0.051 ± 0.007°C/min. The run times declined (80%, 64% and 48% of control) as rate of rise of core temperature increased (116%, 180%, and 214% of control) in a dose-dependent manner (50, 100, 200 ug/kg PH). Cholinergic sysmptoms such as salivation, tremors, and defecation were also affected in a dose-dependent manner by PH administration. Since cholinergic symptoms, thermoregulatory effects, and endurance decrements all vary in a dose-dependent manner with physostigmine administration, the exercising rat represents a useful model for examining the relative potency of cholinergic therapies.

Physostigmine improves cerebral blood flow in human focal cerebral ischemia

The effect of intravenous physostigmine on cerebral perfusion of patients with cortical stroke was investigated using hexamethyl-propyleneamine oxime (HMPAO) single-photon emission computed tomography. Each patient was studied twice, afteran intravenous infusion of either 1 mg of physostigmine salicylate or saline. A marked increase in HMPAO activity was observed in all regions of post-physostigmine scans when compared to the corresponding post-saline scans, except for the area of infarction and its mirror area in the contralateral hemisphere. In conclusion, physostigmine improves perfusion in the area of penumbra of patients with cortical infarction.

Reciprocal Changes in Psychosis and Mood After Physostigmine in a Patient With Alzheimer's Disease

To the Editor.— The role of the cholinergic system in neuropsychiatric disease has been the topic of two recent articles in theArchives. 1,2 The cognitive and behavioral effects of the cholinesterase inhibitor physostigmine salicylate in patients with Alzheimer's disease has been the subject of an ongoing study. We describe the fluctuation in one patient's psychotic and depressive symptoms that were consistent with the hypotheses that associate increased muscarinic activity with depressive and negative symptoms. The patient's psychotic symptoms were alleviated, although the depressive symptoms increased with physostigmine treatment. This agent presumably increases the functional activity of acetylcholine and causes a relative decrease in dopaminergic activity (as reflected by a decrease in cerebrospinal fluid homovanillic acid). This fluctuation of symptoms and biochemical profile suggests certain parallels to patients with schizophrenia, in whom increased muscarinic activity has been associated with depressive and negative symptoms, and increased mesocorticolimbic dopaminergic activity with psychosis. 1

In Vitro Release and Intestinal Absorption of Physostigmine Salicylate from Submicron Emulsions

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 ± 0.86 and 9.98 ± 2.04 (log%/min) × 10−3 in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 ± 1.2-14.8 ± 1.1 (log%/min) × 10−3 in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.

Effects of Subacute Pretreatment Uite Carbamate Togetiieb with Acute Adjunct Pretreatment Against Nerve Agent Exposure

Visual observations were made to compare the pretreatment benefits of subacute (75 micrograms/hr, sc) and acute (146 micrograms/kg, im, at 30 min) deliveries of physostigmine salicylate (Phy) against 2 or 5 LD50s (60 or 150 micrograms/kg, sc) of soman in guinea pigs; scopolamine, 80 micrograms/kg, im, was given routinely at 30 min. In a second set of studies, pretreatment with subacute carbamate [sc, Phy 36 micrograms/hr or pyridostigmine (Pyr), 50 micrograms/hr] and acute adjunct (im, scopolamine, 0.48 mg/kg, or trihexyphenidyl, 2 mg/kg) at 30 min, was used against soman (5 LD50s, sc) and VX (18.4 micrograms/kg, sc; 2 LD50s); atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) were given at 1 min post soman. In all studies, lethality, % convulsing, convulsive/subconvulsive score, and recovery time were noted. Subacute dosing for 7 days was done via 14-day osmotic minipumps (OMPs). Results of the first set of studies indicate that subacute and acute deliveries of Phy give essentially comparable protection against 2 or 5 LD50s of soman. The second set of studies show that against soman, the adjuncts scopolamine and trihexyphenidyl when compared, and the carbamates, Phy and Pyr when compared, gave similar protective benefits as indicated by all four monitored measures of toxicity. Phy with either adjunct provided excellent protection against VX induced mortality and convulsions. With both carbamates, trihexyphenidyl gave similar protective benefits against VX. Scopolamine, however, under the conditions used herein, failed to act beneficially with Pyr against VX.

Enhanced stability of physostigmine salicylate in submicron o/w emulsion

Submicronized emulsions of physostigmine salicylate (PS) with high batch to batch uniformity were prepared using phospholipids and poloxamer as a complex emulgator. The mean droplet size of the various emulsions was distributed around the value of 150 nm and no single droplet was larger than 400 nm. The chemical stability of PS was strongly affected by the adjusted pH. In accelerated tests, it was found that PS was most stable in the emulsion at pH 5.0 while rapid degradation was observed in aqueous solutions at the same pH regardless of the storage temperatures. In view of the overall results, it was deduced that despite its high aqueous solubility, PS appeared to be localized at the oil-water interface of the dispersed oil droplets of the emulsion. The observed protective effect displayed by the emulsion was partly due to the interaction of physostigmine with phospholipids at the oil-water interface and partly due to physostigmine dissolution in the internal phase of the emulsion.

Cerebrospinal Fluid as a Reflector of Central Cholinergic and Amino Acid Neurotransmitter Activity in Cerebellar Ataxia

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Long-term behavioral and learning abnormalities produced by the irreversible cholinesterase inhibitor soman: Effect of a standard pretreatment regimen and clonidine

Previous studies in this laboratory have demonstrated that the α 2-adrenergic agonist clonidine and related drugs can offer significant protection against both the acute and chronic toxicity to soman administration in rats and mice. The purpose of this study was to determine whether addition of clonidine to a standard pretreatment protective regimen against soman toxicity could offer added protection or benefit. The standard regimen employed was a mixture of physostigmine salicylate (150 μg/kg) and artane (trihexyphenidyl hydrochloride 2 mg kg ). Rats were randomly assigned to one of 4 experimental groups: (1) those receiving i.m. sterile saline injection followed 30 min later by s.c. saline injection (normal controls); (2) saline i.m. followed 30 min later by one of several doses (60–110 μg/kg) of soman s.c.; (3) saline i.m., followed 10 min later by the standard pretreatment regimen i.m., followed by one of several doses of soman (160–300 μg/kg), s.c.; and (4) clonidine hydrochloride (1 mg kg ) i.m., followed 10 min later by the pretreatment regimen, followed 30 min later by soman. All animals were examined acutely and survivors were examined over a 3-week period following soman administration. The following observations were made: (1) Addition of clonidine to the standard pretreatment regimen did not enhance survival rate over the standard regimen alone (unless the clonidine was administered after the regimen). (2) Of the acutely toxic behavioral signs promoted by soman, clonidine addition to the standard regimen was of benefit only in reducing soman-induced tremor. (3) Addition of clonidine to the standard regimen appeared to hasten the return to normal motor behavior after soman; however, all groups exhibited normal motor behavior in 9 days. (4) Despite apparent normal motor behavior, soman-treated animals exhibited a marked per formance deficit in the passive avoidance parameter 3 weeks after injection. The standard regimen partially preserved this effect; addition of clonidine to the standard regimen completely reversed the effect. These results indicate that clonidine provides a measure of protection against chronic behavioral deficits caused by soman intoxication.

Central anticholinergic syndrome after ofloxacin overdose and therapeutic doses of diphenhydramine and chlormezanone

A 14-year-old female with no history of psychiatric disease ingested an unknown amount of ofloxacin, diphenhydramine and chlormezanone after an argument with her patients. Approximately 12 hours after ingestion, the patient was admitted to the hospital in a delirious state with extreme mydriasis and warm and dry skin. Analytical data on admission were consistent with ofloxacin overdose and ingestion of therapeutic doses of diphenhydramine and chlormezanone. The patient received activated charcoal and forced diuresis was instituted. Psychosis and anticholinergic symptoms lasted in the next 2 days. On day 3, the psychotic and anticholinergic symptoms were nearly completely reversed by 2 mg physostigmine salicylate, given IV x 2. Since anticholinergic symptoms have not been observed after ofloxacin overdose or after therapeutic doses of diphenhydramine or chlormezanone, this case suggests a potentiation of the anticholinergic effects of diphenhydramine and chlormezanone by ofloxacin overdose.

Effects of physostigmine on the cardiopulmonary system of conscious pigs

Physostigmine, as a pretreatment candidate for nerve agent poisoning, was examined for cardiopulmonary side effects. Cardiovascular and pulmonary parameters were monitored in unanesthetized domestic pigs which received pulmonary arterial infusion of 5 μg/kg/min physostigmine salicylate for 2 hr. A level of 74% inhibition of red blood cell (RBC) acetylcholinesterase (AChE) activity was attained in 45 min, and this level of carbamylation increased only slightly during the remaining infusion period. In addition to this large change in AChE activity, minor changes were observed in hematocrit, heart rate, body temperature, mean aortic pressure, pulmonary arterial wedge pressure, and pulmonary artery pressure. Typically, these parameters showed a trend toward elevated levels. Blood gases, pH, respiratory rate, tidal and minute volume, cardiac output, nonelastic resistance, and dynamic compliance were not significantly different from baseline values. The unanesthetized pig responds to physostigmine in a manner similar to that reported for other species and appears to be a suitable model for evaluating cardiopulmonary effects of cholinesterase inhibitors.

Effects of Physostigmine on the Cardiopulmonary System of Conscious Pigs

Effects of Physostigmine on the Cardiopulmonary System of Conscious Pigs. STEMLER, F. W., CORCORAN, K. D., PARRISH, J. H., HURT, H. H., TEZAK-REID, T. M., KAMINSKJS, A., AND JAEGER, J. J. (1990). Fundam. Appl. Toxicol. 14, 96–103. Physostigmine, as a pretreatment candidate for nerve agent poisoning, was examined for cardiopulmonary side effects. Cardiovascular and pulmonary parameters were monitored in unanesthetized domestic pigs which received pulmonary arterial infusion of 5 μg/kg/min physostigmine salicylate for 2 hr. A level of 74% inhibition of red blood cell (RBC) acetylcholinesterase (AChE) activity was attained in 45 min, and this level of carbamylation increased only slightly during the remaining infusion period. In addition to this large change in AChE activity, minor changes were observed in hemato-crit, heart rate, body temperature, mean aortic pressure, pulmonary arterial wedge pressure, and pulmonary artery pressure. Typically, these parameters showed a trend toward elevated levels. Blood gases, pH, respiratory rate, tidal and minute volume, cardiac output, nonelastic resistance, and dynamic compliance were not significantly different from baseline values. The unanesthetized pig responds to physostigmine in a manner similar to that reported for other species and appears to be a suitable model for evaluating cardiopulmonary effects of cholinesterase inhibitors.