Physostigmine Salicylate Research Articles

Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage

Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage

Physostigmine Salicylate in the Treatment of Tricyclic Antidepressant Overdosage

Following intravenous administration of physostigmine salicylate for tricyclic antidepressant poisoning in 21 patients, convulsions occurred in two patients, and severe cholinergic manifestations occurred in two others. Because of these untoward effects and the very short duration of its beneficial action, it is very doubtful that physostigmine has any place in the routine management of tricyclic antidepressant poisoning.

Tricyclic Antidepressant Poisoning

Two patients with coma, choreoathetoid movements, and myoclonus were found to be poisoned with tricyclic antidepressants. Physostigmine salicylate, a centrally active anticholinergic agent, promptly reversed the neurologic abnormalities. It appears to be the drug of choice in tricyclic antidepressant poisoning as well as in treating classical anticholinergic intoxication. It is relatively safe and can be used as a diagnostic test for suspected poisoning from these agents. These cases also support the cholinergic deficiency/dopaminergic excess hypothesis of chorea. ( JAMA 230:1405-1407, 1974)

Reversal of Amitriptyline Intoxication by Physostigmine

THIS article illustrates the rapid reversal of coma due to amitriptyline hydrochloride overdose by the administration of physostigmine salicylate. Physostigmine is the only commonly used specific cholinesterase inhibitor that readily penetrates the blood brain barrier. 1 Slovis et al 2 reported that physostigmine rapidly restored alertness and reversed tachycardia in four patients with amitriptyline intoxication. Rumack 3 reported the successful use of physostigmine to treat children who became intoxicated by various agents with anticholinergic properties as well as the tricyclic antidepressants. Report of Cases Case 1.— A 27-year-old woman was admitted in coma to Martin Army Hospital on April 2, 1974. History provided by a friend indicated that after an alleged altercation with her estranged husband, the patient ingested 20 amitriptyline hydrochloride tablets (50 mg) and about 20 diazepam tablets (5 mg). When discovered by a neighbor, approximately 10 to 12 hours later, she could not be aroused. When seen

Tricyclic antidepressant poisoning. Reversal of coma, choreoathetosis, and myoclonus by physostigmine.

Two patients with coma, choreoathetoid movements, and myoclonus were found to be poisoned with tricyclic antidepressants. Physostigmine salicylate, a centrally active anticholinergic agent, promptly reversed the neurologic abnormalities. It appears to be the drug of choice in tricyclic antidepressant poisoning as well as in treating classical anticholinergic intoxication. It is relatively safe and can be used as a diagnostic test for suspected poisoning from these agents. These cases also support the cholinergic deficiency/dopaminergic excess hypothesis of chorea. ( JAMA 230:1405-1407, 1974)

The Nervous System of Larval Schistosoma mansoni as Revealed by Acetylcholinesterase Staining

A complex AChE-positive neural network is described in miracidia and cercariae of Schistosoma mansoni. Longitudinal tracts in miracidia connect the anterior and posterior regions of the body to the central ganglia. A fine network of circular fibers was also found in the posterior region of the miracidium. In freshly shed cercariae only external papillae and regions with natural openings were positive for AChE staining. Staining after the alteration of the cercarial coat revealed a network of longitudinal and circular fibers near the surface, as well as nerve trunks and commissures in the interior of the organism. Extracts of adult Schistosoma mansoni have been demonstrated to contain acetylcholinesterase (AChE), choline acetylase activities (Bueding, 1952), and to contain a substance with properties similar to those of acetylcholine (ACh) (Barker et al., 1966). Histochemical evidence for the occurrence of AChE in adult worms was reported by Bueding et al. (1967). The occurrence of ACh in larval forms of S. mansoni has been inferred through histochemical demonstrations of AChE. Pepler (1958) and Lewert and Hopkins (1965) found AChE staining activity to be confined to the central neural mass of miracidia and cercariae. Fripp (1967) demonstrated trueand pseudo-cholinesterase activity to occur in adult worms but detected only true cholinesterase activity to occur in larval stages. Fripp described AChE distribution in greater detail than Pepler, and Lewert and Hopkins, but much of his description was based upon the use of nonspecific substrates. In this paper, the staining results in miracidia and cercariae, using acetylthiocholine iodide (ASChI) and butyrylthiocholine iodide (BSChI) as substrates, are described. MATERIALS AND METHODS AChE histochemical localization was carried out according to the methods of Koelle and Friedenwald (1949) and Gomori (1952) as described by Bueding et al. (1967) following further modifications. Organisms were individually collected and placed in watch glasses for incubation, Received for publication 12 November 1973. * Supported in part by Research Grant AI11107-01 from the NIH, U. S. Public Health Service, Bethesda, Maryland. using glass tubing drawn out to a fine point. The maximum number of organisms in any one incubation was 50. Inhibitors were added 60 min before the addition of substrates and maintained until completion of incubation. Substrate concentrations and their incubation periods varied with the experiment. After completion of incubation, organisms were washed twice in 20% Na2SO4 for 5 min each. During the last minute of the second wash, distilled water was added to the Na2SO4 solution. Organisms were transferred to distilled water for 5 min, reacted with H2S-saturated 70% ethanol for 45 sec, transferred to 50% ethanol, and finally water. For slide preparations, organisms (in water) were added to a drop of PVP in 30% glacial acetic acid and covered with a cover slip for examination. After reaction with H2S-saturated ethanol, some organisms were transferred to 70% ethanol and dehydrated through 80, 95, and 100% ethanol. These organisms were mounted in Spurr medium (Spurr, 1969). All organisms were of the Puerto Rican strain of Schistosoma mansoni. ASChI, BSChI, and physostigmine salicylate were obtained from Sigma Chemical Co., St. Louis, Mo.

Influence of acute pretreatment with Δ 9-tetrahydrocannabinol on the LD50 of various substances that alter neurohumoral transmission

Δ 9-THC significantly influenced the acute lethal effects (24 hr after a single dose) in mice of several drugs which alter cholinergic, adrenergic and serotoninergic neurotransmission. The LD50 values of carbachol chloride, arecoline HCl, physostigmine salicylate and neostigmine methylsalicylate were all significantly potentiated after pretreatment with 20.0 mg/kg of Δ 9-THC. Paradoxically, lethality produced by methacholine and exogenously administered acetylcholine were attenuated. Evidence for an α-adrenergic receptor blocking effect of Δ 9-THC was noted by the significantly larger LD50 values for 1-norepinephrine bitartrate and phenylephrine HCl when each was given in combination with Δ 9-THC. Moreover, bretylium tosylate and dl-α-methyl- p-tyrosine toxicities were also attenuated by pretreatment with Δ 9-THC. Finally, the combination of Δ 9-THC and cyproheptadine HCl was more toxic than the latter compound alone, suggesting an additive antiserotonin effect.

Quantitative Measurements of Endogenous Levels of Acetylcholine and Choline in Tetrathyridia of Mesocestoides corti (Cestoda) by Means of Combined Gas Chromatograph-Mass Spectrometry

Endogenous levels of choline and acetylcholine in tetrathyridia of Mesocestoides corti were determined under different environmental conditions. The highest values of choline and ACh were obtained when tetrathyridia were washed in media NCTC 135 and Eagle's Basal Medium. The lowest values were obtained when organisms were washed in 0.85% NaCl, or BME without choline chloride. Incubation of organisms in different concentrations of physostigmine showed an increase in the ACh level. The levels of choline and ACh decreased with decreasing drug concentration. DFP also showed a similar effect on choline and ACh. Oxotremorine increased choline and ACh levels but the increase was considerably lower than in physostigmine or DFP-treated organisms. While the histochemical association of acetylcholinesterase (AChE) with the nervous system has been the primary means of claiming the presence of acetylcholine (ACh) in helminthic tissue, a few workers have demonstrated ACh by biochemical isolation. Bueding (1952) showed that extracts of Schistosoma mansoni contain high levels of AChE and choline acetylase activities. Barker et al. (1966) reported the level of ACh in S. mansoni to be 5.3 jug/g wet weight. Chance and Mansour (1953) demonstrated AChE and choline acetylase activities in the liver fluke, Fasciola hepatica. Furthermore, they reported that this parasite contains an ACh-like substance. The presence of ACh was demonstrated in Ascaris by Mellanby (1955) who showed that the head region contains a much higher level than the body. Several biochemical methods are routinely used for determining ACh-like activity in extremely small amounts, but their reliability has been questioned (Hosein and Orzek, 1966; Stockley, 1969) in view of the fact that their response is not specific to one compound alone. Definitive identification of ACh and choline Received for publication 2 November 1973. * This investigation was aided in part by research grant USPHS AI-11107-01 from the NIH, Bethesda, Maryland. t Recipient of USPHS-NIAID Training Grant No. TOI-A1-00249. + Grand Island Biological Company, 519 Aldo Avenue, Santa Clara, California 95050. was made in tetrathyridia of Mesocestoides corti by means of a combined gas chromatograph-mass spectrometry (GC-MS) system. The functional aspects of ACh in this parasite will be reported elsewhere. MATERIALS AND METHODS Tetrathyridia of Mesocestoides, originally isolated from lizards (Specht and Voge, 1965), were maintained in Swiss albino mice. The animals were killed by cervical dislocation and tetrathyridia were transferred from the body cavity into petri dishes containing GIBCOt NCTC 135, "Eagle's Basal Medium" (BME) with or without choline chloride, or physiological saline solution (0.85% NaCl). Worms were preincubated in BME without choline chloride for a maximum of 1/2 hr before exposure to drug. The number of worms never exceeded 20 per ml of medium. The maximum period of incubation was 1 hr. For each drug concentration, the motility of worms was observed under the dissecting microscope at 15, 30, 45, and 60 min. The effect on choline and ACh levels by 3 different concentrations of physostigmine salicylate and 2 concentrations of oxotremorine and diisopropylfluorophosphate (DFP) was tested. The effect of each concentration was tested 3 times and organisms for each concentration were obtained from a different mouse. After incubation at 37 C, parasites were washed and dried by use of aspiration of fluids or by means of a Millipore filter. Organisms were then removed with a frozen spatula and immediately immersed in liquid nitrogen. The entire process of washing and drying lasted 6 to 8 min. Organisms were pulverized by the method of Campbell et al. (1970). The finely powdered tissue, 0.066 to 1.11 g, was transferred to a tared, chilled glass homogenizer to prevent thawing, and weighed. With few exceptions, the

Physostigmine effects on phenothiazine-induced extrapyramidal reactions.

The effect of an intravenous injection of physostigmine salicylate (1 mg) on the extrapyramidal side effects of phenothiazine therapy was investigated in ten psychiatric patients. Six of the ten patients who had developed minimal rigidity or tremor or both during phenothiazine therapy exhibited a worsening of these neurological signs after the physostigmine injection. It is concluded that cholinergic hyperactivity or hypersensitivity or both occur in phenothiazine-induced Parkinsonism as well as idiopathic Parkinson disease.

Effects of food deprivation, discrimination experience and physostigmine on choline acetylase and acetylcholine esterase in the dorsal hippocampus and frontal cortex of rats.

The effects of food deprivation and preliminary training treatments on choline acetylase and acetylcholine esterase activity in the dorsal hippocampus and frontal cortex of rats have been investigated. In addition, blood sugar and adrenal epinephrine levels were examined. The activity of choline acetylase and the levels of blood sugar and adrenal epinephrine were significantly altered during various stages of preliminary training but all values were comparable to pre-experimental levels before discrimination commenced. In addition, rats were injected physostigmine salicylate (0.25 mg/kg) or saline i.p. each day immediately after receiving three training trials on a food-motivated black-white task. The physostigmine injected rats were significantly better than the controls in rate learning.

Identification and treatment of acute psychotic states secondary to the usage of over-the-counter sleeping preparations.

Within eight months, 36 patients seen at the Washington Hospital Center, Washington, D.C., presented the problem of differentiating between a toxic psychosis caused by ingestion of over-the-counter sleeping medications containing scopolamine and a schizophrenic episode. Clinical evaluations, case histories, and thin-layer chromatography were used to identify these patients. Urinalysis revealed the presence of at least two ingredients of over-the-counter sleeping medications in ten patients. Intramuscular injections of physostigmine salicylate reversed the toxic psychosis presumed to be the result of the scopolamine content in these preparations.

Reversal of Systemic Toxic Effects of Scopolamine with Physostigmine Salicylate

Reversal of Systemic Toxic Effects of Scopolamine with Physostigmine Salicylate

Some fish muscle esterases and their variation in stocks of the herring ( Clupea harengus L.). The nature of esterase variation

1. 1. Electrophoretograms of α-naphthyl acetate and α-naphthyl butyrate esterases from white muscle of one-hundred Blackwater, ninety-nine Dunmore and fifty Ballantrae herring contained from two to ten bands of activity, but no single esterase band occurred in every fish. 2. 2. There was no evidence for allelic variation or multiple forms produced by subunit interaction but the relative intensities of bands 1 and 10 indicated that these could be inherited as full dose, half-dose or no dose. 3. 3. Esterase distribution was markedly different in the Dunmore and Blackwater stocks. The Ballantrae stock was intermediate in character. 4. 4. Different properties of the esterases were revealed by selective inhibition with N-ethylmaleimide, parachlormercuribenzoate, phenylmethylsulphonyl fluoride and physostigmine salicylate. Neuraminidase altered the electrophoretic mobility of bands 1, 3, 4 and 7. 5. 5. Esterase variation is suggested to result, in part, from the binding of sialic acid residues.

The water-loading test in rabbits. A method to detect potential ocular hypotensive drugs.

Tap (100 ml/kg) was administered by oral gavage to normal adult rabbits. Significant elevation of the intraocular pressure (IOP), lasting for at least 30 minutes, was observed. Following topical treatment, the IOP was significantly reduced by epinephrine bitartrate, carbachol, isoproterenol bitartrate (Isolevin [Britain]), hexamethonium chloride, propranolol hydrochloride, pilocarpine hydrochloride, and physostigmine salicylate, but not by phenoxybenzamine hydrochloride or atropine sulfate. Oral administration of dichlorphenamide or acetazolamide, three hours prior to water loading, resulted in a lower IOP than that observed for normal control animals. Based on these data, the water-loading test in rabbits appears to represent a valid procedure for screening drugs with potential antiglaucoma activity.

Reversal of Central Anticholinergic Syndrome in Man by Physostigmine

Physostigmine salicylate in doses of 1 to 2 mg administered parenterally was found to be an effective antidote to intoxication with centrally active anticholinergic agents. Confusion, agitation, hallucinations, stupor, ataxia, dysarthria, and other symptoms were promptly reversed in 26 consecutive patients in whom toxic reactions developed after receiving scopolamine, atropine, or drugs for Parkinson's disease. Physostigmine deserves a place in therapeutics as an antidote to anticholinergic intoxication.

Effects of oxotremorine on brain acetylcholine formation in vivo and in vitro

Under our experimental conditions rat brain normally contains 14.4 ± 1.3 ( M ± SD) m μmole acetylcholine (AcCh)/g. If oxotremorine (OT), 2 mg/kg body wt. i.p., is given to rats, this increases the level of AcCh to 22.1 ± 2.3. Homogenates of rat brain left for 15 min at 20° in the presence of physostigmine salicylate (10 −5 M) contain 13·5 ± 1·4 ( M ± SD) m μmole AcCh/g tissue. OT (10 −5 M) added to the homogenate increases the AcCh level to 20·9 ± 3·4/ g tissue. Addition of 5–8 m μmole AcCh/g tissue to a homogenate of normal rat brain followed by hydrolysis of the free acetylcholine before incubation has no inhibitory effect on the formation of AcCh produced by OT in vitro. The ability of OT to increase the AcCh level in a brain homogenate from rats pretreated with OT seems to be inversely proportional to its effect in vivo. The amount of AcCh produced by OT either in vivo or in vitro does not exceed a certain limit. In combined experiments mirror-like time curves for the concentration of AcCh are obtained. This observation suggests that OT has a similar mechanism of action in vivo and in vitro. The possibility for the presented results to be reconciled with an increased biosynthesis of AcCh has been discussed.

The Effect of Physostigmine and Atropine on some Behavioral and Electrophysiological Functions in Rats

Publisher Summary The dissociation of electroencephalogram (EEG) and behavior raised an important question about the correlation of electrophysiological and behavioral events. These are obviously the reasons why so much attention is paid to the behavioral role of the cholinergic systems. This chapter attempts to test some of the present hypotheses about their role. The chapter examines the behavioral significance of cholinergic systems in rats injected with physostigmine salicylate or atropine sulphate. Physostigmine but not atropine impaired spontaneous alternation of left and right turns in an H-shaped maze. Both drugs disrupted delayed alternation in a T-maze. With repeated drug applications, the effect became less marked. Atropine increased more than physostigmine the discharge rate of high voltage spikes elicited by local application of penicillin on the motor cortex of unanesthetized curarized rats. Physostigmine caused an extreme prolongation of cortical after discharge, which could be prevented by atropine. Both physostigmine and atropine slightly impaired the acquisition of a simple avoidance reaction in normal rats. The same avoidance reaction required more criterion trials in functionally decorticated animals, the learning ability of which was unaffected by physostigmine and seemingly improved by atropine. The latter drug increased the overall activity of the animal and thus raised the probability of correct as well as of incorrect responding.

End-plate cholinesterase in dystrophic muscle.

THE cholinesterase activity at the motor end-plate of dystrophic muscle was investigated histochemically by the thiolacetic acid method of Barrnett1, a modification of that of Crevier and Belanger2, which results in deposition of lead sulphide at the reactive site. A relatively quantitative method was developed to study this reaction by utilizing varying concentrations of physostigmine salicylate, a competitive inhibitor of cholinesterase.

Physostigmine induced hippocampal theta activity and learning in rats.

The effect of physostigmine on EEG activity and conditioning was studied in rats. Theta activity develops in the hippocampus of curarized or freely moving unanesthetized animals 3–7 min after i.p. injection of 1 mg/kg physostigmine salicylate, attains maximum after 10 min and disappears after 30–60 min. Gradual impairment of learning corresponds to the development of theta waves. One-trial acquisition of a passive avoidance reaction (avoiding a compartment with electrifiable floor) is completely suppressed 10 min after application of 1.0 or 0.5 mg/kg physostigmine and to a lesser extent even after 0.2 mg/kg physostigmine. No retention of this reaction was found 24 h after onetrial learning when physostigmine (0.5 mg/kg) was applied 8 min before the retention test. On the contrary the same physostigmine dose does not impair the retention of an overtrained (four times) passive avoidance reaction. Also retention of an overlearned active avoidance reaction (running to the safe part of the apparatus is not affected by 0.5 mg/kg physostigmine and only partly impaired by 1 mg/kg physostigmine. The functional significance of the hippocampal theta activity is discussed.

Effect of neuroactive drugs on production of fibrinolytic activity.

Neuroactive drugs were investigated for their ability to produce a blood plasma fibrinolysin in experimental animals. Following intravenous injections of these drugs, blood samples were drawn and the plasma studied for fibrinolytic activity as indicated by the Astrup fibrin plate technique. Drugs inducing a small degree of fibrinolytic activity in dogs were acetylcholine hydrochloride, epinephrine hydrochloride, carbamylcholine chloride, physostigmine salicylate and prostigmine methylsulfate. The possible mechanism of drug-induced fibrinolysin as compared with the biological activation of profibrinolysin is interpreted on the basis of stimulation and release of catecholamines resulting from stimulation of sympathetic ganglia and the adrenal medulla.