Acute-onset psychosis induced by a therapeutic dose of parenteral hyoscine butylbromide: A case report

Anticholinergic medications are frequently prescribed for gastrointestinal and genitourinary spasms. Psychosis, when present, results from anticholinergic overdose or toxicity. In the literature, anticholinergic-induced psychosis at therapeutic doses in patients with normal cognition is extremely uncommon. Here, we describe the case of a 28-year-old female who presented with auditory and visual hallucinations, stereotypy, and agitation after receiving a single intramuscular injection of 20 mg hyoscine butylbromide for dysmenorrhea. Even though it is rare for a therapeutic dose of hyoscine butylbromide to cause psychosis, clinicians should maintain a high index of suspicion and be cautious when administering or prescribing anticholinergics.

Effectiveness of low dose physostigmine for dose reduction of morphine in pain management

Background: This is an interventional study, undertaken in the experimental animal models for the evaluation of the antinociceptive potential of Physostigmine and its combination with Morphine at their sub-analgesic doses. The objective of the study was to evaluate the antinociceptive potential of Physostigmine alone and in combination with morphine.Methods: Antinociceptive effect of Physostigmine in three graded doses (50, 100 and 200 ?g/kg) and combination of Physostigmine at low dose (50 ?g/kg) with sub-analgesic dose of Morphine (0.1 mg/kg) and Morphine in analgesic dose (1 mg/kg) was evaluated by using Hot Water Bath method in albino rats.Results: Comparison of maximal possible effect in percentage (MPE in %) between groups at 90 minutes in control, Morphine, Physostigmine in 50, 100, 200 ?g/ kg doses and combination group respectively, demonstrated significant difference (p <0.001) when compared by one way ANOVA test. There was no much increase in maximal possible effect in the tail withdrawal latency in Physostigmine 50 ?g/kg (SC) treatment at 90 min (5.50±0.88) in comparison to control (NS) treatment group. Combination treatment of low doses of both Physostigmine 50 ?g/kg + Morphine 0.1 mg/kg increased in maximal possible effect the tail withdrawal latency 90 min (53.87±1.38) in-comparison to control (NS) treatment group (6.17±0.92).Conclusions: Physostigmine is more potent antinociceptive than Morphine and Physostigmine potentiated the antinociceptive activity of low dose of standard drug Morphine.

Mary Broadfoot Walker: 83 years since a historical discovery / Mary Broadfoot Walker: 83 anos desde uma descoberta histórica

ABSTRACT Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.

RESUMO Mary Broadfoot Walker foi uma médica escocesa que em 1935 descreveu em grande detalhe o efeito de uma droga anticolinesterásica (fisostigmina) nos sinais e sintomas da myasthenia gravis. Um filme original com cinco minutos de duração está disponível online e a reação cética dos colegas médicos contemporâneos de Mary é compreensível dado o drástico efeito terapêutico mostrado neste filme. O que Mary Walker nos ensinou mais de oito décadas atrás continua a ser a base de um teste diagnóstico farmacológico e do tratamento da myasthenia gravis.

Maytenus distichophylla and Salacia crassifolia: source of products with potential acetylcholinesterase inhibition

ABSTRACT The phytochemical study of the extract leaves from Maytenus distichophylla Mart. and Salacia crassifolia (Mart. ex Schult.) G. Don, Celastraceae, resulted in the isolation of 3-oxofriedelane, 3β-hydroxyfriedelane, 3β,24-dihydroxyfriedelane, 3-oxo-28,29-dihydroxyfriedelane, two mixtures of pentacyclic triterpenes (α-amyrin with β-amyrin and 3β-stearyloxy-urs-12-ene with 3β-stearyloxy-olean-12-ene), 3β-palmityloxy-urs-12-ene, the steroid β-sitosterol and its glycosylated derivative β-glucosyl-β-sitosterol, tritriacontanoic acid and the natural polymer gutta percha. The chemical structures of these constituents were established by IR, 1H and 13C NMR spectral data. Crude extracts, the mixtures of triterpenes and the isolated constituents were subjected to in vitro acetylcholinesterase inhibitory evaluation. Acetylcholinesterase inhibitory effect was observed for crude chloroform extract leaves from M. distichophylla (100%) and S. crassifolia (97.93 ± 5.63%) and for the triterpenes 3β,24-dihydroxyfriedelane (99.05 ± 1.12%), 3-oxo-28,29-dihydroxyfriedelane (90.59 ± 3.76%) and 3β-palmityloxy-urs-12-ene (97.93 ± 1.47%). The percent inhibitions induced by these natural products were very similar to those produced by physostigmine (93.94 ± 2.10%) a standard acetylcholinesterase inhibitor. Therefore, these results open perspectives for the use of these species as source of compounds with similar physostigmine pharmacological effect.

Differences between Physostigmine- and Yohimbine-induced States Are Visualized in Canonical Space Constructed from EEG during Natural Sleep-wake Cycle in Rats

Although quantitative EEG parameters, such as spectral band powers, are sensitive to centrally acting drugs in dose- and time-related manners, changes of the EEG parameters are redundant. It is desirable to reduce multiple EEG parameters to a few components that can be manageable in a real space as well as be considered as parameters representing drug effects. We calculated factor loadings from normalized values of eight relative band powers (powers of 0.5, 1.0~2.0, 2.5~4.0, 4.5~5.5, 6.0~8.0, 8.5~12.0, 12.5~24.5, and 25~49.5 Hz bands expressed as ratios of the power of 0.5-49.5 Hz band) of EEG during pre-drug periods (11:00~12:00) by factor analysis and constructed a two-dimensional canonical space (reference canonical space) by canonical correlation analysis. Eight relative band powers of EEG produced by either physostigmine or yohimbine were reduced to two canonical scores in the reference canonical space. While changes of the band powers produced by physostigmine and yohimbine were too redundant to describe the difference between two drugs, locations of two drugs in the reference canonical space represented the difference between two drug's effects on EEG. Because the distance between two locations in the canonical space (Mahalanobis distance) indicates the magnitude of difference between two different sets of EEG parameters statistically, the canonical scores and the distance may be used to quantitatively and qualitatively describe the dose-dependent and time-dependent effects and also tell similarity and dissimilarity among effects. Then, the combination of power spectral analysis and statistical analysis may help to classify actions of centrally acting drugs.

A Case of Seizure in Diphenhydramine Overdose

A 21-year-old woman ingested 1,250 mg of diphenhydramine in a single overdose. Diphenhydramine, a rare ingredient in over-the-counter medication, is used to treat insomnia in Korea. Toxicity is usually limited to anticholinergic symptoms. The standard approach to therapy for the treatment of diphenhydramine overdose is supportive care, including physostigmines and sodium bicarbonates. Here, we review the literature and for the first time report a case of acute diphenhydramine overdosage in Korea, complicated with seizures.

Correlative Changes of Endothelial Nitric Oxide Synthase and Choline Acetyltransferase in the Hippocampus after Exercise / 대한해부학회지

We found that the expression and activity of endothelial nitric oxide synthase (eNOS) is increased in the hippocampus during exercise (Moon et al., 2006). However, the upstream regulatory factor on the eNOS expression in the hippocampus during exercise has not been clear. In this study, we investigate the role of acetylcholine (ACh) as a regulatory factor for the eNOS expression and activity in the hippocampus during exercise. The results of the present study demonstrate that voluntary wheel running exercise for two weeks increases the expression and activity eNOS. In addition, choline acetyltransferase (ChAT) immnunoreacitvity within the hippocampus was increased after 2 weeks exercise. We further found that the upregulation of ACh with treatment of physostigmine, a booster of ACh releasing, increase the expression and activity of eNOS in the hippocampus. This present study provides the evidence that the upregulation of eNOS during exercise may be mediated by ACh in the hippocampus.

Role of Endogenous Arginine Vasopressin in Physostigmine Induced Hypothermic Response in Rats / 医学研究杂志

Objective To study the subcutaneous injection of physostigmine (PHY) inducing hypothermic response and its relationship with endogenous arginine vasopressin ( AVP). Methods Core temperature and motor activity were monitored by telemetry in female rats maintained at an ambient temperature of 25℃. Tail skin temperature was measured at 30 min intervals with digital thermometer. The central cholinergic antagonist, scopolamine ( lmg/kg ) and AVP V_1 receptor antagonist were administered during the period of PHY (0. 25mg/kg) induced hypothermia. Plasma AVP concentration was measured at 50 min after administration of PHY. Results Subcutaneous injection of PHY led to a rapid reduction in core temperature concomitant with a marked elevation in the heat loss from the tail. The hypothermic response of PHY was blocked by scopolamine and AVP V1 antagonist. Plasma AVP concentration increased markedly at 50 min after PHY. Conclusion The results suggest that endogenous A VP could be involved in PHY -induced hypothermic processes. This may be a novel mechanisms of action for a reversible anticholinesterase drug ( such as PHY ) - induced hypothermia.

Influence of Tacrine on Catecholamine Secretion in the Perfused Rat Adrenal Gland

The present study was designed to clarify whether tacrine affects the release of catecholamines (CA) from the isolated perfused model of rat adrenal gland or not and to elucidate the mechanism of its action. Tacrine (3 X 10(-5)~3 X 10(-4) M) perfused into an adrenal vein for 60 min inhibited CA secretory responses evoked by ACh (5.32 X 10(-3) M), DMPP (a selective neuronal nicotinic agonist, 10(-4) M for 2 min) and McN-A-343 (a selective muscarinic M1-agonist, 10(-4) M for 2 min) in relatively dose- and time- dependent manners. However, tacrine failed to affect CA secretion by high K+ (5.6 X 10(-2) M). Tacrine itself at concentrations used in the present experiments did not also affect spontaneous CA output. Furthermore, in the presence of tacrine (10(-4) M), CA secretory responses evoked by Bay-K-8644 (an activator of L-type Ca2+ channels, 10(-4) M), but not by cyclopiazonic acid (an inhibitor of cytoplasmic Ca2+-ATPase, 10(-4) M), was relatively time-dependently attenuated. Also, physostigmine (10(-4) M), given into the adrenal gland for 60 min, depressed CA secretory responses evoked by ACh, McN-A-343 and DMPP while did not affect that evoked by high K+. Collectively, these results obtained from the present study demonstrate that tacrine greatly inhibits CA secretion from the perfused rat adrenal gland evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors, but does fail to affect that by direct membrane-depolarization. It is suggested that this inhibitory effect of tacrine may be exerted by blocking both the calcium influx into the rat adrenal medullary chromaffin cells without Ca2+ release from the cytoplasmic calcium store, that is relevant to the cholinergic blockade. Also, the mode of action between tacrine and physostigmine in rat adrenomedullary CA secretion seems to be similar.

Central Anticholinergic Syndrome Confirmed with Physostigmine after Open Heart Surgery / 대한마취과학회지

Central anticholinergic syndrome (CAS) can be caused by many anesthetic drugs. Early diagnosis and treatment are very important because untreated CAS may result in a life-threatening condition. Physostigmine, though not available in Korea, is the only drug which can confirm and treat CAS. A forty five year old patient underwent open heart surgery due to patent foramen ovale. Anesthetic agents which were used for anesthetic induction and maintenance were midazolam, fentanyl and isoflurane. Following anesthesia, he showed irritated and excited behavior and delayed recovery from anesthesia more than 3 h after operation in the ICU, even though flumazenil and naloxone were given to rule out the residual anesthetic effect. After physostigmine 4 mg was administered intravenously, he calmed down and became more coherent. There was no evidence of neurologic deficit in the following brain MRI and neurologic examination. We report the first case of CAS confirmed with physostigmine in Korea.

Antinociceptive effect of physostigmine and interaction of intravenous physostigmine with intrathecal morphine in rats / 中国新药与临床杂志

AIM: To investigate the antinociceptive effect of anticholinesterase agent physostigmine at different postoperative time, and the interaction of intravenous physostigmine with intrathecal morphine in rats. METHODS: Six groups of rats were operated on for intrathecal and intravenous catheterization. Nociceptive responses of hind paws of each animal were measured with "plantar stimulation" test 1-3 h and 3 d postoperatively. Animals received intravenous (iv) physostigmine, intrathecal (ith) morphine, or combination of both. The antinociceptive effect of each group was converted to the percent maximum possible effect (% MPE). RESULTS: Administration of physostigmine 1-3 h after operation resulted in dramatic increase in % MPE. The effects of combinations of iv physostigmine and ith morphine were more pronounced at early postoperative time. The potency of low dose combination was significantly greater than that of double doses of both drugs. The % MPE of the observed effects of all combinations was significantly higher than that of the expected additive effects. CONCLUSION: The antinociception of physostigmine occurs at early postoperative time. The interaction of iv physostigmine with ith morphine indicates their synergistic effect.

Suppressive Effects of Kambaku-taiso-to on the Yawning Induced by Cholinergic Agonists / 日本東洋医学雑誌

The present experiments were performed to investigate effects of a Kampo (Japanese herbal) medicine, Kambaku-taiso-to (Gan-mai-da-zao-tang), on incidence of yawning in rats. Physostigmine, a cholinesterase inhibitor, 0.05-0.1mg/kg s. c., induced yawning responses with a marked effect at 0.05mg/kg. Pilocarpine, a muscarinic receptor agonist, 1-2mg/kg s. c., also induced yawning responses, the maximum effect being observed at a dose of 2mg/kg. Talipexole, a dopaminergic D-2 receptor agonist, 0.02mg/kg s. c., also induced yawning. Kambaku-taiso-to, 250-1, 000mg/kg, was orally administered 30min before injection of physostigmine, pilocarpine or talipexole. The yawning induced by both cholinergic and dopaminergic agents was reduced in a dose-dependent manner by Kambaku-taiso-to. All the yawning responses to cholinergic and dopaminergic agents were also reduced by rauwolscine 0.5mg/kg, yohimbine 2.5mg/kg, α-2 adrenoceptor antagonists, and by scopolamine 0.5mg/kg—muscarinic receptor antagonist. The present findings thus suggest that Kambaku-taiso-to exerts a suppressive effect on the incidence of yawning, and dopaminergic and cholinergic suppression and the indirect suppressive mechanism mediated by the central adrenergic nerve are associated with this suppression.

The Effect of Physostigmine on Arousal and Respiration after General Anesthesia with Enflurane / 대한마취과학회지

Physostigmine has been used to counteract somnolence or coma induced by different types of pharmacological agent, such as anticholinergics, opioids, ketamine, tricyclic antidepressants and inhalational anesthetics. In this study, we have assessed the effect of physostigmine on arousal and respiration after 50% N2O-50% O2-enflurane general anesthesia under controlled condition such as no premedication, no neuromuscular blockade, same operative procedure and duration. Fifty healthy gynecologic patients scheduled for dilatation & curettage and cervical cone biopsy were divided randomly into two groups such as control group and physostigmine group. In physostigmine group, 0.02 mg/kg of physostigmine was administered intravenously at the end of operation. We evaluated the recovery time of pain response, eye opening on verbal command and orientation after the end of operation. We also checked the end-tidal enflurane concentration with SARACAP spectrometry. Blood pressure, pulse rate, respiration rate and tidal volume were checked at the end of operation and at the time of each recovery parameters returned. The results were as follows; first, pain response time was 5.1+/-2.4 min in control group compared with 3.5+/-2.1 min in physostigmine group. Second, on simple order to patients, eye opening time was 8.5+/-2.3 min in control group compared with 6.5+/-2.1 min in physostigmine group. Third, recovery of orientation to time, place and person was 9.7+/-2.8 min in control group compared with 7.5+/-2.1 min in physostigmine group. Fourth, there was no significant difference in respiratory parameters between the two groups. But there was no significant difference in end-tidal enflurane concentration between the two groups inspite of rapid recovery time in physostigmine group. In conclusion, 0.02mg/kg of physostigmine has the effect of early arousal after enflurane anesthesia without specific problems.

Chemical ejaculation using physostigmine in anejaculatory spinal cord injury patients / 대한비뇨기과학회지

We tried subcutaneous physostigmine 31 times in 24 spinal cord injured patients who had lost ejaculatory capacity. Normal semens were obtained in 4 patients(6.7 %), subnormal semen in 1 patient(4.2 %), a few sperms in 5 patients(20.8 %), and no sperm in 14 patients(58.3%). Sperm appearance rate was 41.7%. Patients with injuries in cervical and upper thoracic levels ejaculated successfully mere frequently than those with injuries in lower thoracic and lumbar levels. The results or T, L1, L2 injured patients were not successful. Side effects included nausea and vomiting (91.7%), dizziness(45.8%) and headache(25.0%), but all patients could tolerate them. Significant adverse effects, particularly autonomic dysreflexia, were not found. Artificial uterine inseminations with sperms induced by subcutaneous physostigmine were performed in 3 cases, and all of these attempts were successful. We have 3 live births. In conclusion, subcutaneous physostigmine for provoking ejaculation in anejaculatory spinal cord injury is cheap, easy to be performed and has no significant side effect.

The Effects of Physostigmine on Arousal after Laryngomicroscopic surgery / 대한마취과학회지

Physostigmine has been used to counteract somnolence or coma induced by different types of phamacological agent, such as anticholinergics, opioids, ketamine and tricyclic antidepressants. In this study, we have assesed the effects of physostigmine on arousal after laryngomicroscopic surgery under enflurane-N2O general anesthesia and the effects of muscle relaxants. Forty patients were divided randomly into four groups such as I (succinylcholine only), II (vecuronium only), III(succinylcholine and physostigmine) and IV(vecuronium and physostigmine). Physostigmine 1mg was administered intravenously at the end of operation. We evaluated the recovery time of spontaneous respiration, gag reflex, pain response, extubation, eye opening on command and orientation after the end of operation. We also observed the end tidal CO2 and expired enflurane concentration with SARA(R) spectrometry at the end of operation and at the time of each recovery parameters returned . Our results revealed that physostigmine groups(group III and IV) were recovered more rapidly in the recovery time of eye opening to verbal command and orientation than non-physostigmine groups(group I and II ). But there was no difference in recovery time of spontaneous respiration, gag reflex, pain response and extubation. Therefore, we concluded that physostigmine 1 mg, i.v. has the effects of early arousal after short and deep general anesthesia and it did not show any specific complications such as bradycardia, bronchospasm, nausea and vomiting.

The mechanisms of protective effects of ginseng root saponins on immunity in heat-stressed mice / 中国药理学通报

The peripheral blood T- lymphocyte percentage, lympocyte percentage in white blood cell (WBC) of mice in heat environment (45C, 15 min) were diminished, and serum corticosterone increased. Ginseng root saponins (GRS) 50, 100 mg/kg were administered ip at 15 min before the heat-stress, the suppression of peripheral blood T-lymphocyte percentage were prevented, but could not inhibit the increase ofserum corticosterone. GRS 50mg?kg-1ip could inhibit the redution of peripheral lymphocyte percentage. GRS 50mg?kg-1 ,reserpine 0.5mg? kg-1or physostigmine salicylate 0.3 mg?kg-1ip abolished the inhibiting effect of heat-stress on DTH reaction in mice.