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PubMed2005

Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo-possible involvement of different mechanisms.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2D measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1-day or 2-weeks (twice a day) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine, perazine 10 mg kg(-1); chlorpromazine 3 mg kg(-1); haloperidol 0.3 mg kg(-1); risperidone 0.1 mg kg(-1); sertindole 0.05 mg kg(-1)), in the absence of the neuroleptics in vitro. Neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2D by competitive or mixed inhibition of the enzyme. Thioridazine (Ki=15 microM) was the most potent inhibitor of the rat CYP2D among the drugs studied, whose effect was more pronounced than that of the other neuroleptics tested: phenothiazines (Ki=18-23 microM), haloperidol (Ki=32 microM), sertindole (Ki=51 microM) or risperidone (Ki=165 microM). The investigated neuroleptics-when given to rats in vivo-also seemed to exert an inhibitory effect on CYP2D via other mechanisms. One-day exposure of rats to the classic neuroleptics decreased the activity of CYP2D in rat liver microsomes. After chronic treatment with the investigated neuroleptics, the decreased CYP2D activity produced by the phenothiazines was still maintained, while that caused by haloperidol diminished. Moreover, risperidone decreased the activity of that enzyme. The obtained results indicate drug- and time-dependent interactions between the investigated neuroleptics and the CYP2D subfamily of rat cytochrome P-450, which may proceed via different mechanisms: (1) competitive or mixed inhibition of CYP2D shown in vitro, the inhibitory effects of phenothiazines being stronger than those of haloperidol or atypical neuroleptics, but weaker than the effects of the respective drugs on human CYP2D6; (2) in vivo inhibition of CYP2D, produced by both 1-day and chronic treatment with phenothiazines, which suggests inactivation of enzyme by intermediate metabolites; (3) in vivo inhibition of CYP2D by risperidone, produced only by chronic treatment with the drug, which suggests its influence on the enzyme regulation.

Animals↗

PubMed2005

Determination of several psychiatric drugs in whole blood using capillary gas-liquid chromatography with nitrogen phosphorus detection: comparison of two solid phase extraction procedures.

A simple and reliable gas chromatographic method with nitrogen-phosphorus detection without derivatization was developed for the detection of several psychiatric drugs in whole blood as part of systematic toxicological analyses (STA). Drugs included mirtazapine, chlorpromazine, methotrimeprazine (levomepromazine), clothiapine, olanzapine, clozapine, haloperidol, and thioridazine. All drugs were studied at concentrations of 100-2,000 microg/L, except haloperidol that was studied at concentrations of 400-8,000 microg/L. In order to select the best blood purification procedure and therefore increase the signal to noise ratio we have compared two solid-phase extraction (SPE) columns, Chem Elut and Bond Elut Certify, for their recovery, precision, sensitivity and matrix purification efficiency. Recoveries for these drugs using Chem Elut columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 21-65%, with intra-assay and inter-assay precisions of less than 17% and 19%, respectively. Limits of detection (LODs) and limits of quantitation (LOQs) for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 62 to 161 microg/L and from 205 to 531 microg/L, respectively. LOD and LOQ for haloperidol were 442 and 1,458 microg/L, respectively. Recoveries of these compounds using Bond Elut Certify columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 44-97%, with intra-assay and inter-assay precisions of less than 7% and 14%, respectively. LODs and LOQs for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 37 to 66 microg/L and from 122 to 218 microg/L, respectively. LOD and LOQ for haloperidol were 156 and 515 microg/L, respectively. Linearity was observed in the studied range for all compounds with r(2) values of >0.999. The use of the mixed-mode bonded-silica Bond Elut Certify columns showed advantages comparing with Chem Elut columns for the screening of these psychotropic agents such as higher recoveries, cleaner extracts, better sensitivity, better precision and less solvent consumption and subsequent disposal.

Adult↗

PubMed2006

Quantitative determination of forty-eight antidepressants and antipsychotics in human serum by HPLC tandem mass spectrometry: a multi-level, single-sample approach.

This method describes the simultaneous determination of amisulpride, amitriptyline, aripiprazole, benperidol, chlorpromazine, chlorprothixene, citalopram, clomipramine, clozapine, desipramine, doxepin, fluoxetine, flupentixol, fluphenazine, fluvoxamine, haloperidol, hydroxyrisperidone, imipramine, levomepromazine, maprotiline, mianserine, mirtazapine, moclobemide, norclomipramine, nordoxepin, norfluoxetine, nortriptyline, O-desmethylvenlafaxine, olanzapine, opipramol, paroxetine, perazine, perphenazine, pimozide, pipamperone, quetiapine, reboxetine, risperidone, sertraline, sulpiride, thioridazine, trazodone, trimipramine, venlafaxine, viloxazine, ziprasidone, zotepine and zuclopenthixol with a single sample/triple injection approach. Drugs were assigned to subgroups covering low, medium and high concentrations (overall range of therapeutic levels to be considered: 0.5-2000 ng/mL) by further dilution of the supernatant obtained after the first protein precipitation. Chromatographic separation was necessary for isobaric mass fragments and performed on a monolithic C18 column (50mmx4.6mm) with methanol gradient and 5mM acetate buffer at pH 3.9. The injection interval was 8 min. A set of three internal standards was used for quantification of drugs with widely varying hydrophobicity. After electrospray ionization positive ion fragments were detected in the multiple reaction monitoring (MRM) mode with an API 4000 tandem mass spectrometer. Regression parameters of calibration curves and limits of quantification showed good covering of therapeutic and subtherapeutic ranges with an average correlation coefficient of 0.9988. Imprecision and inaccuracy measures were prepared for intra- and inter-assay comparisons at three concentration ranges in all subgroups. Average coefficients of variation were 6.1% for intra-assay and 7.4% for inter-assay comparisons, while average deviations from spiked concentrations were 4.8% for intra-assay and 4.2% for inter-assay comparisons, respectively. Recovery rates, measured as the percent recoveries of spiked serum samples against standard solutions without serum matrix, varied between 92 and 111%, with an average of 101%. As the only exception, the olanzapine response was much higher (185%) in serum matrix than in matrix-free controls.

Antidepressive Agents↗

PubMed2004

Atypical properties of several classes of antipsychotic drugs on the basis of differential induction of Fos-like immunoreactivity in the rat brain.

Acute administration of typical and atypical antipsychotics has been reported to induce regionally distinct patterns of c-Fos expression in the rat forebrain. Furthermore, atypical index, the difference in the extent of increased Fos-like immunoreactivity (Fos-LI) in the nucleus accumbens (NAc) shell versus the dorsolateral striatum (DLSt), has been proposed to classify antipsychotics into typical or atypical antipsychotics. The present study was conducted to investigate the atypical properties of 24 antipsychotics that are used in Japan and blonanserin, a novel 5-HT2A and D2 receptor antagonist. We systematically examined the effects of the drugs on Fos-LI in the NAc and DLSt in the rat brain using immunohistochemistry and calculated the atypical index, comparing with those of haloperidol and clozapine. Floropipamide, oxypertine, nemonapride, pimozide and mosapramine, as well as clozapine, olanzapine, quetiapine and risperidone, showed high positive atypical index. Zotepine, perospirone, sulpiride, moperone, sultopride, thioridazine, carpipramine, clocapramine and blonanserin showed moderate ones. In contrast, fluphenazine, bromperidol, timiperone, spiperone, propericiazine, perphenazine, chlorpromazine and levomepromazine had negative atypical index like haloperidol. These results suggest that not only so-called atypical antipsychotics, but also several conventional drugs, possess atypical properties.

Animals↗

PubMed2002

Neuroleptic malignant syndrome complicated by massive intestinal bleeding in a patient with chronic renal failure.

A patient with chronic renal failure (CRF) developed neuroleptic malignant syndrome (NMS) after administration of risperidone and levomepromazine. In addition to the typical symptoms of NMS, massive intestinal bleeding was observed during the episode. This report suggests that NMS in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication.

Adult↗

PubMed2002

Bile analysis of drugs in postmortem cases.

Bile is, in certain cases, collected together with blood from different sites (heart, brain, femoral), urine and other organs or matrices. This study reports comparative results obtained from the analysis of blood and bile for different drugs found: acetaminophen, amphetamine and related compounds, several antidepressants, several benzodiazepines, cocaine and its metabolites, dextropropoxyphene and its metabolite, hydroxyzine, methadone and metabolite, morphine and codeine, levomepromazine, thioridazine, propranolol, tramadol and its metabolite. Several findings are presented: (1) There were no significant differences in the levels of the compounds among the samples of blood obtained from different sites. (2) Levels in bile are generally several fold higher than those in blood. The mean bile to blood ratios vary from about 1 (for acetaminophen, amphetamine) to about 2000 (for desmethylclobazam). (3) In certain cases (16 over 44), although the drug or its metabolite was not detected in blood from different sites, it was detected in bile. As other authors had advocated, it is very useful to ask the pathologist to take the gall bladder with its contents together with the other samples, in order that the sample of bile can be used in the comprehensive toxicological analysis and therefore be complementary to the other fluids or matrices. An additional advantage for using bile is that the concentrations of drugs or their metabolites are generally several fold higher than their blood concentrations.

Bile↗

PubMed1999

[Severe intoxication probably from olanzapine (Zyprexa). Beneficial effect of glucagon].

We report the case of a 43-year-old schizophrenic who sustained, after 12 days of treatment including olanzapine (20 mg.day-1), carbamazepine, levomepromazine and alprazolan, a severe shock with bradycardia (HR: 40 b.min-1), circulatory collapse (SAP: 60 mmHg), hypothermia (T: 27 degrees C), coma and disseminated intravascular coagulation. A significant improvement was obtained with high doses of intravenous glucagon, whereas the normalization of central temperature, atropine, adrenaline and volume loading had been inefficient. Olanzapine, alone of associated with other psychotropics, could cause severe circulatory collapse with hypothermia and coma responding to a treatment including glucagon.

Adult↗

PubMed2000

Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions.

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (-)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT(2) receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT(2) receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.

Animals↗

PubMed2001

Different fatal toxicity of neuroleptics identified by autopsy.

Autopsies and toxicological analyses at the Institute of Forensic Medicine revealed 85 fatal intoxications with neuroleptics in Vienna from 1991 to 1997. A total of 17 cases were linked to a single neuroleptic (NL) alone, while 68 deaths were attributed to a combination of NLs with other drugs. The most frequently detected agent was prothipendyl (n=41). During the study period the number of defined daily doses of high-potency NLs prescribed increased significantly (P< or =0.001) due to increased prescribing of new atypical antipsychotics. The quantity of intermediate- and low-potency NLs dispensed remained stable. The most frequently prescribed NL was haloperidol. The relative toxicities of different NLs were calculated by dividing the number of deaths caused by this NL into the number of defined daily doses prescribed in the observation period (f-value). Single-substance intoxications and multiple-substance intoxications were distinguished. The highest f-values were associated with low-potency NLs, especially with prothipendyl, chlorprothixene and levomepromazine. Low f-values were found for the group of high-potency NLs, including flupentixol, fluphenazine, haloperidol and pimozide, as well as olanzapine. Compared to the f-values for all NLs prescribed, f-values for low-potency NLs were shown to be significantly higher concerning single-substance intoxications (P< or = 0.05) and multiple-substance intoxications (P < or = 0.001), while f-values for high-potency NLs were significantly lower (P< or = 0.05 and P< or = 0.001). We are not aware of the psychiatric diagnoses in our post-mortem sample. However, the present results indicate that careless use of low-potent NLs should be avoided in patients with a potential risk of accidental or suicidal overdose.

Adult↗

PubMedDate not supplied

A TLC visualisation reagent for dimethylamphetamine and other abused tertiary amines.

Application of citric acid/acetic anhydride reagent (CAR), a colour reagent selective for tertiary amines in solution, improves detection of abused tertiary amino drugs on the TLC plate. The plate is pretreated by a brief immersion in phosphoric acid/acetone solution to suppress colouration. After suppressing, the plate is sprayed with CAR and heated at 100 degrees C, causing tertiary amines to turn red purple within 3 minutes. The sensitivity of this new CAR method is 2.5 to 15-times greater than that of conventional detection with Dragendorff reagent for some of the tertiary amines dimethylamphetamine, methylephedrine, levomepromazine, chlorpromazine, caffeine, theophylline, theobromine and nicotine. This present method provides rapid TLC detection of abused tertiary amino drugs such as phenethylamine, phenothiazine, xanthine derivative, nicotine and narcotics.

Acetic Anhydrides↗

PubMed2003

Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions.

A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma after liquid-liquid extraction has been developed. The limit of quantitation was 5 nmol/L, and the inter-day coefficient of variation was less than 8% for both compounds. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were 96.8 and 99.4%, with an intra-day coefficient of variation of under 5 and 6%, respectively. Studies of analytical interference showed that the most commonly co-administered antidepressants and benzodiazepines did not interfere. The method was used for the determination of the plasma concentrations of a schizophrenic patient treated daily with an oral dose of 4.5 mg risperidone. The patient suffered severe extrapyramidal side-effects after adding risperidone to his previous medication of haloperidol and levomepromazine. The risperidone plasma concentration was well above the average (182 nmol/L), which suggests that a pharmacokinetic interaction occurred, presumably due to inhibition of the enzyme CYP2D6.

Adult↗

PubMed2006

Periventricular leukomalacia and retinopathy in a term infant born to a mother with asthma.

A male child, born at 37+5 gestational weeks (GWs) (birthweight 2000g) after intrauterine growth retardation (IUG; -3 SD), to a mother treated during pregnancy for asthma, developed periventricular leukomalacia and retinopathy with total retinal detachment in the left eye and partial detachment in the right eye. Apart from basic asthma treatment with terbutalin, budesonid, and fenoterolhydrobromid throughout the pregnancy, she was treated with intravenous or oral cortisone for 6.5 weeks from 28+5 GWs. In addition she developed deep venous thrombosis at 29 GWs and was treated with heparin until delivery. Psychotic symptoms during the 31st GW were treated with diazepam, haloperidol, and levomepromazin. Functional sequelae for the child were visual impairment (visual acuity 5/60), uneven intellectual profile (Wechsler Pre-school and Primary Scale of Intelligence, Verbal IQ 94 and Performance IQ 32 at 8y of age), and autistic-like behaviour. The possibility that pre- and perinatal risk factors (e.g. severe maternal illness, IUGR, and cortisone treatment) in a term infant may create conditions for developing eye and brain pathologies commonly closely related to preterm birth should be considered.

Anti-Asthmatic Agents↗

PubMed2003

Effect of phenothiazines on protein kinase C- and calcium-dependent activation of peritoneal macrophages.

The effects of some phenothiazines (promethazine, PMZ; chlorpromazine, CPZ; levomepromazine, LVPZ; thioridazine, TRDZ; trifluoperazine, TFPZ) on the activation and viability of rat peritoneal macrophages were investigated. The macrophage activation was estimated by measuring of luminol-dependent chemiluminescence, induced by phorbol-12-myristate-13-acetate (PMA) (a protein kinase C activator) or calcium ionophore A23187. The viability of macrophages was determined using ATP bioluminescence as a criterion of cell viability. It was observed that all drugs, in concentrations higher than 1 micromol/L, markedly decreased the chemiluminescent index of PMA-activated or A23187-activated macrophages. The inhibitory effect was dose-dependent. It was better expressed in the case of CPZ, followed by TFPZ and TRDZ, and less expressed in the case of PMZ and LVPZ. The suppression of chemiluminescence of PMA-/A23187-activated macrophages by phenothiazines was not a result of their cytotoxic effect. Moreover, it was found that all drugs dose-dependently enhanced the viability of macrophages, estimated by ATP production. The inhibitory effects of phenothiazines on the chemiluminescence of PMA-/A23187-activated macrophages were greater than their ability to decrease KO2-induced chemiluminescence as a result of interaction with superoxide radicals. It may be supposed that the inhibitory effect of phenothiazines on PMA-/A23187-induced chemiluminescence of macrophages is a result not only of interaction between drugs and superoxide radicals, generated during the "oxidative burst" of activated cells. Presumably the drugs have an immunomodulating effect on rat peritoneal macrophages.

Adjuvants, Immunologic↗

PubMed1991

Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine.

The formation of three oxidative metabolites of imipramine, N-desmethylimipramine (desipramine), 2-hydroxyimipramine, and 10-hydroxyimipramine was studied in microsomes of an extensive metabolizer liver (KDL 26) and of a poor metabolizer liver (KDL 31) and in a homogenate of COS-1 cells in which the P450IID6 complementary deoxyribonucleic acid had been expressed. The following data support the role of P450IID6 in the 2-hydroxylation of imipramine: (1) The formation of 2-hydroxyimipramine was reduced to less than 20% of the control value when microsomes were incubated with serum containing inhibitory antibodies against P450IID6 (anti-LKM1), whereas no effect was seen with regard to formation of desipramine and 10-hydroxyimipramine, (2) quinidine and levomepromazine were potent competitive inhibitors of 2-hydroxylation of imipramine (ki approximately 70 nmol/L, and ki approximately 1 mumol/L, respectively) but had no effect on N-demethylation and 10-hydroxylation, and (3) in the COS-1 cell, homogenate, 10-hydroxyimipramine, 2-hydroxyimipramine, and desipramine were formed at rates of 48, 164, and 256 pmol per hour per milligram of homogenate protein, respectively. The P450 isozymes that are responsible for N-demethylation and 10-hydroxylation of imipramine have not yet been identified.

Antibodies↗

PubMed1999

Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil.

1. Power spectra (0-30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug-related differential display of the power spectra, the profile of EEG effects. 2. The profiles of a range of antipsychotic agents of different classes were compared. Haloperidol (0.5 mg kg-1 and 1 mg kg-1 s.c., peak 8 - 12 Hz), chlorpromazine (0.5 mg kg-1, i. p., peak 8 Hz), levomepromazine (1 mg kg-1, i.p., peak 8 Hz), quetiapine (2.5 mg kg-1, s.c., peak 9 - 12 Hz), sertindole (2.5 mg kg-1, s.c., peak 6 - 14 Hz), risperidone (0.5 and 1 mg kg-1 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg-1, s.c., peak 8 Hz) and MDL100907 (0.01 mg kg-1 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked differences between the individual profile of EEG effects for each drug. 3. In contrast, the benzamides, sulpiride (7.5 and 15 mg kg-1 i.p.), and amisulpiride (1 and 15 mg kg-1 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg-1 i.p.), caused an initial peak at 9 Hz, but the effects of raclopride desynchronized over a 3 h time period. 4 Modafinil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4. Hz. Modafinil (62.4 mg kg-1, i.p.) selectively antagonized the effects of clozapine, but did not antagonize the effects of raclopride. 5. Different pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a specific interaction between modafinil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

Animals↗

PubMed1998

Effects of metaraminol bitartrate on intraocular pressure in dogs under halothane anesthesia.

The effects of metaraminol bitartrate on intraocular pressure (IOP) were studied in dogs anesthetized with halothane. Forty-five healthy, adult, mixed-breed dogs, of both sexes, were divided into three groups of 15 dogs each (GI, GII and GIII) and maintained under general anesthesia with halothane after tranquilization with levomepromazine and induction with thiopental. Saline (0.9%) was administered intravenously (IV) to GI through continuous infusion, at a velocity of 0.125 mL kg-1 min-1. GII and GIII received metaraminol 0.004% IV, at a dose of 5 &mgr;g kg-1 min-1, at 0.125 mL kg-1 min-1 and at a dose of 2 &mgr;g kg-1 min-1, at 0.06 mL kg-1 min-1, respectively. IOP was measured by applanation tonometry (Tono-Pen) before and during anesthesia. Results showed that IOP decreased in GI, increased in GII, and remained at basal levels in GIII. Continuous infusion of metaraminol at 2 &mgr;g kg min-1 maintained IOP at pretest levels, while infusion at 5 &mgr;g kg-1 min-1 produced an elevation of IOP.

Journal Article↗

PubMed1988

[Delirium syndrome in biperiden poisoning].

We report on two cases of self-induced intoxication with the anticholinergic agent biperiden (oral ingestion of at least 200 mgs. in case 1, and of 60 mgs. in combination with 300-400 mgs levomepromazine in case 2). An acute delirious state and other somatic symptoms of a toxic anticholinergic action dominated the clinical picture. Serial measurements of biperiden serum levels revealed values up to 50-fold (case 1) and 15-fold (case 2) of those usually observed under therapeutic doses of biperiden. In both cases, the intoxication was controlled by the application of physostigmine and general therapeutic measures. We discuss the prognosis of biperiden intoxications, and the clinical symptomatology and therapy of drug-induced anticholinergic syndromes.

Adult↗

PubMed1986

[A case of malignant neuroleptic syndrome with rhabdomyolysis and a therapeutic trial using physostigmine].

We report the case of a 22-year-old schizophrenic patient who developed a neuroleptic malignant syndrome under treatment with Benperidol, Levomepromazin and Biperiden. Clinical signs were: fever, rigidity, altered consciousness and rhabdomyolysis of hip-abductors. Intravenous injection of physostigmine led to clearing of consciousness, whereas there seemed to be no impact on fever and rigidity.

Adult↗