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PubMed1979

Ethopropazine and benztropine in neuroleptic-induced parkinsonism.

In a 12-week controlled study ethopropazine was compared to benztropine in the treatment of parkinsonism induced by fluphenazine enanthate in 60 schizophrenic outpatients. Ethopropazine and benztropine were found to be equally effective in controlling parkinsonian symptoms and were as efficacious as procyclidine, their previous antiparkinsonian drug. However, benztropine treated patients had a significant increase in tardive dyskinesia compared to their condition during procyclindine treatment, and significantly more anxiety and depression than ethopropazine treated patients. This suggests that benztropine is not the anticholinergic drug of choice in the treatment of neuroleptic-induced parkinsonian symptoms, because of its more toxic central and peripheral atropinic effect.

Adult↗
PubMedDate not supplied

[Anti-epileptic and side effects of Didepil].

UNLABELLED: The action of the new antiepileptic preparation Didepil which is a combination of the anticholinergic agent procyclidine (dl-1-cyclohexyl-1-phenyl-3-pyrolidinopropane-1-ol hydrochloride) with phenobarbitone was evaluated in a group of 20 patients of either sex, mean age 28.5 years. These patients had mostly (14 cases) two types of seizures occurring up to several times daily. The mean duration of epilepsy was 12.5 years, the aetiology of the disease was different, and the patients were usually refractory to previously used drugs. Didepil was administered during 3 months, on the average, in doses of 3--4 tablets daily as the only antiepileptic drug or in combination with other anticonvulsants. The duration of follow-up of the patients before, during and after treatment was from 6 to 15 months. In each repeated EEG investigations, biochemical investigation of the blood, liver function tests, and urine analysis were performed. RESULTS: improvement was observed in cases of grand mal as well as temporal lobe seizures in 70% of patients, EEG improvement was found in 50% of patients. Side effects including oral dryness, accomodation disturbances developed in 17 patients but were usually slight and transient, in only 4 cases they were sufficiently severe as to justify reduction of dosage. Improvement of mood and contact with surroundings was noted in 60% of cases. CONCLUSIONS: Didepil seems to be an effective antiepileptic agent in maximal generalized seizures as well as in temporal lobe seizures.

Adolescent↗
PubMed2000

Anticholinergic medication for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Neuroleptic medication is used extensively to treat people with chronic mental illnesses. However, it is associated with a wide range of adverse effects, including movement disorders. Because of this, many acutely psychotic patients being treated with neuroleptic medication also receive anticholinergic drugs in order to reduce some of the associated movement side-effects. OBJECTIVES: To determine whether the use or the withdrawal of anticholinergic drugs (benzhexol or benztropine or biperiden or orphenadrine or procyclidine or scopolamine or trihexylphenidyl) were clinically effective for the treatment of people with both neuroleptic-induced TD and schizophrenia or other chronic mental illnesses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), Cochrane Schizophrenia Group's Register of trials (1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995), PsycLIT (1974-1995), and SCISEARCH (1995) were undertaken. References of all identified studies were searched for further trial citations. Principle authors of trials were contacted. SELECTION CRITERIA: Reports identified in the search were included if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia or other chronic mental illness who had been randomly allocated to either an anticholinergic agent or to a placebo (or no intervention). DATA COLLECTION AND ANALYSIS: No data could be extracted from the seven randomised controlled trials identified. MAIN RESULTS: No data were synthesized. The authors have been contacted to provide the relevant information. Two studies were excluded because no data are available and six others are still awaiting further information from the authors. REVIEWER'S CONCLUSIONS: Based on currently available information, no confident statement can be made about the effectiveness of anticholinergics to treat people with neuroleptic-induced tardive dyskinesia. The same applies for the withdrawal of such medications. Whether the withdrawal of anticholinergics may benefit people with neuroleptic-induced TD, this should be evaluated in a parallel-group, placebo-controlled randomised trial, with adequate sample size and at least 6 weeks of follow up.

Antipsychotic Agents↗
PubMed2001

Combination anticonvulsant treatment of soman-induced seizures.

These studies investigated the effectiveness of combination treatment with a benzodiazepine and an anticholinergic drug against soman-induced seizures. The anticholinergic drugs considered were biperiden, scopolamine, trihexaphenidyl, and procyclidine; the benzodiazepines were diazepam and midazolam. Male guinea pigs were implanted surgically with cortical screw electrodes. Electrocorticograms were displayed continually and recorded on a computerized electroencephalographic system. Pyridostigmine (0.026 mg x kg(-1), i.m.) was injected as a pretreatment to inhibit red blood cell acetylcholinesterase by 30-40%. Thirty minutes after pyridostigmine, 2 x LD50 (56 microg x kg(-1)) of soman was injected s.c., followed 1 min later by i.m. treatment with atropine (2 mg x kg(-1)) + 2-PAM (25 mg x kg(-1)). Electrographic seizures occurred in all animals. Anticonvulsant treatment combinations were administered i.m. at 5 or 40 min after seizure onset. Treatment consisted of diazepam or midazolam plus one of the above-mentioned anticholinergic drugs. All doses of the treatment compounds exhibited little or no antiseizure efficacy when given individually. The combination of a benzodiazepine and an anticholinergic drug was effective in terminating soman-induced seizure, whether given 5 or 40 min after seizure onset. The results suggest a strong synergistic effect of combining benzodiazepines with centrally active anticholinergic drugs and support the concept of using an adjunct to supplement diazepam for the treatment of nerve-agent-induced seizures.

Animals↗
PubMed2001

Effects of selected anticholinergics on acoustic startle response in rats.

The present study compared the effects of the anticholinergics aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide and trihexyphenidyl hydrochloride on acoustic startle response in rats. Peak startle amplitude, latency to peak startle amplitude and prepulse inhibition following 100- and 120-dB tones were recorded 15 min following drug administration in food-restricted rats. Aprophen, atropine, azaprophen, benactyzine, biperiden and scopolamine significantly increased peak startle amplitude and decreased latency to peak startle amplitude following 100-dB pulses. In contrast, only biperiden increased peak startle amplitude following 120-dB pulses, whereas atropine and trihexyphenidyl decreased latency to peak startle amplitude following 120-dB pulses. Benactyzine decreased prepulse inhibition following both 100- and 120-dB pulses, whereas both biperiden and scopolamine decreased prepulse inhibition following 120-dB pulses. Acoustic startle response measures were effective in differentiating the effects of anticholinergic compounds. The comparison of drug effects on the acoustic startle response may be useful in selecting efficacious anticholinergic drug therapies with a minimal range of side-effects. In addition, these data may be useful in down-selecting the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Acoustic Stimulation↗
PubMed1996

Interactions of excitatory amino acid antagonists with conventional antiepileptic drugs.

Excitatory amino acid antagonists possess anticonvulsant properties in many experimental models of epilepsy and were shown to potentiate the protective activity of conventional antiepileptics against maximal electroshock-induced seizures in mice. Combined treatments of valproate with either D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid or dizocilpine (NMDA antagonists), which provided a 50% protection against maximal electroshock, produced no side-effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). Valproate alone at its ED50 against maximal electroshock, induced severe adverse effects. The NMDA antagonists, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid, memantine, procyclidine, and trihexyphenidyl also potentiated the protective activity of conventional antiepileptics but these treatments were associated with considerable side-effects. The non-NMDA receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline and 1-(amino-phenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, also enhanced the anticonvulsive action of antiepileptic drugs against maximal electroshock, and these combinations generally resulted in no adverse effects. The potential clinical importance of some combinations of common antiepileptics with excitatory amino acid antagonists is postulated.

Animals↗
PubMed1991

Selectivity of antimuscarinic compounds for muscarinic receptors of human brain and heart.

Seven antimuscarinic compounds, used mostly for the treatment of extrapyramidal problems, were tested in vitro in radioligand binding assays for evidence of selectivity for two different pharmacological subtypes of the human muscarinic receptor, M1, a predominant form in brain, and M2, a predominant form in heart. Although biperiden, scopolamine, procyclidine, and benztropine showed significant selectivity in the in vitro assays, it is likely that in clinical practice biperiden would be the drug of choice to avoid any antimuscarinic effects on the heart.

Brain↗
PubMed1989

Muscarinic receptor subclassification and G-proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics.

The classification of muscarinic receptors into M1 and M2 subtypes and the involvement of guanine nucleotide binding proteins (G-proteins) as major mediators of receptor information transduction in the cholinergic and other neurotransmitter systems have prompted us to undertake studies both at receptor and postreceptor levels that may shed light on the importance of these new findings to the pharmacotherapy of manic-depressive illness and of extrapyramidal syndromes. We searched for patterns of muscarinic selectivity among the commonly used anticholinergics (biperiden, procyclidine, trihexyphenidyl, benztropine, and methixen) through radioligand receptor studies in various rat tissues. The drugs showed a range of selectivity, from the totally nonselective methixen to the highly M1-selective biperiden. Sinus arrhythmia measurements were undertaken in psychiatric patients treated with different antiparkinsonian anticholinergics. The extent of sinus arrhythmia suppression was inversely correlated with the degree of M1 selectivity of the drugs used, advocating the use of M1-selective antiparkinsonian anticholinergics like biperiden in the treatment of extrapyramidal side effects. The implications of muscarinic receptor subclassification were further extended to include postreceptor phenomena. We have directly studied G-protein function by measuring cholinergic agonist-induced increases in guanosine triphosphate (GTP) binding to these proteins. This cholinergic agonistic effect was shown to be exerted by G-proteins other than Gs (the adenylate cyclase stimulatory G-protein), i.e., Gi (the adenylate cyclase inhibitory G-protein) or Gp [the G-protein activating phosphatidylinositol (PI) turnover], as ribosylation by pertussis toxin abolished this cholinergic effect, whereas it was unaffected by cholera toxin. Pertussis toxin-blockable, carbamylcholine-induced increases in GTP binding capacity were found to be mediated through M1 muscarinic receptors, as M1-selective antagonists were 100-fold more effective than M2 selective antagonists in blocking carbamylcholine effects. Moreover, carbamylcholine effect was exclusively detected in tissues predominantly populated by M1 receptors. Our results thus suggest that carbamylcholine-induced increases in GTP binding are exerted through M1 receptors interacting with Gp. At therapeutically efficacious concentrations, lithium completely blocked carbamylcholine-induced increases in GTP binding capacity in both in vitro and in vivo experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs.

Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonized NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > trihexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinuclidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.

Animals↗
PubMed1984

Comparison of the stimulatory effects of eight antiparkinsonian drugs.

The effects of eight antiparkinsonian anticholinergic drugs on motor activity in mice were studied. Trihexyphenidyl, biperiden, benztropine, etybenztropine, procyclidine and tropacine clearly stimulated motor activity. Orphenadrine did not change motor activity, and profenamine had sedative properties. The classification of these drugs by order of their effect on this animal model does not agree with the classification proposed by Deniker et al (1980).

Animals↗
PubMed2004

Screening and semi-quantitative analysis of post mortem blood for basic drugs using gas chromatography/ion trap mass spectrometry.

The study presented here shows that GC-MS with ion trap detection can be used for screening post mortem blood. The method described was used to simultaneously screen for unknowns, identify basic drugs present and semi-quantitate 14 drugs commonly encountered in coroner's toxicology (i.e. was used to determine whether the drugs were present in sub-therapeutic, therapeutic or greater than therapeutic amounts). The equipment used included a Varian Saturn 2000 GC-MS operating in full scan mode, a CP-3800 GC, a CP-8400 autosampler and Saturn GC-MS workstation Version 5.5 software. Post mortem blood samples were extracted using a standard liquid-liquid procedure; diethylether followed by back extraction into 0.1 M HCl. Standard curves for the 14 drugs which were semi-quantitated (amitriptyline, citalopram, clozapine, cocaine, cyclizine, diazepam, dihydrocodeine, dothiepin, methadone, mirtazapine, procyclidine, sertraline, tramadol, venlafaxine) were prepared covering the concentration range 0-1.0 ug/mL. The procedure is in routine use for coroners toxicology; semi-quantitation has been used (i) to speed-up the through put of cases where drugs are an incidental finding and (ii) for cases where the amount of sample submitted for analysis was too small to allow for screening, identification and quantitation on separate sample volumes.

Gas Chromatography-Mass Spectrometry↗
PubMed2005

Soman-induced convulsions in rats terminated with pharmacological agents after 45 min: neuropathology and cognitive performance.

It has been demonstrated that a triple regimen consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg) and pentobarbital (30 mg/kg) can effectively terminate soman-induced (1 x LD50) seizures/convulsions in rats when administered 30-40 min following onset. However, convulsive activity lasting for only 45 min can result in marked neuronal pathology. The purpose of the present study was to examine potential cognitive impairments of such brain lesions. The results showed that the neuronal pathology (assessed with Fluoro-Jade B) varied from none at all to 30% damage in the index areas (hippocampus, amygdala, piriform cortex). Cognitive deficits were seen in a novelty test (11 days post-exposure) and retention of a brightness discrimination task (28 days post-exposure) among the rats with neuropathology. Furthermore, significant correlations between neuropathology scores and behavioral measures were found for the animals that convulsed. Among these rats, the mortality rate was relatively high (60%) compared with rats in a previous study that had undergone implantation of hippocampal electrodes (17%). Neither the soman poisoning in the absence of convulsions nor the triple regimen alone affected behavior. It is concluded that early management of soman-induced convulsions is of major importance in preventing neuropathology and accompanying cognitive impairments.

Animals↗
PubMed2001

Simultaneous determination of enantiomers of structurally related anticholinergic analogs in human serum by liquid chromatography-electrospray ionization mass spectrometry with on-line sample cleanup.

Trihexyphenidyl, biperiden and procyclidine are anticholinergic drugs produced as racemates for the treatment of Parkinson's disease. This paper describes a simple and sensitive LC-MS method for the simultaneous determination of these compounds in human serum. An on-line sample clean-up procedure was used, where serum samples were directly injected into a "restricted-access media" pre-column. After the exclusion of the serum proteins, the drug molecules were eluted to a beta-cyclodextrin analytical column for chiral separation. The quantitation was done by electrospray ionization MS using diphenidol as an internal standard. The method developed has limits of detection of 1 ng/ml, at least two-orders-of-magnitude linear dynamic ranges (r>0.999), and RSDs of less than 10%. The system can be completely automated for increased sample throughput and unattended analyses.

Cholinergic Antagonists↗
PubMed1992

Recurrent neuroleptic malignant syndrome in a man with mild mental handicap.

A case of recurrent neuroleptic malignant syndrome (NMS) occurring in a 29-year-old man with mild mental handicap and a superadded psychotic disorder is described. The case illustrates a number of unusual features such as recurrent episodes and resolution with administration of intravenous Procyclidine. The possibility of NMS occurring in people with mental handicap, who have a high level of neuroleptic drug prescription, must be borne in mind.

Adult↗
PubMed1993

Thermodynamics of antagonist binding to rat muscarinic M2 receptors: antimuscarinics of the pridinol, sila-pridinol, diphenidol and sila-diphenidol type.

1. We studied the effect of temperature on the binding to rat heart M2 muscarinic receptors of antagonists related to the carbon/silicon pairs pridinol/sila-pridinol and diphenidol/sila-diphenidol (including three germanium compounds) and six structurally related pairs of enantiomers [(R)- and (S)-procyclidine, (R)- and (S)-trihexyphenidyl, (R)- and (S)-tricyclamol, (R)- and (S)-trihexyphenidyl methiodide, (R)- and (S)-hexahydro-diphenidol and (R)- and (S)-hexbutinol]. Binding affinities were determined in competition experiments using [3H]-N-methyl-scopolamine chloride as radioligand. The reference drugs were scopolamine and N-methyl-scopolamine bromide. 2. The affinity of the antagonists either increased or decreased with temperature. van't Hoff plots were linear in the 278-310 degrees K temperature range. Binding of all antagonists was entropy driven. Enthalpy changes varied from large negative values (down to -29 kJ mol-1) to large positive values (up to +30 kJ mol-1). 3. (R)-configurated drugs had a 10 to 100 fold greater affinity for M2 receptors than the corresponding (S)-enantiomers. Enthalpy and entropy changes of the respective enantiomers were different but no consistent pattern was observed. 4. When silanols (R3SiOH) were compared to carbinols (R3COH), the affinity increase caused by C/Si exchange varied between 3 and 10 fold for achiral drugs but was negligible in the case of chiral drugs. Silanols induced more favourable enthalpy and less favourable entropy changes than the corresponding carbinols when binding. Organogermanium compounds (R4Ge) when compared to their silicon counterparts (R4Si) showed no significant difference in affinity as well as in enthalpy and entropy changes. 5. Exchange of a cyclohexyl by a phenyl moiety was associated with an increase or a decrease in drug affinity (depending on the absolute configuration in the case of chiral drugs) and generally also with a more favourable enthalpy change and a less favourable entropy change of drug binding. 6. Replacement of a pyrrolidino by a piperidino group and increasing the length of the alkylene chain bridging the amino group and the central carbon or silicon atom were associated with either an increase or a decrease of entropy and enthalpy changes of drug binding. However, there was no clear correlation between these structural variations and the thermodynamic effects. 7. Taken together, these results suggest that hydrogen bond-forming OH groups and, to a lesser extent, polarizable phenyl groups contribute significantly to the thermodynamics of interactions between these classes of muscarinic antagonists and M2 muscarinic receptors.

Animals↗
PubMed2003

Variable effects of previously untested muscarinic receptor antagonists on experimental myopia.

PURPOSE: Atropine, pirenzepine, and himbacine prevent form-deprivation myopia (FDM) when administered intravitreously. The mechanisms and sites of action of these drugs against myopia are not clear. To shed further light on whether this mechanism is muscarinic, several other muscarinic antagonists were tested. METHODS: Various concentrations of atropine, pirenzepine, dexetimide, scopolamine, tropicamide, benztropine, dicyclomine, gallamine, mepenzolate, oxyphenonium, propantheline, procyclidine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), hexahydro-sila-difenidol (HHSiD), p-fluorohexahydro-sila-difenidol (pf-HHSiD), methoctramine, AFDX-116, and quinuclidinyl benzilate (QNB) were injected into goggled eyes of Leghorn cockerels three times at 48-hour intervals. Fellow control eyes received saline. Control animals received saline in both eyes. Twenty-four hours after final injections, refraction, eye weight, and axial length were measured, and eyes were prepared for microscopy. RESULTS: Other than atropine and pirenzepine, only oxyphenonium caused full rescue from FDM (goggled versus control; mean +/- SD; refraction differences: -9.50 +/- 0.22 D vs. 0.83 +/- 0.31 D, P < 0.001; wet weight differences: 75.67 +/- 3.84 mg vs. 2.33 +/- 6.14 mg, P < 0.001; axial length differences: 0.80 +/- 0.05 mm vs. 0.03 +/- 0.04 mm, P < 0.001). Oxyphenonium-treated retinas showed no damage. Of the other compounds, several elicited partial rescue and/or damaged the retina, whereas others had no effect. CONCLUSIONS: Oxyphenonium prevents FDM in chicks. The ineffectiveness or partial effectiveness of other compounds, coupled with the high concentrations of effective compounds required to prevent FDM, suggests that muscarinic antagonists act to prevent FDM, either at sites distant from the retina, or through a nonmuscarinic mechanism, on which only some of these drugs act.

Animals↗
PubMed1978

Comparison of the incidence and severity of extrapyramidal side effects with fluphenazine enanthate and fluphenazine decanoate.

Forty-nine schizophrenic outpatients stabilized on oral antipsychotic medication and procyclidine received 12.5 mg or 18.75 mg of fluphenazine enanthate or fluphenazine decanoate and were examined for extrapyramidal side effects one and two weeks later. Extrapyramidal side effects were present in 30 patients (61%) but were clinically significant in only 11 (22%). Fluphenazine enanthate produced more clinically significant extrapyramidal symptoms, particularly akathisia, than did fluphenazine decanoate.

Adolescent↗
PubMed1986

Prevalence of the rabbit syndrome.

Among 266 chronic inpatients receiving neuroleptics, six of the 137 (4.4%) receiving neuroleptics alone and none of the 129 receiving concomitant anticholinergics manifested the rabbit syndrome. Procyclidine resolved the signs of all affected patients. The syndrome's potential prevalence remains unknown.

Adult↗