A case of Gilles de la Tourette syndrome in a mildly mentally retarded adult female is described. The clinical features, natural history and response to treatment were typical of the condition but the association with mental retardation, epilepsy and psychotic phenomena were unusual.
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We examined the ability of a range of tricyclic antidepressants (TCADs) and phenothiazine derivatives and their metabolites to inhibit the N-methyl-D-aspartate (NMDA) receptor complex using a [3H]MK801 binding assay. Desmethylation of the side chain of both TCADs and phenothiazines increased their potency against [3H]MK801 binding, as did removal of Cl substituted on the conjugated ring. Other side chain modifications further increased the potency of phenothiazines such as in the case of ethopropazine. Generally, the increase in potency of drugs at the NMDA receptor complex was associated with a decrease in the potency at other sites of action of these compounds. This finding suggests that it may be possible to separate the established actions of these compounds from their NMDA inhibitory effects. We also examined the mechanism of action of a number of compounds by monitoring drug effects on the dissociation rate of [3H]MK801 in the presence of Mg++. Phenothiazines and TCADs generally slow the dissociation of [3H]MK801, although to differing extents. Drugs such as 9-aminoacridine, cyproheptadine and ethopropazine also slowed the dissociation rate. These findings suggest a Zn++-like action of these compounds. In contrast, mecamylamine, methapyrilene and procyclidine had very little effect on the dissociation rate, suggesting a competitive action at the [3H]MK801/phencyclidine binding site. Chlorpromazine at low concentrations slowed the dissociation rate, while increasing it at higher concentrations. Thus, chlorpromazine demonstrated both Zn++ and Mg++-like effects. These studies demonstrate novel inhibitory actions of TCAD and phenothiazine derivatives at the NMDA receptor complex that are apparently mediated by the Zn++ binding site.
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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.
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A transdermal patch system containing procyclidine, an N-methyl-d-aspartate receptor antagonist possessing anticholinergic action, and physostigmine, a reversible cholinesterase inhibitor, was developed, and its prophylactic efficacy against soman intoxication was investigated. Male rhesus monkeys were shaved on the dorsal area, attached with a matrix-type patch with various sizes (2×2 to 7×7 cm) for 24 or 72 h, and challenged with 2×LD₅₀ doses (13μg/kg) of soman. The smallest patch size for the protection against lethality induced by soman intoxication was 3×3cm, resulting in blood procyclidine concentration of 10.8 ng/ml, blood physostigmine concentration of 0.54 ng/ml, which are much lower concentrations than maximum sign-free doses, and blood cholinesterase inhibition of 42%. The drug concentrations and enzyme inhibition rate corresponding to a diverging point of survivability were presumably estimated to be around 7 ng/ml for procyclidine, 0.35 ng/ml for physostigmine, and 37% of enzyme inhibition. Separately, in combination with the patch treatment, the post treatment consisting of atropine (0.5 mg/kg) plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 50 mg/kg) exerted protection against 5×LD₅₀ challenge of soman, which means the posttreatment remarkably augmented the efficacy of the patch. Additionally, it was found that brain injuries induced by soman toxicity were effectively prevented by the patch treatment according to histopathological examinations. These results suggest that the patch system could be an effective alternative for diazepam, an anticonvulsant, and the current pyridostigmine pretreatment, and especially in combination with atropine plus HI-6, could be a choice for quality survival from nerve-agent poisoning.
After pretreatment of adult male Wistar rats with phenobarbital, a well-known cytochrome P-450 inductor, the liver microsomal cytochrome P-450 content increased significantly compared to that of control rats. At the same time the amount of procyclidine, metabolized by the 9000 g supernatant fraction of rat liver homogenate fortified with a NADPH generating system, increased significantly as well. However when related to the liver microsomal cytochrome P-450 content, the amount of metabolized procyclidine does not differ anymore between phenobarbital treated and control rats. Therefore phenobarbital induces the in vitro metabolism of procyclidine.
In study 1, baseline IL-6 (P= 0.003) and IL-8 levels (P= 0.001) were higher in IBS than in controls. Pyridostigmine stimulated the release of IL-6 and GH, but not IL-8 or IL-10; these responses were significantly augmented in IBS patients relative to controls. The IL-6 level following pyridostigmine administration correlated significantly with the symptom score (P < 0.01). In study 2, IL-6 rose following pyridostigmine in IBS but not depression and procyclidine blocked the rise. The GH response was abolished by procyclidine in all three groups.
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The purpose of the present study was to examine the efficacy of a triple combination of drugs with adequate anticonvulsant effects and a dual combination with inadequate anticonvulsant effects followed by adjunct therapy. The results showed that combined intramuscular injections of HI-6 (42 mg/kg), atropine (14 mg/kg), and avizafone (3 mg/kg) administered 1, 16, and 31 min. after exposure to a soman dose of 4 x LD(50) completely terminated seizures with a moderate mortality rate (25%). When the soman dose was lowered to 3 x LD(50) the anticonvulsant effect was complete, and no rats died within 24 hr. Rats challenged with 5 x LD(50) of soman all died within 10 min. Without avizafone in the combination, seizures induced by 3 or 4 x LD(50) of soman could not be terminated unless an adjunct therapy consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg), and pentobarbital (30 kg/kg) was given, and the mortality rate was comparatively high (78%). Administration of the adjunct therapy alone 6-16 min. after 4 x LD(50) of soman stopped the seizure activity, but all the rats died within 24 hr. Marked neuropathology was found in the piriform cortex and amygdala, whereas the hippocampal CA1 field was effectively protected when both the triple combination and the dual combination plus adjuncts had stopped seizures 35-55 min. after onset. It is concluded that termination of soman-induced seizures at an early stage (<20 min.) is crucial to avoid neuronal pathology.
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A group of antiparkinson drugs (benactyzine, biperiden, caramiphen, procyclidine, and trihexyphenidyl) has been shown to possess both anticholinergic and antiglutamatergic properties, making these agents very well suited as anticonvulsants against nerve agents. The first purpose of this study was to make a comparative assessment of the anticonvulsant potencies of the antiparkinson agents when microinfused (1 microl) into the seizure controlling area tempestas (AT) of rats 20 min before subcutaneous injection of soman (100 microg/kg). The second purpose was to determine whether cholinergic and/or glutamatergic antagonism was the effective property. The results showed that only procyclidine (6 microg) and caramiphen (10 microg) antagonized soman-induced seizures. Cholinergic, and not glutamatergic, antagonism was likely the active property, since atropine (100 microg), and scopolamine (1 microg) caused anticonvulsant effects, whereas MK-801 (1 microg), and ketamine (50 microg) did not. Soman (11 nmol) injected into AT resulted more frequently in clonic convulsions than full tonic-clonic convulsions. AT may serve as both a trigger site for soman-evoked seizures and a site for screening anticonvulsant potencies of future countermeasures.
Didepil seems to be an effective antiepileptic agent in maximal generalized seizures as well as in temporal lobe seizures.
Prepulse inhibition (PPI) of the startle response refers to a reduction in response to a strong stimulus (pulse) if this is preceded shortly by a weak non-startling stimulus (prepulse). Consistent with theories of deficiencies in early stages of information processing, PPI is found to be reduced in patients with schizophrenia. Atypical antipsychotics are found to be more effective than typical antipsychotics in improving PPI in this population. Anticholinergic drugs are often used to control extrapyramidal symptoms induced by antipsychotic medication, especially by typical antipsychotics, in schizophrenic patients and are known to disrupt cognitive functions in both normal and schizophrenic populations. The effect of anticholinergics on PPI in schizophrenia has not yet been examined. This study determined the effects of procyclidine, an anticholinergic drug, on PPI in patients with schizophrenia given risperidone or quetiapine and not on any anticholinergic drugs, employing a placebo-controlled, cross-over design. Under double-blind conditions, subjects were administered oral 15 mg procyclidine and placebo on separate occasions, 2 weeks apart, and tested for acoustic PPI (prepulse 8 dB and 15 dB above the background and delivered with 30-ms, 60-ms and 120-ms prepulse-to-pulse intervals). Procyclidine significantly impaired PPI compared to placebo (assessed as percentage reduction) with 60-ms prepulse-to-pulse trials and increased the latencies to response peak across all trials. The use of anticholinergics needs to be carefully controlled/examined in investigations of information processing deficits using a PPI model and reduced to the minimum level in clinical care of schizophrenia.
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There is great interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of N-methyl-D-aspartate (NMDA) receptors. As an alternative to in vivo testing in animal models, we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the effectiveness of the Alzheimer's disease drug, memantine, the Parkinson's disease drug, procyclidine, and the novel neuroprotectant, gacyclidine (GK11), against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open-channel blockers that inhibit excitotoxic injury, and their neuroprotective capacities have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in hippocampal regions CA1, CA3 and DG, showed that, after exposure to 10microM NMDA for 24 hours, GK11 was the most potent of the three drugs, with an IC50 of about 50nM and complete protection at 250nM. When applied at high doses, GK11 was still the more potent neuroprotectant, and also the least cytotoxic. These findings are consistent with those from in vivo tests in rodents. We conclude that the slice culture model provides valuable pre-clinical data, and that applying the model to the screening of neuroprotectants might significantly limit the use of in vivo tests in animals.
In an era when it is generally believed that the acute symptoms of schizophrenia can be controlled pharmacologically, the case of a young man who has remained almost continuously floridly psychotic for 13 years, despite treatment, is disquieting. Conventional psychiatric treatment appears to be rendered impotent. It is in this context that it may be of interest to report a summary of the proceedings of a Special Problems Conference held at the Institute of Psychiatry on 18 February 1985 to discuss such a case.
The authors administered haloperidol 4.5 mg t.i.d. to 33 drug-free schizophrenic patients. Ten patients did not receive anything else (group HPL), while ten patients received procyclidine 5 mg t.i.d., and 13 patients were given promethazine 25 mg t.i.d. (groups HPRC and HPRM respectively) in addition. Seven patients dropped out of the HPL group and three out of the HPRM group, but none out of the HPRC group. These drop outs were due to the development of early extrapyramidal side effects, which were absent in the HPRC group. The findings suggest that antiparkinson prophylaxis is useful during commencement of therapy with high-potency neuroleptic agents.
Compliance to the prescription of anticholinergic drugs in 274 consecutive schizophrenic outpatients has been assessed retrospectively from their clinical records. Ten point four percent of the sample (22 patients) took these drugs in amounts greater than those prescribed. Some possible explanations of this excessive use are discussed.
Balamuthia mandrillaris is a free-living protist pathogen that can cause life-threatening granulomatous amoebic encephalitis. Given the lack of effective available drugs against B. mandrillaris encephalitis with a mortality rate of more than 90%, here we screened drugs, targeting vital cellular receptors and biochemical pathways, that are already in approved clinical use for their potential clinical usefulness. Amoebicidal assays were performed by incubating B. mandrillaris with drugs (3 × 10(5) cells/0.5 mL/well) in phosphate buffered saline for 24 h and viability was determined using Trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. To determine whether effects are reversible, B. mandrillaris were pre-exposed to drugs for 24 h, washed twice, and incubated with human brain microvascular endothelial cells, which constitute the blood-brain barrier as food source, for up to 48 h. Of the ten drugs tested, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol showed potent amoebicidal effects, while amiodarone and digoxin exhibited minimal effectiveness. When pre-treated with these drugs, no viable trophozoites re-emerged, suggesting that drugs destroyed parasite irreversibly. Based on the in vitro assay, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol are potential antimicrobials for further testing against B. mandrillaris encephalitis. These findings may provide novel strategies for therapy but further research is needed to determine clinical usefulness of aforementioned drugs against granulomatous amoebic encephalitis caused by B. mandrillaris, and other free-living amoebae, such as Acanthamoeba spp., and Naegleria fowleri.
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On the basis of the hypothesis that there is a common structural basis for central nervous system (CNS) drug action consisting primarily of an aromatic group and a nitrogen atom, a four-point model for a common pharmacophore is defined with use of five semirigid CNS-active drug molecules: morphine, strychnine, LSD, apomorphine, and mianserin. Two of the points of the model represent possible hydrophobic interactions between the aromatic group and the receptor, while the other two represent hydrogen bonding between the nitrogen atom and the receptor. The model is then extended by the inclusion of nine additional CNS-active drug molecules: phenobarbitone, clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine, imipramine, chlorpromazine, and procyclidine, each being chosen as a key representative of a different CNS-active drug class or neurotransmitter system. Consideration of all phenyl group and nitrogen atom combinations, as well as all feasible conformations, shows that all nine molecules closely fit the common model in low-energy conformations. It is proposed that the model may eventually be used to design CNS-active drugs by mapping the relative locations of secondary binding sites. It can also be used to predict whether a given structure is likely to show CNS activity: a search over 1000 entries in the Merck Index shows a high probability of CNS activity in compounds fitting the common structural model.
After intraperitoneal administration of procyclidine, eight metabolites were isolated from rat urine. They were identified as 1-(4-oxocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydrocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol , (1R,3R,4S,7R)- and (1R,3R,4S,7S)-1-(cis-3,cis-4-dihydroxycyclohexyl)-1-phenyl-3-(1-py rrolidinyl)- 1-propanol, (1R,3R,4R,7R)- and (1R,3R,4R,7S)-1-(cis-3,trans-4-dihydroxycyclohexyl)-1-phenyl- 3-(1-pyrrolidinyl)-1-propanol, and one of both (1R,3S,4R,7R)- or (1R,3S,4R,7S)- 1-(trans-3,trans-4-dihydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl )-1-propanol by comparative TLC, GLC-MS and 13C-NMR spectroscopy.
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.
Vomiting is one of the most distressing adverse effects of cancer chemotherapy. Metoclopramide by continuous infusion (400 micrograms/kg/h after a loading dose of 2.5 mg/kg) is a novel administration method for optimizing efficacy. A two-year-old boy developed urinary retention on three occasions, once accompanied by priapism and slurred speech, while receiving a continuous infusion. This was reversed by procyclidine, suggesting that it may have been a dystonic reaction.
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.
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A case is described in which a patient developed acute pancreatitis following an overdose of amoxapine and procyclidine. Pancreatitis is not at this time a recognized complication of the use or abuse of these two drugs. Other drugs were used in the medical management of the complications of the overdose, but none of these are drugs known to be associated with pancreatitis. Amoxapine is probably, but not certainly the cause of the pancreatitis. Possible mechanisms for this unusual and serious complication are described.
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A double-blind, placebo-controlled, crossover study with long-term follow-up of amantadien i- Parkinson's disease was performed on 26 patients. Other antiparkinsonian medications were discontinued in all but three patients. Amantadine resulted in a statistically significant 12 percent overall improvement over placebo. Twenty of 26 patients, without breaking the code, selected amantadine for long-term usage. Ten patients continued treatment for 10 to 12 months, and an overall statistically significant improvement was noted at 2 weeks and at 1, 2, 3, and 10 to 12 months. Improvements in tremor and rigidity remained relatively constant, while there was some apparent loss of efficacy in timed tests and quality of timed tests. Amantadine appears effective in the long-term treatment of some patients with Parkinson's disease.
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Serum anticholinergic levels were measured by radioreceptor assay (RRA) in schizophrenic patients treated for drug-induced Parkinsonism; 68 patients stabilized on a single neuroleptic and an anticholinergic antiparkinsonian agent (benzhexol, benztropine or procyclidine) were assessed using the extrapyramidal side effects (EPS) scale prior to each blood sampling. Serum anticholinergic levels showed a significant inverse correlation with EPS but did not appear to be dose-related in any of the three anticholinergic drug groups. Percentage binding to proteins was significantly less with benztropine than either benzhexol or procyclidine. Serum-free anticholinergic levels correlated significantly with total serum levels in the benzhexol and procyclidine groups but not in the benztropine group. At serum levels above 4.5 pmol/ml atropine equivalents, EPS was significantly less than at levels below that. We discuss the implications of this finding and suggest practical clinical applications of measurement of serum anticholinergic levels. Serum neuroleptic and serum prolactin levels did not correlate with either dose or serum level of anticholinergics.
In a fatal case of neuroleptic malignant syndrome, a muscle sample taken within 1 h of death showed acute myopathic features with absence of muscle glycogen and neutral lipid. These features suggest that hyperpyrexia in this syndrome may be caused by heat production from uncoupled phosphorylation in muscle and imply that the primary biochemical abnormality responsible for this uncontrolled heat production might be muscular rather than hypothalamic.
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The case history presented illustrates that, following an overdose of 'Whizz' and alcohol, a protracted dystonic syndrome can develop, clinically indistinguishable from tetanus. A prolonged period of ventilation may be necessary, but, in this case, complete recovery eventually occurred.
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This is a study of 10 men presenting with priapism and a further 25 men with impotence following priapism. Recurrent episodes of prolonged erection were a common finding and the priapism was present in most men on waking. Abnormal nocturnal tumescence was observed in one patient. The role of medical and surgical treatment was assessed.
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The authors review the literature on fatal complications of clozapine-related constipation and bowel obstruction.
Anticholinergic drugs were the first pharmacological agents used in the treatment of Parkinson"s disease. Although levodopa and other centrally acting dopaminergic agonists have largely supplanted their use, they still have a place in treatment of the disease. As a therapeutic class, there is little pharmacokinetic information available for these drugs, which is inclusive of benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine and trihexyphenidyl. Pharmacokinetic information is largely restricted to studies involving young health volunteers given single doses. In general, this class of drugs is rapidly absorbed after oral administration to humans. Oral bioavailability is variable between the different drugs, ranging from 30% to over 70%. Each of the drugs appears to possess a large Vd in humans and animals, and distribution to tissues is rapid. The drugs are all characterized by relatively low clearance relative to hepatic blood flow, and appear to be extensively metabolized, primarily to N-dealkylated and hydroxylated metabolites. The available information suggests that excretion of parent drug and metabolite is via the urine and bile. Although the existence of a plasma concentration vs. therapeutic effect relationship has not been explored, there is some evidence suggesting a relationship between concentration and peripheral side effects. Elderly tolerate the drugs less well than do younger patients. There is a notable lack of pharmacokinetic information for these drugs in the elderly. The lack of pharmacokinetic information for multiple dose administration and in the elderly may be a possible hindrance in the safe and effective use of these drugs in patients with Parkinson"s disease.
Four schizophrenic patients are reported in whom the acute development of dystonic muscle spasms, usually involving gaze deviation, was accompanied by the exacerbation or appearance of psychotic symptoms. In all cases the relationship between the neurological and psychiatric phenomena was close, and sometimes the presentation was bizarre or dramatic. The similarity of these states to the complex neuropsychiatric disturbances seen in post-encephalitic Parkinsonism is emphasised.
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The protective effect of cholinolytics such as procyclidine and atropine, in combination with carbamate prophylactics, against diisopropylfluorophosphate poisoning was examined in mice. Doses of carbamates were optimized, based on the maximum sign-free dose, the time course of cholinesterase inhibition and the protective potential against diisopropylfluorophosphate poisoning. Centrally-active physostigmine was more toxic than centrally-inactive pyridostigmine and the toxic signs of carbamates appeared to be closely related to the level of inhibition of brain cholinesterase activity. In combination with atropine, physostigmine was more effective than pyridostigmine in protecting mice intoxicated with diisopropylfluorophosphate. Moreover, centrally-active atropine sulfate was a more effective co-antidote to carbamates than centrally-inactive atropine methylnitrate. The most prominent protection was achieved with the combination of carbamates and procyclidine, a centrally-active cholinolytic showing anticonvulsion, which was also observed to prevent diisopropylfluorophosphate-induced convulsions (Kim et al., 1997). Taken together, it is suggested that procyclidine could be a possible substitute for atropine as an antidote to diisopropylfluorophosphate poisoning.