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.
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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The combined effects of physostigmine and procyclidine (antagonizing muscarinic, nicotinic, and NMDA receptors) were tested against various doses of soman. Physostigmine (0.1 mg/kg) in combination with procyclidine doses of 1, 3, or 6 mg/kg effectively prevented the development of convulsions and hippocampally monitored seizures when the doses of soman were 1.3, 1.6, or 2 x LD50, respectively. Results from [(3)H]MK-801-binding experiments showed that procyclidine inhibits the phencyclidine site at the NMDA receptor in a concentration-dependent manner. Physostigmine (0.1 mg/kg) and procyclidine in a dose of 1 mg/kg did not prevent convulsions or seizures when the soman dose was 1.6 x LD50. Subsequent treatment with scopolamine in doses of 0.5 or 1 mg/kg immediately after (3 min) seizure onset showed that only the highest dose produced a reliable termination. When scopolamine (1 mg/kg) was given later (10 min) after onset of seizures, no effect was obtained. The sustained seizures were subsequently treated with diazepam (10 mg/kg) and pentobarbital (30 mg/kg) and finally terminated 25 min after onset. In rats given inadequate prophylaxis, both modified convulsions and seizures were seen. It is suggested that moderate doses of prophylactics should be preferred to avoid adverse effects on cognitive functions because insufficient prophylaxis can be compensated for by adjunct treatment.
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This study determined the effects of procyclidine, an anticholinergic drug, on PPI in healthy male volunteers, employing a double-blind placebo-controlled cross-over design.
Systemic administration does not allow a clear differentiation between the anticonvulsant properties of GABAA (gamma-aminobutyric acid) modulators. For this reason, various GABAA modulators have previously been micro-infused into seizure controlling substrates (area tempestas, substantia nigra) in the rat brain as a screening method for potential systemic administration. The purpose of the present study was to examine the anticonvulsant impact of the GABAergic modulators muscimol, ethanol, and propofol (screened by micro-infusions) when each drug was combined with procyclidine and administered systemically. The results showed that all 3 combinations could effectively terminate soman-induced (100 microg/kg s.c.) seizures when administered 30-35 min after onset. Procyclidine and propofol were considered as the most relevant double regimen to replace a previous triple regimen (procyclidine, diazepam, pentobarbital) against soman-induced seizures. Additionally, it was shown that unilateral implantation of hippocampal electrodes resulted in increased resistance to aphagia/adipsia and neuropathology, but not to lethality following soman. Efficient pharmacological treatment of soman-induced seizures at an early stage (< 20 min) is crucial to avoid neuropathology and cognitive deficits.
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Of 55 aftercare patients receiving long-term treatment with antipsychotic and antiparkinson (AP) drugs, 37 were switched to being given placebo, and 18 remained on a regimen of procyclidine hydrochloride. The dose of antipsychotic was kept constant. After three weeks extrapyramidal side effects (EPS) developed in 54% of those patients receiving placebo and in none of those receiving procyclidine (P less than .002): Twenty-seven percent of the placebo group had EPS without akinesia, and in the same percentage akinesia developed (P = .003). We believe the risk-benefit ratio favors the routine use of AP drugs for prophylaxis and maintenance so as to avoid misdiagnosing as psychopathology, unspontaneity due to akinesia, and to reduce unreliable pill-taking due to EPS.
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.
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Atropine (5 mg/kg, s.c., twice daily) had no significant effect on 24-h water consumption on day 1 of treatment; on subsequent days the rats showed a significant increase. Procyclidine (5 mg/kg, s.c., twice daily) had a similar effect, except that the increase in daily water consumption began on the third day of treatment. Methylatropine (5 mg/kg, s.c., twice daily) markedly depressed water consumption on day 1; from the second day on no significant effects on 24-h water consumption were seen. The results suggest that the dipsogenic actions of cholinergic blocking agents on 24-h water consumption involve central rather than purely peripheral actions.
A new technique for investigating drug-protein binding was developed employing capillary electrophoresis (CE) coupled with tris(2,2'-bipyridyl) ruthenium(II) [Ru(bpy)(3) (2+)] electrochemiluminescence (ECL) (CE-ECL) detection after equilibrium dialysis. Three basic drugs, namely pridinol, procyclidine and its analogue trihexyphenidyl, were successfully separated by capillary zone electrophoresis with end-column Ru(bpy)(3) (2+) ECL detection. The relative drug binding to human serum albumin (HSA) for each single drug as well as for the three drugs binding simultaneously was calculated. It was found that the three antiparkinsonian drugs compete for the same binding site on HSA. This work demonstrated that Ru(bpy)(3) (2+) CE-ECL can be a suitable technique for studying drug-protein binding.
A treatment regimen consisting of HI-6, scopolamine, and physostigmine (termed the physostigmine regimen) has been based on the serendipitous discovery that it exerts powerful antidotal effects against high levels of soman poisoning if it is administered 1 min after exposure. A medical therapy with corresponding efficacy, but without the time limitation of the latter regimen, has been developed through studies of microinfusions of anticonvulsants into seizure controlling sites in the forebrain of rats. From these studies procyclidine emerged as the most potent anticonvulsant, and its potency was further enhanced when being combined with the antiepileptic levetiracetam during systemic administration. In the present study, the capacity of HI-6, levetiracetam, and procyclidine (termed the procyclidine regimen) was tested against that of the physostigmine regimen. The results showed that both regimens were very effective against supralethal doses of soman (3, 4, 5 × LD₅₀) when given 1 and 5 min after intoxication. When the treatments were administered 10 and 14 or 20 and 24 min after soman exposure, only the procyclidine regimen was able to terminate seizures and preserve lives. When used as prophylactic therapies, both regimens protected equally well against seizures, but only the procyclidine regimen provided neuroprotection. The procyclidine regimen has apparently capacities to serve as a universal therapy against soman intoxication in rats.
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Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.
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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.
In an attempt to obtain more selective antagonists acting at muscarinic M2-receptors, analogues of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP methobromide) have been synthesized. These were tested, along with silabenzhexol, procyclidine, sila-procyclidine and AFDX-116, in dose-ratio experiments with guinea-pig isolated atria at 30 degrees C and ileum at 30 degrees C and 37 degrees C. The agonist was carbachol and the selectivity was assessed from the difference between log K for receptors in ileum and log K for receptors in atria. The selectivity was not related to the affinity and some weakly active compounds retained appreciable selectivity but no compound had greater selectivity than 4-DAMP methobromide or pentamethylene bis-(4-diphenylacetoxy-N-methylpiperidinium) bromide. Structure-activity relations are discussed. There seem to be steric limits to affinity but there are no obvious indications of the structural features associated with selectivity. It is suggested that more selective drugs may be obtained by introducing groups which may reduce affinity.
This study evaluated the effect of anticholinergic discontinuation on movement disorders, cognition and general psychopathology after a 4-week taper in 20 outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics.
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.
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Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4× LD50 VX in IPA. The results showed that RSDL decontamination at 15 min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90 min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment.
Neuroleptic Malignant Syndrome (NMS) is an adverse reaction to dopamine receptor antagonists, characterised by hyperpyrexia, extrapyramidal rigidity and impaired autonomic function. It might result from central dopamine receptor blockade that causes severe muscle contraction.
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Eighty-eight subjects took part in two studies, 37 IBS patients (Rome II), 14 depressed patients, and 37 healthy volunteers. Eighteen IBS patients had diarrhea predominant IBS, 14 were alternators, and 5 were predominantly constipated. In study 1, blood was drawn for baseline measurement of growth hormone (GH) and cytokines IL-6, IL-8, and IL-10. Pyridostigmine 120 mg was administered orally and further blood sampling took place for 180 min. In study 2, patients with IBS, depressed patients, and healthy subjects underwent the pyridostigmine test on two separate occasions with procyclidine (antimuscarinic) pre-treatment on one test occasion. Both GH and IL-6 were monitored.
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Procyclidine (up to 20 mg/kg i.p.) did not influence the electroconvulsive threshold per se, but when given in a dose of 10 mg/kg, it potentiated the protective activity of carbamazepine, diphenylhydantoin, phenobarbital and valproate, and in a dose of 20 mg/kg, that of diazepam against maximal electroshock-induced convulsions in mice. Ifenprodil increased the threshold for electroconvulsions when applied at 20 and 40 mg/kg (i.p.), but surprisingly, when combined with all antiepileptics tested, it did not influence their anticonvulsant actions. The chimney test in mice revealed, that application of procyclidine at 10 mg/kg together with phenobarbital and valproate, and procyclidine at 20 mg/kg with diazepam resulted in motor impairment. However, when procyclidine was applied at 10 mg/kg together with carbamazepine or diphenylhydantoin, no motor impairment was noted. The combined treatment of procyclidine (10 mg/kg) with carbamazepine, diphenylhydantoin, phenobarbital or valproate, as well as procyclidine (20 mg/kg) with diazepam caused significant worsening of long-term memory. Finally, procyclidine did not alter the total plasma levels of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate. It may be concluded that not all agents interfering with NMDA receptor complex-mediated events lead to the potentiation of the anticonvulsant activity of antiepileptic drugs.
In a double-blind, between-patient clinical trial carbamazepine (CBZ) (n = 8) was compared to haloperidol (HP) (n = 9) in patients presenting with mania (DSM III). Seven patients on HP and 2 on CBZ failed to complete 4 weeks treatment. In 4 of the HP group this was because of extrapyramidal side-effects (EPS). Two patients on CBZ and 2 on HP were withdrawn because of lack of efficacy. Statistically significant clinical improvement was seen in both groups within the first 2 weeks of treatment with HP acting more quickly. In addition to EPS which occurred in HP patients, drowsiness was experienced in 4 on CBZ and 3 on HP, and gastrointestinal symptoms in 3 on CBZ. No serious haematological changes, nor abnormalities in clinical chemistry occurred in either group. We conclude that CBZ appears to be a potentially useful drug in the treatment of acute mania.
Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of the brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6 x LD(50)) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.
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Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2-6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2-3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined.
Didepil seems to be an effective antiepileptic agent in maximal generalized seizures as well as in temporal lobe seizures.
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.
The critical flicker fusion threshold (CFFT) is thought to index alertness and cortical arousal. Sedative drugs reduce CFFT while psychostimulants increase it. Procyclidine is an anticholinergic that is used to control the extrapyramidal side-effects of antipsychotics in schizophrenia. This study examined the effects of clinically relevant doses of oral procyclidine administration on CFFT and heart rate in two separate experiments (Experiment 1, drug dose: 10 mg, n = 16; Experiment 2, drug dose: 15 mg, n = 12) involving healthy subjects using a double-blind, placebo-controlled, cross-over design. 10 mg procyclidine had no significant effect on CFFT, heart rate or self-ratings of mood, but the 15 mg dose significantly lowered CFFT at 1 h and 2 h after procyclidine administration, increased drowsiness ratings and produced a drop in heart rate. The effects observed in this study may have implications for treatment compliance of schizophrenic patients, choice of antipsychotics, prescribing to patients with heart disease and monitoring of cardiac function under treatment. Further investigations are required to quantify the effects of procyclidine on CFFT and cardiac function in patients with schizophrenia.
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In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure.