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PubMed2004

Cognitive side effects in rats caused by pharmacological agents used to prevent soman-induced lethality.

It is important that prophylactics used to protect military and emergency personnel against lethal doses of nerve agents do not by themselves produce impairment of cognitive capability. The purpose of the present study was to examine whether physostigmine, scopolamine, and various doses of procyclidine might reduce rats' innate preference for novelty. When these drugs were tested separately, the results showed that physostigmine (0.1 mg/kg) and procyclidine (3 mg/kg) did not affect preference for novelty, whereas scopolamine (0.15 mg/kg) and procyclidine in a higher dose (6 mg/kg) resulted in a preference deficit (Experiment 1). In Experiment 2, the combination of physostigmine and scopolamine or physostigmine and procyclidine (6 mg/kg) caused a marked deficit in preference for novelty. A much milder deficit was observed when physostigmine was combined with lower doses (1 or 3 mg/kg) of procyclidine. The latter combinations also had milder adverse impact on the animals' interest in the test environment and activity measures than the former combinations. By combining physostigmine with anticholinergics, a potentiation of adverse effects on behavior was seen. It is concluded that a slight cognitive impairment might be unavoidable with effective prophylactics.

Animals↗
PubMed2004

Protection against soman-induced seizures in rats: relationship among doses of prophylactics, soman, and adjuncts.

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.

Animals↗
PubMed2003

Pharmacological agents, hippocampal EEG, and anticonvulsant effects on soman-induced seizures in rats.

Changes in the hippocampal theta rhythm were used as a model in which anticonvulsant drugs may be screened for their potential to antagonize soman-induced (1xLD(50)) seizures. The zinc chelator, ethylenediaminetetra acetic acid (EDTA) (300mg/kg), and the NMDA receptor antagonist, HA-966 (60mg/kg), both disrupted the theta rhythm, but did not antagonize soman-induced seizures, neither separately, nor in combination. The anticholinergic and antiglutamatergic procyclidine (6mg/kg) did not influence the theta activity. The GABAergic agonists, diazepam (10mg/kg) and pentobarbital (30mg/kg), both reduced the theta frequency. Procyclidine, diazepam, and pentobarbital did not stop soman-induced seizures when administered separately, but both convulsions and seizure activity terminated when these agents were given together, and the rats slept through the critical convulsion period. This triple therapy was 100% effective, when administered 30-40min following onset of convulsions, and the rats displayed apparently normal behavior the next day. A screening model of potential anticonvulsants cannot be based on alterations in hippocampal EEG activity. Procyclidine, diazepam, and pentobarbital in combination disrupted the theta rhythm like the combination of EDTA and HA-966, but the latter combination did not have anticonvulsant effect. It is concluded that a triple regimen consisting of procyclidine, diazepam, and pentobarbital can effectively terminate soman-induced seizures that have lasted 30min or more.

Animals↗
PubMed1988

Receptor binding profiles of some selective muscarinic antagonists.

The binding of hexahydrosiladifenidol, procyclidine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine) and AF-DX 116 to muscarinic receptors in the heart, ileum, urinary bladder, parotid gland and cerebral cortex from guinea pig was studied in competition experiments with (-)-[3H]QNB. The affinity of AF-DX 116 was higher in the heart than in the cortex and it was extremely low in the parotid gland. The affinities of hexahydrosiladefinidol, procyclidine and 4-DAMP were higher in the cortex and parotid gland than in the heart, bladder and ileum. Hexahydrosiladifenidol and 4-DAMP recognized two classes of muscarinic binding sites in the cortex. However, in contrast to functional data, binding results showed that 4-DAMP hexahydrosiladifenidol and procyclidine did not distinguish between the sites in the smooth muscles and those in the heart. Nevertheless, the present data support the view that the putative M2-receptors are heterogeneous, since the four drugs examined were found to distinguish between the muscarinic binding sites in the parotid gland and those in smooth muscles and heart.

Animals↗
PubMed2006

Pharmacological therapies against soman-induced seizures in rats 30 min following onset and anticonvulsant impact.

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.

Animals↗
PubMed1983

Adverse effects of anticholinergic medication on positive schizophrenic symptoms.

In a series of 36 patients with acute schizophrenia flupenthixol dosage was blindly adjusted to give a fixed level of sedation. Patients were than randomly allocated to procyclidine or placebo. The patients receiving procyclidine experienced more positive schizophrenic symptoms and less severe extrapyramidal features by comparison with placebo patients. Blood levels of prolactin and flupenthixol estimated by radioimmunoassay were not significantly changed by the addition of procyclidine. Flupenthixol dosage and levels and prolactin levels were significantly related. There was no significant association between clinical and laboratory measures, with the exception that a curvilinear (inverted U) relationship was demonstrated between flupenthixol levels and antipsychotic and extrapyramidal effects. This relationship may be due to the fact that, in a study of this design, patients resistant to the effects of neuroleptic medication are likely to be given the highest doses. The findings support earlier claims that anticholinergic medication has adverse effects on schizophrenic symptoms.

Adult↗
PubMed1999

Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats.

RATIONALE: In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. OBJECTIVE: The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. METHODS: Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. RESULTS: 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. CONCLUSIONS: 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.

Animals↗
PubMed1998

Anti-nicotinic properties of anticholinergic antiparkinson drugs.

The nature of the antagonism by anticholinergic compounds of nicotine-induced convulsion in mice has not been defined clearly. Although, because they do not compete effectively for agonist binding to brain tissue in-vitro, these compounds are thought to be non-competitive antagonists in the brain, pharmacological evidence is lacking. This study describes the anti-nicotinic properties of the clinically used anticholinergic antiparkinson drugs, benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl. Nicotine-induced convulsion and arecoline-induced tremor in mice were effectively prevented by these drugs. The concentrations of benztropine, biperiden, caramiphen, ethopropazine, procyclidine and trihexyphenidyl affording 50% prevention of nicotine-induced convulsion (ED50 values) were 7.4, 4.6, 7.8, 4.9, 3.1 and 3.3 mg kg(-1), respectively. The classical muscarinic receptor antagonist atropine had potent anti-muscarinic effects but very weak anti-nicotinic activity. The classical nicotinic receptor antagonist mecamylamine had potent anti-nicotinic activity but no anti-muscarinic effects. The pattern of shift of the dose-response curve for nicotine-induced convulsion in mice was determined in the presence of increasing concentrations of the anticholinergic antiparkinson drugs. These drugs were found to increase the ED50 (0.49 mg kg(-1)) of nicotine-induced convulsion in a dose-related manner. The maximum effect of nicotine and the slope of nicotine dose-response curve were not significantly influenced by either low or high doses of benztropine, procyclidine or trihexylphenidyl, which suggests competitive action. Biperiden, caramiphen and ethopropazine, at low doses which significantly increased the ED50 of nicotine, did not affect the maximum effect of nicotine or the slope of the nicotine dose-response curve; at higher doses, however, they reduced the maximum effect and the slope, which suggests that these drugs have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice. The experiments demonstrate that the anticholinergic antiparkinson drugs and mecamylamine effectively antagonize nicotine-induced convulsion, but atropine does not; some of these drugs have competitive properties whereas others seem to have both competitive and non-competitive properties in antagonizing nicotine-induced convulsion in mice.

Animals↗
PubMed1986

Effects of mianserin in neuroleptic-induced parkinsonism.

It has been proposed that serotonin (5-HT) antagonists counteract neuroleptic-induced extrapyramidal symptoms by disinhibition of dopamine activity. The effects of the 5-HT antagonist mianserin, the anticholinergic drug procyclidine and placebo were evaluated in 16 psychiatric patients with chronic neuroleptic-induced parkinsonism in a double-blind cross-over trial. The patients received each drug in random order in 3-week periods separated by washout periods of 2 weeks. The effect of mianserin did not significantly differ from that of placebo, while parkinsonian symptoms were significantly reduced during treatment with procyclidine (P less than 0.05). Although mianserin was ineffective in chronic neuroleptic-induced parkinsonism, it cannot be excluded that 5-HT antagonists may be effective in the treatment of acute extrapyramidal side effects.

Adult↗
PubMed1979

Changes in the human light reflex as a measure of the anticholinergic effects of drugs. A comparison with other measures.

Single oral doses of atropine, nortriptyline, procyclidine and lactose dummy were administered double-blind to eight healthy young subjects in a balanced, crossover study. Television pupillometry was used to measure the anticholinergic effects of these drugs on the pupil diameter in darkness and the reflex response to light flashes. The sensitivity of this method was compared with conventional autonomic function tests, viz. salivary secretion, radial pulse, forearm sweat gland activity and distance to visual near point. Visual analogue scales were used to obtain subjective measures of sedative drug effects. The expected inhibition of parasympathetic activity was found in most instances with two exceptions: firstly, that nortriptyline failed to affect the pupil despite causing a tachycardia and secondly, that procyclidine gave a bradycardia. The results are discussed with reference to the possible advantages of television pupillometry over conventional pupil measurement in the detection of anticholinergic drug effects.

Adolescent↗
PubMed1995

Microbore liquid chromatography of tertiary amine anticholinergic pharmaceuticals with tris(2,2'-bipyridine)ruthenium(III) chemiluminescence detection.

The post-column chemiluminescent reaction of six anticholinergic alkaloid compounds with tris(2,2'-bipyridine)ruthenium(III) (Ru(bpy)3(3+)) is applied to microbore high-performance liquid chromatography (HPLC). At flow rates less than 200 microL/min, the capillary mixing cell in which Ru(bpy)3(3+) and the analyte are mixed directly allows for good light detection. In contrast, a diminished signal occurs at these low flow rates with conventional post-column mixing in a tee. Optimal chemiluminescent pH conditions for atropine, scopolamine, dicyclomine, cyclopentolate, cyclobenzaprine, and procyclidine are determined at moderately basic conditions (pH 7 to 9). 2-Butanone is found to be compatible with the chemiluminescent reaction, whereas tetrahydrofuran and propionitrile cause an increase in background noise and a chemiluminescent signal loss. As 2-butanone is more nonpolar than acetonitrile, it assists in the elution of these hydrophobic anticholinergic compounds. Five anticholinergic compounds are resolved successfully with a PRP-1 polymeric column and a slightly basic mobile phase, but a C8 silica column is better suited for the more hydrophobic compounds (cyclobenzaprine, procyclidine, and dicyclomine).

2,2'-Dipyridyl↗