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PubMed2001

Effects of advanced candidate anticonvulsants under two rodent models of 'counting'.

The behavioral effects of a variety of advanced candidate anticonvulsants for organophosphate-induced seizures were evaluated under two rodent 'counting' models. Rats pressed the left of two levers a number of times (a 'run') before pressing the right lever. The targeted performance was a run of 12. The training contingency was a targeted percentile schedule, which provided food if the current run was closer to 12 than two-thirds of the most recent runs. Baseline performance was well controlled by the target, with mean run lengths slightly less than 12. Once this performance was acquired, half the subjects were switched to a procedure providing food following runs of different lengths with a probability yoked to previous percentile schedule performance. The two procedures generate comparable baseline performances, but behavioral disruptions generate reinforcement loss only under the yoked procedure. Atropine, scopolamine, azaprophen, aprophen, trihexyphenidyl, procyclidine, benactyzine, biperiden and diazepam were tested. All produced dose-related decreases in overall run length and response rate. Responding was disrupted more readily under the yoked procedure than under the percentile procedure. Only atropine affected responding at doses below those effective against soman-induced seizures. Of the present candidates, trihexyphenidyl, procyclidine, benactyzine and biperiden appear most promising for further development.

Animals↗
PubMed2000

Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs.

A total of eight anticholinergic drugs (aprophen, atropine, azaprophen, benactyzine, biperiden, procyclidine, scopolamine, trihexyphenidyl) were tested in parallel with diazepam for the ability to terminate seizure activity induced by the nerve agent soman. Guinea pigs, implanted with electrodes to record cortical electroencephalographic (EEG) activity, were pretreated with pyridostigmine Br (0.026 mg/kg, i.m.) and 30 min later challenged with 2 x LD50 soman (56 microg/kg, s.c.) followed 1 min later by treatment with atropine SO4 (2 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All guinea pigs developed sustained seizure activity following this treatment. Dose-effect curves were determined for the ability of each drug to terminate seizure activity when anticonvulsant treatment was given either 5 or 40 min after seizure onset. Body weight gain and recovery of behavioral performance of a previously trained one-way avoidance task were measured after exposure. With the exception of atropine, all anticholinergic drugs were effective at lower doses than diazepam in terminating seizures when given 5 min after seizure onset; benactyzine, procyclidine and aprophen terminated seizures most rapidly while scopolamine, trihexyphenidyl, biperiden, and diazepam were significantly slower. When given 40 min after seizure onset, diazepam was the most potent compound tested, followed by scopolamine, benactyzine and biperiden; atropine was not effective when tested 40 min after seizure onset. For diazepam, the time to terminate the seizure was the same whether it was given at the 5- or 40-min delay. In contrast, most anticholinergics were significantly slower in terminating seizure activity when

Animals↗
PubMed1986

A further search for selective antagonists at M2-muscarinic receptors.

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.

Animals↗
PubMed1988

Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung.

The anticholinergic antiparkinsonian drugs biperiden, benztropine, trihexyphenidyl, methixene, and procyclidine were compared with atropine and pirenzepine, as well as with orphenadrine, amantadine and some standard antidepressives and neuroleptics in their ability to inhibit the binding of tritiated quinuclidinyl benzilate (QNB) to the muscarinic receptors in rat brain cortical tissue. Most of the antiparkinsonian drugs studied were potent inhibitors of (-)3H-QNB binding, when compared to atropine (IC50-value = 0.22 microM), the IC50-values ranging from 0.0084 microM (biperiden) to 0.07 microM (procyclidine). Orphenadrine had a low and amantadine no evident affinity for muscarinic receptors. With the exception of pirenzepine and biperiden the inhibition curves were steep and parallel, giving linear Hill plots with coefficients close to unity. The binding profile of atropine, pirenzepine, and biperiden was further studied in heart and lung tissues, atropine showing only small divergences in its binding to the different tissues, but biperiden and pirenzepine having five to ten times lower affinity in the peripheral tissues than in the brain. The results confirm the high affinity of most of the antiparkinsonian drugs for brain muscarinic receptors. The dissociation constants agree with the average clinical doses of the drugs. It must be remembered, however, that the binding data may represent multiple events at receptor sites because most of the drugs used are mixtures of stereoisomers. Thus further studies using individual enantiomers are needed to compare more directly binding data between the compounds.

Animals↗
PubMed2004

Drug-human serum albumin binding studied by capillary electrophoresis with electrochemiluminescence detection.

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.

Antiparkinson Agents↗
PubMed1989

Betel nut-induced extrapyramidal syndrome: an unusual drug interaction.

Two cases are described of chronic schizophrenic patients maintained on depot neuroleptics, who developed severe extrapyramidal symptoms following a period of heavy betel nut consumption. A mechanism for this effect is proposed based on the pharmacological antagonism of the anticholinergic agent, procyclidine, by the active alkaloid ingredient of the betel, arecoline.

Antipsychotic Agents↗
PubMedDate not supplied

Differential effects of central and peripheral cholinergic blockade on water consumption by rats.

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.

Animals↗
PubMed1986

A common structural model for central nervous system drugs and their receptors.

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.

Amphetamine↗
PubMed2003

Probable dystonic reaction after a single dose of cyclizine in a patient with a history of encephalitis.

A patient underwent an emergency Caesarean section under general anaesthesia for an antepartum haemorrhage. Following delivery of a live infant, cyclizine was administered in accordance with departmental anti-emetic protocol. On awakening she was confused, slow to articulate and had slurred speech. A computed tomography (CT) scan, which was performed to exclude an intracranial event, was normal. Her symptoms were suggestive of a lingual-facial-buccal dyskinesia as seen with dopamine antagonists. A presumptive diagnosis of a dystonic reaction to cyclizine was made. She received two doses of procyclidine before her symptoms completely resolved. Cyclizine has had a resurgence in popularity owing to the recent withdrawal of droperidol and anaesthetists should be aware that, although extremely rare, dystonic reactions may occur with this agent.

Acute Disease↗
PubMed1989

A pilot study of the role of prophylactic antiparkinson treatment during neuroleptic therapy.

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.

Adult↗
PubMed1996

Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents.

Neuroleptic malignant syndrome (NMS) is a severe side-effect of neuroleptic treatment. It is usually related to hypodopaminergic activity. A young schizophrenic patient who developed a typical episode of NMS during abrupt withdrawal of long-acting neuroleptic combined with anticholinergic treatment is described. NMS appeared following combined neuroleptic/ anticholinergic withdrawal and responded to procyclidine administration. The appearance of NMS after discontinuation of antidopaminergic treatment seems to be in conflict with the hypodopaminergic theory of this adverse effect. It is suggested that simultaneous withdrawal of both anticholinergic and neuroleptic medications, mainly long-acting neuroleptics, seems to be a risk factor for NMS.

Adult↗
PubMed1986

An experimental evaluation of the euphoric properties of antiparkinson drugs on psychotic patients.

Seven psychotic inpatients (two women and five men) aged between 18 and 74 years, treated with neuroleptic and antiparkinson drugs, participated in a double-blind study with 1/3 DDD (Defined Daily Dose) of procyclidine, orphenadrine, or trihexyphenidyl hydrochloride against placebo. Euphoric effects were scored on a self-rating scale and extrapyramidal side-effects on the Simpson-Angus rating scale at drug administration and 1, 3 and 6 h thereafter. With regard to euphoric effect, there was a significant (P less than 0.02) difference between start and end point (0 and 6 h) for placebo but not for the active antiparkinson drugs. There was no significant difference in extrapyramidal side-effects. No preference of drug was found, and it was not possible to recognize the patient's own drug among the tested drugs. Side-effects from the antiparkinson drugs were also measured prior to the administration. Five patients did not return to their earlier antiparkinson drugs after the study.

Adolescent↗
PubMed2006

Efficacy of immediate and subsequent therapies against soman-induced seizures and lethality in rats.

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.

Animals↗
PubMed1973

Development of extrapyramidal symptoms in hypertensive patients treated with diazoxide.

Extrapyramidal symptoms developed a variable time after the start of treatment with oral diazoxide in 15% of a series of 100 severely hypertensive patients. Six illustrative cases are described. Treatment with diazoxide could be continued in four of these. The symptoms are usually controllable either by dosage adjustment or by the use of diazepam or procyclidine. There was no evidence of irreversibility of the extrapyramidal syndromes observed.

Adult↗
PubMed1991

Urinary retention--an unusual dystonic reaction to continuous metoclopramide infusion.

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.

Child, Preschool↗
PubMed2001

Lessons to be learned: a case study approach. 'Spontaneous' intraperitoneal bladder rupture in a psychiatric patient--with diagnostic difficulties.

The case described here is that of a 34-year-old woman with a psychiatric disorder who was referred to the local surgical receiving unit with abdominal pain and vomiting. She remained well and fully mobile but refused blood investigations until the day following admission. At that time the tests showed a picture of acute renal failure. With the development of increasing abdominal tenderness and pyrexia she was persuaded to have a laparotomy which demonstrated a small tear at the dome of the bladder. Her deranged blood biochemistry returned to normal within 11 h following surgery. The important points demonstrated in this case study are the special clinical difficulties encountered in psychiatric patients, which may consequently lead to delay in diagnosis. This delay allowed significant peritoneal reabsorption of urea and creatinine, which masqueraded as 'acute renal failure' on biochemical testing. The case also highlights the use of procyclidine, commonly used in patients with psychiatric disorders; urinary retention is a recognised side effect of this drug--and it is possible that such retention together with a minor and hence easily overlooked episode of trauma, may have contributed to the patient's condition.

Adult↗
PubMed1995

Antipsychotic drug-induced dysphoria.

BACKGROUND: Dysphoric reactions to antipsychotic medication are well recognised in association with akathisia, but can also occur independently. METHOD: Fifty-one healthy volunteers were given haloperidol 5 mg in two consecutive pharmacokinetic studies. RESULTS: Dysphoria occurred in about 40% of the subjects on both occasions, but akathisia was only detected in 8% (first study) and 16% (second study). All adverse effects were transient and were abolished in nine of the ten subjects given procyclidine. CONCLUSIONS: While dysphoria is a well-recognized reaction in healthy volunteers, it is probably insufficiently recognised in patients, particularly if it occurs in the absence of akathisia. Better detection could improve compliance in patients.

Adult↗
PubMedDate not supplied

[Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs].

Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. However, according to different epidemiological studies clozapine can induce neutropenia in less than 3% of patients and may represent a major problem for the management of treatment-resistant patients not responding to conventional or other atypical antipsychotics. Recently, a few case of neutropenia have been reported following the addition of other medications to clozapine, notably paroxetine, risperidone, trimethoprim-sulfamethoxazole and erythromycin. In our report we present the case of Mr A., a 40-year-old Caucasian patient with a 20-year history of paranoid schizophrenia. After numerous trials with conventional antipsychotics, partial remission of psychotic symptoms was obtained with clozapine. Over the past eight years during his treatment with clozapine, the patient presented 2 episodes of neutropenia. The first episode came five years after starting clozapine and was attributed to the addition 6 weeks earlier of haloperidol (2 mg/day) to clozapine (250 mg/day) and divalproex (1,500 mg/day). Recently, one week after the addition of risperidone (2 mg/day) to clozapine (550 mg/day), leukocytes count dropped from 12 100/mm(3) to 5 700/mm(3) and neutrophils from 7 400/mm(3) to 900/mm(3). The patient was also taking haloperidol (4 mg/day), methotrimeprazine (35 mg/day), procyclidine (5 mg/day) and valproic acid (1,500 mg/day). Twelve days after discontinuation of risperidone, leukocytes and neutrophils count increased to 11,100/mm(3) and 6,300/mm(3) respectively while the treatment with clozapine was continued. The first eighteen weeks of treatment represent the period where the risk of neutropenia is the highest. In our patient neutropenia occurred 5 and 7 years after starting clozapine. It is proposed that the two neutropenic episode were precipitated by adding respectively haloperidol and risperidone to clozapine. Also, divalproex can potentially cause a decrease in white blood cell count and may have contributed to the two neutropenic episode. It is suggested that drug interactions may be responsible for neutropenia in clozapine treated patients and that clozapine should not necessarily be discontinued in the presence of neutropenia. Also we propose that hematological surveillance should be done on a weekly basis for 4 to 6 weeks following the addition of psychotropic drugs known for their potential to cause neutropenia when associated with clozapine. Therefore polypharmacy may contribute to cause neutropenia in clozapine treated patients and that discontinuation of an antipsychotic should be done before introducing another one.

Adult↗