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A 51-year-old gentleman was admitted with a history of severe depression with marked agitation in the background of cocaine abuse. He had multiple medical problems like deep vein thrombosis, hepatitis C and tardive dyskinesia. Besides him being on antidepressant medication, risperidone was prescribed by his previous physician for a period of 2 years. Since commencement on this medication, he developed tardive dyskinesia that was never recognised and managed. This side effect caused additional anxiety to the patient and affected his social life. Upon admission, his medications were reviewed, risperidone was gradually withdrawn and procyclidine 2 mg twice daily was added. After being discharged from hospital, he was regularly seen in the out patient clinic. Within 3 months, his tardive dyskinesia improved tremendously, his quality of social life got better and by virtue of this, there was a faster remission in his depression and anxiety symptoms.
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.
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.
Dysphoric reactions to antipsychotic medication are well recognised in association with akathisia, but can also occur independently.
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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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.
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.
The goals of the present study were: (1) to investigate the binding properties of (R)- and (S)-procyclidine and two achiral derivatives of muscarinic M1, M2 and M4 receptor subtypes and (2) to identify the interactions which allow these receptors to discriminate between the two stereoisomers. (R)-Procyclidine showed a higher affinity for human neuroblastoma NB-OK 1 muscarinic M1 and rat striatum muscarinic M4 receptors, as compared to rat cardiac M2 receptors. (S)-Procyclidine had a 130-fold lower affinity than (R)-procyclidine for M1 and M4 receptors, and a 40-fold lower affinity for M2 receptors. Pyrrinol, the achiral diphenyl derivative with the cyclohexyl group of (S)-procyclidine replaced by a phenyl group, has an eight-fold lower affinity for M1 and M4 receptors, as compared to (R)-procyclidine, and a three-fold lower affinity for M2 receptors. Hexahydro-procyclidine, the corresponding achiral dicyclohexyl compound, had a 10- to 20-fold lower affinity than (R)-procyclidine for the three receptors. The increase in binding free energy, which is observed when the phenyl and cyclohexyl groups of procyclidine are separately replaced by cyclohexyl and phenyl groups, respectively, was additive in the case of M1, M2 and M4 receptors. This indicates that the muscarinic receptor stereoselectivity was based on the coexistence of two binding sites, one preferring a phenyl rather than cyclohexyl group and the second preferring a cyclohexyl rather than a phenyl group. In addition, there were also binding sites for the hydroxy moiety and the protonated amino group of the ligands. The greater affinity and stereoselectivity of M1 and M4 muscarinic receptors for (R)-procyclidine reflected the better fit of the cyclohexyl group of (R)-procyclidine to the subsite of M1 and M4 as compared to M2 receptors.
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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.
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Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endophenotypes, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder. However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acoustically elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version) were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endophenotypes, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.
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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.
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.
The effects of clinically available drugs targeting muscarinic cholinergic, adrenergic, dopaminergic, and serotonergic receptors; intracellular calcium levels and/or the function of calcium-dependent biochemical pathways; ion channels; and cellular pumps were tested against a keratitis isolate of Acanthamoeba castellanii belonging to the T4 genotype. In vitro growth inhibition (amoebistatic) assays were performed by incubating A. castellanii with various concentrations of drugs in the growth medium for 48 h at 30°C. To determine amoebicidal effects, amoebae were incubated with drugs 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. Of the eight drugs tested, amlodipine, prochlorperazine, and loperamide showed potent amoebicidal effects, as no viable trophozoites were observed (>95% kill rate), while amiodarone, procyclidine, digoxin, and apomorphine exhibited up to 50% amoebicidal effects. In contrast, haloperidol did not affect viability, but all the drugs tested inhibited A. castellanii growth. Importantly, amlodipine, prochlorperazine, and loperamide showed compelling cysticidal effects. The cysticidal effects were irreversible, as cysts treated with the aforementioned drugs did not reemerge as viable amoebae upon inoculation in the growth medium. Except for apomorphine and haloperidol, all the tested drugs blocked trophozoite differentiation into cysts in encystation assays. Given the limited availability of effective drugs to treat amoebal infections, the clinically available drugs tested in this study represent potential agents for managing keratitis and granulomatous amoebic encephalitis caused by Acanthamoeba spp. and possibly against other meningoencephalitis-causing amoebae, such as Balamuthia mandrillaris and Naegleria fowleri.
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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.