Development of a new inhibitor of glucosylceramide synthase.
(1/8)
Analogs of the potent inhibitor of glucosylceramide (GlcCer) synthase, D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), based on substitutions in the palmitoyl group were made by means of a stereo-selective synthetic method in order to elucidate the role of the hydrophobic portion in both the inhibitory action toward the enzyme and the biological effects. While P4 strongly inhibited GlcCer synthase with an IC(50) of 0.5 microM in vitro, it also inhibited cell growth by 50% at the concentration of 7 microM. The shorter N-acyl chain analogs including decanoyl, octanoyl, and hexanoyl groups showed similar IC(50) values for GlcCer synthase (around 2 microM) but the hexanoyl analog exhibited only a slight inhibitory effect on cell growth, showing the dissociation between GlcCer depletion and cell growth. Several compounds which exhibit similar hydrophobicity to the hexanoyl analog of P4 were subsequently designed. We found that D-threo-1-phenyl-2-benzyloxycarbonylamino-3-pyrrolidino-1-pr opanol (PBPP) was a most potent inhibitor, showing an IC50 of 0.3 microM. In cultured cells, PBPP was able to deplete glycosphingolipids without affecting cell growth or the ceramide level. (+info)
Effects of procyclidine on eye movements in schizophrenia.
(2/8)
Smooth pursuit eye movement (SPEM) and antisaccade deficits are observed in the schizophrenia spectrum and have been used to study the pathophysiology as well as the genetic basis of this condition. The neurotransmitter acetylcholine has been implicated in a number of cognitive processes thought to underlie SPEM and antisaccade performance. This study investigates effects on eye movements of procyclidine, an anticholinergic drug often administered to schizophrenic patients. A total of 13 patients completed a double-blind placebo-controlled crossover design, receiving 15 mg procyclidine and placebo. Seven participants received procyclidine first and placebo second, six participants were tested in the reverse order. SPEM and antisaccade (as well as fixation and prosaccade) eye movements were recorded using infrared oculography. Results showed that procyclidine overall, relative to placebo, mildly worsened SPEM performance, as indicated by nonsignificantly reduced gain (p=0.08) and increased frequency of intrusive anticipatory saccades during pursuit (p=0.06). A significant interaction of group and order of administration indicated that procyclidine increased the rate of antisaccade reflexive errors only when administered first; the opposite pattern was observed when placebo was administered first, likely due to the operation of practice effects at second assessment. These findings indicate that acute administration of a clinically relevant dose of procyclidine leads to mild impairments in eye movement performance in schizophrenic patients, suggesting the need to consider this compound in oculomotor studies in schizophrenia. The action of this anticholinergic drug on oculomotor performance is consistent with the hypothesized role of the cholinergic system in the cognitive mechanisms of attention and working memory, processes thought to underlie SPEM and antisaccade performance. Effects of order of administration and practice on the antisaccade task suggest that these factors need to be taken into consideration in future pharmacological studies. (+info)
Target urinary analytes for the gas chromatographic- mass spectrometric detection of procyclidine and benzhexol in drug abuse cases.
(3/8)
The two antiparkinsonian drugs procyclidine and benzhexol are presently finding considerable favor for their euphoric hallucinogenic effects among drug abusers in some countries. In anticipation of their possible scheduling in national drug laws, gas chromatography-mass spectrometry (GC-MS) methods for their detection in urine will be required. However, because of uncertainty of the metabolic fate of the two drugs in humans, the urinary target analytes for GC-MS detection were not well defined. The problem was addressed in the present study in which it was found that mono-hydroxy metabolites, where hydroxylation took place at the cyclohexane ring in both drugs, could be endorsed as the major target analytes. The metabolites could only be detected as the mono- and/or di-trimethylsilyl (TMS) derivatives. The predominance of either derivative depended on the temperature and time of heating with the derivatizing reagent. Because of the basic properties of the hydroxy metabolites, analytic method optimization was needed for their detection in urine included extraction under basic pH conditions. Urine hydrolysis with beta-glucuronidase did not have an effect on the recovery of the metabolites, but was usually performed in search for other drugs. Because of the relative abundance of ions, the electron impact mass spectra of the mono-TMS derivatives and the chemical ionization (CI) mass spectra of the mono- and di-TMS derivatives of the hydroxy metabolites of both drugs were found to be more structurally informative. The CI mass spectra of the di- TMS derivatives have the additive advantage of being potentially useful for quantitative analysis. (+info)
Interaction of atropine-like drugs with dopamine-containing neurones in rat brain.
(4/8)
1. A variety of atropine-like drugs effective in the treatment of drug-induced extrapyramidal syndromes have been investigated with regard to their interaction with dopamine-containing neurones in rat brain.2. Under some conditions benztropine, trihexyphenidyl, atropine and ethopropazine significantly antagonized the chlorpromazine-induced increase in subcortical concentrations of homovanillic acid.3. Most of the atropine-like drugs investigated also decreased the turnover of dopamine in the subcortex as measured by following the disappearance of dopamine after administration of alpha-methyl-p-tyrosine.4. These findings are suggestive that an imbalance between a dopaminergic and cholinergic system might be closely linked to the pathogenesis of extra-pyramidal movement disorders. (+info)
Development of extrapyramidal symptoms in hypertensive patients treated with diazoxide.
(5/8)
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. (+info)
A comparison of stereospecificity at central and peripheral 'muscarine-sensitive' acetylcholine receptors: observations with the enantiomeric forms of procyclidine and tricyclamol.
(6/8)
1 Procyclidine resembles hyoscine in enhancing the effects of amphetamine on ipsiversive turning by mice with a unilateral central dopamine lesion. 2 The stereospecific index for procyclidine is not greater than 10, in contrast to 173 for acetylcholine receptors in ileum from the same mice. 3 This suggests that although the central effects of procyclidine in this test involve acetylcholine receptors similar to those at peripheral sites, they cannot be identical with them unless there are differences at some secondary site, for example, if the weaker enantiomer were a stronger inhibitor of dopamine uptake or if there were a stereoselective uptake process for procyclidine itself. (+info)
Microbore liquid chromatography of tertiary amine anticholinergic pharmaceuticals with tris(2,2'-bipyridine)ruthenium(III) chemiluminescence detection.
(7/8)
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). (+info)
Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.
(8/8)
I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them. (+info)