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Enantioseparation of atropine by capillary electrophoresis using sulfated beta-cyclodextrin: application to a plant extract.

Mateus L, Cherkaoui S, Christen P, Veuthey JL.

Laboratory of Pharmaceutical Analytical Chemistry, University of Geneva, Switzerland.

A capillary zone electrophoresis (CZE) method, with sulfated beta-CD as chiral selector, was optimized by means of an experimental design for the enantioseparation of atropine. In this study, a central composite design was used and the following factors were varied simultaneously: buffer concentration, buffer pH and sulfated beta-CD concentration. The resolutions between littorine and its positional isomer ((-)-hyoscyamine) and between atropine enantiomers, as well as the separation time and generated current were established as responses. A model was obtained for each response by linear multiple regression of a second-degree mathematical expression. The most favorable conditions were determined by maximizing the resolution between atropine enantiomers and by setting the other responses at threshold values. Successful results were obtained with a 55 mM phosphate buffer at pH 7 in the presence of 2.9 mM sulfated-beta-CD at 20 degrees C and 20 kV. Under these optimized conditions, a baseline separation of littorine and atropine enantiomers was achieved in less than 5 min. Finally, the method allowed the enantiomeric separation of atropine in a pharmaceutical formulation and was also found to be suitable for the enantiomeric purity evaluation of (-)-hyoscyamine in plant extracts, in relation with the extraction procedure. It was demonstrated that supercritical fluid extraction induced less racemization than classical liquid-solid extraction procedures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10701678&dopt=Abstract hyoscyamine Levbid SL



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Biosynthetic studies on the tropane ring system of the tropane alkaloids from Datura stramonium.

Duran-Patron R, O'Hagan D, Hamilton JT, Wong CW.

Department of Chemistry, University of Durham Science Laboratories, UK.

Isotopic labelling experiments have been carried out in Datura stramonium root cultures with the following isotopically labelled precursors; [2H3]- [2-13C, 2H3]-, [1-13C, 18O2]-acetates, 2H2O, [2H3-methyl]-methionine, [2-13C]-phenyllactate, [3-2H]-tropine and [2'-13C, 3-2H]-littorine. The study explored the incorporation of isotope into the tropane ring system of littorine 1 and hyoscyamine 2 and revealed that deuterium from acetate is incorporated only into C-6 and C-7, and not into C-2 and C-4 as previously reported. Oxygen-18 was not retained at a detectable level into the C(3)-O bond from [1-13C, 18O2]-acetate. The intramolecular nature of the rearrangement of littorine 1 to hyoscyamine 2 is revealed again by a labelling study using [2'-13C, 3-2H]-littorine, [2-13C]-phenyllactate and [3-2H]-tropine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10783983&dopt=Abstract hyoscyamine Levbid SL



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Modulation of acetylcholine release by presynaptic muscarinic autoreceptors.

Re L.

Institute of Experimental and Clinical Medicine, University of Ancona, Italy. lambertore popcsi.unian.it

The existence of a modulatory system controlling the acetylcholine (ACh) release was first proposed for the nicotinic subtype in 1962. Following the first observation of a possible positive feedback loop activated by the released Ach, many studies were oriented in the investigation of the involved presynaptic autoreceptors. Most of the data have been obtained at the motor end-plate, commonly defined as the simplest model of peripheral synapse. The characterization of the chemical transmission since its first proposal showed a more complex pattern involving both the cholinergic and the adrenergic systems. It is now evident that this regulation is widespread both in the central and in the peripheral nervous system. The evidence that the release of ACh can be up- or down-regulated by the transmitter itself (autoregulation) or other neuromediators (heteroregulation) is now proved. In the last decades the attention was focused to the identification of the receptor subtypes located on the releasing nerve terminal. For the purpose, different techniques were used in the various laboratories. The functional approach was based mainly on the electrophysiological characterization of the events evolved prior, during and after the activation of the motor endplate nicotinic receptor. On the other hand, the overflow studies were carried out using radiolabeled ACh (rACh) obtained treating muscle fibers with radioactive choline (rCh). Many scientific papers proposed common data indicating a clear positive (nicotinic) or negative (muscarinic) modulation of the ACh release. Temporally, the description of the muscarinic regulation followed the discovery of the nicotinic one. However, by a pure pharmacological point of view it represents a challenge due to the more complex organization and function. In the peripheral nervous system, i.e. neuromuscular, the meaning of both the muscarinic and nicotinic modulations may appear as free of function. Conversely, in the central systems some effects, such as antinociception and others, could represent the basis of a functional activity such as proposed by Corrado group. The complete characterization of this phenomenon by a physiological and a pharmacological point of view could represents the goal for future uses and therapeutic potential. The present review illustrates the know how and the efforts in the characterisation of the muscarinic regulation of transmitter release from the beginning of its discovery trying to order the numerous scientific data published in this field. Furthermore, our personal data obtained with the Loose Patch Clamp (LPC) technique will be briefly presented and discussed. Our work was built up using agonists and antagonists of the muscarinic receptor subtype in the aim of better characterize the modulation function of the mediator Ach. We used carbachol (Cch), oxotremorine (Oxo) and dl-muscarine as agonists and 1-hyoscyamine, pirenzepine, ipratropium, 11[[2-1[(diethylamino) methyl-1-piperidinyl]-acetyl]-5, 11-dihydro-6H-pyrido [2,3-b][1,4] benzodiazepine-6-one (AFDX-116), methoctramine and 1,1-dimethyl-4 diphenylacetoxy-N-methylpiperidine (4-DAMP) as antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10797864&dopt=Abstract hyoscyamine Levbid SL



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Tropane alkaloids from Latua pubiflora.

Munoz O, Casale JF.

Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile. omunoz uchile.cl

Four known tropane alkaloids were isolated from the leaves of the endemic Chilean plant Latua pubiflora (Solanaceae). For the first time; 3alpha-cinnamoyloxitropane and apoatropine are reported in this plant. Scopolamine and hyoscyamine were previously reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14577619&dopt=Abstract hyoscyamine Levbid SL



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Pro-cognitive activity induced in the rat by low doses of R-(+)-hyoscyamine.

Ghelardini C, Galeotti N, Bartolini A.

Department of Pharmacology, Viale G. Pieraccini 6, 1-50139, Florence, Italy.

In the passive-avoidance test R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) prevented amnesia induced by antimuscarinic treatment with AF-64A and benzhexol. The antiamnesic effect of R-(+)-hyoscyamine was comparable to that exerted by the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) i.p) and the M(1) selective agonist AF-102B (10 mg kg(-1) i.p.). In the social learning test, R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) in adults rats, reduced the duration of active exploration of the familiar partner in the second session of the test similar to the nootropic drug piracetam (30 mg kg(-1) i.p.). These results demonstrated the ability of R-(+)-hyoscyamine to modulate memory functions and suggest that R-(+)-hyoscyamine could be useful in the treatment of cognitive deficits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10930723&dopt=Abstract hyoscyamine Levbid SL