Decomposition of pilocarpine eye drops assessed by a highly efficient high pressure liquid chromatographic method

Kuks, Paul F. M.; Weekers, L. E. A.; Goldhoorn, P. B.

doi:10.1007/bf01980046

Cited by 7 publications

(2 citation statements)

References 21 publications

(5 reference statements)

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“…The other chemicals used were of analytical reagent grade. Chromatographic system and conditions: The chromatographic analysis was carried out according to a method previously described by Kuks et al (1990). The HPLC system used was an Agilent 1100 s HPLC (Agilent, Santa Clara, CA, U.S.A.) consisting of a quaternary pump and a Diode Array Detector (DAD) set at wavelength of 220 nm.…”

Section: Hplcmentioning

confidence: 99%

In Vivo and In Vitro Effects of Pilocarpine: Relevance to Ictogenesis

Marchi¹,

Oby²,

Batra³

et al. 2007

Epilepsia

134

144

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Summary:Objectives: A common experimental model of status epilepticus (SE) utilizes intraperitoneal administration of the cholinergic agonist pilocarpine preceded by methylscopolamine treatment. Currently, activation of cholinergic neurons is recognized as the only factor triggering pilocarpine SE. However, cholinergic receptors are also widely distributed systemically and pretreatment with methyl-scopolamine may not be sufficient to counteract the effects of systemically injected pilocarpine. The extent of such peripheral events and the contribution to SE are unknown and the possibility that pilocarpine also induces SE by peripheral actions is yet untested.Methods: We measured in vivo at onset of SE: brain and blood pilocarpine levels, blood-brain barrier (BBB) permeability, Tlymphocyte activation and serum levels of IL-1β and TNF-α. The effects of pilocarpine on neuronal excitability was assessed in vitro on hippocampal slices or whole guinea pig brain preparations in presence of physiologic or elevated [K + ] out .Results: Pilocarpine blood and brain levels at SE were 1400 ± 200 µM and 200 ± 80 µM, respectively. In vivo, after pilocarpine injection, increased serum IL-1β, decreased CD4:CD8 T-lymphocyte ratios and focal BBB leakage were observed. In vitro, pilocarpine failed to exert significant synchronized epileptiform activity when applied at concentrations identical or higher to levels measured in vivo. Intense electrographic seizure-like events occurred only in the copresence of levels of K + (6 mM) mimicking BBB leakage.Conclusions: Early systemic events increasing BBB permeability may promote entry of cofactors (e. g. K + ) into the brain leading to pilocarpine-induced SE. Disturbance of brain homeostasis represents an etiological factor contributing to pilocarpine seizures.

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Section: Hplcmentioning

confidence: 99%

In Vivo and In Vitro Effects of Pilocarpine: Relevance to Ictogenesis

Marchi¹,

Oby²,

Batra³

et al. 2007

Epilepsia

134

144

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“…Kuks et al (1990). Tissue samples were weighed and transferred to round bottom 15 ml tubes with 2 ml of ice-cold saline.…”

Section: Published In Final Edited Form Asmentioning

confidence: 99%

Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability

et al. 2008

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Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood-brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20-25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 μM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 μM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography.We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 November 9. Published in final edited form as:Neuroscience. Pilocarpine is a non-selective muscarinic agonist (Maslanski et al., 1994) with a relatively high affinity for CNS muscarinic receptors (Hedlund and Bartfai, 1981) commonly utilized to develop an experimental model of temporal lobe epilepsy (Turski et al., 1989;Cavalheiro et al., 2006; but see Sloviter, 2005). In different animal species, i.p. injection of pilocarpine induces a convulsive status epilepticus (SE; i.e. sub-continuous generalized seizures that recur for several hours), followed within 2 weeks by a chronic epileptic condition that mimics human temporal lobe epilepsy (Cavalheiro et al., 2006). The initial SE is thought to be triggered by a cholinergic activation of excitatory neurons in specific brain regions that include limbic cortices. Such an effect is supposedly mediated by micro-molar concentrations of pilocarpine, since this drug shows a relatively poor brain penetration (Omori et al., 2004). Although studies directly assessing pilocarpine penetration across the ...

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Organic Stereochemistry. Part 2

Testa

2013

Helvetica Chimica Acta

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This review continues a general presentation of the principles of stereochemistry with special reference to medicinal compounds. Here, we explore stereoisomeric compounds characterized by a single or several stereogenic centers (often also called centers of chirality). The main focus will be on chiral tetrahedral structures, namely a) tetracoordinate centers, and b) tricoordinate centers where an electron lone pair plays the role of the fourth substituent, forming a tetrahedron. Following an overview of the main tetrahedral structures of interest in biological and medicinal stereochemistry, the review places emphasis on explaining the two dominant conventions, namely the d,l‐ and (R,S)‐convention, the latter being known as the CIP (CahnIngoldPrelog) convention. The review ends with a discussion of reactions of stereoisomerization at stereogenic C‐centers and its relevance to drug research.

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Decomposition of pilocarpine eye drops assessed by a highly efficient high pressure liquid chromatographic method

Cited by 7 publications

References 21 publications

In Vivo and In Vitro Effects of Pilocarpine: Relevance to Ictogenesis

In Vivo and In Vitro Effects of Pilocarpine: Relevance to Ictogenesis

Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability

Organic Stereochemistry. Part 2

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