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Dushyant Patel Introduction

S.K.P.C.P.E.R., Kherva 5 M .Pharm. Thesis

1.2.3 MECHANISM OF ACTION:

¾ The mechanism by which GBP exerts its analgesic action is unknown, but in animal

models of analgesia, GBP prevents allodynia (pain-related behavior in response to a

normally innocuous stimulus) and hyperalgesia (exaggerated response to painful

stimuli). In particular, GBP prevents pain-related responses in several models of

neuropathic pain in rats or mice (e.g. spinal nerve ligation models, streptozocin-induced

diabetes model, spinal cord injury model, acute herpes zoster infection model). GBP also

decreases pain-related responses after peripheral inflammation (carrageenan footpad test,

late phase of formalin test). GBP did not alter immediate pain-related behaviors (rat tail

flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad

heat irradiation test). The relevance of these models to human pain is not known.

¾ The mechanism by which GBP exerts its anticonvulsant action is unknown, but in animal

test systems designed to detect anticonvulsant activity, GBP prevents seizures as do other

marketed anticonvulsants. GBP exhibits antiseizure activity in mice and rats in both the

maximal electroshock and pentylenetetrazole seizure models and other preclinical

models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human

epilepsy is not known.

¾ GBP is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid)

but it does not modify GABA

or GABA

radioligand binding, it is not converted

metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake

or degradation. GBP was tested in radioligand binding assays at concentrations up to 100

µM and did not exhibit affinity for a number of other common receptor sites, including

benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate,

strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta

adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or

D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-

sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-

sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate.

Furthermore, GBP did not alter the cellular uptake of dopamine, noradrenaline, or

serotonin.

¾ In vitro studies with radiolabeled GBP have revealed a GBP binding site in areas of rat

brain including neocortex and hippocampus. A high-affinity binding protein in animal

brain tissue has been identified as an auxiliary subunit of voltage-activated calcium

channels. However, functional correlates of GBP binding, if any, remain to be

elucidated.

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Samsung RT34M Manuale Utente Pagina 17