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Usi innovativi di farmaci antichi
L'attuale rivalutazione medica della Cannabis e dei cannabinoidi
Cannabis e glaucoma
Dott.ssa Anna Porcella
Istituto di Neurogenetica e Neurofarmacologia
Consiglio Nazionale delle Ricerche, Cagliari
Roma 6 ottobre 2001
UNIVERSITÀ "LA SAPIENZA"
Glaucoma
A condition of the eye where the
intraocular pressure is elevated beyond the
limit that will permit normal function of
the optic nerve.
 Almost 100 million people affected
world wide
 7 million totally blind due to the
progression of their glaucomas
PRIMARY OPEN ANGLE GLAUCOMA
(POAG)
Open anterior
chamber
The obstruction of the trabecular
meshwork – Schlemm’s canal system
blocks the outflow of aqueous humor
OUTFLOW OF AQUEOUS HUMOR
Marijuana smoking was first reported to reduce
intraocular pressure (IOP) in 1971 (Hepler and
Frank, 1971)
Cloning of CB1 and CB2 receptors and the
discovery of Endocannabinoids has opened the
field for research into their physiological roles
Distribution studies in both
the brain and the periphery
have shown that in some
tissues these receptors are
colocalized
DIAGRAMMATIC CROSS SECTION
OF THE ANTERIOR CHAMBER
ANTERIOR CHAMBER
CORNEA
SCHLEMM’S CANAL
SYSTEM
IRIS
SCLERA
CILIARY MUSCLE
LENS
CILIARY BODY
CB1 mRNA IN THE RAT EYE
Porcella et al. Mol. Br. Res, 1998
CB1 mRNA IN THE HUMAN EYE
Porcella et al. Eur. J. Neurosci, 2000
CB1 PROTEIN IN THE HUMAN EYE
Porcella et al. Eur. J. Neurosci, 2000
ARMAMENTARIUM OF DRUGS IN
USE TO TREAT GLAUCOMA
a2 Adrenoreceptor agonists
b2 Adrenoreceptor antagonists
Prostaglandin Agonist
Dopamninergic agonist
Cholinergic Agonist
Carbonic Anhydrase Inhibitors
Guanylate Cyclase Activators
Adenosine agonist
NMDA Antagonist
Cannabinoids ?
Natural cannabinoids
9-THC
Cannabinol
8-tetrahydrocannabinol
Cannabidiol
Endogenous cannabinoids
Anandamide
2-AG
Synthetic cannabinoids
Nabilone
WIN 55,212-2
CP 55,940
HU 210
LY320135
SR141716A
Palmitoyl-EA
(CB2 only)
SR144528
DRUG
AEA
WIN-55,212-2
ANIMAL
MODEL
ROUTE OF
ADMIN
EFFECT ON
IOP
Normotensive
rabbits
EYE DROPS
Normotensive
rabbits
I.V.
REFERENCE
Pate et al, 1996
NONE
Hodges et al, 1997
CP-55,940
Normotensive
EYE DROPS
rabbits
Pate et al, 1998
WIN-55,212-2
Normotensive
EYE DROPS
rabbits
Song, 2000
8-THC
Normotensive
9-THC
rabbits
CANNABINOL
NABILONE
I.V.
Elsohly, 1981
EFFECT OF TOPIC WIN55212-2 ON
IOP OF GLAUCOMATOUS PATIENTS
Porcella et al. Eur. J. Neurosci, 2001
SUMMARY (1)
THE HIGH LEVEL OF CB1 mRNA AND PROTEIN IN THE
CILIARY BODY SUGGEST A LOCALIZED VASODILATION BY
CANNABINOIDS
IN ADDITION INHIBITION OF PRESYNAPTIC Ca++
CHANNELS
BY
CANNABINOIDS
MAY
REDUCE
NORADRENALINE RELEASE IN THE EYE AND THE
PRODUCTION OF AQUEOUS HUMOR
SR141716A ANTAGONIZES IOP LOWERING EFFECTS OF
CANNABINOIDS IN RABBITS SUGGESTING A DIRECT CB1
INVOLVEMENT IN THIS MECHANISM
HOWEVER THE MECHANISM BY WHICH CANNABINOIDS
ARE ABLE TO DECREASE IOP REMAINS TO BE FURTHER
ELUCIDATED
SUMMARY (2)
IOP LOWERING EFFECTS OF TOPIC WIN55212-2 IN
GLAUCOMATOUS PATIENTS ARE TIME AND DOSE
DEPENDENT
SYNTHETIC CB1 AGONISTS SHOULD DESERVE
FURTHER RESEARCH AND CLINICAL DEVELOPMENT