Effects of Pirenzepine on Pupil Size and Accommodation in Rhesus Monkeys

Ostrin, Lisa A; Frishman, Laura J.; Glasser, Adrian

doi:10.1167/iovs.04-0258

Cited by 22 publications

(15 citation statements)

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“…However, the specific site of action of these antagonists remains unclear, partly due to the lack of specificity and high doses required to inhibit myopia. Although pirenzepine is termed an M 1 selective antagonist, it also demonstrates subtype cross-reactivity to other receptors causing significant increase in pupil diameter in tree shrews, 7 significant increase in pupil size and decrease in accommodation in rhesus monkeys, 11 and blurred near vision in human children. 12 As the constriction of the iris sphincter muscle is mediated through M 3 muscarinic receptors this highlights the crossreactivity.…”

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confidence: 99%

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Arumugam

McBrien²

2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The broadband muscarinic antagonist atropine is effective in stopping the progression of myopia in animals and humans. The partially selective M 1 /M 4 antagonist pirenzepine also slows progression of myopia, although not as effectively as atropine. Due to the supra maximal doses utilized in these studies, it is unclear if this antimyopia effect occurs through a receptoral-based mechanism, and if so, which receptors are involved. Studies in chicks indicate the involvement of the M 4 muscarinic receptor. The current study investigated the effect of the highly selective muscarinic antagonists Muscarinic Toxin 3 (MT3) (M 4 selective) and Muscarinic Toxin 7 (MT7) (M 1 selective) on experimental myopia in a mammalian model. METHODS.Tree shrews (n ¼ 23) underwent daily intravitreal injections of MT3, MT7, or vehicle (phosphate buffered saline) for five days in the treated eye, combined with deprivation of vision with a translucent occluder (MD). The contralateral eye was unocccluded and underwent intravitreal injections of vehicle for the same period. Two additional groups (n ¼ 10) underwent daily intravitreal injections of MT7 or vehicle for 10 days in the treated eye combined with negative lens (À9.5 diopter [D]) defocus (LIM). The control eye was injected with saline and wore a plano lens. RESULTS. Both MT3 and MT7 treatment reduced the development of deprivation-induced myopia (treated-control eye [T-C]; vehicle-MD; À4.3 6 0.6 D versus MT3-MD; À0.7 6 0.2 D and MT7-MD; À0.7 6 0.4 D; P < 0.001). MT7 treatment was effective at inhibiting lens-induced myopia (T-C; vehicle-LIM; À4.6 6 0.5 D versus MT7-LIM; 0.2 6 0.2 D; P < 0.05). CONCLUSIONS. The findings demonstrate that inhibition of formdeprivation myopia by muscarinic antagonists involves both M 4 and M 1 muscarinic receptor signaling pathways in mammals. (Invest Ophthalmol Vis Sci. 2012;53:5827-5837) DOI: 10.1167/iovs.12-9943T he broadband muscarinic antagonist, atropine, has been shown to prevent the development of myopia in humans. [1][2][3] In addition, atropine and the partially selective muscarinic antagonist, pirenzepine, have been shown to reduce the development of myopia in several animal models, including rhesus monkeys, 4 chicks, 5,6 and tree shrews. 7,8 However, the disadvantage of atropine is that it is a nonselective muscarinic antagonist and has unwanted ocular and gastric adverse effects. Studies of pirenzepine, a partially selective M 1 /M 4, 6,7,9 and himbacine, a partially selective M 4 /M 2 antagonist, 10 have shown them to be effective at slowing the progression of myopia. However, the specific site of action of these antagonists remains unclear, partly due to the lack of specificity and high doses required to inhibit myopia. Although pirenzepine is termed an M 1 selective antagonist, it also demonstrates subtype cross-reactivity to other receptors causing significant increase in pupil diameter in tree shrews, 7 significant increase in pupil size and decrease in accommodation in rhesus monkeys, 11 and blurred near vision in human childr...

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Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Arumugam

McBrien²

2012

Invest. Ophthalmol. Vis. Sci.

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“…In particular, muscarinic antagonists have been promising and were successfully tested in animal models [18,35,37] and children (e.g., [25,31,32]). However, they have side effects like mydriasis (e.g., [21]), cycloplegia (atropine is the most common and powerful cycloplegic drug), corneal dryness [32] and tend to lose their effects after extended periods of application [25,32]. Linked to cycloplegia, the children treated also need to wear reading glasses.…”

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confidence: 99%

Glucagon-related peptides in the mouse retina and the effects of deprivation of form vision

Mathis

Schaeffel

2006

Graefe's Arch Clin Exp Ophthalmol

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“…The corneal permeation is low [3]. Ostrin et al [4] in University of Houston reported that subconjunctival injections of 0.02% or greater pirenzepine resulted in a significant decrease in accommodation, while subconjunctival injections of 0.002% or less pirenzepine did not decrease accommodation. The results indicated that ocular bioavailability of pirenzepine is important to prevent form-deprivation myopia.…”

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confidence: 99%

HPLC determination of pirenzepine dihydrochloride in rabbit aqueous humor

Yang

et al. 2005

Journal of Chromatography B

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Effects of Pirenzepine on Pupil Size and Accommodation in Rhesus Monkeys

Abstract: Subconjunctival injections of 0.02% or greater pirenzepine result in a significant decrease in accommodation and are probably acting through nonselective muscarinic antagonism. Subconjunctival injections of 0.002% or less pirenzepine do not decrease EW-stimulated accommodation.

Cited by 22 publications

References 27 publications

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Glucagon-related peptides in the mouse retina and the effects of deprivation of form vision

HPLC determination of pirenzepine dihydrochloride in rabbit aqueous humor

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Effects of Pirenzepine on Pupil Size and Accommodation in Rhesus Monkeys

Abstract: Subconjunctival injections of 0.02% or greater pirenzepine result in a significant decrease in accommodation and are probably acting through nonselective muscarinic antagonism. Subconjunctival injections of 0.002% or less pirenzepine do not decrease EW-stimulated accommodation.

Cited by 22 publications

References 27 publications

Muscarinic Antagonist Control of Myopia: Evidence for M4and M1Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M4and M1Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Glucagon-related peptides in the mouse retina and the effects of deprivation of form vision

HPLC determination of pirenzepine dihydrochloride in rabbit aqueous humor

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Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew

Muscarinic Antagonist Control of Myopia: Evidence for M₄and M₁Receptor-Based Pathways in the Inhibition of Experimentally-Induced Axial Myopia in the Tree Shrew