Preclinical Efficacy of Travoprost, a Potent and Selective FP Prostaglandin Receptor Agonist

Hellberg, Mark R.; Sallee, Verney L.; McLaughlin, Marsha A.; Sharif, Naj; DeSantis, Louis; Dean, Tom R.; Zinke, Paul W.

doi:10.1089/108076801753266802

Cited by 116 publications

(87 citation statements)

References 12 publications

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“…3,4) They lower IOP by increasing the outflow of aqueous humor via the uveoscleral pathway. 5,6) Some studies have reported the ability of PGF2α to elevate blood pressure. 7,8) Although some clinical trials have reported that topical PGF2α analogs are safe, [9][10][11] they are thought to cause systemic adverse events.…”

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confidence: 99%

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Ohyama

Kawakami

Inoue

2017

Biological & Pharmaceutical Bulletin

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Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with β-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical Key words prostaglandin F2α analog; blood pressure elevation; spontaneous reporting database; adverse event; reporting odds ratio Glaucoma is a progressive, chronic condition prevalent worldwide that causes damage to the optic nerve, resulting in irreversible visual impairment and blindness. Based on the status of the internal drainage system, this condition is divided into two major subtypes i.e., open angle and angle closure.1) Reducing intraocular pressure (IOP) is one of the best ways to prevent the development of glaucoma, although there is a kind of open angle glaucoma in which optic neuropathy occurs without IOP exceeding the normal range. The approximate number of glaucoma patients was 60.5 million in 2010 and is estimated to increase to 79.6 million by 2020.2)

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confidence: 99%

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Ohyama

Kawakami

Inoue

2017

Biological & Pharmaceutical Bulletin

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“…This is a model that we have found to be highly predictive of ocular hypotensive activity in humans (Hellberg et al, 2001;Sharif et al, 2001). Toward this end, we chose to evaluate both selective and nonselective 5-HT 1A agonists and selective 5-HT 2 antagonists.…”

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confidence: 99%

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

May¹,

McLaughlin²,

Sharif³

et al. 2003

J Pharmacol Exp Ther

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106

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Published investigations of serotonin-1A (5-hydroxytryptamine 1A ; 5-HT 1A ) receptor agonists and serotonin-2A (5-hydroxytryptamine 2A ; 5-HT 2A ) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressurelowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT 1A agonists and 5-HT 2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT 1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT 2 receptor antagonists [e.g.,pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT 1A and 5-HT 2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-␣-methyltryptamine, 5-methoxy-␣-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT 2 receptor agonist R-(Ϫ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT 2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT 2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.Identification of several of the numerous serotonin receptors in ocular tissues of the anterior segment of the eye, including the iris-ciliary body of rabbit (Chidlow et al., 1998) and human (Martin et al., 1992), suggests that this neurotransmitter may play an important role in the regulation of intraocular pressure (IOP). Serotonin (5-hydroxytryptamine; 5-HT) is also found in the aqueous humor of humans (Veglio et al., 1998) and other mammals (Boerrigter et al., 1992). These observations have generated considerable interest in the role that serotonin might have in aqueous humor dynamics and even whether 5-HT might be involved in the development of ocular hypertension and glaucoma. There have been numerous conflicting reports on the effect of 5-HT and various 5-HT receptor ligands on IOP in the rabbit, dog, and humans. These observed differences in IOP response may be due to species differences, route of administration, or the lack of 5-HT receptor selectivity of the agents evaluated. For example, 5-HT has been shown to lower IOP in rabbits following intravenous injection (Chiang, 1974). However, when injected intracamerally in the rabbit, a rise in IOP was observed (Krootila et al., 1987). Furthermore, topical ocular administration of 5-HT to the rabbit was reported to result in either a decrease (Krootila et al., 1987) or an increase (Meyer-Bothling et al., 1993) in IOP.Article, publication date, and citation information can be found at

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“…A number of prostaglandin F 2␣ (PGF 2␣ ) analogs are marketed for the treatment of ocular hypertension, a major risk factor for glaucoma. The ocular antihypertensive drugs travoprost (TRAVATAN) and latanoprost (Xalatan) are well characterized prodrugs of FP receptor agonists (Hellberg et al, 2001;Stjernschantz et al, 1995). However, two additional IOPlowering prostaglandin analogs, bimatoprost (Lumigan ) and unoprostone isopropyl ester (Rescula ), have recently been reported to have no observed activity at FP or other known prostaglandin receptors (Bhattacherjee et al, 2001;Woodward et al, 2001) despite being PGF 2␣ analogs.…”

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confidence: 99%

Real-Time Intracellular Ca²⁺ Mobilization by Travoprost Acid, Bimatoprost, Unoprostone, and Other Analogs via Endogenous Mouse, Rat, and Cloned Human FP Prostaglandin Receptors

Kelly

Williams²,

Sharif³

2003

J Pharmacol Exp Ther

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The ability of a number of prostaglandin F 2␣ (PGF 2␣) . In FP functional studies, travoprost acid (EC 50 ϭ 17.5-37 nM, n ϭ 13), bimatoprost acid (EC 50 ϭ 23.3-49.0 nM, n ϭ 6 -12), unoprostone (EC 50 ϭ 306-1270 nM, n ϭ 4 -8), bimatoprost (EC 50 ϭ 3070-3940 nM, n ϭ 4 -9), and Lumigan (EC 50 ϭ 1470 -3190 nM, n ϭ 5-9) concentration dependently stimulated [Ca 2ϩ ] i mobilization via the rat (A7r5 cells), mouse (3T3 cells), and cloned human ocular FP prostanoid receptors. The rank order of potency of these compounds at the FP receptor of the three species was similar and in good agreement with the determined binding affinities. The agonist effects of these compounds were concentration dependently blocked by the FP receptor-selective antagonist, AL-8810 (11␤-fluoro-15-epi-15-indanyl-tetranor PGF 2␣ ) (K i ϭ 0.6 -1.3 M). These studies have demonstrated that bimatoprost, unoprostone, and bimatoprost acid possess direct agonist activities at the rat, mouse, and human FP prostanoid receptor and that travoprost acid is the most potent of the synthetic FP prostaglandin analogs tested.

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Preclinical Efficacy of Travoprost, a Potent and Selective FP Prostaglandin Receptor Agonist

Cited by 116 publications

References 12 publications

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Real-Time Intracellular Ca²⁺ Mobilization by Travoprost Acid, Bimatoprost, Unoprostone, and Other Analogs via Endogenous Mouse, Rat, and Cloned Human FP Prostaglandin Receptors

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Preclinical Efficacy of Travoprost, a Potent and Selective FP Prostaglandin Receptor Agonist

Cited by 116 publications

References 12 publications

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Real-Time Intracellular Ca2+ Mobilization by Travoprost Acid, Bimatoprost, Unoprostone, and Other Analogs via Endogenous Mouse, Rat, and Cloned Human FP Prostaglandin Receptors

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About

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Real-Time Intracellular Ca²⁺ Mobilization by Travoprost Acid, Bimatoprost, Unoprostone, and Other Analogs via Endogenous Mouse, Rat, and Cloned Human FP Prostaglandin Receptors