Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin F2 alpha (PGF 2 alpha) and its analog latanoprost are effective in lowering intraocular pressure (IOP) in both animal and human subjects. There is mounting experimental evidence now which indicates that the IOP-lowering effect of these PGs occurs through an increased uveoscleral outflow of aqueous humor. The ciliary muscle constitutes the main resistance in this pathway. Work from several laboratories, including our own, has shown that in this smooth muscle PGF 2 alpha has little effect on cAMP accumulation or on Ca2+ mobilization. In the present study, we hypothesized that some of the effects of PGF2 alpha and its analogs may be mediated through the release of endogenous PGs. The purpose of this work was to determine whether or not PGF2 alpha and its analogs can enhance the release of endogenous PGs in iris and ciliary muscles isolated from different species. This report documents for the first time that exogenous PGF2 alpha and its analogs, PhXA85 and latanoprost, stimulate the formation of PGE2, PGD2 and PGF2 alpha in iris and ciliary muscles isolated from cat, bovine, rabbit, dog, rhesus monkey and human. PG-induced PG release was demonstrated by means of both radioimmunoassay and radiochromatography. Kinetic studies on cat iris revealed that PGF2 alpha-induced PGE2 release is time (t 1/2 = 1.7 min) and dose-dependent (EC50 = 45 nM). The increase in PGE2 release was blocked by indomethacin (Indo) and by dexamethasone in a dose-dependent manner with IC50 s of 9.2 nM and 2.6 microM, respectively. Furthermore, dexamethasone inhibited arachidonic acid (AA) release, suggesting the involvement of phospholipase A2 in PGF2 alpha-induced PG release. The data presented demonstrate that PGF2 alpha and its analogs interact with the PG receptor to stimulate phospholipase A2 and release AA for PG synthesis. Relaxation of ciliary muscle by PGF2 alpha and its analogs, via release of endogenous PGE2, a potent activator of the adenylate cyclase system, could in part explain how these PGs may increase uveoscleral outflow and consequently lower IOP.
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PMID:Prostaglandin F2 alpha and its analogs induce release of endogenous prostaglandins in iris and ciliary muscles isolated from cat and other mammalian species. 894 3

The cellular mechanisms mediating intraocular pressure reduction following topical prostaglandin (PG) treatments are poorly understood. To determine if PG treatments might induce altered metabolism of extracellular matrix surrounding ciliary muscle cells, confluent human ciliary smooth muscle cell cultures were exposed to PGF 2 alpha' 17-phenyltrinor-PGF2 alpha' or 11-deoxy-PGE1 for one to four days and the distributions of collagen types I, III and IV as well as laminin were determined immunocytochemically. In addition, collagen type IV and promatrix metalloproteinase III (proMMP-3) content within treated cultures was determined using sandwich ELISAs. Compared with vehicle-treated cultures, there were substantial reductions in the density and branching of the collagen type IV-immunoreactive lattice accompanied by thickening of remaining strands in all PG-treated cultures. Similar changes were seen in the distribution of laminin within all PG-treated cultures. Reductions in collagen type III immunoreactivity were seen in cultures treated with either PGF2 alpha or 17-phenyltrinor-PGF2 alpha. No changes were observed in collagen type I immunoreactivity. Quantitative analyses revealed increased amounts of collagen type IV in both the culture medium and in extracts of the cell layer in all PG-treated cultures. In addition, there were substantial increases in the concentrations of proMMP-3 in all PG-treated cultures. These results indicate that PGs induce increased turnover and remodeling of ECM adjacent to ciliary muscle cells. Such changes may contribute to increased uveoscleral outflow in vivo following topical PG treatment.
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PMID:Prostaglandin action on ciliary smooth muscle extracellular matrix metabolism: implications for uveoscleral outflow. 915 77

Prostaglandin F(2alpha) analogues have recently been introduced on the market for glaucoma treatment. While these drugs have a well-documented intraocular pressure reducing effect only a limited number of studies have been published regarding their effects on the microvasculature in the eye. Since many naturally occurring prostaglandins have marked effects on the cardiovascular system it is conceivable that synthetic prostaglandins used as glaucoma drugs may exert microvascular effects in the eye, even if they exhibit receptor selectivity. Latanoprost, the active principle of Xalatan((R)) eye drops, is a selective FP prostanoid receptor agonist, and much of the paper is focused on the microvascular effects of latanoprost and some closely related prostaglandin analogues. The purpose of the paper is to review the literature on the microvascular effects of prostaglandins in the eye, and to present some unpublished data on the effects of selective prostaglandin analogues. Most of the prostaglandin analogues studied exhibit selectivity for the FP prostanoid receptor. Results from studies with the following prostaglandin analogues are presented in the paper: PGF(2alpha)-isopropyl ester (PGF(2alpha)-IE), 17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropyl ester (17-phenyl-PGF(2a)-IE), 15-keto-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (15-keto-17-phenyl-PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19, 20-trinor-PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH-PGE(2)). The regional blood flow has been determined with radioactively labelled microspheres, the blood volume with (51)Cr labelled erythrocytes and the capillary permeability to albumin with (125)I and (131)I labelled albumin. PGF(2alpha)-IE has been shown to exert marked microvascular effects in the rabbit anterior segment including vasodilatation, increased capillary permeability, and a breakdown of the blood-aqueous barrier. 17-phenyl-PGF(2alpha)-IE, 15-keto-17-phenyl-PGF(2alpha)-IE, and PhXA34/latanoprost exerted significantly less vasodilatory effect, and little effect on capillary permeability was seen with the FP receptor agonists when studied with Evans blue. Intravenous administration of PhXA34 at a dose range of 1-100 microg/kg b.w. had no consistent effect on the regional blood flow in the eye indicating that FP receptors in the ocular blood vessels are not expressed in the rabbit, or alternatively are not functionally coupled to regulation of vascular tone. In cats topical application of PGF(2alpha)-IE had no significant effect the on the regional blood flow in cannulated eyes. No blood flow experiments were performed in intact eyes with PGF(2alpha)-IE. 17-phenyl-PGF(2alpha)-IE and latanoprost caused some vasodilation in the anterior segment. None of the analogues had any significant effect on the blood volume in the ocular tissues, but an increase in capillary permeability to albumin was seen in several tissues of the eye. However, in the eyelid, nictitating membrane and conjunctiva exposed to high concentrations of the prostaglandins no or only little leakage of albumin was detected. It appears that the intraocular microvasculature in the cat exhibits some sensitivity to FP prostanoid receptor agonists. (ABSTRACT TRUNCATED)
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PMID:Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment. 1078 18

The signal transduction pathways initiated by Ca(2+)-mobilizing agonists, such as prostaglandin F(2alpha)(PGF(2alpha)) and carbachol (CCh), leading to activation of cytosolic phospholipase A(2)(cPLA(2)) and arachidonic acid (AA) release in a wide variety of tissues remain obscure. To further define the role of protein kinases in receptor mediated stimulation of cPLA(2)and consequently AA release we have investigated the role of mitogen-activated protein (MAP) kinases and protein kinase C (PKC) in PGF(2alpha)- and CCh-induced cPLA(2)phosphorylation and AA release in cat iris sphincter smooth muscle (CISM) cells. The cells were prelabeled with [(3)H]AA for 24 hr and incubated in the absence or presence of the agonist for 5-10 min as indicated. MAP kinases activities and cPLA(2)phosphorylation were determined in immunoprecipitates obtained by using anti-p38 MAP kinase and anti-cPLA(2)antibodies. We found that: (a) PGF(2alpha)and CCh increased p38 MAP kinase activity by 197 and 215%, respectively, and increased p42/p44 MAP kinase activity by 200 and 125%, respectively. (b) SB202190, a p38 MAP kinase specific inhibitor, inhibited PGF(2alpha)- and CCh-induced cPLA(2)phosphorylation by 92 and 85%, respectively, and AA release by 62 and 78%, respectively. (c) PD98059, a p42/p44 MAP kinase inhibitor, inhibited CCh-induced cPLA(2)phosphorylation by 70% and AA release by 71%, but had no effect on that of PGF(2alpha). (d) Inhibition of PKC activity by RO 31-8220 inhibited both PGF(2alpha)- and CCh-stimulation of p38 MAP kinase, p42/p44 MAP kinases and cPLA(2)phosphorylation. We conclude from these results that in CISM cells PGF(2alpha)-induced cPLA(2)phosphorylation and AA release is mediated through p38 MAP kinase, but not through p42/p44 MAP kinases, whereas that of CCh is mediated through both p38 MAP kinase and p42/p44 MAP kinases. These effects of PGF(2alpha)and CCh are regulated by the MAP kinases in a PKC-dependent manner. Studies aimed at elucidating the role of protein kinases in the coupling mechanism between the activation of PGF(2alpha)and muscarinic receptors, and the stimulation of cPLA(2)and AA release in the smooth muscles of the iris-ciliary body will provide important information about the role of protein kinases signaling pathways in smooth muscle function, as well as about the mechanism of the intraocular pressure-lowering effects of PGF(2alpha)and its analog, latanoprost, in glaucoma therapy.
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PMID:Effects of prostaglandin F(2alpha)and carbachol on MAP kinases, cytosolic phospholipase A(2)and arachidonic acid release in cat iris sphincter smooth muscle cells. 1131 Oct 50

A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.
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PMID:3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. 1193 63

Travoprost, a highly selective and potent analogue of the prostaglandin PGF(2)(alpha), has recently been approved and marketed as a topical ocular hypotensive agent for the treatment of ocular hypertension and glaucoma. Following absorption into the eye, the free acid form of travoprost interacts with the endogenous FP prostanoid receptor to enhance aqueous humor outflow and lower intraocular pressure (IOP). Travoprost is distinguished from other marketed prostaglandin analogues in that it is a full agonist at the prostaglandin receptor. It is also highly selective with little or no affinity for other prostanoid or non-prostanoid receptors in the eye. Travoprost provides robust lowering of IOP with little diurnal fluctuation and results in low target pressures in a large percentage of patients. In controlled clinical trials, travoprost 0.004% o.d. used as monotherapy produced greater IOP reduction than timolol 0.5% b.i.d. and equal or greater reduction than latanoprost 0.005%o.d. Travoprost 0.004% was also shown to be an effective adjunctive agent offering an additional 5 - 7 mmHg IOP reduction in patients inadequately controlled on timolol 0.5%. Subgroup analysis of a large Phase III trial revealed travoprost 0.004% to be significantly more effective at lowering IOP in African American patients by almost 2 mmHg compared to non-African Americans. Moreover, a higher percentage of African American patients responded to travoprost 0.004% and reached lower target pressures than with either latanoprost 0.005% or timolol 0.5%. Travoprost is a very stable compound, maintaining its efficacy following exposure to extremely low and high temperatures, repeated freezing and thawing and exposure to light. Throughout all clinical trials, travoprost was found to be safe and well-tolerated with very few (< 5%) discontinuations due to adverse events. Travoprost 0.004% represents a clinically significant advance for the treatment of glaucoma and ocular hypertension, offering superior IOP reduction and diurnal control, especially among African American patients, in a safe, well-tolerated, stable formulation.
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PMID:Travoprost--a new prostaglandin analogue for the treatment of glaucoma. 1208 96

Latanoprost, a prodrug of a prostaglandin F(2alpha) analog, is a potent ocular hypotensive agent, reducing intraocular pressure (IOP) primarily by increasing aqueous humor drainage through the uveoscleral outflow pathway. Initial assessments in animals found that high concentrations of cholinergic agonists reduced drainage through this pathway and attenuated the effects of a PGF(2alpha) analog. This raised the question of whether latanoprost would be effective when added to the treatment regimen of patients on pilocarpine or strong miotics. In published clinical studies, latanoprost was additive to the maximally tolerated medical therapy (which included cholinergic agonists) of glaucoma patients. Multiple doses of physostigmine in healthy volunteers did not block the effect of a single drop of latanoprost during a 1-day study. One study attempting to find the optimal timing of administration of latanoprost and pilocarpine claimed to show that additivity was best when pilocarpine was given one hour after latanoprost in the evening. Two other studies found that the timing of the doses was not important. To explain the additivity of latanoprost and pilocarpine, aqueous humor dynamics were assessed in ocular hypertensive patients treated for 1 week with each drug alone and then for one week in combination. The results showed that latanoprost increased uveoscleral outflow, pilocarpine increased outflow facility, and pilocarpine did not block or attenuate the uveoscleral outflow effect of latanoprost. The result was greater IOP reduction when these drugs were used in combination than when either drug was used alone. All available evidence demonstrates that addition of latanoprost to the treatment regime of patients already taking cholinergic agonists is an effective, although not necessarily the preferred, combination of medications for the treatment of elevated IOP.
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PMID:Latanoprost and cholinergic agonists in combination. 1220 11

Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.
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PMID:Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024). 1260 40

The effects of the ocular hypotensive agents prostaglandin F(2alpha) (PGF(2alpha)) and its analog latanoprost on intraocular pressure (IOP) in both animals and human have been investigated extensively in the last two decades. While there is general agreement that application of these PGs to the eye alters IOP by altering the aqueous humor outflow of the eye via the uveoscleral and trabecular meshwork pathways, the mechanism of action of these agents on IOP lowering remains unclear. There is evidence which suggests that myosin light kinase (MLC kinase) may be involved in the IOP-lowering effects of these agents. Thus, the purpose of the present work was to investigate in cat iris sphincter the effects of these PGs on the MLC kinase signaling pathway, inositol phosphates production, MLC phosphorylation and contraction, in order to gain more information about the mechanism through which these agents modulate smooth muscle function and lower IOP. [(3)H]myo-inositol phosphates production was measured by ion-exchange chromatography, MLC kinase activity was measured by incorporation of (32)Pi into MLC, and changes in muscle tension were recorded isometrically. PGF(2alpha) and latanoprost induced contraction in a concentration-dependent manner with EC(50) values of 18.6 and 29.9 nM, respectively, and increased inositol phosphates production in a concentration-dependent manner. At 1 microM, PGF(2alpha) and latanoprost increased inositol phosphates formation by 125 and 102% over basal, respectively. PGF(2alpha) and latanoprost increased MLC phosphorylation in a concentration- and time-dependent manner, at 1 microM and 5 min incubation, the PGs increased the MLC response by 181 and 176% over basal, respectively. In general, PGF(2alpha) was slightly more potent in inducing the biochemical and pharmacological responses. Wortmannin, ML-7 and ML-9, selective inhibitors of MLC kinase, inhibited significantly PGF(2alpha)- and latanoprost-induced MLC phosphorylation and contraction. These results demonstrate for the first time involvement of the MLC kinase pathway in the FP receptor function of this ocular tissue. Contraction-relaxation of smooth muscle alters the shape and stiffness of smooth muscle cells and MLC kinase, through myosin phosphorylation and dephosphorylation, has been shown to be involved in cytoskeletal remodeling, cytoskeletal alterations, and IOP lowering. In light of these reports and the findings presented here we suggest that alterations in the MLC kinase signaling pathway and its derived second messengers, which leads to changes in contraction-relaxation of the smooth muscles of the anterior segment, could facilitate aqueous humor outflow and thus contribute to the IOP-lowering effects of the FP-class PGs.
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PMID:Effects of prostaglandin F2alpha and latanoprost on phosphoinositide turnover, myosin light chain phosphorylation and contraction in cat iris sphincter. 1282 40

Prostanoid pathway in hair follicle gained closer attention since trichogenic side-effects on hair growth has been observed concomitantly with prostaglandin F(2alpha) receptor (FP) agonist treatment of intraocular pressure. We thus investigated prostanoid receptor distribution in anagen hair follicle and different cell types from hair and skin. Using RT-PCR, Western blot and immunohistochemistry (IHC), we found that all receptors were present in hair follicle. This data shed new light on an underestimated complex network involved in hair growth control. Indeed most of these receptors showed a wide spectrum of expression in cultured cells and the whole hair follicle. Using IHC, we observed that expression of prostaglandin E(2) receptors (EP(2), EP(3), EP(4)), prostaglandin D(2) receptor (DP(2)), prostanoid thromboxane A(2) receptor (TP) and to a lesser extent EP(1) involved several hair follicle compartments. On the opposite, Prostaglandin I(2) receptor (IP) and DP(1) were more specifically expressed in hair cuticle layer and outer root sheath (ORS) basal layer, respectively. FP expression was essentially restricted to ORS companion layer and dermal papilla (DP). Although extracting a clear functional significance from this intricate network remains open challenge, FP labelling, i.e. could explain the biological effect of PGF(2alpha) on hair regrowth, by directly modulating DP function.
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PMID:Prostanoid receptors in anagen human hair follicles. 1800 48


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