dinoprost and Hyperemia

Topics: Animals; Dinoprost; Humans; Hyperemia; Microcirculation; Oxidative Stress; Raynaud Disease; Scleroderma, Systemic; Skin

We aimed to evaluate whether 4-week of dietary treatment with rice containing resistant starch reduces blood glucose and oxidative stress as well as improves endothelial function.. Patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (n = 90) were randomly assigned to either a group ingesting rice containing 6.51 g resistant starch daily or a control rice group for 4-weeks. We assessed fasting and postprandial levels of glucose and insulin, oxidative stress markers and endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT).. The diet containing rice with resistant starch reduced fasting insulin and insulin resistance, postprandial glucose (P = 0.010) and insulin levels at 30 min, and glucose and insulin areas under the response curve after the standard meal. Rice with resistant starch also decreased urinary 8-epi-PGF(2α) and plasma malondialdehyde (MDA) and increased the RH-PAT index (P < 0.001) and total nitric oxide (NO). Postprandial changes in glucose at 60 and 120 min and areas under the glucose response curve, MDA, RH-PAT, and total NO of the test group differed significantly from those in the control even after adjusting for baseline values. Overall, changes in the RH-PAT index correlated positively with changes in total NO (r = 0.336, P = 0.003) and superoxide dismutase activity (r = 0.381, P = 0.001) and negatively with changes in MDA (r = -0.358, P = 0.002) and 8-epi-PGF(2α).. In patients with IFG, IGT or newly diagnosed type 2 diabetes, 4-weeks of dietary treatment with rice containing resistant starch was associated with improved endothelial function with reduction of postprandial glucose and oxidative stress compared with control.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Digestion; Dinoprost; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hydrolysis; Hyperemia; Insulin; Insulin Resistance; Male; Malondialdehyde; Manometry; Middle Aged; Nitric Oxide; Oryza; Oxidative Stress; Plants, Genetically Modified; Postprandial Period; Prediabetic State; Republic of Korea; Starch; Superoxide Dismutase; Time Factors; Treatment Outcome

Particulate air pollution is associated with cardiovascular morbidity. One hypothesized mechanism involves oxidative stress, systemic inflammation, and endothelial dysfunction.. To assess an intervention's impact on particle exposures and endothelial function among healthy adults in a woodsmoke-impacted community. We also investigated the underlying role of oxidative stress and inflammation in relation to exposure reductions.. Portable air filters were used in a randomized crossover intervention study of 45 healthy adults exposed to consecutive 7-day periods of filtered and nonfiltered air.. Reactive hyperemia index was measured as an indicator of endothelial function via peripheral artery tonometry, and markers of inflammation (C-reactive protein, interleukin-6, and band cells) and lipid peroxidation (malondialdehyde and 8-iso-prostaglandin F(2α)) were quantified. Air filters reduced indoor fine particle concentrations by 60%. Filtration was associated with a 9.4% (95% confidence interval, 0.9-18%) increase in reactive hyperemia index and a 32.6% (4.4-60.9%) decrease in C-reactive protein. Decreases in particulate matter and the woodsmoke tracer levoglucosan were associated with reduced band cell counts. There was limited evidence of more pronounced effects on endothelial function and level of systemic inflammation among males, overweight participants, younger participants, and residents of wood-burning homes. No associations were noted for oxidative stress markers.. Air filtration was associated with improved endothelial function and decreased concentrations of inflammatory biomarkers but not markers of oxidative stress. Our results support the hypothesis that systemic inflammation and impaired endothelial function, both predictors of cardiovascular morbidity, can be favorably influenced by reducing indoor particle concentrations.

Topics: Adult; Air Pollutants; Biomarkers; British Columbia; C-Reactive Protein; Cross-Over Studies; Dinoprost; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Female; Filtration; Humans; Hyperemia; Inflammation; Inhalation Exposure; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Reference Values; Smoke; Young Adult

1. Previous clinical studies with prostaglandin I(2) (PGI(2)) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2. Beraprost sodium (120 microg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium-dependent vasodilatation was assessed by plethysmography, and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) was measured at baseline, 4 weeks and 8 weeks. 3. Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8-iso-PGF(2alpha) remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8-iso-PGF(2alpha) decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8-iso-PGF(2alpha) (P < 0.001). 4. Beraprost sodium decreased oxidative stress and improved forearm endothelium-dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.

Topics: Aged; Coronary Artery Disease; Dinoprost; Double-Blind Method; Endothelium, Vascular; Epoprostenol; Female; Forearm; Hemodynamics; Humans; Hyperemia; Male; Prospective Studies; Regional Blood Flow; Vasodilation; Vasodilator Agents

Four clinical studies were performed in 54 healthy Japanese volunteers to assess the efficacy and the safety of two phenyl-substituted PGF2 alpha-isopropyl ester analogues, PhXA34 and PhXA41 after both single and repeated administrations. PhXA34 and PhXA41 reduced intraocular pressure (IOP) significantly in a dose-dependent way. The maximum IOP reductions were 14.5% to 17.5% with baseline adjustment at 10 to 12 hours after a single administration. No transient early elevation in IOP after treatment was observed. Based on the maximum IOP reducing effect of 1 microgram of PhXA34 and PhXA41, PhXA41 appeared to be at least 1.5 times more active than PhXA34. Tachyphylaxis of the ocular hypotensive effect did not develop during repeated administration for 5 days. A mild conjunctival hyperemia occurred in some subjects at high doses; it tended to diminish with time during the repeated administration of both drugs. Neither PhXA34 nor PhXA41 caused any change at any time in the aqueous flare intensity measured with a laser flare-cell meter. There were no changes in pupillary diameter after treatment. Each drug was well tolerated and caused no other ocular or systemic side effects.

Topics: Adolescent; Adult; Aqueous Humor; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Evaluation Studies as Topic; Glaucoma; Humans; Hyperemia; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic

A study was carried out to assess the clinical efficacy of PhXA41, a new phenyl-substituted prostaglandin F2 alpha-isopropyl ester analogue, using a single administration in 35 subjects with ocular hypertension or primary open-angle glaucoma. PhXA41 caused a dose-dependent intraocular pressure (IOP) reduction which continued 24 hours or more after administration. The mean IOP reduction 8 hours after treatment compared with the baseline IOP was 3.4, 4.9 and 5.9 mmHg for the doses of 25, 50 and 100 micrograms/ml, respectively. Although slight conjunctival hyperemia occurred in some patients, it disappeared by the next day with no treatment. No aqueous flare or cells were detected, no significant change in pupillary diameter was found, and no systemic symptom was reported. Thus, PhXA41 was well tolerated in subjects with ocular hypertension or primary open-angle glaucoma. Furthermore, its IOP-reducing effect was so long-lasting that a once daily application may suffice for clinical use.

Topics: Adult; Aged; Conjunctiva; Dinoprost; Dose-Response Relationship, Drug; Drug Tolerance; Female; Glaucoma, Open-Angle; Humans; Hyperemia; Intraocular Pressure; Latanoprost; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic

Ocular hypotensive effects and side effects of two different topically applied prostaglandin (PG) esters were evaluated in a double masked study in 12 healthy males. Three doses of 15-propionat-PGF2 alpha-isopropylester (15-prop-PGF2 alpha-IE), two doses of PGF2 alpha-isopropylester (PGF2 alpha-IE), and placebo were compared. At equipotent doses 15-prop-PGF2 alpha-IE caused similar ocular side effects as PGF2 alpha-IE. It is concluded that both PGF2 alpha-IE and 15-prop-PGF2 alpha-IE reduce the IOP in normal eyes, but the use of a diester such as 15-prop-PGF2 alpha-IE does not provide a better separation between effect on IOP and side effects than PGF2 alpha-IE.

Topics: Administration, Topical; Adult; Dinoprost; Double-Blind Method; Drug Evaluation; Humans; Hyperemia; Intraocular Pressure; Male; Ocular Hypotension

The effects of PGF2 alpha-isopropylester eye drops on intraocular pressure (IOP) and aqueous humour dynamics were investigated in healthy male volunteers. The other eye was treated with vehicle and used as a control. Special attention was also paid to adverse effects. Single and repeated doses were tested. There was a dose related effect on IOP. Significant reductions were observed 4, 8, and 12 hours after application of 1.0, 2.5, or 10 micrograms PGF2 alpha equivalents of the drug. With 10 micrograms the effect lasted 24 hours. An initial tendency towards an increase in IOP was observed for these doses. Repeated doses of 1.0 microgram daily or 0.5 microgram twice daily produced a significant and lasting IOP reduction of about 2 mmHg for 1-2 weeks. Aqueous humour production was not altered, and outflow facility was not significantly changed. There was a dose dependent hyperaemia with a maximum within 2 hours after application. A foreign body sensation, some pain, and photophobia were noted with increasing doses. A slight miosis of 1 mm was seen in three of six eyes treated with 10 micrograms. No signs of intraocular inflammation were recorded, but a slight increase in penetration of fluorescein into the anterior chamber was observed after 16 days of treatment.

Topics: Adult; Aqueous Humor; Dinoprost; Dose-Response Relationship, Drug; Eye; Humans; Hyperemia; Intraocular Pressure; Male; Middle Aged; Ophthalmic Solutions

In a randomized, double-masked, placebo-controlled study, 0.25 microgram (n = 11) or 0.5 microgram (n = 13) of prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) was applied topically twice daily for 8 days to one eye of ocular hypertensive or chronic open-angle glaucoma patients. Compared with contralateral, vehicle-treated eyes, PGF2 alpha-IE significantly (P less than 0.05) reduced intraocular pressure (IOP), beginning 4 hours after the first 0.5-microgram dose and lasting at least 12 hours after the fourteenth dose, with a significant (P less than 0.005) mean reduction of 4 to 6 mmHg maintained throughout the last day of therapy with either dose. A contralateral effect was not observed. Mean tonographic outflow facility was significantly (P less than 0.05) higher in PG-treated compared with vehicle-treated eyes (0.17 +/- 0.02 versus 0.12 +/- 0.01 microliter/minute/mmHg, respectively; +/- standard error of the mean) for the 0.5 microgram dose. Conjunctival hyperemia reached a maximum at 30 to 60 minutes after PGF2 alpha-IE application. Some patients reported mild irritation lasting several minutes after some doses. Visual acuity, accommodative amplitude, pupillary diameter, aqueous humor flare, anterior chamber cellular response, Schirmer's test, pulse rate, and blood pressure were not significantly altered. Our findings show that PGF2 alpha-IE is a potent ocular hypotensive agent and a promising drug for glaucoma therapy.

Topics: Aged; Conjunctiva; Dinoprost; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glaucoma, Open-Angle; Humans; Hyperemia; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Patient Compliance; Random Allocation; Tonometry, Ocular

Hypotensive and other ocular effects were studied for 24 hr after topical application of prostaglandin F2 alpha as the tromethamine salt (PGF2 alpha) in 45 normotensive human subjects. After baseline intraocular pressure (IOP) measurements, 62.5 micrograms, 125 micrograms and 250 micrograms of PGF2 alpha dissolved in 50 microliter of saline was applied to one eye of 15 subjects for each dose tested. Contralateral control eyes received 50 microliter of saline. As compared with the IOP of the contralateral control eyes, topical application of 62.5 micrograms PGF2 alpha caused a significant IOP reduction at 1-12 hr, with a maximal IOP reduction of 2.2 mm Hg at 2 hr. Treatment with 125 micrograms of PGF2 alpha lowered IOP significantly at 1-21 hr, with a maximal reduction of 3.1 mm Hg at 9 hr. Administration of 250 micrograms PGF2 alpha produced a significant reduction of IOP, which lasted for at least 24 hr. A maximal IOP reduction of 2.9 mm Hg occurred at 7 hr. Pupillary diameter was not altered. Aqueous flare and anterior chamber cellular response were not seen in any of the eyes of the subjects at any time after topical application of 62.5-250 micrograms PGF2 alpha. The drug caused side effects consisting of reddened skin of lower lid, ocular irritation, conjunctival hyperemia and headache.

Topics: Administration, Topical; Adult; Dinoprost; Erythema; Eye; Female; Headache; Humans; Hyperemia; Intraocular Pressure; Male; Middle Aged; Reference Values; Time Factors

The ocular effects of 200 micrograms of topically applied prostaglandin F2 alpha were studied in 18 nonglaucomatous volunteers. A fall in intraocular pressure was seen in the prostaglandin-treated eyes when compared with the placebo-treated control eyes. The maximum intraocular pressure reduction was observed at the 7th h and hypotensive ocular effect persisted for 24 h. Prostaglandins did not produce any change in pupillary diameter or signs of intraocular inflammation visible by anterior segment biomicroscopy or iris fluorescein angiography. The drug caused side effects: conjunctival hyperemia was constant and many patients complained of ocular smarting and headache. It could be useful in the treatment of ocular hypertension, although its usefulness would be limited by the side effects.

Topics: Adult; Aged; Conjunctiva; Dinoprost; Eye; Female; Headache; Humans; Hyperemia; Intraocular Pressure; Male; Middle Aged; Prostaglandins F

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.

Topics: Animals; Arachidonic Acid; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Dinoprost; Endothelium, Vascular; Female; Heart; Humans; Hyperemia; Male; Mice; Mice, Inbred C57BL; Myocardium; Oxylipins; Reperfusion Injury

Microvascular dysfunction and increased oxidative stress are major hallmarks of the systemic sclerosis disease process. The primary objective of this study was to test whether there is a link between peak postocclusive hyperemia and urinary levels of the F2-isoprostane 15-F2t-IsoP (8-iso-PGF2alpha) in patients suffering from systemic sclerosis. We enrolled 43 patients suffering from systemic sclerosis, 33 patients with primary Raynaud's phenomenon (RP), and 25 healthy volunteers. Microvascular function was assessed using the postocclusive hyperemia monitored by laser Doppler flowmetry. Endothelium-independent response was monitored after 0.4 mg sublingual nitroglycerin. Oxidative stress status was assessed by urinary levels of the F2-isoprostane 15-F2t-IsoP using GC-MS. The peak postocclusive vascular conductance was altered in subjects with systemic sclerosis and primary RP compared to controls (respectively 28 (7-48), 30 (13-48), and 39.9 (13-63) mV/mm Hg, p = 0.01). F2-isoprostanes were increased in the systemic sclerosis group compared to primary Raynaud's phenomenon and healthy controls (respectively 230 (155-387), 182 (101-284), and 207 (109-291) pg/mg, p = 0.006). In patients suffering from systemic sclerosis, there was a significant inverse correlation between F2-isoprostanes and postocclusive hyperemia, expressed as raw data (R = -0.45, p = 0.007) or as an increase over baseline (R = -0.28, p = 0.04). Conversely, no correlation was found with the nitroglycerin response. In conclusion, we provide evidence that there is an inverse correlation between postocclusive hyperemia and urinary F2-isoprostane levels in patients suffering from systemic sclerosis. Whether oxygen free radicals initiate the vascular dysfunction or whether there is an initial trigger that initiates both processes will need to be further clarified in future studies.

Topics: Dinoprost; Humans; Hyperemia; Interleukin-1; Interleukin-6; Laser-Doppler Flowmetry; Lipid Peroxidation; Microcirculation; Oxidative Stress; Raynaud Disease; Scleroderma, Systemic; Skin

Topics: Animals; Dinoprost; Disease Models, Animal; Endothelium, Vascular; Hyperemia; Rabbits; Receptors, Prostaglandin; Retinal Vessels; Vasodilation; Vasodilator Agents

Prostaglandin F2 alpha (PGF2 alpha) and several other prostaglandins cause surface hyperemia of the eye when applied topically. The purpose of the present study was to investigate the role of sensory nerves in prostaglandin-induced ocular hyperemia.. The ophthalmic branch of the trigeminal nerve was unilaterally electrocoagulated in rabbits using a stereotaxic technique. Two weeks later the animals received bilaterally one drop of PGF2 alpha-isopropyl ester (PGF2 alpha-IE) at a dose of 1 microgram/ eye. The blood flow to the different parts of the eye was measured with the radioactively labeled microsphere technique before, 30 and 60 min after treatment with PGF2 alpha-IE.. In the control eyes with intact sensory innervation, PGF2 alpha-IE caused a marked increase in blood flow to the surface structures of the eye (conjunctiva, anterior sclera, eyelids and nictitating membrane) and the iris, and a moderate increase in the blood flow to the ciliary processes, but no increase in the choroidal blood flow. In the denervated eyes the increase in blood flow to the surface structures was almost completely abolished, and there was also a tendency toward less increase in blood flow in the anterior uvea.. These results indicate that PGF2 alpha-induced ocular surface hyperemia, at least at the early stage, is mediated to a large extent by sensory nerves.

Topics: Animals; Denervation; Dinoprost; Eye; Female; Hyperemia; Male; Microspheres; Neurons, Afferent; Rabbits; Regional Blood Flow

The objective of this study was to identify prostaglandin F2alpha (PGF2alpha) prodrugs that have an optimal ocular absorption profile and therefore could be potentially useful for the treatment of glaucoma. Rabbit cornea, conjunctiva, and iris/ciliary body were mounted in a flow-through chamber to evaluate the permeability and bioconversion of PGF2alpha and its prodrugs. The prodrugs tested were PGF2alpha 1-isopropyl, 1,11-lactone, 15-acetyl, 15-pivaloyl, 15-valeryl, and 11,15-dipivaloyl esters. After 4 h in the donor or acceptor compartments, the products and formation of PGF2alpha were analyzed by HPLC. Effects on intraocular pressure and ocular surface hyperemia were also determined. All prodrugs penetrated the rabbit cornea faster than PGF2alpha by 4- to 83-fold. All prodrugs penetrated conjunctiva faster than PGF2alpha, except the 15-acetyl ester prodrug, which was equally permeable. No direct correlation between drug lipophilicity and permeability across the cornea or conjunctiva was apparent. The most metabolically stable prodrug was the 1,11-lactone, followed by the 11,15-dipivaloyl, 15-pivaloyl, 15-acetyl, 1-isopropyl, and the 15-valeryl esters, the latter of which was extensively converted to PGF2alpha. A separation index for various prodrugs was calculated from the ratio of the bioavailable PGF2alpha for ocular hypotension to the bioavailable PGF2alpha for hyperemia. The highest separation index was observed for the 1,11-lactone prodrug (2.33), followed by the 11,15-dipivaloyl ester prodrug (1.80). Thus the 1,11-lactone and 11,15-dipivaloyl ester prodrugs appeared to be superior to the others in providing bioavailable PGF2alpha for ocular hypotension, while minimizing hyperemia. The favorable separation index for these compounds appeared to be due to their metabolic stability at the corneal surface and conjunctiva combined with sufficient bioavailability for ocular hypotension.

Topics: Absorption; Animals; Biotransformation; Conjunctiva; Cornea; Dinoprost; Eye; Female; Hyperemia; Intraocular Pressure; Ocular Hypotension; Permeability; Prodrugs; Rabbits

Enzymatic hydrolysis and in-vivo ocular studies were performed on a novel series of prostaglandin F2 alpha (PGF2 alpha) pivaloyl ester prodrugs to assess their therapeutic potential. These novel PGF2 prodrugs were esterified at the 9-, 11-, and 15-OH positions. Their enzymatic hydrolysis rates were compared to PGF2 alpha 1-isopropyl ester in dog, monkey, and human ocular tissues. Intraocular pressure (IOP) studies were performed in monkeys and dogs, and ocular surface hyperemia was monitored in dogs. PGF2 alpha 9-monopivaloyl ester was not enzymatically hydrolysed in dog and human ocular tissues. PGF2 alpha 11- and 15-monopivaloyl esters and PGF2 alpha 11,15-dipivaloyl ester were converted to PGF2 alpha by all ocular tissues at a substantially slower rate than PGF2 alpha l-isopropyl ester. Despite their slow enzymatic hydrolysis rates, the ocular hypotensive activity of PGF2 alpha mono and dipivaloyl esters, where positions 11- and 15- were functionalized, closely approached the activity achieved with PGF2 alpha l-isopropyl ester. The degree of ocular surface hyperemia associated with PGF2 alpha 11-pivaloyl ester and PGF2 alpha 11,15-dipivaloyl ester was less than that associated with equivalent doses of PGF2 alpha l-isopropyl ester. It appears that rapid enzymatic hydrolysis rates are not necessary to obtain efficacious ocular hypotensive PGF2 alpha ester prodrugs. Slow enzymatic hydrolysis rates may assist in reducing the degree of ocular surface hyperemia. A further contributory factor in this regard could be the approximately ten-fold favorable difference in enzymatic hydrolysis rates between iris-ciliary body and conjunctival tissue for these novel pivaloyl esters of PGF2 alpha. These factors appear to translate into an improved therapeutic index for separating ocular hypotensive and ocular surface hyperemic effects.

Topics: Animals; Antihypertensive Agents; Ciliary Body; Conjunctiva; Cornea; Culture Techniques; Dinoprost; Dogs; Dose-Response Relationship, Drug; Esters; Eye; Female; Humans; Hydrolysis; Hyperemia; Intraocular Pressure; Iris; Macaca fascicularis; Male; Prodrugs; Pupil

The effect of nitric oxide synthase inhibition on prostaglandin F2 alpha (PGF2 alpha)-induced ocular hyperemia in the rabbit has been studied. PGF2 alpha was administered topically as the isopropyl ester (PGF2 alpha-IE) unilaterally, with the other eye serving as a control. The regional blood flow in the eye was determined with radioactively-labelled microspheres in conscious animals. Synthesis of nitric oxide (NO) was blocked by L-NMMA (200 mg kg-1 b.w., i.v.). PGF2 alpha-IE induced marked hyperemia of the surface structures of the eye (conjunctiva, eye lids, nictitating membrane, anterior sclera), as well as increased blood flow of the anterior uvea. L-NMMA blocked the hyperemia of the surface structures but not completely the increase in blood flow of the anterior uvea. PhXA41 (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester), a selective prostaglandin FP-receptor agonist, had no significant effect on the ocular blood flow. These results indicate that PGF2 alpha causes surface hyperemia of the eye by activating nitric oxide synthase, but this mechanism seems to be only partly involved in the increase in blood flow of the ciliary processes and the iris. The PGF2 alpha-induced ocular hyperemia is unlikely to be mediated by FP receptors.

Topics: Amino Acid Oxidoreductases; Animals; Dinoprost; Eye; Female; Hyperemia; Latanoprost; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandins F, Synthetic; Rabbits; Receptors, Prostaglandin; Regional Blood Flow; Time Factors

A novel series of prostaglandin F2 alpha (PGF2 alpha) prodrugs, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 alpha prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues.

Topics: 3T3 Cells; Animals; Calcium; Dinoprost; Drug Design; Eye; Female; Glaucoma; Hydrolysis; Hyperemia; Intraocular Pressure; Male; Mice; Prodrugs; Rabbits

The study was devised to assess the effects of a protein load (2 g/kg BW) on urinary prostaglandin E2 (PGE2), 6-keto-PGF1 alpha and thromboxane A2 (TxA2) in patients with renal failure of glomerular origin. To this end, 8 women with a glomerular filtration rate of 55 +/- 12 ml/min x 1.73 m2 underwent the following studies: study 1: control; study 2: meat meal; study 3: meat meal+intravenous aspirin; study 4: pretreatment with oral aspirin for 2 days+protocol in study 3. Glomerular hyperfiltration was seen after the meat meal (study 2) and was not suppressed by aspirin (studies 3 and 4). Urinary PGE2, 6-keto-PGF1 alpha and TxA2 increased after the meat meal in study 2 and were suppressed by aspirin in studies 3 and 4. The ratio between vasodilative (PGE2 + 6-keto-PGF1 alpha) and vasoconstrictive (TxA2) autacoids increased during the meat meal (study 2) and was suppressed when aspirin was injected at the time of the oral protein load, thus, the effect of aspirin was much greater for PGE2 and PGF1 alpha than for TxA2. These data do not support that urinary prostaglandin and TxA2 have a direct role in renal hyperfiltration due to an acute protein load.

Topics: Adult; Arachidonic Acids; Aspirin; Dietary Proteins; Dinoprost; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Hyperemia; Kidney Diseases; Prostaglandins; Thromboxane A2

One and 2 micrograms of prostaglandin F2 alpha isopropyl ester (PGF2 alpha -IE) applied topically to the rabbit eye caused a biphasic response. The hypotensive phase was dose-dependent with a maximum reduction in intraocular pressure (IOP) of 9.4 +/- 1.7 mmHg at a dose of 2 micrograms. In beagles, 0.4 to 2 micrograms topical PGF2 alpha-IE resulted in a sustained IOP reduction; 2 micrograms produced the maximum reduction of 7-9 mmHg. No initial hypertensive response was observed. Iloprost phenacyl ester (Iloprost-PE) caused a greater decrease in IOP when dissolved in 0.5% hydroxypropyl methylcellulose (AT) than in saline. In rabbits, doses of 0.1 to 1 microgram in AT caused a biphasic response with a sustained IOP decrease fluctuating between 7 and 8 mmHg. In beagles 1 and 2 micrograms Iloprost-PE resulted in a mean IOP reduction of 5.8 +/- 0.4 mmHg and 5.8 +/- 0.5 mmHg (P less than 0.005), respectively; the decrease persisted for 5 hrs. No initial hypertensive response was observed. In beagles PGF2 alpha-IE induced a strong miosis lasting more than 6 hours; Iloprost-PE had no effect on pupil size. Both PG-esters induced a slight hyperemia in rabbit and beagle eyes. In rabbits Iloprost-PE affects the blood-aqueous barrier more than PGF2 alpha-IE, since higher protein concentrations are seen in the aqueous humor after application of Iloprost-PE. Neither PG-ester had a noticeable effect on aqueous protein in beagles. In rabbits, both PG-esters led to slightly increased aqueous humor cyclic-AMP concentrations. In beagles aqueous humor cyclic-AMP was elevated only after Iloprost-PE.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Topical; Animals; Aqueous Humor; Cyclic AMP; Dinoprost; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Hyperemia; Hypromellose Derivatives; Iloprost; Intraocular Pressure; Methylcellulose; Pupil; Rabbits; Time Factors; Tonometry, Ocular

In this study the effect of topical administration of prostaglandins (PGs) on a human serum albumin (HSA)-induced uveitis is evaluated. Topical prostaglandin E1 (PGE1) and prostaglandin F2 alpha (PGF2 alpha) partly inhibited hyperaemia and flare in the anterior chamber after the induction of immune complex uveitis. A marked increase in the cellular response was observed in the aqueous humour after topical PGE1 and PGF2 alpha. Topical prostaglandins may decrease endogenous prostaglandin formation and reduce the prostaglandin-mediated inflammatory symptoms; on the other hand, they also stimulate the aqueous cellular response, possibly by facilitation of leukotriene formation. These results indicate that topical prostaglandins should not be used to treat immunogenic uveitis.

Topics: Administration, Topical; Alprostadil; Animals; Antigen-Antibody Reactions; Aqueous Humor; Conjunctiva; Dinoprost; Disease Models, Animal; Drug Evaluation, Preclinical; Hyperemia; Prostaglandins E; Rabbits; Serum Albumin; Uveitis, Anterior

Studies were carried out of the effects of topically applied prostaglandin (PG) D2 and its metabolites and analogues on the intraocular pressure (IOP) in rabbits, and the results were compared with those of studies using PGE2 and F2 alpha. The application of PGD2 (0.4-250 micrograms) reduced the IOP, in a dose-dependent manner without causing a hypertensive phase. The hypotensive effect was observed within 30 minutes after the application and lasted for over 7 hours. Higher doses of PGE2 (10, 50 micrograms) or PGF2 alpha (50 micrograms) caused initial IOP elevation followed by a prolonged hypotensive phase. Lower doses of PGF2 alpha (2, 10 micrograms) caused a prolonged (over 7 hours) reduction in the IOP following a latency of over 2 hours. The IOP reduction by 2 micrograms of PGE2 lasted for 5 hours. No miotic response followed the use of these PG's. Conjunctival and iridal hyperemia, aqueous flare, irritation (defined by lid-closing), and aqueous protein content were examined at equi-hypotensive doses of the three PG's (50 micrograms for PGD2, 2 micrograms for PGE2, and 10 micrograms for PGF2 alpha). PGE2 was the strongest in causing these side effects, followed by PGF2 alpha. PGD2 did not cause any of these responses except for some development of conjunctival hyperemia. All of the 4 PGD2 metabolites were ineffective in reducing IOP. Among 6 PGD2 analogues, BW245C, PGD3, and PGD2 methyl ester more effectively reduced IOP than did PGD2. PGD1 and 16,16-dimethyl PGD2 were not effective.

Topics: Administration, Topical; Animals; Aqueous Humor; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Hyperemia; Intraocular Pressure; Iris; Prostaglandin D2; Rabbits; Reflex, Pupillary; Time Factors; Tonometry, Ocular