Effect of Latanoprost on Regional Blood Flow and Capillary Permeability in the Monkey Eye

LABORATORY SCIENCES Effect of Latanoprost on Regional Blood Flow and Capillary Permeability in the Monkey Eye

Johan Stjernschantz, MD, PhD; Go¨ran Sele´n, PhD; Maria Astin, PhD; Maritha Karlsson; Bahram Resul, PhD

Objective: To evaluate the effects of latanoprost on ception of the anterior sclera, in which a moderate increase regional blood flow and capillary permeability in the in blood flow was detected. No effect on capillary perme- monkey eye. ability to albumin was detected when studied 30 minutes to 21⁄2 hours and 5 to 6 hours after dose administration. Methods: Anesthetized cynomolgus monkeys were unilaterally treated with a single dose containing 6 µg of Conclusion: Latanoprost, a selective prostaglandin F re- latanoprost; or 10 µg of PhXA34 (13,14-dihydro-15R, ceptor agonist, exerted no or only slight vascular effects S-17-phenyl-18,19,20-trinor-prostaglandin F2␣ [PGF2␣]- for up to 6 hours after dose administration in the mon- isopropyl ester), which contains about 50% latano- key eye, with the exception of the anterior sclera, in which prost. Regional blood flow in the eye was measured with a moderate increase in blood flow was detected. radioactively labeled microspheres; capillary permeability was measured by determining the extravascular Clinical Relevance: Naturally occurring prostaglan- plasma-equivalent albumin space using 125I-albumin, 131I- dins may cause marked microcirculatory changes in the albumin, and 51Cr-labeled erythrocytes. eye that could be of clinical concern. Latanoprost, a selective prostaglandin F receptor agonist, seems to be Results: Latanoprost or PhXA34 had no or only a slight devoid of such effects. effect on the regional blood flow when measured 1, 21⁄2, 3, 41⁄2, and 6 hours after dose administration, with the ex- Arch Ophthalmol. 1999;117:1363-1367

ATANOPROST (13,14-dihydro- induce vasoconstriction in the eye, par- 17-phenyl-18,19,20-trinor- ticularly in the posterior pole, that could prostaglandin F2␣ [PGF2␣]- be detrimental and aggravate the glauco- isopropyl ester), the active matous disease.13 Conversely, it may also principal in latanoprost eye- be of interest to know whether latano- dropsL (Xalatan, Pharmacia & Upjohn), is prost induces increased blood flow in the a selective prostaglandin F receptor ago- eye, and particularly in the posterior pole, nist that is used for the reduction of the which could be advantageous in the treat- intraocular pressure in the treatment of ment of glaucoma. Finally, since natu- glaucoma. Latanoprost has been shown to rally occurring prostaglandins have been reduce the intraocular pressure effectively implicated to play a role in ocular inflam- during long-term treatment in patients with mation, it is of interest to investigate open-angle glaucoma and ocular hyperten- whether latanoprost has any effect on the 1-4 From the Department of sion. While PGF2␣ as well as PGF2␣– capillary permeability. The present study Neuroscience, Unit of isopropyl ester have been shown to in- determined the vascular effects of latano- Pharmacology, Uppsala duce marked conjunctival hyperemia in prost in the primate eye to address the University (Drs Stjernschantz healthy volunteers and in patients with points raised. and Resul), and the Research glaucoma,5,6(pp447-458) latanoprost induces Laboratories of Pharmacia & significantly less hyperemia.7,8 Upjohn (Drs Sele´n and Astin RESULTS and Ms Karlsson), Uppsala, The regional blood flow in the eye 1 to 6 Sweden. All authors were See also page 1305 employees of Pharmacia & hours after topical application of PhXA34 Upjohn at the time of the study. Prostaglandin F2␣ is a known vaso- or latanoprost is provided in Table 1.Inthe None of the authors have any dilator but can also cause vasoconstric- eyelid,conjunctiva,andanteriorsclera,there proprietary interest in tion (eg, in the brain).9-12 The question has, was a tendency toward lower blood flow in latanoprost. therefore, arisen whether latanoprost could theexperimentaleyecomparedwiththecon-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 MATERIALS AND METHODS cobalt 57, ruthenium 103, or niobium 95 (New England Nuclear Life Science Products, Boston, Mass) as described previously.14 A bolus of approximately 106 microspheres per Animals were treated according to the tenets of the Asso- injection was introduced into the left ventricle of the heart. ciation for Research in Vision and Ophthalmology State- A reference blood sample was collected from a femoral ar- ment on the Use of Animals in Ophthalmic and Vision Re- tery in test tubes under free flow conditions for 1 minute from search, and the experiments were approved by the local the start of the injection of the microspheres. By using mi- ethics committee for animal experimentation. Ten cyno- crospheres with different radioactive labels, it was possible molgus monkeys of either sex, weighing 2 to 4 kg, were to determine the blood flow at different occasions in each used for the experiments. Anesthesia was induced with ket- experiment. At the end of the experiment, the animal was amine hydrochloride, 25 mg/kg body weight intramuscu- euthanized and the eyes were dissected as described. larly. Polyethylene tubings were inserted into both fem- The capillary permeability in the different tissues of oral arteries for registration of arterial blood pressure and the eye was determined by measuring the extravascular collection of blood samples, and into both femoral veins plasma-equivalent albumin space.15,16 Human serum albu- for intravenous (IV) injections. A Ringer-acetate solution min labeled with iodine 125 (125I) or iodine 131 (131I) (In- was infused IV at a rate of 10 mL/h. A catheter for injec- stitutt for Energiteknikk, Kjeller, Norway) was used as a tion of the microspheres was inserted into the left heart ven- tracer, and free iodine was separated from labeled albu- tricle through the right brachial artery. Anesthesia was main- min immediately before the experiment using gel filtra- tained by IV injections of a diluted pentobarbital sodium tion (Sephadex G-25M, PD-10; Amersham Pharmacia Bio- solution, 15 mg/mL. The animals underwent a trache- tech AB, Uppsala, Sweden). The amount of free iodine in otomy and were connected to a ventilator for artificial ven- the infusion solution was less than 1%. Heparinized blood tilation. The PO2,PCO2, and pH of the arterial blood were was collected from the animal and incubated for 1 hour at regularly checked and adjusted when necessary, by chang- 37°C with a chromium 51 (51Cr)–labeled sodium cromate ing the ventilation, by administering a sodium bicarbon- solution (New England Nuclear Life Science Products). The ate solution IV, or both. A heating pad was used to main- blood was centrifuged, and the supernatant discarded. The tain normal body temperature. erythrocytes were washed with isotonic saline solution and Two series of experiments were performed. In the first, 5 centrifuged 6 times to remove unbound 51Cr. The final sus- animals were treated with PhXA34 (13,14-dihydro-15R, S-17- pension of erythrocytes contained less than 1% free 51Cr. phenyl-18,19,20-trinor-PGF2␣-isopropyl ester), which con- In the first series of experiments, an IV bolus injection tains about 50% latanoprost, and the blood flow was mea- of 125I-albumin was given 30 minutes after topical instilla- sured 1 and 21⁄2 hours after dose administration. The capillary tion of PhXA34, followed by an IV infusion to maintain a stable permeability was determined during 2 postdosing periods: plasma level until the end of the experiment. Similarly, but 131 30 minutes to 21⁄2 hours and 11⁄2 to 21⁄2 hours. In the second 11⁄2 hours after instillation of PhXA34, I-albumin was in- series of experiments, 5 animals were treated with latano- jected IV and then infused to maintain a stable plasma level prost and the blood flow was determined 3, 41⁄2, and 6 hours until the end of the experiment; finally, the labeled eryth- after dose administration. The capillary permeability was de- rocytes were injected IV at 2 hours, ie, 30 minutes before termined between 5 and 6 hours after dose administration. the end of the experiment. Thus, it was possible to deter- Regional blood flow was measured using micro- mine the extravascular plasma-equivalent albumin space spheres (mean ± SEM size, 15.5 ± 0.1 µm) labeled with during 2 periods, 30 minutes to 21⁄2 hours and 11⁄2 to 21⁄2

trol eye at 1 hr after dose administration, although the dif- The values of the extravascular plasma-equivalent ferencewasnotstatisticallysignificant(P = .11,P = .40,P = .18, albumin space measured 30 minutes to 21⁄2 hours, 11⁄2 respectively). With time, the blood flow of these tissues to 21⁄2 hours, and 5 to 6 hours after topical application tended to become higher in the experimental eyes than in of PhXA34 or latanoprost are provided in Table 2. There the control eyes, and the difference reached statistical sig- was no difference between the experimental and con- nificance in the anterior sclera (Table 1). In the posterior trol eyes in the extravascular plasma-equivalent albu- sclera, the blood flow was low in the experimental and min space of any of the tissues studied. Thus, the capil- control eyes throughout the experiment, with a tendency lary permeability to albumin was not increased by the toward higher blood flow in the experimental eye through- administration of latanoprost or PhXA34 to the eye. The out the postdosing period. The blood flow of the intraocu- largest extravascular plasma-equivalent albumin space in lar tissues, the iris, the ciliary body, the choroid, and the the control and experimental eyes generally was found retina did not change 1 to 6 hours after instillation of the at the end of the 30 minutes to 21⁄2-hour period after dos- test drugs, with the exception of the ciliary body, in which ing, which is logical since the labeled albumin had time a small but statistically significant increase was found at 21⁄2 to circulate 1 hour longer than during the other periods hours after application of PhXA34 (Table 1). The mean ar- and reflects the physiological albumin turnover in the tis- terial blood pressure at the time of the blood flow determi- sues. The protein concentration of the aqueous humor nations was 94.3 ± 5.7 mm Hg at 1 hour, 91.2 ± 3.2 mm Hg 21⁄2 hours after topical application of PhXA34 was at 21⁄2 hours, 75.8 ± 3.4 mm Hg at 3 hours, 75.4 ± 2.7 mm 0.09 ± 0.01 and 0.11 ± 0.03 mg/mL in the experimental Hg at 41⁄2, hours and 77.8 ± 4.2 mm Hg at 6 hours after dose and control eyes, respectively. The corresponding fig- administration. The 1 and 21⁄2-hour values are based on the ures 6 hours after topical application of latanoprost were first series of experiments; the 3-, 41⁄2-, and 6-hour values 0.19 ± 0.08 and 0.36 ± 0.28 mg/mL in the experimental are based on the second series of experiments. and contralateral control eyes, respectively.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 hours after instillation of PhXA34. The regional blood flow of 125I and 131I, respectively, in the tissue samples with the to the different tissues of the eye was measured 1 and 21⁄2 corresponding radioactivity in the reference blood sample hours after instillation of PhXA34 in the same animals. In obtained at the end of the experiment, and multiplied by the second series of experiments, the regional blood flow the relative volume of plasma in the blood sample (1 − he- was measured 3, 41⁄2, and 6 hours after topical instillation matocrit). The intravascular plasma volume was calcu- of latanoprost, and the capillary permeability was mea- lated from the 51Cr radioactivity in the tissue sample and sured between 5 and 6 hours after instillation of latano- blood sample and the hematocrit. The intravascular plasma prost using 131I-albumin and 51Cr-erythrocytes essentially volume is equal to the intravascular plasma-equivalent al- as previously described. bumin space. The extravascular plasma-equivalent albu- Blood samples for the determination of PO2,PCO2, and min space in the tissue samples was then calculated by sub- pH of arterial blood were obtained 5 minutes before each tracting the intravascular plasma volume from the total microsphere injection. In addition, blood samples were ob- plasma-equivalent albumin space. tained at about 15-minute intervals during the experi- The test drugs, latanoprost and PhXA34, were syn- ment to follow the concentration of the radioactively la- thetized at the Department of Medicinal Chemistry, Glau- beled albumin and erythrocytes in the blood and for coma Research Laboratories, Pharmacia & Upjohn, Uppsala, hematocrit determination. The animals were euthanized Sweden. PhXA34, the 15R,S epimeric mixture, contained with an overdose of pentobarbital. Aqueous humor was about 50% of the R epimer (latanoprost) and was used at a withdrawn, and the eyes were quickly enucleated, rinsed, higher concentration than latanoprost as the 15S epimer and placed on ice. Tissue samples of the upper eyelid and exhibits only about 10% of the pharmacological activity of the conjunctiva were collected. Periocular tissue adhering latanoprost (J.S. and G.S.,unpublished data, 1992). The to the globe was removed, and the eye was then dissected doses used in the experiment were 6 µg of latanoprost and into 6 parts: the retina, choroid, posterior sclera, iris, cili- 10 µg of PhXA34 (equivalent to about 6 µg of latano- ary body, and anterior sclera with the cornea. Tissue and prost), which is about 4 times higher than the clinical dose blood samples were weighed, and the radioactivity was of latanoprost (1.5 µg) in Xalatan eyedrops. The prosta- counted in a multichannel gamma spectrometer (model glandin analogues were dissolved in 0.9% sodium chlo- 1282 Compu-Gamma; Wallac, Turku, Finland). The pro- ride with 0.5% polysorbate 80 as solubilizer. The contra- tein concentration in the aqueous humor was determined lateral control eye received the same volume of the vehicle using a protein assay (Bio-Rad Laboratories Inc, Brussels, only. Belgium).17 The results are expressed as the arithmetical mean The blood flow to the different tissues of the eye was value ± SEM, and have been statistically analyzed with the calculated from the quotient of the radioactivity of micro- matched pair t test. PՅ.05 was considered statistically sig- spheres in the tissue and the reference blood sample mul- nificant. Statistical power calculations demonstrated that tiplied by the reference blood flow (volume of the refer- a 50% change in blood flow of the intraocular tissues could ence blood sample collected during 1 minute). The blood be detected at the P = .05 level with 80% power of the test flow of the eyelid and the conjunctiva was calculated per for n = 5, while the corresponding figure for the extraocu- weight of tissue, whereas the blood flow of the other tis- lar tissues was 75% to 100%. The corresponding figures for sues is given as blood flow of the whole tissue. The total the changes in extravascular plasma-equivalent albumin plasma-equivalent albumin space (intravascular and ex- space were 20% to 50% for the intraocular tissues and 40% travascular) was calculated by dividing the radioactivity to 100% for the extraocular tissues.

COMMENT it is not possible to make comparisons of the blood flow sequentially from 1 to 6 hours after dose administration. Latanoprost, a selective prostaglandin F receptor agonist, It should also be noted that the mean arterial blood pres- has been shown to induce significantly less surface hyper- sures were lower in the second series of experiments emia of the eye than PGF2␣–isopropyl ester in animals and compared with the first series. Since no baseline value was humans.8,18-21 In vitro concentrations of latanoprost acid obtainedbeforetheadministrationoflatanoprostorPhXA34, exceeding 10−6 mol/L have been shown to cause mild to the experimental eye should always be compared with the moderate constriction of arteries and veins, whereas lower contralateral control eye. A prerequisite for such a compari- 21,22 concentrations tend to cause vasodilation. Since PGF2␣ son is that there is no effect of the drug in the contralateral is a known constrictor of some blood vessels (eg, in the control eye. We have seen no indications of such an effect 9-12 brain), and since PGF2␣ can cause leakage of capillaries in the contralateral eye during treatment with latanoprost and postcapillary venules,23 it was considered important in animals (J.S. and G.S., unpublished data, 1991), and ef- to investigate the vascular effects of latanoprost in the eye, fects in the contralateral eye have not been seen with PGF2␣ 24 although it has previously been shown that PGF2␣– after single-dose administration. It is thus adequate to use isopropyl ester causes increased blood flow in the anterior the contralateral vehicle-treated eye as a control. uvea of rabbits and monkeys.6(pp155-170) The topical administration of latanoprost or PhXA34 When evaluating the results of the present study, it at a dose of approximately 4 times the clinical dose had should be remembered that the study consists of 2 sepa- minimal effects on the intraocular and extraocular blood rate series of experiments. In the first series, 5 animals were flow. In the surface structures of the eye, the eyelids, con- followed up for 21⁄2 hours after administration of PhXA34; junctiva, and anterior sclera, there was a tendency to- in the second series, another 5 animals were followed up ward reduced blood flow at 1 hour after dose administra- for 6 hours after the administration of latanoprost. Thus, tion. This could reflect a moderate vasoconstriction and

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Effect of Topically Applied PhXA34 or Latanoprost on the Ocular Blood Flow in Cynomolgus Monkeys*

Ocular Blood Flow, µL/min

PhXA34 Latanoprost

Tissue Eye 1h 21⁄2h3h41⁄2h6h Eyelid C 602.0 ± 185.0 422.0 ±109.0 322.0 ± 41.0 293.0 ± 55.0 358.0 ± 111.0 E 425.0 ± 169.0 562.0 ± 179.0 405.0 ± 116.0 290.0 ± 109.0 266.0 ± 70.0 Conjunctiva C 298.0 ± 214.0 217.0 ± 118.0 170.0 ± 23.0 230.0 ± 58.0 112.0 ± 37.0 E 130.0 ± 49.0 259.0 ± 80.0 251.0 ± 43.0 223.0 ± 40.0 300.0 ± 129.0 Anterior sclera C 10.4 ± 5.4 9.3 ± 3.7 4.2 ± 0.7 7.1 ± 1.3 4.6 ± 1.7 E 6.8 ± 3.4 18.6 ± 4.5† 13.4 ± 3.2‡ 9.7 ± 2.9 13.2 ± 3.2 Posterior sclera C 3.4 ± 1.5 4.0 ± 1.0 2.4 ± 0.5 2.4 ± 0.8 3.1 ± 0.5 E 4.8 ± 2.5 7.7 ± 2.3 8.8 ± 2.4 5.9 ± 2.6 4.1 ± 1.6 Iris C 9.4 ± 2.6 15.1 ± 4.2 13.2 ± 2.3 13.8 ± 3.6 19.6 ± 7.2 E 8.2 ± 3.0 20.4 ± 4.2 13.1 ± 2.1 13.1 ± 2.1 15.3 ± 2.1 Ciliary body C 45.3 ± 7.6 57.2 ± 11.9 50.5 ± 5.9 45.8 ± 4.1 63.6 ± 6.4 E 47.0 ± 7.3 68.6 ± 13.4§ 54.5 ± 9.6 57.8 ± 8.4 69.7 ± 13.3 Choroid C 417.0 ± 102.0 355.0 ± 60.0 290.0 ± 47.0 278.0 ± 37.0 221.0 ± 14.0 E 459.0 ± 98.0 328.0 ± 55.0 296.0 ± 44.0 282.0 ± 33.0 266.0 ± 24.0 Retina C 19.9 ± 3.2 18.1 ± 2.5 15.3 ± 4.6 15.3 ± 3.4 13.2 ± 3.8 E 22.3 ± 5.4 16.1 ± 2.3 12.3 ± 1.5 14.5 ± 1.0 16.9 ± 3.1

*The dose used was 10 µg of PhXA34 (13,14-dihydro-15 R, S-17-phenyl-18,19,20-trinor-prostaglandin F2␣-isopropyl ester) or 6 µg of latanoprost. Data are given as mean ± SEM (n = 5). For the eyelid and conjunctiva, the results are expressed per gram of tissue. C indicates contralateral control eyes; E, experimental eyes. †P = .02. ‡P = .05. §P = .002.

Table 2. Effect of Topically Applied PhXA34 or Latanoprost on the Extravascular Plasma-Equivalent Albumin Space (Capillary Permeability) in Cynomolgus Monkeys*

Albumin Space, µL

PhXA34 Latanoprost Tissue Eye 30 min to 21⁄2 h11⁄2to 21⁄2 h (5 to 6 h) Eyelid C 16.00 ± 4.00 12.00 ± 4.00 29.00 ± 15.00 E 15.00 ± 3.00 11.00 ± 3.00 15.00 ± 4.00 Conjunctiva C 18.00 ± 4.00 9.00 ± 4.00 27.00 ± 16.00 E 16.00 ± 4.00 9.00 ± 3.00 17.00 ± 3.00 Anterior sclera C 0.82 ± 0.08 0.42 ± 0.06 0.61 ± 0.30 E 0.93 ± 0.19 0.45 ± 0.10 0.58 ± 0.14 Posterior sclera C 4.10 ± 0.50 2.40 ± 0.30 1.70 ± 0.20 E 4.10 ± 0.60 2.50 ± 0.40 1.80 ± 0.10 Iris C 0.15 ± 0.02 0.15 ± 0.02 0.15 ± 0.05 E 0.19 ± 0.03 0.16 ± 0.02 0.13 ± 0.02 Ciliary body C 7.00 ± 0.40 4.70 ± 0.30 2.70 ± 0.20 E 6.50 ± 0.30 4.30 ± 0.30 2.80 ± 0.30 Choroid C 10.20 ± 1.50 8.50 ± 1.10 6.00 ± 0.60 E 9.80 ± 1.50 8.40 ± 0.90 6.00 ± 0.60 Retina C 0.92 ± 0.09 0.61 ± 0.10 0.37 ± 0.08 E 0.76 ± 0.09 0.49 ± 0.07 0.29 ± 0.08

*The dose used was 10 µg of PhXA34 (13,14-dihydro-15 R,S-17-phenyl-18,19,20-trinor-prostaglandin F2␣-isopropyl ester) or 6 µg of latanoprost. Data are given as mean ± SEM (n = 5). For the eyelid and conjunctiva, the results are expressed per gram of tissue. C indicates contralateral control eyes; E, experimental eyes.

would be logical with respect to the rather high concen- some patients treated with Xalatan eyedrops. This is what tration of latanoprost in these structures. It can be esti- can be anticipated with a decreasing concentration of la- mated that the concentration of latanoprost in the sur- tanoprost in the tissues, ie, a concentration range is reached face structures early may have been around 10−6 to 10−5 at which latanoprost may cause vasodilatation.22 mol/L, and that would be in the concentration range at In the posterior sclera, there was no tendency to- which latanoprost can be anticipated to cause mild to mod- ward vasoconstriction at any time, if anything there was erate vasoconstriction.21,22 Subsequently, vasodilation or a tendency toward vasodilation, although the low blood a tendency toward vasodilation was seen in the surface flow in this tissue makes the blood flow determination structures, which agrees well with the hyperemia seen in with the microsphere method somewhat unreliable.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 We found no or only minimal effects of latano- sity, Biomedical Center, Box 593, S-751 24 Uppsala, Swe- prost or PhXA34 on the blood flow in the anterior uvea, den (e-mail: [email protected]). choroid, or retina. In particular, there was not even a tendency toward vasoconstriction in the posterior seg- ment. In the anterior uvea, there was slight vasodilation REFERENCES at 21⁄2 hours after dose administration, which coincides with the submaximum concentration of latanoprost acid 1. Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group. Effects on −7 25 intraocular pressure and side effects of 0.005% latanoprost applied once daily, in the aqueous humor (approximately 10 mol/L, ie, evening or morning: a comparison with timolol. Ophthalmology. 1995;102:1743- the concentration range at which the drug causes mod- 1752. erate vasodilation). Thus, the effect of topically applied 2. Watson P, Stjernschantz J, the Latanoprost Study Group in United Kingdom. A six-month, randomized, double-masked study comparing latanoprost with timo- latanoprost on the intraocular blood flow was negligible lol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103: or at the most minimal in the monkey eye, which is in 126-137. 3. Camras CB, the USA Latanoprost Study Group. Comparison of latanoprost and sharp contrast to the effect of PGF2␣–isopropyl ester, which timolol in patients with ocular hypertension and glaucoma: a six-month, masked, 6(pp155-170) in a previous study was shown to increase the multicenter trial in the United States. Ophthalmology. 1996;103:138-147. blood flow in the ciliary body by about 400% and in the 4. Camras CB, Alm A, Watson P, Stjernschantz J, the Latanoprost Study Groups. Latanoprost, a prostaglandin analog, for glaucoma therapy: efficacy and safety anterior sclera by about 500% in the monkey. after 1 year of treatment in 198 patients. Ophthalmology. 1996;103:1916-1924. Latanoprost or PhXA34 had no effect on the plasma- 5. Giuffre` G. The effects of prostaglandin F2␣ in the human eye. Graefes Arch Clin equivalent extravascular albumin space in any of the tis- Exp Ophthalmol. 1985;222:139-141. 6. Bito LZ, Stjernschantz J, eds. The Ocular Effects of Prostaglandins and Other sues studied. We measured the albumin leakage at 3 dif- Eicosanoids. New York, NY: Alan R Liss Inc; 1989. ferent periods after administration of the drug since there 7. Alm A, Villumsen J, To¨rnquist P, et al. Intraocular pressure–reducing effect of PhXA41 in patients with increased eye pressure: a one-month study. Ophthal- could be an early, in-between, or late effect on capillary mology. 1993;103:1312-1317. permeability, and it is not known how quickly a leakage 8. Stjernschantz J, Alm A. Latanoprost as a new horizon in the medical manage- of albumin (eg, in the iris) is washed away. In contrast, ment of glaucoma. Curr Opin Ophthalmol. 1996;7:11-17. 9. Denton JCJR, White KP, Robertson JT. The effects of prostaglandins E1,A1 we found that topically applied PGF ␣–isopropyl ester in 2 and F2␣ on the cerebral circulation of dogs and monkeys. J Neurosurg. 1972; the cynomolgus monkey causes a slight increase of cap- 36:34-42. illary permeability to albumin in the anterior uvea (J.S. 10. Uski TK, Andersson K-E. Effects of prostanoids on isolated feline cerebral arteries, II: roles of extra- and intracellular calcium for the prostaglandin F2␣– in- and G.S., unpublished data, 1992). The difference be- duced contraction. Acta Physiol Scand. 1984;120:197-205. tween the present results and the results previously 11. Uski TK, Andersson K-E, Brandt L, Ljunggren B. Characterization of the prosta- 8 noid receptors and of the contractile effects of prostaglandin F2␣ in the human obtained with PGF2␣–isopropyl ester may be due to the pial arteries. Acta Physiol Scand. 1984;121:369-378.

different receptor profile of the 2 compounds, latano- 12. Wendling WW, Harakal C. Effects of prostaglandin F2␣ and thromboxane A2 prost being a much more selective prostaglandin F recep- analogue on bovine cerebral arterial tone and calcium fluxes. Stroke. 1991;22: 66-72. tor agonist. These data are important because they clearly 13. Hoste AM. Reduction of IOP with latanoprost [letter]. Ophthalmology. 1997;104: indicate that latanoprost does not induce capillary leak- 895-896. age and are thus in good agreement with the results of clini- 14. Alm A, Bill A. The oxygen supply to the retina, II: effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood cal trials with latanoprost in which various techniques have flow in cats. Acta Physiol Scand. 1972;84:306-309. been used to measure barrier permeability.26-28 15. Bill A. The albumin exchange in the rabbit eye. Acta Physiol Scand. 1964;60:18- 29. In conclusion, latanoprost used at 4 times the clini- 16. Bill A. Capillary permeability to and extravascular dynamics of myoglobin, albu- cal dose had no or a negligible effect on the intraocular min and gammaglobulin in the uvea. Acta Physiol Scand. 1968;73:204-219. blood flow in phakic monkey eyes and only moderate ef- 17. Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilising the principle of protein-dye binding. Anal Bio- fects on the blood flow in the extraocular structures. As chem. 1976;72:248-254. the present data were obtained after a single dose, it can- 18. Stjernschantz J, Resul B. Phenyl substituted prostaglandin analogs for glau- not with certainty be stated that the response would be coma treatment. Drugs Future. 1992;17: 691-704. 19. Resul B, Stjernschantz J, No K, et al. Phenyl-substituted prostaglandins: potent identical during long-term treatment with latanoprost. and selective antiglaucoma agents. J Med Chem. 1993;36:243-248. However, latanoprost does not seem to cumulate in the 20. Astin M, Stjernschantz J, Sele´n G. Role of nitric oxide in PGF2␣-induced ocular eye during repeated once-daily administration,25 and the hyperemia. Exp Eye Res. 1994;59:401-408. 21. Astin M. Effects of prostaglandin E2,F2␣ and latanoprost acid on isolated ocular most marked effects with many drugs are frequently blood vessels in vitro. J Ocul Pharmacol Ther. 1998;14:119-128. obtained after the first dose. The effect of latanoprost 22. Astin M, Stjernschantz J. Mechanism of prostaglandin E2-, F2␣- and latanoprost on the microcirculation was studied in anesthetized ani- acid–induced relaxation of submental veins. Eur J Pharmacol. 1997;340:195- 201. 23. Svensjo¨ E. Bradykinin and prostaglandin E1,E2 and F2␣-induced macro- mals, and the anesthesia may have affected the cardio- molecular leakage in the hamster cheek pouch. Prostaglandins Med. 1978;1: vascular system. However, since the prostaglandin 397-410. 24. Camras CB, Podos SM, Rosenthal JS, Lee P-Y, Severin CH. Multiple dosing of

effects at the microcirculatory level most likely are prostaglandin F2␣ or epinephrine on cynomolgus monkey eyes, I: aqueous hu- based on a direct action on the arterioles, capillaries, mor dynamics. Invest Ophthalmol Vis Sci. 1987;28:463-469. 25. Sjo¨quist B, Johansson A, Stjernschantz J. Pharmacokinetics of latanoprost in and venules, it is unlikely that the general anesthesia the cynomolgus monkey: 3rd communication: tissue distribution after topical ad- would have altered the response compared with that ministration on the eye studied by whole body autoradiography. Arzneimittel- in conscious animals, although this possibility cannot forschung Drug Res. 1999;49:240-249. 26. Alm A, Villumsen J. PhXA34, a new potent ocular hypotensive drug: a study on be excluded. dose-response relationship and on aqueous humor dynamics in healthy volunteers. Arch Ophthalmol. 1991;109:1564-1568. Accepted for publication May 13, 1999. 27. Ziai N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous humor dynamics of PhXA41, a new prostaglandin F2␣ analogue, after topical application We thank Ire´ne Aspman for help with editing the manu- in normal and ocular hypertensive human eyes. Arch Ophthalmol. 1993;111: script. 1351-1358. Reprints: Johan Stjernschantz, MD, PhD, Department 28. Hotehama Y, Mishima HK. Clinical efficacy of PhXA34 and PhXA41, two novel prostaglandin F2␣–isopropyl ester analogues for glaucoma treatment. Jpn J Oph- of Neuroscience, Unit of Pharmacology, Uppsala Univer- thalmol. 1993;37:259-269.

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