SURVEY OF OPHTHALMOLOGY VOLUME 41 • SUPPLEMENT 2 ° FEBRUARY 1997 Circadian Intraocular Pressure Management with Latanoprost: Diurnal and Nocturnal Intraocular Pressure Reduction and Increased Uveoscleral Outflow HIROMU K. MISHIMA, MD, t YOSHIAKI KIUCHI, MD, 1 MICHIYA TAKAMATSU, MD, t PI~TER RACZ, MD, 2 AND LASZLO Z. BITO, PhD 3 Departments of Ophthalmology, ~ Hiroshima University School of Medicine, Japan, ~-Markusovszky Hospital, Szombathely, Hungary, and ~Columbia Universitv, College of Physicians and Surgeons, USA Abstract. Based on their mechanism of action, the most frequently used ocular hypertensive agents, the beta-blockers, cannot be assumed to reduce lOP during sleep. The need for drugs that reduce IOP around- the-clock is underscored, however, by the fact that inadequate nocturnal ocular perfusion pressure is con- sidered to be one of the likely causes of glaucomatous optic neuropathy especially in some cases of normal tension glaucoma. The studies reviewed here demonstrate that latanoprost, a new ocular hypotensive pros- taglandin F,_,, analogue, applied once a day at a concentration of 0.005%, maintains a statistically highly significant IOP reduction around-the-clock. The magnitude of this IOP reduction was found to be essen- tially identical during the day and at night, both in patients maintained on timolol and in those not receiving other glaucoma medication. Latanoprost-induced IOP reduction was also found to be associated with increased uveoscleral outflow in normotensive vohmteers, both during the day and at night. These circadian studies suggest that this new ocular hypotensive agent can be expected to be particularly useful fbr the medical management of some t'orms of glaucoma, such as normal tension glaucoma, when the cause of the glaucomatous damage cannot be linked specifically to diurnal lOP abnormalities. (Surv Ophthalmol 41 [Suppl 2]: S 139-S 144, 1997) Key words, aqueous humor dynamics • circadian • diurnal • intraocular pressure • latanoprost • nocturnal • prostaglandins • timolol • uveoscleralouttlow In some cases of glaucoma, especially in so-called normal tension glaucoma, intraocular perfusion pres- sure can be particularly compromised during noc- turnal episodes of systemic hypotension. ~0.~:~ Noctur- nal intraocular pressure (IOP) and blood pressure abnormalities may be the primary cause of the glau- comatous damage directly, or by increasing the chances of permanent loci of microvascular compro- mise following episodic ocular hypertension or IOP spikes. 3'4'1:~ In spite of this, the nocturnal hypoten- sive efficacy of glaucoma drugs have not been rou- tinely evaluated, even after it was reported that timolol does not reduce IOP at night, and that beta- blockers do not reduce aqueous humor production during sleep. 8'2''2~ In ['act, timolol continues to be used even for the management of normotensive glaucoma, in spite of the fact that its cardiovascular side effects may compromise ocular perfusion pres- sure. m:l Recently, a new group of ocular hypotensive agents, the prostaglandins (PGs), have been introduced and the PGFz~ derivative prodrug, latanoprost (previ- ously known as PhXA41), has been found to pro- vide effective IOP reduction as measured during the daytime, even when applied only once-a-day, either in the morning or in the evening, at a concentra- tion of 0.005%,1,9'24 Furthermore, latanoprost or its naturally-occurring parent compound, PGF,_,. in its esterified prodrug form, was shown not to reduce aqueous humor production either during the day or at night, 7'~6 and both animal and human studies show that PGs of the F2~ type, including latano- prost, reduce IOP primarily by increasing uveoscleral out[low. 2,7,17,22,23,26 Recently published studies 6:6:'-' have shown that once-daily latanoprost application yields an IOP re- duction throughout the night that is comparable in extent to its daytime IOP reduction. A third study performed in Japan by the first three authors of this review (HKM, YK, MK and coworkers) has S139 © 1997. Stellar Medical Publications. (7 Kent Street, Brookline, MA 02146. Tel: 617-566-2138. Fax: 617-566-4019)
`
`Micro Labs Exhibit 1038
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`S140 Surv Ophthalmol 41 (Suppl 2) February 1997 MISHIMA ET AL 0'3 -r 0 E E ~.-1 U,I 0 ~-e a. I -3 LU o n o .J e- o_ Treatment # 7 AM : .L Day 6 3 6 9 1'2 1'5 1'8 21 2J4 i ! :ii Trea~enti iii:{i:::::: :i :: i:i::: :: !: :: i Day i :::~iX~i: -2 :! : i::iiii:iii ~: "::::i: ii Time after treatment (hr.) Fig. 1. The ocular hypotensive effect of a single dose of 0.005% latanoprost, when applied unilaterally at 7 AM (Panel A) or 7 PM (Panel B) to eyes ofnormotensive volunteers whose contralateral eyes were treated with a placebo solution at the same time. The asterisks indicate statistically significant IOP differences between the latanoprost- and placebo-treated eyes (*P < 0.05; **P < 0.001).The points represent means _+ SEM, n=16. shown that this lOP reduction can be accounted for, both during the day and at night, by increasing uveoscleral outflow, without reducing the produc- tion of aqueous humor. These circadian IOP and aqueous humor dynamics studies will be reviewed here, briefly. Circadian IOP Study on Normal Volunteers After a Single (Morning or Evening) Treatment with 0.005% Latanoprost Sixteen healthy male volunteers (21-23 years of age) were recruited at the Hiroshima University School of Medicine) 6 For the first of two tests, eight subjects (Group 1) received one drop oflatanoprost in one eye and its vehicle solution in the contralat- eral eye at 7 AM, while the other eight subjects (Group 2) received vehicle in both eyes. Three days later, Group 1 was treated bilaterally with placebo, and Group 2 received unilateral latanoprost (and contralateral placebo) treatment at 7 AM. Thereaf- ter, the procedure was repeated, but the latanoprost and the placebo were administered at 7 PM. IOP was measured directly before, and at 3-hour intervals for 24 hours after the administration of latanoprost or placebo, using a Goldmann appla- nation tonometer. The analyses reviewed here were based on comparing the IOP of the latanoprost- treated eye to the simultaneously measured IOP of the contralateral control eye of each subject. Unilateral application of a single-dose of 0.005% latanoprost at either 7 AM (Fig. 1, Panel A) or at 7 PM (Fig. 1, Panel B) caused an IOP reduction in the latanoprost-treated eyes that was statistically significant at all time points indicated by asterisks in Fig. 1, as compared to the IOP of the contralat- eral placebo-treated eyes. The morning versus evening application of the drug had no apparent effect on the extent of IOP reduction in this small group of patients. In contrast, in a much larger long- term cross-over study/the IOP reduction was found to be significantly greater following evening as com- pared to morning application of latanoprost. This circadian study clearly shows that a single dose of latanoprost decreases IOP in normotensive volun- teers both during the dayand throughout the night. A Comparison of Nocturnal Versus Diurnal IOP Reduction in Ocular Hypertensive and Glaucoma Patients During the Course of Nine Days of Once Daily (Morning) Application of Latanoprost, with or without Concomitant Twice-Daily Treatment with Timolol In contrast to the study conducted in Japan on normotensive volunteers, a study in Szombathely, Hungary, enlisted 17 glaucoma patients and two ocular hypertensives with lOPs >22 mm Hg, at the beginning of an up to four-week pre-enrollment period. These 19 patients (38-81 years of age)were divided into two groups. In group 2 (n = 10), all previous glaucoma medications were washed out, while patients in Group 1 (n = 9) continued on twice-daily timolol treatment, m In the morning of Day 1 of the study period, patients were admitted to the hospital for baseline examinations and lOP measurements.19 One drop of 0.005% latanoprost was then applied the next morning at 8 AM to one eye of each patient and placebo to the other eye by hospital staff in a ran- domized, double-masked protocol, using coded vials supplied by Pharmacia A.B. (Uppsala, Swe- den). The patients left the hospital in the morning of the second day. On days 3-5, the patients came to the hospital, or were visited at their homes, and were treated by hospital staff between 8 and 10 AM,
`
`Micro Labs Exhibit 1038-2
`
`

`

`CIRCADIAN INTRAOCULAR PRESSURE MANAGEMENT WITH LATANOPROST S141 to eliminate uncertainties about compliance with the application of the eye drops. On the morning of Day 6, the patients were ad- mitted again to the hospital. Their eyes were treated with latanoprost/placebo by hospital staff at 8 AM on that day and on the following four days (Days 7-10). In Group 1, timolol was also applied in the morning and evening by hospital staff. During these days of hospitalization, symptoms and ocular signs of possible side effects were registered as previously described is and lOP was measured at different times of the day and night, according to a schedule de- scribed in the original publication, ~9 but not more than four times over any 24-hour period, and not more than once during each night, to minimize interference with normal sleep patterns. In most cases, and always at night, IOP was first measured with a Tono-Pen XL electronic tonom- eter (Bio-Rad, Glendale, California) with the pa- tient in the supine position, and in most cases also with a Goldmann applanation tonometer, followed by a second Tono-Pen reading, this time in the sit- ting position. On the 1 lth day, the last IOP meas- urements were taken at noon, 28 hours after the last treatment, and a closing examination was per- formed. The lOP of these patients was measured over this five-day period on 20 occasions, on most occasions with all three of the methods described above. Thus, both sitting and supine IOP values were accumulated over these five days of hospital- ization to cover each two-hour period, represent- ing a complete circadian cycle, with some duplicate time periods of measurements. In both groups, the mean IOP values of the latanoprost-treated eyes were significantly reduced, but they essentially paralleled the mean IOP values of the placebo-treated contralateral eyes through- out the circadian cycle, regardless of whether the IOP was measured in the sitting or in the supine position. 19 This is illustrated in Fig. 2 for the IOP readings obtained with the Tono-Pen with the pa- tients in the supine position, both during the day and at night. The supine Tono-Pen readings were taken at night with minimum disturbance, while the patient remained in bed. The mean diurnal versus nocturnal latanoprost- induced IOP reduction (test eye versus placebo- treated eye) was -2.26 -+ 0.30 versus -2.03 +- 0.33, and -3.19 + 0.32 versus -3.26 + 0.30 mm Hg as measured with the Tono-Pen in the supine position during the day and at night for Group 1 and Group 2, respectively. This <0.03 mm Hg difference be- tween the diurnal and nocturnal mean IOP values, or these differences based on the Goldmann or Tono-Pen values obtained in the sitting position at 19 A. On timolol 00 02 04 06 08 10 12 O. _~ B. No timolol ~= Z4 O .m _= 19 14 16 18 20 22 12" 24 14 00 02 04 06 08 10 12 14 16 18 20 22 12" Time of the Day in Clock Hours *)28 hrs after treatment Fig. 2. The mean IOPs (_+SEM) of ocular hypertensive or glaucomatous eyes collected between the fourth and ninth days of once-daily (8 AM) topical application of 0.005% latanoprost to one eye (solid circles) and its vehicle solution (placebo) to the contralateral control eye (open circle) of each patient. IOP values shown here were measured with a Tono- Pen XL applanation tonometer on patients in the supine po- sition. In Panel A, the patients (n = 9) were maintained on twice-daily bilateral 0.5% timolol treatment, whereas patients shown in Panel B (n = 10) had all glaucoma medications washed-out before the beginning of nine days oflatanoprost/ placebo treatment. Shaded areas indicate measurements taken at night. the same time points, were not statistically signifi- cant 19 (P > 0.40). Side effects were not noted and the local signs and symptoms observed or reported by the patient were not significantly different for the latanoprost- and placebo-treated eyes. TM The ocular hypotensive efficacy of latanoprost was also analyzed in terms of its ability to reduce the peak lOP value experienced by each patient. The highest IOP measurement of the control eye of each patient, obtained over the six-day in-hospital pe- riod, was compared to the corresponding IOP val- ues measured at the same time in the latanoprost- treated test eyes. As shown in Table 1, the mean of the peak IOP values in the placebo-treated control eyes, both in Group 1 and Group 2, were signifi- cantly higher (P < 0.03 to P < 0.0005) than the mean of the corresponding IOP values of the con- tralateral latanoprost-treated test eyes. This reduc- tion of IOP at the peak circadian IOP value of each patient was at least as much, or greater than the circadian IOP reduction shown in Fig. 2 here, or in the original publication for circadian IOP measure- ment taken in the sitting position, l" Thus, the once- daily topical application of 0.005% latanoprost is effective in blunting circadian IOP peaks, as well as
`
`Micro Labs Exhibit 1038-3
`
`

`

`S142 Surv Ophthalmol 41 (Suppl 2) February 1997 MISHIMA ET AL TABLE 1 The Means (+ SEM) of the Peak Circadian 10P Values (mm Hg) of Each Control Eye During the Six-day Measurement Period, the Mean of the Corresponding lOP Value in the Contralateral Latanoprost-treated Test Eyes, and the Mean Percent lOP Difference Between the Latanoprost Treated Eyes and Contralateral Control Eyes at These Peak Values Tonopen Goldmann Supine Sitting Sitting Group 1" Group 2t Group 1 Group 2 Group 1 Group 2 Mean of peak IOPs in control eyes 24.3 + 1.0 25.3 + 0.5 23.0 + 1.2 24.0 + 0.8 23.1 + 1.3 24.4 + 0.7 Mean of corresponding IOPs in test eyes 21.2+1.4 20.4+0.9 19.4+1.4 19.4+0.8 20.0+1.1 19.3+0.5 Percent of IOP reduction at peak 12.9 + 4.5 19.2 + 3.3 15.5 + 4.8 18.5 + 4.5 12.9 + 3.8 20.3 + 3.0 Significance:~ (P) <0.03 <0.0005 <0.03 <0.005 <0.006 <0.0005 *Group 1, timolol + latanoprost vs. timolol + placebo (n = 9) tGroup 2, latanoprost only vs. placebo (n = 10) :~P values, based on paired t-test of the IOP differences between test and control eyes reducing the mean diurnal and nocturnal IOPs. The significance of this observation becomes clear if we consider the hypothesis, based on studies performed on other organ systems, that even relatively brief focal ischemic episodes, such as those caused by lOP spikes, may lead to the accumulation of small sites of permanent vascular damage in the optic nerve head.3. 4 Diurnal and Nocturnal Latanoprost- induced Effects on Uveoscleral Outflow A study was performed by the first three authors of this review (HKM, YK, and MT) on 13 normo- tensive (IOP <21 mm Hg) Japanese males of 21 to 23 years of age. The left eyes were treated with 30 pA of 0.005% latanoprost and the right eyes with placebo, five times over a three-day period, accord- ing to the treatment schedule shown in Table 2. This table also shows the schedule of oral carbonic anhydrase inhibitor (CAI), acetazolamide, and topi- TABLE 2 Schedule of Measurements and Administrations Day 1 Day 2 Day 3 Latanoprost/placebo 8 AM, 8 AM, 8 PM 8 PM Oral acetazolamide -- -- Topical fluorescein -- 6 PM Fluorophotometry -- -- Tonography Tonometry 12 AM, 12 PM 8 AM 2 AM, 4 PM 6 AM 12,2,4, 6 AM 12,2,4, 6 PM 2, 6PM cal fluorescein administration, as well as the times of performance of measurements, required to cal- culate aqueous humor flow rate according to the Jones-Maurice method, 14 under two different rates of aqueous humor secretion, according to the method of Yablonski and coworkers? ~ The dimen- sion of the cornea and the anterior chamber were estimated during the first day of the study with slit- lamp biomicroscopy. ~5 Tonography was performed with a Mfiller tonometer over a four-minute period, while tonometry was performed with a Goldmann applanation tonometer at times shown in Table 2. The reported value 25 of 8 mm Hg was used for epi- scleral venous pressure in all calculations. The measured and calculated values of aqueous humor dynamics are presented in Table 3. There was no significant difference in aqueous humor flow between latanoprost- and placebo-treated eyes dur- ing the daytime, but a significantly (P < 0.05) greater aqueous humor flow was measured with fluorophotometry at night in the latanoprost-treated eyes, as compared to the contralateral placebo- treated eyes of these normotensive volunteers. As measured during the day, the IOP values were 13.1 _+ 1.3 versus 10.5 + 2.2 in the latanoprost- treated eyes and 15.1 _+ 2.1 versus 12.9 + 2.3 mm Hg in the control eyes for the pre-CAI versus post- CAI measurements, respectively. As measured dur- ing the night, these values were 12.5 _+ 1.1 versus 11.6 _+ 2.7 and 14.9 _+ 2.0versus 11.9 _+ 2.3, respec- tively. There was no significant difference between latanoprost-treated and control eyes in trabecular outflow facility, as measured during the daytime or at night (Table 3). In contrast, there was a signifi- cant increase in the calculated uveoscleral outflow in the latanoprost-treated eyes as compared to the
`
`Micro Labs Exhibit 1038-4
`
`

`

`CIRCADIAN INTRAOCULAR PRESSURE MANAGEMENT WITH LATANOPROST TABLE 3 Calculated Parameters of Aqueous Humor Dynamics* S143 Day Time PhXA4 l Control Difference PhXA41 Night Time Control Difference Aqueous humor flow rate (p~l/min) 2.23 ± 0.38 2.24 ± 0.25 ns Fluorophotometric Method: Outflow Facility (I.L1/min/mmHg) 0.22 ± 0.25 0.25 ± 0.03 ns Uveoscleral Outflow (p~l/min) 1.19 ± 0.24 0.57 ± 0.07 p < 0.05 Tonographic Method: Outflow Facility (~zl/min/mmHg) 0.37 ± 0.03 0.28 ± 0.37 ns Uveoscleral Outflow (~l/min) 0.33 ± 0.4 -0.38 ± 0.56 p < 0.05 *Mean ± S.E. (Day time: n = 7, Night time: n = 9) paired t-test ns = not significant 1.66±0.05 1.44±0.15 p<0.05 0.09±0.04 0.09±0.02 ns 1.28±0.16 0.78±0.20 p<0.05 0.37±0.04 0.35±0.03 ns 1.51±0.12 1.23±0.04 p<0.05 contralateral placebo-treated eyes both during the daytime and at night. The extent of the apparent latanoprost-induced increase in uveoscleral outflow, measured by the fluorophotometric method dur- ing the daytime (Table 3), was comparable to the 0.87 + 0.22 versus 0.14 _+ 0.30 I~l/min uveoscleral outflow, calculated for the latanoprost versus pla- cebo-treated eyes using the same method in a pre- vious study. 22'23 However, the study described here also shows that a comparable, statistically signifi- cant (P < 0.05) increase in uveoscleral outflow also occurs at night. The uveoscleral outflow calculated from tono- graphic measurements yielded a smaller, albeit still statistically significant, difference between the latanoprost-treated and control eyes (Table 3). The interpretation of these tonographic values is made less reliable by the negative mean value obtained in the placebo-treated eyes during the daytime measurements, which may simply reflect random statistical variability in each of the measured pa- rameters. The fluorophotometric outflow facility measured at night was less than one half of that measured during the day, whereas the tonographic outflow facility was equal during the day and at night, higher in both cases than the daytime fluorophotometric outflow facility value. While we cannot rule out the possibility that this difference was simply due to errors in the measurements which were exagger- ated by the calculations that are required to find the outflow facility by this fluorophotometric tech- nique, it is possible that this reflects differences in outflow facility during sleep and during wakeful- ness. The fluorophotometric value represents the average flow rate between periods of sleep during the nighttime while the tonographic method is a direct determination of outflow facility obtained over four-minute periods at 12 noon and at mid- night while the subjects were presumably awake, both during the daytime and at night. The observed decreased outflow facility during sleep is worthy of further investigation because of its implications re- garding possible fundamental differences between diurnal and nocturnal patterns of aqueous humor dynamics, as it was discussed previously with respect to the required repair and maintenance of the ca- nal of Schlemn? ,5 The fact that latanoprost reduces IOP by increas- ing uveoscleral outflow, both during the day and at night, is of great potential therapeutic significance with respect to the management of normal tension glaucoma (NTG). The nature of this outflow that reaches the zero pressure environment of the orbit 2 allows the IOP reduction to be very effective at low IOP values. As opposed to the effect of pilocarpine on outflow facility, for example, increased uveo- scleral outflow allows the IOP to be reduced below the level of episcleral venous pressure, as it may be required in some cases of NTG. Conclusion These studies clearly demonstrated that once- daily topical application of 0.005% latanoprost pro- vides significant around-the-clock IOP reduction, by increasing uveoscleral outflow, both during the daytime and at night. Once-daily latanoprost has been shown to be more effective, or at least as ef- fective an ocular hypotensive agent as twice-daily timolol, ~ based on daytime IOP measurements, when timolol can also reduce IOP. The studies re- viewed here suggest that latanoprost may be a par- ticularly useful ocular hypotensive agent when the likely cause of the glaucomatous damage cannot be specifically associated with daytime events. The demonstrated nocturnal ocular hypotensive efficacy oflatanoprost suggests that this new glaucoma drug can have particular therapeutic advantage over beta- blockers when the glaucomatous damage is associ- ated with such nocturnal events as episodic systemic
`
`Micro Labs Exhibit 1038-5
`
`

`

`S144 Surv Ophthalmol 41 (Suppl 2) February 1997 MISHIMA ET AL hypotension, ~°,13 for example. Latanoprost may be particularly well suited for combined therapy with timolol, or other beta-blockers, to provide IOP re- duction during sleep, when beta-blockers have no demonstrated or predictable ocular hypotensive effects. References 1. Alm A, Camras CB, Watson PG: Phase 3 latanoprost studies: Masked 6-month comparisons with timolol, in the United Kingdom, Scandinavia, and USA. Surv Ophthalmol 41 (Suppl 2):S105-S110, 1997 2. Bill A: Uveoscleral drainage of aqueous humor: Physiology and pharmacology. Prog Clin Biol Res 312:417--427, 1989 3. Bito LZ: Glaucoma: A physiologic perspective with Darwin- ian overtones.J Glaucoma 1:193-205, 1992 4. Bito LZ: The impact ofintraocular pressure on venous out- flow from the globe: A hypothesis regarding IOP-dependent vascular damage in normal-tension and hypertensive glau- coma. J Glaucoma (in press) 5. Bito LZ: Physiologic aspects of glaucoma and its manage- ment, in Zimmerman T, Kooner K, Sharir M (eds): Textbook of Ocular Pharmacology. Philadelphia, Lippincott-Raven Press (in press) 6. Bito LZ, Racz P, Ruzsony MR, et al: The prostaglandin ana- logue, PhXA41, significantly reduces daytime and nighttime intraocular pressure (IOP) by itself, and in timolol-treated glaucomatous eyes (abstract). Invest Ophthalmol Vis Sci 35 (Suppl):2178, 1994 7. Brubaker RF: Fluorophotometric studies of prostaglandin effects on the human eye: The lack of association of reduced intraocular pressure with altered flow or barrier function. Prog Clin Biol Res 312:477-481, 1989 8. Brubaker RF: Flow of aqueous humor in humans. Invest Ophthalmol Vis Sci 32:3145-3165, 1991 9. Camras Cb and the United States Latanoprost Study Group: Comparison of latanoprost and timolol in patients with ocu- lar hypertension and glaucoma: A six-month, masked, multicenter trial in the United States. Ophthalmology 103: 138-147, 1996 10. Drance SM: Glaucoma -- Changing concepts. Eye 6:337-345, 1992 11. Greve E, Rulo A, Hoyng FPJ, Drance SM: Reduction ofin- traocular pressure in normal tension glaucoma with differ- ent therapeutic regimens of latanoprost: A review of short- term studies with three dose regimens. Surv Ophthalmol 41 (Suppl 2):$89-$92, 1997 12. Hayashi M, Yablonski ME, Novack GD: Trabecular outflow facility determined by fluorophotometry in human subjects. Exp Eye Res 8:621-625, 1989 13. Hayreh SS: Progress in the understanding of the vascular etiology of glaucoma. Curr Opin Ophthalmol 5:26-35, 1994 14. Jones RF, Maurice DM: New methods of measuring the rate of aqueous flow in man with fluorescein. Exp Eye Res 5:208- 220, 1966 15. Johnson SB, Coakes RL, Brubaker RF: A simple photogram- metric method of measuring anterior chamber volume. Am J Ophthalmo185:469-474, 1978 16. Kiuchi Y, Takamatsu M, Mishima HK: PhXA41, a prosta- glandin F2~ analogue reduces the intraocular pressure (IOP) in human volunteers during day and night (abstract). Invest Ophthalmol Vis Sci (Suppl):2178, 1994 17. Nilsson SEE Sperber GO, Bill A: The effect of prostaglan- din F2 -isopropyl ester (PGF2 -IE ) on uveoscleral outflow. Prog Clin Biol Res 312:429-436, 1989 18. Racz P, Ruzsonyi MR, Nagy ZT, Bito LZ: Maintained intraocu- lar pressure reduction with once-a-day application of a new prostaglandin F~ analogue (PhXA41). Arch Ophthalmol 111:657-661, 1993 19. Racz P, Ruzsonyi MR, Nagy ZT, et al: Around-the-clock (cir- cadian) intraocular pressure reduction with once-daily appli- cation of 0.005% latanoprost, by itself or in combination with timolol. Arch Ophthalmol 114:268-273, 1996 20. Reiss GR, Lee DA, Topper J, Brubaker RF: Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci 25:776-778, 1984 21. TopperJE, Brubaker RF: Effects oftimolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest Ophthal- mol Vis Sci 26:1315-1319, 1985 22. Toris CB, Camras CB, Yablonski ME: Effects of PhXA41, a new prostaglandin F~ analog, on aqueous humor dynamics in human eyes. Ophthalmology 100:1297-1304, 1993 23. Toris CB, Yablonski ME, Camras CB, Brubaker RF: Mecha- nism of the ocular hypotensive effect of latanoprost and the maintenance of normal blood-aqueous barrier function. Surv Ophthalmo141 (Suppl 2):$69-$75, 1997 24. Watson P, StjernschantzJ and the Latanoprost Study Group: A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology 103:126-137, 1996 25. Zeimer RC, Gieser DK, Wilensky JT et al: A practical venomanometer: Measurement ofepiscleral venous pressure assessment of the normal range. Arch Ophthalmol 101 : 1447- 1449, 1983. 26. Ziai N, Dolan JW, Kacere RD, Brubaker RF: The effects on aqueous dynamics of PhXA41, a new prostaglandin F2~ ana- logue, after topical application in normal and ocular hyper- tensive human eyes. Arch Ophthalmol 111 : 1351-1358, 1993 The studies reviewed here were supported by Pharmacia AB of Uppsala and its Japanese subsidiary. The original statistical analyses and additional analyses performed for this review were provided by Ms. Katarina Hedman of Pharmacia (Uppsala) and Mrs. Junko Tanaka of Hiroshima University School of Medicine. The authors also wish to thank Dr. Johan Stjernschantz of Pharmacia (Uppsala) for his support and most valuable sugges- tions, as well as Dr. Olivia B. Carifio for her invaluable help with the preparation of this manuscript. Dr. Bito has a pro- prietary interest in the use of prostaglandins for the medical management of glaucoma, through patents he has assigned to Columbia University according to the policies of the National Institutes of Health (USPHS), that has supported the research program of his laboratory in this field, between 1970 and 1989. He is currently a consultant to Pharmacia and Upjohn. Reprint address: Laszlo Z. Bito, Ph.D., Department of Oph- thalmology, Columbia University, 630 West 168th Street, New York, NY 10032.
`
`Micro Labs Exhibit 1038-6
`
`