November 2003
Volume 44, Issue 11
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Physiology and Pharmacology  |   November 2003
Effects of Lomerizine, a Calcium Channel Antagonist, on Retinal and Optic Nerve Head Circulation in Rabbits and Humans
Author Affiliations
  • Yasuhiro Tamaki
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Makoto Araie
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Yasuhiro Fukaya
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Miyuki Nagahara
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Asuka Imamura
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Maiko Honda
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Ryo Obata
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Ken Tomita
    From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
Investigative Ophthalmology & Visual Science November 2003, Vol.44, 4864-4871. doi:10.1167/iovs.02-1173
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      Yasuhiro Tamaki, Makoto Araie, Yasuhiro Fukaya, Miyuki Nagahara, Asuka Imamura, Maiko Honda, Ryo Obata, Ken Tomita; Effects of Lomerizine, a Calcium Channel Antagonist, on Retinal and Optic Nerve Head Circulation in Rabbits and Humans. Invest. Ophthalmol. Vis. Sci. 2003;44(11):4864-4871. doi: 10.1167/iovs.02-1173.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To investigate the effects of lomerizine, a Ca2+ antagonist, on the ocular tissue circulation in rabbits and on the circulation in the optic nerve head (ONH) and choroid in healthy volunteers.

methods. Lomerizine (0.1 [n = 10] or 0.3 [n = 11] mg/kg) or vehicle solution (n = 11) was injected intravenously in urethane-anesthetized rabbits, and blood flow in the retina, choroid, and iris-ciliary body was measured by the microsphere method and that in the ONH by the H2 gas-clearance method (0.1 [n = 6] or 0.3 [n = 9] mg/kg or vehicle, n = 6). Oral 5 mg lomerizine or placebo was administered to volunteers (n = 8) in a crossover study, and in areas of the fovea and ONH, the normalized blur (NB), a quantitative index of blood velocity, was measured, together with blood pressure, heart rate, and intraocular pressure (IOP), before and 1.5, 3, 6, and 9 hours after administration.

results. Blood flow in the rabbit retina increased significantly in the lomerizine-treated group, but blood flow changed little in the choroid or iris-ciliary body. Blood flow in the rabbit ONH also showed a significant increase in the lomerizine-treated group. In human studies, the NB obtained from the ONH during the experimental period showed a small but significant increase in the lomerizine-treated group compared with the placebo-treated group, but no significant intergroup difference was detected in the NB obtained from the fovea or in blood pressure, heart rate, or IOP.

conclusions. Lomerizine increases blood velocity, and probably blood flow, in the ONH and retina in rabbits, and it also increases blood velocity in the ONH in healthy humans, without significantly altering blood pressure or heart rate.

The development of several ocular disorders has been attributed to an insufficient blood flow. Moreover, the development of glaucomatous optic neuropathy may be associated with a compromised tissue circulation in the optic nerve head (ONH), in addition to increased intraocular pressure (IOP). 1 2 Calcium antagonists, which are widely used for the treatment of hypertension and coronary vascular diseases, reduce tone in blood vessels by inhibiting Ca2+ influx, thus causing relaxation of smooth muscle cells and increased regional blood flow in several organs. 3 4 5 Systemic administration of a calcium antagonist, such as nifedipine, 6 7 8 nimodipine, 9 or brovincamine, 10 11 reportedly retards the progression of visual field damage, at least temporarily, in a subset of patients with normal-tension glaucoma (NTG). 
Lomerizine, a newly developed calcium antagonist, is clinically used as an oral antimigraine drug at 5 mg twice daily in Japan. 12 It selectively inhibits the constriction of cerebral arteries induced by various stimulants in vitro, 13 and it increases cerebral blood flow in cats. 14 Further, its effects on systemic blood pressure and heart rate are much weaker than its effects on the central nervous system and cerebral arteries in dogs, 15 healthy volunteers, 16 and patients with migraine. 17 Thus, in ocular tissues, especially in the retina or optic nerve, lomerizine might be considered a vasodilator without systemic hypotensive effects. In conscious rabbits, intravenous lomerizine (0.03–0.3 mg/kg) significantly increased blood velocity in the ONH (measured by the laser speckle method) without significantly changing systemic blood pressure. 18 Further, in experiments using the hydrogen gas-clearance method, intravenous lomerizine (0.1 and 0.3 mg/kg) significantly increased ONH blood flow and inhibited the endothelin-1–induced hypoperfusion in this tissue. 19  
The apparent selectivity of lomerizine for cerebral arteries raised our hopes that in the eye this drug’s vascular effect might be selective for ocular neural tissues. Further, the relative lack of effect on systemic blood pressure implies that lomerizine is more suited for ophthalmic use than other calcium antagonists, although occasional sleepiness or flushing is reported as systemic side effects. 12 However, there have been no reports on its effect on the circulation in ocular tissues other than the ONH in experimental animals, nor are any reports available of its effect on ocular circulation in humans. 
In the present study, the effect of lomerizine on blood flow in the retina, choroid, and iris-ciliary body, as well as in the ONH, was evaluated in rabbits by using the microsphere method or the hydrogen gas-clearance method. In addition, the time course of the changes induced by lomerizine in the circulation of the retina and ONH was monitored in rabbits, by the laser speckle method to enable estimation of the duration of the effects. Finally, we used the laser speckle method 20 21 22 23 to examine the effects of oral lomerizine on the circulation in the ONH and choroid in healthy volunteers. 
Materials and Methods
Drug
For animal experiments, lomerizine (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride) was supplied to an investigator (MH) by Kanebo (Osaka, Japan). It was dissolved in a 20% dimethylacetamide solution containing 2% tartaric acid. The vehicle solution was supplied by the same company. Lomerizine was injected intravenously at doses of 0.1 and 0.3 mg/kg in a volume of 0.1 mL/kg body weight, which were chosen on the basis of previous reports. 15 18 19 Human volunteers received either a placebo tablet or oral lomerizine (Mygsis; Pharmacia and Upjohn, Kalamazoo, MI) at a dose of 5 mg. 17  
Animal Experiments
Microsphere Method.
Japanese rabbits weighing 1.8 to 2.5 kg were used and handled in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. General anesthesia was induced by intravenous injection of 0.9 to 1.1 g/kg urethane. The femoral artery was cannulated with a polyethylene catheter connected to a pressure transducer head for measurement of mean femoral artery blood pressure (FABPm) and a heart rate, and the animal was put in a modified restraining box equipped with a heating pad. Arterial partial pressure of O2 (Po 2), partial pressure of CO2 (Pco 2), and pH were checked before and 30 minutes after intravenous injection of lomerizine or vehicle solution (pH/Blood Gas Analyzer, model 170; Corning Glass, Corning, New York, NY), and body temperature was monitored with a rectal thermometer. IOP was measured with a calibrated applanation pneumatonograph. 
Blood flows in the retina, choroid, and iris-ciliary body were determined by the colored-microsphere technique 24 before and after intravenous administration of lomerizine. Heparin (500 IU/kg) was administered intravenously to prevent clotting. A catheter was introduced into the left ventricle through the ipsilateral internal carotid artery, and 0.10 mL of a suspension of nonlabeled red microspheres (15 ± 0.3 μL, 107 spheres/mL; E-Z Trac, Los Angeles, CA) was injected into the left ventricle. A reference blood sample was obtained from the cannulated femoral artery. Withdrawal started at the time of injection and continued until 60 seconds after the injection. Then, lomerizine solution at a dose of 0.1 or 0.3 mg/kg (or its vehicle) was injected intravenously. At 30 minutes after administration, a second microsphere injection was given, except that blue microspheres were used. IOP (in the eye contralateral to the carotid cannulation); FABPm; heart rate; arterial Po 2, Pco 2, and pH; and body temperature were monitored as described earlier. The rabbit was then killed with intravenous pentobarbital sodium, and the eye was enucleated and fixed in 4% formaldehyde for 1 hour. The fixed eyeball was bisected 2 mm posterior to the limbus, and the retina and choroid were excised from the posterior half. The iris-ciliary body complex was excised and divided into the iris (with the iridial process) and the ciliary body and were blotted, weighed, and dissolved in 5 M NaOH solution. The dissolved tissues were passed through a filter paper (2-μm pore size; RAWG-02500; Millipore, Bedford, MA) and mounted on a glass slide. The number of microspheres in samples on the slide was counted under a light microscope (Nikon, Tokyo, Japan) by a blinded examiner (YF). The blood sample was also dissolved in NaOH solution, and the number of spheres counted. The spheres injected before and after the lomerizine injection were distinguished by color, and the blood flows in the retina, choroid, and iris-ciliary body were calculated in milligrams per minute. 24  
Hydrogen Gas-Clearance Method.
Japanese albino rabbits weighing 1.8 to 2.5 kg were anesthetized as described earlier. After the pupil had been dilated with one drop of 0.4% tropicamide (Mydrin M; Santen Pharmaceutical Co., Osaka, Japan), a hydrogen electrode (platinum needle with a 0.3-mm diameter Pt/Ir tip) was inserted through the vitreous body from the pars plana into the lower portion of the ONH to a depth of approximately 0.7 mm, under observation, with a vitrectomy lens. A reference electrode was fixed in the subcutaneous tissue of the animal’s head. Using a hydrogen gas-clearance flowmeter (RBF-222; Biomedical Science, Kanazawa, Japan), the capillary blood flow in the ONH was calculated on the basis of the hydrogen density half-life after inhalation of 4% hydrogen by mask at a rate of 5.0 L/min for 4 minutes. Calculations of blood flow were made before and 15 minutes after drug injection by a blinded investigator (AI). Lomerizine (in one group of rabbits) or vehicle solution (in another group) was given at the same dosage and in the same manner as in the microsphere experiment. FABPm; heart rate; arterial Po 2, Pco 2, and pH; and body temperature were measured before and 15 minutes after the injection, as has been described. 
Laser Speckle Method.
Tissue circulation in the ONH and retina was evaluated by the laser speckle method. Details of this method have been published elsewhere 20 21 22 and are given only briefly herein. An apparatus consisting of a fundus camera equipped with a diode laser (wavelength, 808 nm) was used for monitoring the ONH circulation. 21 22 A second apparatus with the blue component of an argon laser (wavelength, 488 nm) was used for monitoring the retinal circulation. 20 The fundus, on which the laser beam was focused, was observed by means of an infrared CCD camera. The scattered light was imaged on an image sensor of 100 × 100 pixels, corresponding to a field of 0.62 × 0.62 mm in the rabbit fundus, on which a speckle pattern appeared. The difference was then calculated between the average speckle intensity and the speckle intensities for successive scans of the image speckles at the pixels on the sensor plane. This difference (expressed as a percentage of the average speckle intensity) was defined as normalized blur (NB). NB is approximately equivalent to the reciprocal of the speckle contrast given by Fercher and Briers. 25 It is primarily a quantitative index of the tissue blood velocity, although it is also influenced by the number of blood cells in the sampling volume, 23 and it correlates well both with the blood flow determined by the hydrogen gas-clearance method in the ONH 26 27 and that determined by the microsphere method in the retina. 20 The results were displayed in a color graphic showing the two-dimensional variations in the NB level over the field of measurement. The average NB level in any chosen square or rectangular area within the measurement field was calculated and termed NBav
In experiments involving the use of this method, Japanese albino rabbits weighing 1.8 to 2.5 kg were anesthetized as described earlier. The femoral artery was cannulated as described for measurements of FABPm and heart rate, and the animal was put in a modified restraining box equipped with a heating pad. Arterial Po 2, Pco 2, and pH were checked before and 30, 60, and 90 minutes after the injection of lomerizine or vehicle solution, and body temperature was monitored. In each eye, the pupil was dilated as described earlier. For measurement of ONH tissue blood velocity, the NBav in one randomly chosen eye was recorded over a square area of 0.42 × 0.42 mm (70 × 70 pixels in the sensor plane) within the ONH in which no discrete surface vessels were visible. 21 Measurement of NBav was performed every 0.125 second over a 1-second period, 22 during which no eye movement was encountered, using the apparatus equipped with a diode laser. 21 The values obtained during the 1-second measurement period were further averaged, and the value so obtained is hereafter referred to as NBONH. The absence of eye movements during the measurement period was confirmed by a method previously described. 20 21 Lomerizine solution was injected intravenously at a dose of 0.3 mg/kg in a volume of 0.1 mL/kg body weight in one group of rabbits, with the same volume of vehicle solution being injected in another group of rabbits treated in the same manner (control). The NBONH was recorded every 1 minute for the first 5 minutes, and then every 5 minutes from 5 to 90 minutes after the injection. During the experiment, IOP in the eye contralateral to the NB measurement site was measured with a calibrated applanation pneumatonograph before and 30, 60, and 90 minutes after the injection. 
Dutch rabbits weighing 1.0 to 1.5 kg were used for NB measurements in the retina, because in this species the medullary area containing retinal blood vasculature can be easily identified. After mydriasis in both eyes, the average NB level over a square retinal area of 0.62 × 0.62 mm (100 × 100 pixels in the sensor plane) that was free of visible surface vessels and approximately one papillary diameter away from the ONH along the medullary rays was recorded in one randomly chosen eye, using the apparatus equipped with an argon laser. 20 With this apparatus, each measurement took 0.18 second, and the average of three measurements was termed NBretina. General anesthesia was induced, and monitoring of systemic parameters was performed as described earlier. The lomerizine or vehicle-solution injection and the NBretina and IOP measurements were performed in lomerizine and control groups as has been described. NB measurements were performed by a blinded investigator (KT). 
Human Study
NB Measurements in Human ONH and Fovea.
Thirty minutes before measurements were to begin, the pupil was dilated with one drop of 0.4% tropicamide (Mydrin M; Santen Pharmaceutical). During the measurement, the subject was asked to watch a target light, and an electrocardiogram was monitored simultaneously. Image speckles were recorded from the measurement field, which was located on the temporal side of the ONH and corresponded to a field of 0.72 × 0.72 mm (30° visual angle of the fundus camera). We obtained the average NB across the largest rectangular field within the measurement field that was free of visible surface vessels, and then further averaged the values obtained over three cardiac pulses when fixation was satisfactory to give the mean NBav from the ONH (NBONH). The size of this rectangular field varied among subjects because of the need to avoid surface vessels, the range being from 0.22 × 0.29 mm (30 × 40 pixels) to 0.40 × 0.47 mm (55 × 65 pixels). Image speckles from the macular area, corresponding to a field of 1.06 × 1.06 mm (45° visual angle), were recorded, and the NBavs across a foveal area free of retinal vessels were further averaged (as described earlier) to obtain the mean NBav from the foveal area (NBfovea). In this case, the size of the field was 0.32 × 0.32 mm (30 × 30 pixels). 
Satisfactory fixation during the measurement period was confirmed by a method previously described. 20 It was further checked by inspecting the color map and the time-course plot of NBav measurements taken every 0.125 second. When there was no eye movement during the measurement period, visible surface vessels did not change position over the entire color map, and the time-course plot of NBav exhibited periodic fluctuations synchronized with the cardiac pulse. 23 In contrast, when eye movement occurred, visible surface vessels over the entire color map changed position according to the eye movement. 
Experimental Protocol.
The effects of a single dose of oral lomerizine on the circulation in the ONH and foveal area were studied in a group of healthy volunteers in a double-blind, placebo-controlled manner. The human study was approved by the Ethics Committee of the University of Tokyo and was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Before they were admitted to the study, written consent was obtained from all volunteers after the nature of the study had been fully explained and routine eye examinations completed. Eight subjects, 20 to 29 years of age, with no history of smoking, no systemic or ocular disease, and only mild refractive errors, were selected. On any day on which measurements were to be taken, the participants did not drink coffee, tea, or alcohol, and engaged in no strenuous exercise. 
For baseline measurements on day 0, the pupil was dilated with one drop of 0.4% tropicamide in the right eye. NBONH, NBfovea, and IOP in the right eye, brachial arterial blood pressure, and heart rate were measured at 08:00. A fundus photograph (Polaroid; Cambridge, MA) was taken to record the site of measurement. Measurements were repeated 90, 180, 360 and 540 minutes after the initial measurement (i.e., at 09:30, 11:00, 14:00, and 17:00). Five minutes after each measurement, one drop of 0.4% tropicamide was instilled into the right eye. On day 1, the same measurements were performed using the same time schedule as in the baseline experiment (day 0), except that the subjects were randomly assigned to either the lomerizine- or placebo-treated group. The former received oral 5 mg lomerizine (Mygsis; Pharmacia & Upjohn), and the latter a placebo tablet, in each case just after the measurement at 08:00. From days 2 to 20, the subjects received no drugs. On days 21 and 22, the same measurements were performed on the same schedule as on days 0 and 1, except that the subjects received lomerizine or placebo just after the measurement at 08:00 on day 22, in a crossover manner. 
Measurements were made by separate investigators blinded as to the treatment: NBONH and NBfovea (YT), IOP (MH), and arterial blood pressure and heart rate (RO). The results of the laser speckle measurements were digitally stored on magneto-optical disks as color maps from which NBONH and NBfovea were determined by a blinded investigator (MN). 
Data Analysis.
A paired t-test was used to compare values obtained in the same animals or humans, and an unpaired t-test or Dunnett test to compare data between groups. Although NB is primarily a quantitative index of tissue blood velocity, it is also affected by the laser light-scattering properties of the tissue, and therefore it is not advisable to compare NB directly between drug-treated and control groups. Hence, the time-related change in NB after an injection was compared between the lomerizine- and vehicle-treated groups (using data expressed as a percentage of the baseline). Baseline was defined as the preinjection NB in the rabbit experiment, and as the NB obtained at the same time on day 0 (for data obtained on day 1) or on day 21 (for data obtained on day 22) in the human experiment. An analysis of variance (ANOVA) was applied to data obtained by sequential measurements, to allow us to analyze intergroup differences in the series of percentages obtained for NB. P < 0.05 was considered statistically significant. 
Results
Animal Experiments
Rabbits in which data obtained for systemic parameters immediately before the drug or vehicle injection were outside the normal range 28 were not included in the study, and animals in which any of the systemic parameters showed an abnormal change during the experiment were also excluded. On this basis, 3 of 35 rabbits in the microsphere experiment and 2 of 23 rabbits in the hydrogen gas-clearance experiment had to be discarded, probably due to poor physical condition. In the laser speckle experiment, no rabbits were excluded from the study. 
Lomerizine (0.1 [n = 10] or 0.3 [n = 11] mg/kg) or vehicle solution (n = 11) was injected intravenously in urethane-anesthetized rabbits, and blood flow in the retina, choroid, and iris-ciliary body was measured by the microsphere method and that in the ONH by the hydrogen gas-clearance method (0.1 [n = 6] or 0.3 [n = 9] mg/kg or vehicle [n = 6]). 
Microsphere Experiment.
The blood flows in the retina, choroid, and iris-ciliary body determined by the microsphere technique before and 30 minutes after the administration of lomerizine (0.1 [n = 10] or 0.3 [n = 11] mg/kg) or vehicle (n = 11) are shown in Table 1 . In the vehicle-treated group, baseline blood flows in these tissues were 24.3 ± 23.5, 1033 ± 594, and 58.6 ± 36.5 mg/min, respectively. The retinal blood flow increased significantly after administration of lomerizine at doses of 0.1 mg/kg (average increase, 62.5%; P = 0.017, paired t-test) and 0.3 mg/kg (average increase, 82.0%; P = 0.003), but it showed no significant change after vehicle administration. The difference in retinal blood flow between baseline and 30 minutes after the injection was significantly larger in the 0.3 mg/kg lomerizine-treated group than in the vehicle-treated group (Dunnett test, P = 0.008). In contrast, blood flow showed no significant change in the choroid or iris-ciliary body after administration of lomerizine or vehicle, and in these tissues the difference in blood flow between baseline and 30 minutes after the injection was not significant between the 0.1 or 0.3 mg/kg lomerizine-treated and vehicle-treated groups (P > 0.1), compared with baseline. FABPm; heart rate; arterial pH, Pco 2, and Po 2; and body temperature showed no significant change at 30 minutes after administration of lomerizine or vehicle (Table 2)
Hydrogen Gas-Clearance Experiment.
The blood flow in the ONH determined by the hydrogen gas-clearance method before and 15 minutes after the administration of lomerizine (0.1 [n = 6] or 0.3 [n = 9] mg/kg or vehicle [n = 6]) are shown in Table 3 . The baseline ONH capillary blood flow averaged 110.2 ± 32.3 mL/min per 100 g tissue (mean ± SD, n = 6) in the control group. It increased significantly at 15 minutes after intravenous administration of lomerizine at a dose of 0.3 mg/kg (average increase, 17.8%; P = 0.037, paired t-test) and tended to increase at 0.1 mg/kg (average increase, 14.8%; P = 0.065), but it showed no significant change after administration of vehicle (Table 3) . The difference in ONH blood flow between baseline and 15 minutes after the injection tended to be larger in the 0.3 mg/kg lomerizine-treated group than in the vehicle-treated group (Dunnett test, P = 0.092). FABPm; heart rate; arterial pH, Pco 2, and Po 2; and body temperature showed no significant change from baseline at 15 minutes after the administration of lomerizine or vehicle (Table 4)
NB Measurements in ONH.
Both before and during the ONH experiment, there was no significant difference between the lomerizine (n = 9) and control groups (n = 9) in terms of IOP or in any of the systemic parameters (Table 5) . In the lomerizine group, the FABPm tended to decrease just after drug administration, but the decrease was not statistically significant (P = 0.171, Fig. 1 ). 
As shown in Figure 1 , the mean NBONH at the various time-points was significantly different between the lomerizine and control groups (ANOVA of repeated measurements, P < 0.001 [group] P < 0.001 [group × time]). 
NB Measurements in Retina.
Both before and during the retina experiment, there was no significant difference between the lomerizine (n = 10) and control groups (n = 10) in IOP or in any of the systemic parameters (Table 6) . In the lomerizine group, the mean FABPm tended to decrease just after drug administration, but the decrease was not statistically significant (P = 0.065, Fig. 2 ). 
As shown in Figure 2 , the mean NBretina at the various time points was significantly different between the lomerizine and control groups (ANOVA of repeated measurements, P < 0.001 [group], P < 0.001 [group × time]). 
Human Study
Under treatment with lomerizine or placebo, the IOP, mean blood pressure, and heart rate showed no significant change from the baseline, nor was there an intergroup difference at any of the measurement points (paired t-test, P > 0.1; Table 7 ). 
As shown in Figure 3 , the time course of the changes in NBONH was significantly different between the lomerizine and placebo groups (ANOVA of repeated measurements, P = 0.031 [group], P = 0.026 [group × time]), but NBfovea showed evidence of no such significant intergroup difference. 
Discussion
The first part of the present study investigated the effects of systemic lomerizine (a calcium antagonist with less effect on blood pressure in normotensive humans) on the ocular circulation in rabbits and demonstrated that this drug favorably affects the circulation in ocular neural tissues (the retina and ONH) in this species. Baseline values of blood flow rate in the rabbit retina (12.0–26.1 mg/min) and ONH (100.6–114.8 mL/min per 100 g) are compatible with the previously reported retinal (9–15 mg/min) 20 29 30 and ONH (33.4–119 mL/min per 100 g) 26 27 31 32 33 blood flow measured in normal rabbits by the microsphere and hydrogen gas-clearance methods, respectively. Although blood flow rate in the rabbit retina and ONH previously reported have a rather wide range when measured by these two methods, in the present study these methods were used to compare the difference in retinal and ONH blood flow change in the same rabbit eye by using the identical setting when the lomerizine or its vehicle was administrated, so that the error for measurements would be minimized. In the microsphere experiment, lomerizine at an intravenous dose of 0.3 mg/kg significantly increased its blood flow in the retina in urethane-anesthetized rabbits at 30 minutes after administration, but it had no such effect in uveal tissues (the choroid and iris-ciliary body). The microsphere method is not particularly useful for assessing blood flow in the ONH, because only a small number of microspheres becomes trapped in this small tissue. Hence, we also studied the effects of lomerizine on the ONH tissue circulation using the hydrogen gas-clearance method. In this experiment, lomerizine at an intravenous dose of 0.3 mg/kg tended to increase blood flow in the ONH in urethane-anesthetized rabbits at 15 minutes after its administration. This result is consistent with a previous report showing that 0.1 and 0.3 mg/kg lomerizine significantly increased ONH blood flow (as determined by the hydrogen gas-clearance method) in halothane-anesthetized rabbits. 19 These data indicate that lomerizine may selectively increase blood flow in ocular neural tissues, including the retina and ONH, rather than uveal blood flow. 
The NB obtained by the laser speckle method is primarily a quantitative index of tissue blood velocity. 20 21 25 When in rabbits the ocular blood flow was artificially changed by a variety of means—by increasing the IOP, 20 21 inhalation of 10% CO2, 26 intravenous injection of a small amount of endothelin-1, 26 or intravenous administration of calcium antagonists 27 35 —the NB value showed a good correlation with the blood flow determined by the microsphere method in the retina or choroid 20 21 35 and with the blood flow in the ONH 26 27 determined by the hydrogen gas-clearance method (in which a hydrogen electrode was inserted into the ONH tissue to a depth of approximately 0.7 mm, as in the present study). 
In our laser speckle experiment in rabbits, lomerizine (0.3 mg/kg intravenously) significantly increased blood velocity in both retinal and ONH tissue. However, both the amplitude of the effect and its duration were more prominent on the former than on the latter tissue, consistent with those obtained using the microsphere and hydrogen gas-clearance methods, respectively. NBONH was significantly greater in the lomerizine group than in the control group at 5 to 20 minutes after drug administration, whereas NBretina was significantly greater in the lomerizine group than in the control from 5 to 90 minutes. The microsphere experiments indicated that lomerizine is less effective on the short posterior ciliary arteries (choroidal circulation) than on the retinal arteries. Circulation in the prelaminar-to-laminar part of the optic nerve, which is mainly supplied by the short ciliary arteries, may show characteristics intermediate between those of the retinal and choroidal circulations, and this may at least partly explain the less prolonged effect of lomerizine on NBONH. Blood flow in both the surface area and the prelaminar-to-laminar part of the ONH is thought to be reflected in NBONH measurements made using the laser speckle method. 19 26 27 The less prolonged effect of lomerizine on NBONH could also be partly attributable to the surface area of the ONH being nourished by the retinal circulation, whereas the prelaminar-to-laminar part of the ONH is supplied by the short ciliary arteries. A similar explanation may be also applicable to a significant but not remarkable effect of oral lomerizine on the human ONH circulation presently recorded. 
The dose of lomerizine used in the present rabbit experiment was the one that affected the ONH circulation with little effect on systemic blood pressure in conscious rabbits. Plasma concentration 5 and 180 minutes after intravenous administration of 0.3 mg/kg lomerizine in rabbits are 130 and 5 ng/mL, respectively. 18 Because of species difference, the same plasma concentration of a calcium antagonist does not always elicit the same pharmacological effects in rabbit and humans. Maximum concentration (Cmax) after oral 5 mg lomerizine is 4.2 ng/mL in humans, and this dose significantly affected the ONH circulation without any effect on systemic blood pressure in the present subjects. 36 Although the plasma concentration of lomerizine in the present rabbits may be some 10 times higher than that in the present human subjects, as far as the effect on the ONH blood flow and systemic blood pressure are concerned, pharmacological effects of lomerizine in the present human subjects are thought not to be much different from those in the present rabbit experiment. In contrast, NBfovea showed no significant change after oral lomerizine. The retinal capillaries are absent in the foveola, 0.4- to 0.5-mm diameter capillary-free zone. In the present study, NBfovea was obtained from the field of 0.32 × 0.32 mm across a foveal area. Thus, NBfovea should reflect not retinal, but choroidal blood flow. The slight effect of lomerizine on the choroidal blood flow is consistent with the result of the microsphere experiment in rabbits, by which choroidal blood flow was little affected by intravenous lomerizine. In the present human study, we could not investigate the effect of oral lomerizine on the retinal circulation because making laser speckle measurements using argon blue is difficult in human subjects. Further studies using scanning laser Doppler flowmetry are needed to investigate the effect of lomerizine on human retinal tissue circulation. 37 38  
In general, systemic administration of Ca2+ channel blockers may be complicated by side effects such as hypotension, palpitations, reflex tachycardia, peripheral edema, and vertigo. These adverse effects derive from the main action of Ca2+ channel blockers, a blockade of Ca2+ channels in peripheral arteries. It is desirable to use a Ca2+ channel blocker with few systemic effects in clinical practice in ophthalmology. Actually, there is evidence that the effect of lomerizine on blood pressure is weaker than those of other Ca2+ channel blockers (e.g., nicardipine, verapamil, and diltiazem) because lomerizine selectively inhibits KCl-induced Ca2+ influx through Ca2+ channels more potently in cerebral arteries than in mesenteric arteries. 39 In fact, in anesthetized dogs it significantly increases vertebral blood flow with little effect on blood flow in peripheral arteries such as the mesenteric and femoral arteries. 15 Clinical studies have also revealed lomerizine to have little effect on blood pressure or heart rate. 17  
Our finding that lomerizine increased blood flow in retinal and ONH tissues without changing choroidal blood flow suggests that its effect is more prominent on vessels in neural tissues, including those in the ocular circulation. A beneficial effect of oral calcium antagonists on glaucomatous visual-field damage in a subset of patients with open-angle glaucoma, including patients with NTG, has been suggested by several investigators. 6 7 8 9 40 41 This, together with its reported neuroprotective effect against ischemia–reperfusion damage in the rat retina, 34 suggests that lomerizine may have clinical potential for conditions complicated by ocular circulatory disturbances in the retina or ONH. Effects of oral lomerizine in aged subjects or patients with NTG deserve further study. 
 
Table 1.
 
Blood Flow in Retina, Choroid, and Iris-Ciliary Body, before and 30 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
Table 1.
 
Blood Flow in Retina, Choroid, and Iris-Ciliary Body, before and 30 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
n Retina Choroid Iris-Ciliary body
Vehicle
 Pre 11 24.3 ± 23.5 1033 ± 594 58.6 ± 36.5
 Post 25.4 ± 12.9 1097 ± 624 64.0 ± 45.4
 Δ 1.1 ± 16.9 64 ± 275 5.4 ± 20.6
Lomerizine (0.1 mg/kg)
 Pre 10 12.0 ± 5.7 1118 ± 563 94.7 ± 74.3
 Post 19.5 ± 12.3* 1097 ± 522 103.1 ± 65.5
 Δ 7.5 ± 8.2 −21 ± 300 8.5 ± 22.8
Lomerizine (0.3 mg/kg)
 Pre 11 26.1 ± 15.6 1106 ± 405 83.8 ± 53.7
 Post 47.5 ± 29.8, ** , † 1167 ± 431 104.5 ± 72.0
 Δ 21.4 ± 18.2, ‡‡ 60 ± 202 20.7 ± 59.4
Table 2.
 
Systemic Parameters before and 30 minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
Table 2.
 
Systemic Parameters before and 30 minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
n Blood Pressure (mm Hg) Heart Rate (beats/min) pH Pco 2 (mm Hg) Po 2 (mm Hg) Body Temperature (°C)
Vehicle
 Pre 11 91.7 ± 5.3 280 ± 40 7.35 ± 0.03 31.1 ± 2.7 85.2 ± 9.9 37.0 ± 0.3
 30 min 94.6 ± 9.0 287 ± 30 7.35 ± 0.03 23.6 ± 3.3 94.8 ± 7.0 36.7 ± 0.7
Lomerizine (0.1 mg/kg)
 Pre 10 88.6 ± 12.0 287 ± 16 7.31 ± 0.03 32.4 ± 4.4 87.9 ± 12.0 37.2 ± 0.6
 30 min 86.4 ± 8.5 289 ± 16 7.34 ± 0.03 26.2 ± 4.7 92.5 ± 10.1 36.8 ± 0.9
Lomerizine (0.3 mg/kg)
 Pre 11 86.7 ± 8.3 278 ± 20 7.32 ± 0.03 28.9 ± 3.3 91.5 ± 9.0 37.1 ± 0.7
 30 min 82.3 ± 6.6 290 ± 20 7.33 ± 0.07 23.8 ± 3.6 95.7 ± 10.6 37.1 ± 0.7
Table 3.
 
Blood Flow in Optic Nerve Head before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
Table 3.
 
Blood Flow in Optic Nerve Head before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
n ONH Blood Flow
Vehicle
 Pre 6 110.2 ± 32.3
 Post 113.9 ± 33.6
 Δ 3.7 ± 6.4
Lomerizine (0.1 mg/kg)
 Pre 6 114.8 ± 61.0
 Post 132.2 ± 72.0
 Δ 17.4 ± 17.9
Lomerizine (0.3 mg/kg)
 Pre 9 100.6 ± 33.3
 Post 116.0 ± 36.6*
 Δ 15.4 ± 14.7
Table 4.
 
Systemic Parameters before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
Table 4.
 
Systemic Parameters before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
n Blood Pressure (mm Hg) Heart Rate (beats/min) pH Pco 2 (mm Hg) Po 2 (mm Hg) Body Temperature (°C)
Vehicle
 Pre 6 87.2 ± 2.2 281 ± 15 7.36 ± 0.02 35.4 ± 3.4 89.5 ± 8.3 37.0 ± 0.2
 15 min 87.1 ± 2.2 287 ± 15 7.36 ± 0.02 35.2 ± 4.2 90.3 ± 7.8 37.0 ± 0.2
Lomerizine (0.1 mg/kg)
 Pre 6 88.8 ± 2.7 287 ± 17 7.38 ± 0.02 37.3 ± 6.9 86.9 ± 2.9 37.0 ± 0.2
 15 min 86.4 ± 6.1 293 ± 15 7.38 ± 0.02 36.4 ± 6.1 86.2 ± 4.4 36.9 ± 0.2
Lomerizine (0.3 mg/kg)
 Pre 9 86.5 ± 5.1 280 ± 18 7.38 ± 0.03 38.9 ± 3.9 87.2 ± 5.4 36.9 ± 0.2
 15 min 84.3 ± 6.6 284 ± 15 7.37 ± 0.03 36.0 ± 3.3 87.4 ± 3.9 37.0 ± 0.2
Table 5.
 
Systemic Parameters of Albino Rabbits before and after Lomerizine Administration in the Optic Nerve Head Experiment
Table 5.
 
Systemic Parameters of Albino Rabbits before and after Lomerizine Administration in the Optic Nerve Head Experiment
Pre 5 Min 15 Min 30 Min 60 Min 90 Min
Lomerizine group
 IOP (mm Hg) 20.2 ± 3.9 18.5 ± 3.4 18.8 ± 3.1 18.2 ± 4.5 17.2 ± 4.3 16.4 ± 3.9
 HR (beats/min) 293 ± 39 290 ± 22 295 ± 37 304 ± 34 305 ± 31 311 ± 31
 pH 7.39 ± 0.03 7.40 ± 0.03 7.40 ± 0.03 7.41 ± 0.03
 Pco 2 (mm Hg) 35.4 ± 4.6 34.7 ± 1.5 34.6 ± 3.5 33.6 ± 3.6
 Po 2 (mm Hg) 79.8 ± 10.2 85.7 ± 9.1 85.4 ± 5.1 86.3 ± 6.2
 BT (°C) 38.6 ± 0.4 38.5 ± 0.5 38.4 ± 0.7 38.4 ± 0.8
Control group
 IOP (mm Hg) 20.3 ± 5.4 20.6 ± 5.5 19.8 ± 5.6 19.2 ± 4.2 16.1 ± 3.4 16.3 ± 3.9
 HR (beats/min) 277 ± 48 277 ± 56 287 ± 53 287 ± 50 283 ± 46 284 ± 48
 pH 7.38 ± 0.05 7.39 ± 0.03 7.39 ± 0.02 7.39 ± 0.01
 Pco 2 (mm Hg) 38.3 ± 3.0 35.3 ± 5.0 34.2 ± 5.5 34.8 ± 5.2
 Po 2 (mm Hg) 79.0 ± 3.8 86.6 ± 6.6 91.2 ± 4.5 92.8 ± 5.9
 BT (°C) 38.2 ± 0.6 38.1 ± 0.5 38.2 ± 0.6 38.0 ± 0.8
Figure 1.
 
Time course of changes in NBONH and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean ± SD in nine rabbits in each plot. Intergroup difference in NBONH (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 1.
 
Time course of changes in NBONH and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean ± SD in nine rabbits in each plot. Intergroup difference in NBONH (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Table 6.
 
Systemic Parameters of Dutch Rabbits before and after Lomerizine Administration in the Retina Experiment
Table 6.
 
Systemic Parameters of Dutch Rabbits before and after Lomerizine Administration in the Retina Experiment
Pre 5 Min 15 Min 30 Min 60 Min 90 Min
Lomerizine group
 IOP (mm Hg) 14.7 ± 6.1 13.4 ± 4.2 12.8 ± 5.2 13.1 ± 5.5 11.1 ± 4.4 11.2 ± 3.2
 HR (beats/min) 274 ± 18 269 ± 15 266 ± 19 280 ± 19 295 ± 22 305 ± 25
 pH 7.43 ± 0.03 7.44 ± 0.03 7.44 ± 0.02 7.45 ± 0.03
 Pco 2 (mm Hg) 35.1 ± 5.4 31.8 ± 4.0 29.0 ± 5.3 29.5 ± 4.8
 Po 2 (mm Hg) 76.3 ± 7.5 84.5 ± 5.4 89.2 ± 11.7 89.0 ± 8.2
 BT (°C) 38.3 ± 0.3 38.1 ± 0.4 38.1 ± 0.5 38.2 ± 0.6
Control group
 IOP (mm Hg) 17.5 ± 7.2 16.9 ± 5.9 16.5 ± 5.4 14.9 ± 4.4 13.3 ± 5.5 12.4 ± 5.7
 HR (beats/min) 277 ± 30 276 ± 27 274 ± 26 277 ± 29 273 ± 27 283 ± 22
 pH 7.42 ± 0.02 7.43 ± 0.05 7.42 ± 0.03 7.42 ± 0.05
 Pco 2 (mm Hg) 34.6 ± 2.9 32.8 ± 2.8 32.3 ± 4.3 32.8 ± 4.1
 Po 2 (mm Hg) 73.5 ± 8.5 84.5 ± 6.3 87.8 ± 9.1 88.4 ± 9.6
 BT (°C) 38.3 ± 0.6 38.0 ± 0.6 38.0 ± 0.6 38.1 ± 0.8
Figure 2.
 
Time course of changes in NBretina and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean and SD in 10 rabbits in each plot. Intergroup difference in NBretina (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 2.
 
Time course of changes in NBretina and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean and SD in 10 rabbits in each plot. Intergroup difference in NBretina (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Table 7.
 
Systemic Parameters in Human Study
Table 7.
 
Systemic Parameters in Human Study
Pre 90 Min 180 Min 360 Min 540 Min
Lomerizine
 Mean BP (mm Hg) 81.0 ± 4.9 79.1 ± 7.4 77.6 ± 5.7 81.9 ± 7.7 82.3 ± 4.4
 Heart rate (beats/min) 70.0 ± 7.5 69.0 ± 10.6 64.0 ± 8.1 71.0 ± 5.0 65.0 ± 7.9
 IOP (mm Hg) 9.4 ± 2.6 10.9 ± 2.0 10.1 ± 3.0 11.9 ± 0.6 11.0 ± 1.7
Placebo
 Mean BP (mm Hg) 82.3 ± 4.5 79.1 ± 3.9 77.0 ± 5.5 81.4 ± 10.8 80.8 ± 4.8
 Heart rate (beats/min) 70.0 ± 5.2 66.0 ± 4.8 65.0 ± 6.0 72.0 ± 6.9 65.0 ± 6.9
 IOP (mm Hg) 10.9 ± 2.3 11.1 ± 1.6 11.8 ± 4.0 10.9 ± 1.9 13.1 ± 2.2
Figure 3.
 
Time course of changes in NBONH (A) and NBfovea (B) after oral administration of lomerizine (•) or placebo (○) in humans. NBONH and NBfovea indicate the NB value expressed as a percentage of the baseline measurement. Mean ± SD in eight subjects in each plot. The intergroup difference was significant for NBONH (ANOVA for repeated measurements: treatment, P = 0.031; treatment × time, P = 0.026).
Figure 3.
 
Time course of changes in NBONH (A) and NBfovea (B) after oral administration of lomerizine (•) or placebo (○) in humans. NBONH and NBfovea indicate the NB value expressed as a percentage of the baseline measurement. Mean ± SD in eight subjects in each plot. The intergroup difference was significant for NBONH (ANOVA for repeated measurements: treatment, P = 0.031; treatment × time, P = 0.026).
Fechtner, R, Weinreb, RN. (1994) Mechanism of optic nerve damage in primary open angle glaucoma Surv Ophthalmol 39,23-42 [CrossRef] [PubMed]
Flammer, J. (1994) The vascular concept of glaucoma Surv Ophthalmol 38(suppl),S3-S6 [CrossRef] [PubMed]
Cohn, JN. (1983) Calcium, vascular smooth muscle, and calcium entry blockers in hypertension Ann Int Med 98,806-809 [CrossRef] [PubMed]
Hof, RP. (1983) Calcium antagonist and the peripheral circulation: differences and similarities between PY 108-068, nicardipine, verapamil and diltiazem Br J Pharmacol 78,375-394 [CrossRef] [PubMed]
Ohtsuka, M, Yokota, M, Kodama, I, Yamada, K, Shibata, S. (1989) New generation dihydropyridine calcium entry blockers: in search of greater selectivity for one tissue subtype Gen Pharmacol 20,539-556 [CrossRef] [PubMed]
Kitazawa, Y, Shirai, H, Go, FJ. (1989) The effect of Ca2+-antagonist on visual field in low-tension glaucoma Graefes Arch Clin Exp Ophthalmol 227,408-412 [CrossRef] [PubMed]
Netland, PA, Chaturvedi, N, Dreyer, EB. (1993) Calcium channel blockers in the management of low-tension and open-angle glaucoma Am J Ophthalmol 115,608-613 [CrossRef] [PubMed]
Gaspar, AZ, Flammer, J, Hendrickson, P. (1994) Influence of nifedipine on the visual fields of patients with optic-nerve-head diseases Eur J Ophthalmol 4,24-28 [PubMed]
Bose, S, Piltz, JR, Breton, ME. (1995) Nimodipine, a centrally active calcium antagonist, exerts a beneficial effect on contrast sensitivity in patients with normal-tension glaucoma Ophthalmology 102,1236-1241 [CrossRef] [PubMed]
Sawada, A, Kitazawa, Y, Yamamoto, T, Okabe, I, Ichien, K. (1996) Prevention of visual field defect progression with brovincamine in eyes with normal-tension glaucoma Ophthalmology 103,283-288 [CrossRef] [PubMed]
Koseki, N, Araie, M, Yamagami, J, Shirato, S, Yamamoto, S. (1999) Effects of oral brovincamine on visual field damage in normal tension glaucoma with low-normal pressure J Glaucoma 8,117-123 [PubMed]
Hara, H, Morita, T, Sukamoto, T, Cutrer, FM. (1995) Lomerizine (KB-2796), a new antimigraine drug CNS Drug Rev 1,204-226 [CrossRef]
Kanazawa, T, Toda, N. (1987) Inhibition by KB-2796, a new Ca++ entry blocker, of the contractile response of isolated dog cerebral arteries Folia Pharmacol Jpn 89,365-375 [CrossRef]
Kanazawa, T, Nakasu, Y, Masuda, M, Handa, J. (1986) Acute effect of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride, KB-2796, on the cerebral blood flow in unanesthetized cats Arch Jpn Chir 55,682-688
Yamada, C, Harada, K, Shimamoto, A, Sugimoto, H, Nishimura, N, Sukamoto, T. (1997) Effects of lomerizine on cerebral blood flow and systemic arterial blood pressure in anesthetized beagle dogs Jpn Pharmacol Ther 25,797-802
Nakashima, M, Kanamaru, M. (1989) Clinical phase 1 study of KB-2796 [in Japanese] Rinsho Iyaku 5,1791-1811
Gotoh, F, Fukuuchi, Y, Tashiro, K, et al (1995) Long-term trial of lomerizine hydrochloride for migraine Jpn Pharmacol Ther 23,1445-1460
Shimazawa, M, Sugiyama, T, Azuma, I, et al (1999) Effect of lomerizine, a new Ca2+ channel blocker, on the microcirculation in the optic nerve head in conscious rabbits: a study using a laser speckle technique Exp Eye Res 69,185-193 [CrossRef] [PubMed]
Toriu, N, Sasaoka, M, Shimazawa, M, Sugiyama, T, Hara, H. (2001) Effect of lomerizine, a novel Ca2+ channel blocker, on the normal and endothelin-1-disturbed circulation in the optic nerve head of rabbits J Ocul Pharmacol Ther 17,131-149 [CrossRef] [PubMed]
Tamaki, Y, Araie, M, Kawamoto, E, Eguchi, S, Fujii, H. (1994) Noncontact, two-dimensional measurement of retinal microcirculation using laser speckle phenomenon Invest Ophthalmol Vis Sci 35,3825-3834 [PubMed]
Tamaki, Y, Araie, M, Kawamoto, E, Eguchi, S, Fujii, H. (1995) Non-contact, two-dimensional measurement of tissue circulation in choroid and optic nerve head using laser speckle phenomenon Exp Eye Res 60,373-384 [CrossRef] [PubMed]
Tamaki, Y, Araie, M, Tomita, K, Nagahara, M, Tomidokoro, A, Fujii, H. (1997) Real-time measurement of human optic nerve head and choroid circulation using laser speckle phenomenon Jpn J Ophthalmol 41,49-54 [CrossRef] [PubMed]
Nagahara, M, Tamaki, Y, Araie, M, Fujii, H. (1999) Real-time measurements of blood velocity in human retinal veins using the laser speckle phenomenon Jpn J Ophthalmol 43,186-195 [CrossRef] [PubMed]
Hale, SL, Alker, K, Kloner, RA. (1988) Evaluation of nonradioactive, colored microspheres for measurement of regional myocardial blood flow in dogs Circulation 78,428-434 [CrossRef] [PubMed]
Fercher, AF, Briers, JD. (1981) Flow visualization by means of single exposure speckle photography Opt Commun 37,326-330 [CrossRef]
Sugiyama, T, Utsumi, T, Azuma, I, Fujii, H. (1996) Measurement of optic nerve head circulation: comparison of laser speckle and hydrogen clearance methods Jpn J Ophthalmol 40,339-343 [PubMed]
Tomita, K, Araie, M, Tamaki, Y, Nagahara, M, Sugiyama, T. (1999) Effects of nilvadipine, a calcium antagonist, on rabbit ocular circulation and optic nerve head in NTG subjects Invest Ophthalmol Vis Sci 40,1144-1151 [PubMed]
Kozuma, C, Macklin, W, Cummins, LM, Mauer, R. (1974) Anatomy, physiology, and biochemistry of the rabbit Weisbroth, SH Flatt, RE Kraus, AL eds. The Biology of the Laboratory Rabbit ,50-72 Academic Press New York.
Sasaki, Y, Araie, M, Takase, M, Shirasawa, H, Ishii, Y. (1981) Effects of topical befunolol, a beta-adrenergic blocking agent, on blood flow in rabbit eye Jpn J Ophthalmol 25,299-305
Stjernschantz, J, Bill, A. (1979) Effect of intracranial stimulation of the oculomotor nerve on ocular blood flow in the monkey, cat, and rabbit Invest Ophthalmol Vis Sci 18,99-103 [PubMed]
Waki, M, Sugiyama, T, Watanabe, N, Ogawa, T, Shirahase, H, Azuma, I. (2001) Effect of topically applied iganidipine dihydrochloride, a novel calcium antagonist, on optic nerve head circulation in rabbits Jpn J Ophthalmol 45,76-83 [CrossRef] [PubMed]
Takahashi, Y. (1995) Optic nerve head circulation in alloxan-induced diabetic rabbits [in Japanese] Nippon Ganka Gakkai Zasshi 99,166-172 [PubMed]
Hatta, S. (1993) Effects of intraocular pressure on the optic nerve head in albino rabbits [in Japanese] Nippon Ganka Gakkai Zasshi 97,181-189 [PubMed]
Toriu, N, Akaike, A, Yasuyoshi, H, et al (2000) Lomerizine, a Ca2+ channel blocker, reduces glutamate-induced neurotoxicity and ischemia/reperfusion damage in rat retina Exp Eye Res 70,475-484 [CrossRef] [PubMed]
Tamaki, Y, Araie, M, Tomita, K, Tomidokoro, T. (1996) Time change of nicardipine effect on choroidal circulation in rabbit eyes Curr Eye Res 15,543-548 [CrossRef] [PubMed]
Sakai, T, Kawashima, T, Satomi, O, Awata, N. (1994) Pharmacokinetics of lomerizine in healthy male volunteers Jpn Pharmacol Ther 22,4657-4662
Michelson, G, Schmauss, B, Langhans, MJ, Harazny, J, Groh, MJ. (1996) Principle, validity, and reliability of scanning laser Doppler flowmetry J Glaucoma 5,99-105 [PubMed]
Tamaki, Y, Araie, M, Fukaya, Y, Ishii, K. (2002) Validation of scanning laser Doppler flowmetry for retinal blood flow measurements in animal models Curr Eye Res 24,332-340 [CrossRef] [PubMed]
Iwamoto, T, Morita, T, Sukamoto, T. (1991) Calcium antagonism by KB-2796, a new diphenylpiperazine analogue, in dog vascular smooth muscle J Pharm Pharmacol 43,535-539 [CrossRef] [PubMed]
Flammer, J, Guthauser, U, Mahler, F. (1987) Do vasospasms help cause low tension glaucoma? Doc Ophthalmol Proc Series 49,397-399
Gasser, P, Flammer, J. (1987) Influence of vasospasm on visual function Doc Ophthalmol 66,3-18 [CrossRef] [PubMed]
Figure 1.
 
Time course of changes in NBONH and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean ± SD in nine rabbits in each plot. Intergroup difference in NBONH (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 1.
 
Time course of changes in NBONH and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean ± SD in nine rabbits in each plot. Intergroup difference in NBONH (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 2.
 
Time course of changes in NBretina and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean and SD in 10 rabbits in each plot. Intergroup difference in NBretina (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 2.
 
Time course of changes in NBretina and mean blood pressure in rabbits after injection of lomerizine (0.3 mg/kg) (•) or vehicle (○). Mean and SD in 10 rabbits in each plot. Intergroup difference in NBretina (expressed as a percentage of baseline) was significant (ANOVA) for data obtained by sequential measurements (treatment, P < 0.001; treatment × time, P < 0.001).
Figure 3.
 
Time course of changes in NBONH (A) and NBfovea (B) after oral administration of lomerizine (•) or placebo (○) in humans. NBONH and NBfovea indicate the NB value expressed as a percentage of the baseline measurement. Mean ± SD in eight subjects in each plot. The intergroup difference was significant for NBONH (ANOVA for repeated measurements: treatment, P = 0.031; treatment × time, P = 0.026).
Figure 3.
 
Time course of changes in NBONH (A) and NBfovea (B) after oral administration of lomerizine (•) or placebo (○) in humans. NBONH and NBfovea indicate the NB value expressed as a percentage of the baseline measurement. Mean ± SD in eight subjects in each plot. The intergroup difference was significant for NBONH (ANOVA for repeated measurements: treatment, P = 0.031; treatment × time, P = 0.026).
Table 1.
 
Blood Flow in Retina, Choroid, and Iris-Ciliary Body, before and 30 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
Table 1.
 
Blood Flow in Retina, Choroid, and Iris-Ciliary Body, before and 30 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
n Retina Choroid Iris-Ciliary body
Vehicle
 Pre 11 24.3 ± 23.5 1033 ± 594 58.6 ± 36.5
 Post 25.4 ± 12.9 1097 ± 624 64.0 ± 45.4
 Δ 1.1 ± 16.9 64 ± 275 5.4 ± 20.6
Lomerizine (0.1 mg/kg)
 Pre 10 12.0 ± 5.7 1118 ± 563 94.7 ± 74.3
 Post 19.5 ± 12.3* 1097 ± 522 103.1 ± 65.5
 Δ 7.5 ± 8.2 −21 ± 300 8.5 ± 22.8
Lomerizine (0.3 mg/kg)
 Pre 11 26.1 ± 15.6 1106 ± 405 83.8 ± 53.7
 Post 47.5 ± 29.8, ** , † 1167 ± 431 104.5 ± 72.0
 Δ 21.4 ± 18.2, ‡‡ 60 ± 202 20.7 ± 59.4
Table 2.
 
Systemic Parameters before and 30 minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
Table 2.
 
Systemic Parameters before and 30 minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Microsphere Experiment
n Blood Pressure (mm Hg) Heart Rate (beats/min) pH Pco 2 (mm Hg) Po 2 (mm Hg) Body Temperature (°C)
Vehicle
 Pre 11 91.7 ± 5.3 280 ± 40 7.35 ± 0.03 31.1 ± 2.7 85.2 ± 9.9 37.0 ± 0.3
 30 min 94.6 ± 9.0 287 ± 30 7.35 ± 0.03 23.6 ± 3.3 94.8 ± 7.0 36.7 ± 0.7
Lomerizine (0.1 mg/kg)
 Pre 10 88.6 ± 12.0 287 ± 16 7.31 ± 0.03 32.4 ± 4.4 87.9 ± 12.0 37.2 ± 0.6
 30 min 86.4 ± 8.5 289 ± 16 7.34 ± 0.03 26.2 ± 4.7 92.5 ± 10.1 36.8 ± 0.9
Lomerizine (0.3 mg/kg)
 Pre 11 86.7 ± 8.3 278 ± 20 7.32 ± 0.03 28.9 ± 3.3 91.5 ± 9.0 37.1 ± 0.7
 30 min 82.3 ± 6.6 290 ± 20 7.33 ± 0.07 23.8 ± 3.6 95.7 ± 10.6 37.1 ± 0.7
Table 3.
 
Blood Flow in Optic Nerve Head before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
Table 3.
 
Blood Flow in Optic Nerve Head before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
n ONH Blood Flow
Vehicle
 Pre 6 110.2 ± 32.3
 Post 113.9 ± 33.6
 Δ 3.7 ± 6.4
Lomerizine (0.1 mg/kg)
 Pre 6 114.8 ± 61.0
 Post 132.2 ± 72.0
 Δ 17.4 ± 17.9
Lomerizine (0.3 mg/kg)
 Pre 9 100.6 ± 33.3
 Post 116.0 ± 36.6*
 Δ 15.4 ± 14.7
Table 4.
 
Systemic Parameters before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
Table 4.
 
Systemic Parameters before and 15 Minutes after Intravenous Administration of Lomerizine or Vehicle in Rabbits: Hydrogen Gas-Clearance Experiment
n Blood Pressure (mm Hg) Heart Rate (beats/min) pH Pco 2 (mm Hg) Po 2 (mm Hg) Body Temperature (°C)
Vehicle
 Pre 6 87.2 ± 2.2 281 ± 15 7.36 ± 0.02 35.4 ± 3.4 89.5 ± 8.3 37.0 ± 0.2
 15 min 87.1 ± 2.2 287 ± 15 7.36 ± 0.02 35.2 ± 4.2 90.3 ± 7.8 37.0 ± 0.2
Lomerizine (0.1 mg/kg)
 Pre 6 88.8 ± 2.7 287 ± 17 7.38 ± 0.02 37.3 ± 6.9 86.9 ± 2.9 37.0 ± 0.2
 15 min 86.4 ± 6.1 293 ± 15 7.38 ± 0.02 36.4 ± 6.1 86.2 ± 4.4 36.9 ± 0.2
Lomerizine (0.3 mg/kg)
 Pre 9 86.5 ± 5.1 280 ± 18 7.38 ± 0.03 38.9 ± 3.9 87.2 ± 5.4 36.9 ± 0.2
 15 min 84.3 ± 6.6 284 ± 15 7.37 ± 0.03 36.0 ± 3.3 87.4 ± 3.9 37.0 ± 0.2
Table 5.
 
Systemic Parameters of Albino Rabbits before and after Lomerizine Administration in the Optic Nerve Head Experiment
Table 5.
 
Systemic Parameters of Albino Rabbits before and after Lomerizine Administration in the Optic Nerve Head Experiment
Pre 5 Min 15 Min 30 Min 60 Min 90 Min
Lomerizine group
 IOP (mm Hg) 20.2 ± 3.9 18.5 ± 3.4 18.8 ± 3.1 18.2 ± 4.5 17.2 ± 4.3 16.4 ± 3.9
 HR (beats/min) 293 ± 39 290 ± 22 295 ± 37 304 ± 34 305 ± 31 311 ± 31
 pH 7.39 ± 0.03 7.40 ± 0.03 7.40 ± 0.03 7.41 ± 0.03
 Pco 2 (mm Hg) 35.4 ± 4.6 34.7 ± 1.5 34.6 ± 3.5 33.6 ± 3.6
 Po 2 (mm Hg) 79.8 ± 10.2 85.7 ± 9.1 85.4 ± 5.1 86.3 ± 6.2
 BT (°C) 38.6 ± 0.4 38.5 ± 0.5 38.4 ± 0.7 38.4 ± 0.8
Control group
 IOP (mm Hg) 20.3 ± 5.4 20.6 ± 5.5 19.8 ± 5.6 19.2 ± 4.2 16.1 ± 3.4 16.3 ± 3.9
 HR (beats/min) 277 ± 48 277 ± 56 287 ± 53 287 ± 50 283 ± 46 284 ± 48
 pH 7.38 ± 0.05 7.39 ± 0.03 7.39 ± 0.02 7.39 ± 0.01
 Pco 2 (mm Hg) 38.3 ± 3.0 35.3 ± 5.0 34.2 ± 5.5 34.8 ± 5.2
 Po 2 (mm Hg) 79.0 ± 3.8 86.6 ± 6.6 91.2 ± 4.5 92.8 ± 5.9
 BT (°C) 38.2 ± 0.6 38.1 ± 0.5 38.2 ± 0.6 38.0 ± 0.8
Table 6.
 
Systemic Parameters of Dutch Rabbits before and after Lomerizine Administration in the Retina Experiment
Table 6.
 
Systemic Parameters of Dutch Rabbits before and after Lomerizine Administration in the Retina Experiment
Pre 5 Min 15 Min 30 Min 60 Min 90 Min
Lomerizine group
 IOP (mm Hg) 14.7 ± 6.1 13.4 ± 4.2 12.8 ± 5.2 13.1 ± 5.5 11.1 ± 4.4 11.2 ± 3.2
 HR (beats/min) 274 ± 18 269 ± 15 266 ± 19 280 ± 19 295 ± 22 305 ± 25
 pH 7.43 ± 0.03 7.44 ± 0.03 7.44 ± 0.02 7.45 ± 0.03
 Pco 2 (mm Hg) 35.1 ± 5.4 31.8 ± 4.0 29.0 ± 5.3 29.5 ± 4.8
 Po 2 (mm Hg) 76.3 ± 7.5 84.5 ± 5.4 89.2 ± 11.7 89.0 ± 8.2
 BT (°C) 38.3 ± 0.3 38.1 ± 0.4 38.1 ± 0.5 38.2 ± 0.6
Control group
 IOP (mm Hg) 17.5 ± 7.2 16.9 ± 5.9 16.5 ± 5.4 14.9 ± 4.4 13.3 ± 5.5 12.4 ± 5.7
 HR (beats/min) 277 ± 30 276 ± 27 274 ± 26 277 ± 29 273 ± 27 283 ± 22
 pH 7.42 ± 0.02 7.43 ± 0.05 7.42 ± 0.03 7.42 ± 0.05
 Pco 2 (mm Hg) 34.6 ± 2.9 32.8 ± 2.8 32.3 ± 4.3 32.8 ± 4.1
 Po 2 (mm Hg) 73.5 ± 8.5 84.5 ± 6.3 87.8 ± 9.1 88.4 ± 9.6
 BT (°C) 38.3 ± 0.6 38.0 ± 0.6 38.0 ± 0.6 38.1 ± 0.8
Table 7.
 
Systemic Parameters in Human Study
Table 7.
 
Systemic Parameters in Human Study
Pre 90 Min 180 Min 360 Min 540 Min
Lomerizine
 Mean BP (mm Hg) 81.0 ± 4.9 79.1 ± 7.4 77.6 ± 5.7 81.9 ± 7.7 82.3 ± 4.4
 Heart rate (beats/min) 70.0 ± 7.5 69.0 ± 10.6 64.0 ± 8.1 71.0 ± 5.0 65.0 ± 7.9
 IOP (mm Hg) 9.4 ± 2.6 10.9 ± 2.0 10.1 ± 3.0 11.9 ± 0.6 11.0 ± 1.7
Placebo
 Mean BP (mm Hg) 82.3 ± 4.5 79.1 ± 3.9 77.0 ± 5.5 81.4 ± 10.8 80.8 ± 4.8
 Heart rate (beats/min) 70.0 ± 5.2 66.0 ± 4.8 65.0 ± 6.0 72.0 ± 6.9 65.0 ± 6.9
 IOP (mm Hg) 10.9 ± 2.3 11.1 ± 1.6 11.8 ± 4.0 10.9 ± 1.9 13.1 ± 2.2
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