Dorzolamide, a topical carbonic anhydrase inhibitor: a two-week dose-response study in patients with glaucoma or ocular hypertension.

We investigated the dose-response relationship of the intraocular pressure-lowering activity of dorzolamide, a novel topical carbonic anhydrase inhibitor previously known as MK-507. A double-masked, randomized, multicenter study of 113 patients with either primary open-angle glaucoma or ocular hypertension was conducted; dorzolamide (0.2, 0.5, 1, or 2%) was administered three times daily for 14 days. All of the dorzolamide concentrations substantially lowered intraocular pressure from baseline measurements. The percentage change in baseline intraocular pressure with 0.5, 1, and 2% dorzolamide 2, 4, and 6 h after dosing on day 14 ranged from 12.0 to 17.0% on average, which was greater than after treatment with 0.2% dorzolamide. No dose response was seen for 0.5, 1, or 2% dorzolamide. The most frequently reported ocular symptom was transient smarting, which occurred in 35.6-74.1% of every treatment group. Smarting and mild hyperemia were most frequent with 2% dorzolamide (74.1 and 18.5%, respectively). The present results indicate that the 0.5, 1, and 2% concentrations of dorzolamide are almost equally effective and that 2% concentrations may be less well-tolerated than 0.5 or 1% concentrations.

Activation of torularhodin production by Rhodotorula glutinis using weak white light irradiation.

The effects of the irradiation of weak white light on the growth of the red yeast Rhodotorula glutinis and its production of carotenoids were investigated. The ability of beta-carotene and torularhodin, which are final products of carotenoid biosynthesis in R. glutinis, to quench singlet oxygen has also been investigated. Weak white light irradiation that has no effect on the growth of Saccharomyces cerevisiae inhibited the growth of R. glutinis. Simultaneously, the production of torularhodin by R. glutinis markedly increased. In a mutant of R. glutinis, which exhibited increased production of torularhodin, an increase in torularhodin production was shown as a result of light irradiation during the logarithmic growth phase. An experiment using 3-(1,4-epidioxyl-4-methyl-1,4-dehydro-1-naphtyl) propionic acid clarified that torularhodin inhibited 2,5-diphenyl-3,4-benzofran decomposition by singlet oxygen quenching more strongly than did beta-carotene. This result is consistent with the report that carotenoids having a longer polyene chain may exhibit a more potent ability to quench singlet oxygen. These results suggest that the biosynthesis of carotenoids in R. glutinis may play an important role in protecting against oxidative damage caused by light irradiation, and in particular, torularhodin which has a potent singlet oxygen quenching ability may be important. We suggest that acquisition of the ability to produce torularhodin may be an important property for this yeast to promote its wider distribution in the natural world.

Properties of a high-torularhodin-producing mutant of Rhodotorula glutinis cultivated under oxidative stress.

To characterize the properties of torularhodin, which is one of the carotenoid pigments produced by the yeast Rhodotorula sp., a mutant which produces large amounts of torularhodin was constructed and its tolerance against oxidative stress was investigated. The mutant we obtained was capable of producing large amounts of torularhodin in response to irradiation with blue light. The mutant, incubated under irradiation with white light that resulted in an increased production of torularhodin, exhibited resistance to growth inhibition induced by the addition of methylene blue as the generator of singlet oxygen. Leakage of lactate dehydrogenase to the growth medium from the mutant was not increased as compared to that from a parent strain and a high-beta-carotene-producing mutant. These results suggest that an increase in the production of torularhodin reduces the susceptibility to injury induced by an active oxygen species.

Preventive effect of pirfenidone against experimental sclerosing peritonitis in rats.

We investigated the preventive effect of pirfenidone (PFD), a newly developed anti-fibrotic agent, on experimental sclerosing peritonitis (sp) which we had established in rats. Male Wistar rats (150-250 g) were divided into the following two groups; 7 rats were treated with daily intraperitoneal (i.p.) injection of 0.1% chlorhexidine gluconate (CH) and 15% ethanol solved in 2 ml of saline for 26 days as a control of SP model (CH group) and 6 rats were treated daily with peroral (p.o.) administration of 350 mg/kg of PFD in addition to the daily i.p. injection of aforementioned CH-ethanol-saline solution for 26 days (CH + PFD group). Macroscopic intraperitoneal changes and histological fibrotic changes were graded by scoring in a blind manner. Actual subserosal thickness was measured by observation under light microscope. Body weight gain was significantly greater in CH + PFD group than in CH group (P < 0.05). Macroscopic intraperitoneal adhesion changes in CH + PFD group were significantly fewer than in CH group (P < 0.05). Fibrotic changes were fewer and subserosal thickness in liver and intestine were smaller in CH + PFD group with statistical significance (p < 0.1). We concluded that PFD markedly inhibited or prevented fibrotic changes in the experimental sclerosing peritonitis induced by CH.

Sodium hyaluronate eyedrops enhance tear film stability.

Sodium hyaluronate eyedrops can relieve various dry eye symptoms by prolonging the stability of the precorneal tear film. To determine the most effective concentration of sodium hyaluronate, we studied the concentration-dependent effects of sodium hyaluronate eyedrops on the precorneal tear film breakup time (BUT) in 12 volunteers. These subjects had a BUT of 10 seconds or less and a low tear volume determined with the phenol red thread test. They received four different concentrations of sodium hyaluronate eyedrops (0, 0.05, 0.1 and 0.3%). BUT was measured noninvasively using a non-contact specular microscope before the sodium hyaluronate eyedrop instillation and again after 5, 15, 30, 60, 120 and 180 minutes. The tear film stability period was prolonged significantly with 0.1% and 0.3% eyedrops at all measurement times (P < 0.05), while the eyes treated with 0% and 0.05% eyedrops showed no significant prolongation of tear film stability at any measurement times. The findings of this study confirm that sodium hyaluronate at a concentration of at least 0.1% is required to delay the breakup of the precorneal tear film.

[Evaluation of the effect of the sodium hyaluronate ophthalmic solution on tear film stability--non-contact specular microscopic evaluation].

Sodium hyaluronate solution is known to relieve various dry eye symptoms by suppressing the breakup of the preocular tear film. Using tear film stability as a parameter, we examined in 12 volunteers the time and concentration-dependent effects of sodium hyaluronate on their short precorneal tear film breakup time (BUT, 10 sec. or less) at a low tear volume (15 mm or less by using the phenol red thread test). Each subject underwent four separate study periods, receiving one of the following four ophthalmic solutions during each period: 0.05, 0.1, 0.3% w/v sodium hyaluronate (molecular weight, about 1,000,000) or the vehicle alone. BUT was measured non-invasively using a non-contact specular microscope before and 5, 15, 30, 60, 120, and 180 minutes after drug application. While BUT was not significantly prolonged after instilling either the vehicle or 0.05% solution, it was significantly increased at all times after applying either 0.1% or 0.3% solution, as compared to preinstillation. These results indicate that sodium hyaluronate solutions at concentrations of at least 0.1% can be effective in alleviating symptoms of dry eye.

Stimulation of methemoglobin reduction by selenium: a comparative study with erythrocytes of various animals.

The extent of stimulation of methemoglobin (metHb) reduction by selenite depends upon the level of reduced glutathione (GSH) in the erythrocytes. The reason for the species difference in the effect of selenite was discussed with respect to species differences in the GSH levels in erythrocytes.

Biofeedback modification of frontal EMG in normal subjects.

We carried out a controlled study on the voluntary control of the frontalis muscle by biofeedback procedures employing 20 normal subjects. Subjects were randomly divided into two groups of 10: (1) the biofeedback group and (2) the control group. Each of the two groups received five training sessions of about 40 minutes' duration each on different days. The results obtained are as follows: (1) In the biofeedback group, mean EMG levels decreased progressively and markedly from 2. 16 muVp-p min the first session to 1.54 muVp-p min in the last session. On the contrary, the control group did not show constant decreases in EMG levels over sessions. (2) The changes in the heart rate did not correlate with the changes in EMG activity. (3) The changes in the respiratory rate correlated with the changes in EMG activity.

Optimization of biomass productivity and substrate utility of a hydrogen bacterium, Alcaligenes hydrogenophilus.

Optimizations of cell productivity and utility of gaseous substrates were investigated for Alcaligenes hydrogenophilus. Theoretical analyses for the cell productivity and substrate utility were discussed in the light of experimental data. It was proved from the theoretical analyses that the maximum cell productivity was at the following conditions: D = 0.21 h(-1), R(1) ( = H(2) partial pressure/O(2) partial pressure) = 2.25 and R(2) ( =CO(2) partial pressure/O(2) partial pressure) = 0.09, i.e., a molal ratio, H(2):O(2):CO(2) = 67.4:29.9:2,7. The Condition which gave the maximum cell productivity also gave high utilities of gaseous substrates. The growth yield for oxygen increased with increasing R(1) in chemostat culture, and the growth yield for hydrogen slightly increased with increasing R(1). Theoretical cell productivity and substrate and substrate utility were in good agreement with experimental values, taking into account the change of growth yield for oxygen.

[Protective effect of rebamipide (OPC-12759) on the gastric mucosa in rats and humans].

The protective effect of rebamipide against 0.15 N HCl solution containing 40% ethanol (HCl-ethanol)-induced mucosal lesion in the stomach was evaluated in rats and humans. In rat experiments: (1) rebamipide prevented development of mucosal damage induced by HCl-ethanol in a dose-dependent manner when tested at 10, 30, 100 and 300 mg/kg, i.p., and the prevention at 30-300 mg/kg was significant (P less than 0.05); (2) rebamipide significantly (P less than 0.05) increased mucosal blood flow by continuous i.v. dosing at 10 mg/kg/hr by the hydrogen gas clearance method; (3) rebamipide at 10 mg/kg, i.v., also significantly (P less than 0.05) inhibited reduction in gastric mucosal blood volume and tended to suppress oxygen saturation of hemoglobin following hemorrhagic shock by organ reflectance spectrophotometry. A double-blind crossover study was conducted to compare the gastric protective effect of rebamipide with an inactive placebo using 6 healthy male volunteers. Rebamipide was administered to them at a clinical dose of 300 mg/day orally for 7 days, and then HCl-ethanol was given once to induce mucosal damage. Rebamipide significantly (P less than 0.05) inhibited formation of mucosal lesion, decrease in the number of mucous granules and dilatation of intercellular space. These clinical findings indicate that rebamipide was protective against HCl-ethanol-induced gastric lesion at a clinical dose, and the mechanism of this gastric effect was considered to involve, in part, the improvement of mucosal microcirculation.

Recombinant human non-glycosylated granulocyte-macrophage colony-stimulating factor in allogeneic bone marrow transplantation: double-blind placebo-controlled phase III clinical trial.

In a randomized double-blind placebo-controlled phase III clinical trial, the effects of a non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (CSF 39-300) were investigated in patients who had received allogeneic bone marrow transplantation. CSF 39-300 was administered at a daily dose of 10 micrograms/kg (maximum dose, 300 micrograms/body) via three-hour intravenous infusions from days 1 to 21 following reinfusion of the marrow. Twenty-eight patients received CSF 39-300 and 25, placebo. The median number of days to recovery for leucocytes (> or = 1000/mm3), neutrophils (> or = 500/mm3), lymphocytes (> or = 300/mm3) and reticulocytes (> or = 20/1000) were significantly shortened (16 vs 20, 17 vs 21 and 22 vs 28, respectively) with CSF 39-300. The duration of stay in laminar-air-flow room after transplantation was also significantly shortened in the CSF 39-300 group (21 vs 30 days). There was no significant difference in the incidence of acute or chronic graft-versus-host disease between the two groups. A follow-up during the year after transplantation revealed there to be no significant difference in either survival rate or leukemia relapse rate between the two groups. CSF 39-300 is therefore considered useful after allogeneic bone marrow transplantation, especially in the early period.

Effect of sodium hyaluronate ophthalmic solution on peripheral staining of rigid contact lens wearers.

We evaluated the efficacy of sodium hyaluronate ophthalmic solutions on 3 and 9 o'clock staining with rigid contact lens wearers in a double masked multicenter study involving four institutions and 43 patients. Both sodium hyaluronate (0.1%) and control ophthalmic solutions (artificial tears) without preservative were used. Patients were randomly divided into two groups. The test group received sodium hyaluronate ophthalmic solution, and the control group received artificial tears as a control ophthalmic solution. The agents were instilled six times per day for 2 weeks while patients wore contact lenses. Although subjective symptoms improved similarly in the two groups, slit lamp observation, corneal staining, and anterior segment photography demonstrated improved results in eyes having received sodium hyaluronate ophthalmic solutions. We conclude that sodium hyaluronate ophthalmic solution is effective and safe for treating 3 and 9 o'clock staining in rigid contact lens wearers.

Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.