Prevention of diabetic blindness.
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Blindness↗
Biomedical subjects
E Stefánsson
Publications and source records attributed to E Stefánsson.
Optic nerve oxygen tension: the effects of timolol and dorzolamide.
BACKGROUND/AIMS: The authors have previously reported that carbonic anhydrase inhibitors such as acetazolamide and dorzolamide raise optic nerve oxygen tension (ONPO(2)) in pigs. The purpose of the present study was to investigate whether timolol, which belongs to another group of glaucoma drugs called beta blockers, has a similar effect. In addition, the effect of dorzolamide and timolol in combination was studied. METHODS: Polarographic oxygen electrodes were placed transvitreally over the optic disc in anaesthetised pigs and ONPO(2) was recorded continually. Drugs were administered intravenously either as 100 mg timolol followed by 500 mg dorzolamide (n = 5), 500 mg dorzolamide followed by 100 mg timolol (n = 5), or 100 mg timolol and 500 mg dorzolamide given simultaneously (n = 5). Arterial blood pressure, blood gasses, and heart rate were recorded. RESULTS: ONPO(2) was unaffected by administration of 100 mg timolol as an intravenous injection (n = 5). Administration of 500 mg dorzolamide by itself significantly increased ONPO(2) from 2.96 (SD 0.62) kPa to 3.69 (SD 0.88) kPa (n = 4, p = 0.035). The dorzolamide induced ONPO(2) increase was not significantly different from the ONPO(2) increases were seen when dorzolamide was administered simultaneous with (n = 5) or 35 minutes (n = 5) after 100 mg timolol. CONCLUSION: Systemic administration of timolol does not affect the optic nerve oxygen tension despite its lowering effect on the intraocular pressure. Additionally, timolol does not affect the ONPO(2) increasing effect of dorzolamide.
Adrenergic beta-Antagonists↗
Indomethacin lowers optic nerve oxygen tension and reduces the effect of carbonic anhydrase inhibition and carbon dioxide breathing.
BACKGROUND/AIMS: Prostaglandins are important in blood flow regulation. Carbon dioxide (CO(2)) breathing and carbonic anhydrase inhibition increase the oxygen tension in the retina and optic nerve. To study the mechanism of this effect and the role of cyclo-oxygenase in the regulation of optic nerve oxygen tension (ONPO(2)), the authors investigated how indomethacin affects ONPO(2) and the ONPO(2) increases caused by CO(2) breathing and carbonic anhydrase inhibition in the pig. METHODS: Optic nerve oxygen tension was measured in 11 pigs with a polarographic oxygen electrode. The tip of the electrode was placed 0.5 mm above the optic disc. The effects of indomethacin, CO(2) breathing (3%) before and after indomethacin treatment, and carbonic anhydrase inhibition with or without indomethacin treatment were investigated. RESULTS: Administration of 300 mg indomethacin decreased optic nerve oxygen tension significantly. Carbonic anhydrase inhibition and CO(2) breathing increased ONPO(2) significantly. After indomethacin had been given, the rise in ONPO(2) caused by CO(2) breathing and carbonic anhydrase inhibition was significantly reduced. CONCLUSION: Systemic administration of indomethacin decreases the optic nerve oxygen tension; this is probably the result of decreased blood flow through vasoconstriction of vessels in the optic nerve. Additionally, indomethacin diminishes the ONPO(2) increasing effect of CO(2) breathing and carbonic anhydrase inhibition, thus affecting the reactivity of vessels in the optic nerve.
Animals↗
Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray.
The cyclodextrin solubilization of three benzodiazepines, i.e. alprazolam, midazolam and triazolam, was investigated. The cyclodextrin solubilization was enhanced through ring-opening of the benzodiazepine rings and ionization of the ring-open forms. Additional enhancement was obtained through interaction of a water-soluble polymer with the cyclodextrin complexes. The ring-opening was pH-dependent and completely reversible, the ring-open forms dominating at low pH but the ring-closed forms at physiologic pH. The ring-closed forms were rapidly regenerated upon elevation of pH. In freshly collected human serum in vitro at 37 degrees C, the half-life for the first-order rate constant for the ring-closing reaction was estimated to be less than 2 min for both alprazolam and midazolam. Midazolam (17 mg/ml) was solubilized in aqueous pH 4.3 nasal formulation containing 14% (w/v) sulfobutylether beta-cyclodextrin, 0.1% (w/v) hydroxypropyl methylcellulose, preservatives and buffer salts. Six healthy volunteers received 0.06 mg/kg midazolam intranasally and 2 mg intravenously, and blood samples were collected up to 360 min after the administration. Midazolam was absorbed rapidly reaching maximum serum concentrations of 54.3+/-5.0 ng/ml at 15+/-2 min. The elimination half-life of midazolam was 2.2+/-0.3 h and the absolute availability was 73+/-7%. All mean values+/-SEM.
Administration, Intranasal↗
The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology.
The physiologic mechanism of photocoagulation can been seen in the following steps. The physical light energy is absorbed in the melanin of the retinal pigment epithelium. The adjacent photoreceptors are destroyed and are replaced by a glial scar and the oxygen consumption of the outer retina is reduced. Oxygen that normally diffuses from the choriocapillaris into the retina can now diffuse through the laser scars in the photoreceptor layer without being consumed in the mitochondria of the photoreceptors. This oxygen flux reaches the inner retina to relieve inner retinal hypoxia and raise the oxygen tension. As a result, the retinal arteries constrict and the bloodflow decreases. Hypoxia relief reduces production of growth factors such as VEGF and neovascularization is reduced or stopped. Vasoconstriction increases arteriolar resistance, decreases hydrostatic pressure in capillaries and venules and reduces edema formation according to Starling's law. Vitrectomy also improves retinal oxygenation by allowing oxygen and other nutrients to be transported in water currents in the vitreous cavity from well oxygenated to ischemic areas of the retina. Vitrectomy and retinal photocoagulation both improve retinal oxygenation and both reduce diabetic macular edema and retinal neovascularization.
Diabetic Retinopathy↗
Pseudoexfoliation syndrome in Icelandic families.
AIM: To examine the distribution and clinical ophthalmic characteristics of pseudoexfoliation syndrome (pseudoexfoliation) and glaucoma in Icelandic families. METHODS: Icelandic families containing three or more members aged 70 or older with at least one member with pseudoexfoliation were identified. All family members over age 45 were invited to participate. Visual acuity, Goldmann applanation tonometry, gonioscopy, slit lamp examination before and after dilatation, and dilated fundus examination were performed on all available family members. Pertinent data were obtained from medical records, including ophthalmic history and a medical history of cardiovascular disease, cerebrovascular disease, systemic hypertension, and diabetes mellitus. Participants were classified according to affected status for pseudoexfoliation, glaucoma, and age related macular degeneration. RESULTS: Six families were identified who met the criteria for entry into the study. Of 94 family members who were invited to participate 82 were enrolled (87%). Of these 25 (30%) had pseudoexfoliation syndrome, 51 (62%) were unaffected, and six (7%) were suspects. At least one individual with pseudoexfoliation was identified in the second generation of every family. A parent with pseudoexfoliation was identified in all cases either by examination (4/6) or a review of ophthalmic records (2/6). In all cases the mother was the affected parent. The prevalence of glaucoma was significantly greater in the group with pseudoexfoliation (p <0.0001). Although the presence of age related macular degeneration (ARMD) was highly associated with the presence of pseudoexfoliation, the significance was lost after correction for age (p = 0.69). Although the sample size was small, no association between pseudoexfoliation affected status and cardiovascular disease, cerebrovascular disease, systemic hypertension, or diabetes mellitus was found. CONCLUSIONS: Multiple Icelandic families with pseudoexfoliation in two generations were identified. In all cases where determination was possible, transmission to the second generation was through an affected parent. In each case the affected parent was the mother. Pseudoexfoliation was strongly associated with the presence of glaucoma, but was not associated with either ARMD or systemic disease in this study. These data clearly indicate that pseudoexfoliation is a familial condition and although not conclusive, supports the hypothesis that pseudoexfoliation syndrome is genetically inherited.
Aged↗
Screening and prevention of diabetic blindness.
Diabetic eye disease remains a major cause of blindness in the world. Laser treatment for proliferative diabetic retinopathy and diabetic macular edema became available more than two decades ago. The outcome of treatment depends on the timing of laser treatment. The laser treatment is optimally delivered when high-risk characteristics have developed in proliferative retinopathy or diabetic macular edema and before this has significantly affected vision. Laser treatment is usually successful if applied during this optimal period whereas the treatment benefit falls sharply if the treatment is applied too late. In order to optimize the timing of laser treatment in diabetic eye disease screening programs have been established. The oldest screening program is 20 years old and several programs have been established during the last decade. In this paper the organisation and methods of screening programs are described including direct and photographic screening. The incidence and prevalence of blindness is much lower in populations where screening for diabetic eye disease has been established compared to diabetic populations without screening. Technical advantages may allow increased efficiency and telescreening. From a public health standpoint screening for diabetic eye disease is one of the most cost effective health procedures available. Diabetic eye disease can be prevented using existing technology and the cost involved is many times less than the cost of diabetic blindness.
Blindness↗
"With the rule" astigmatism is not the rule in the elderly. Reykjavik Eye Study: a population based study of refraction and visual acuity in citizens of Reykjavik 50 years and older. Iceland-Japan Co-Working Study Groups.
PURPOSE: To study refractive state and visual acuity in citizens of Reykjavik 50 years and older. METHODS: 1700 persons were randomly selected from the national population census. 1379 could be located and qualified whereof 1045 participated. Evaluation of refraction was performed using Nidek ARK 900 autorefracto-keratometer. Visual acuity was tested on a Snellen chart. RESULTS: The prevalence of hypermetropia increases with age by 0.3 D in five years. The prevalence of "against the rule" astigmatism increased on average 5.3% and oblique 3.9% in five years. Analysis of corneal astigmatism measured by keratometer shows an "against the rule" change with age. CONCLUSIONS: Hypermetropia increases by age. The prevalence of astigmatism increases and the axis turns to "against the rule". The changes in total astigmatism and corneal astigmatism is almost parallel which might indicate that the "against the rule" change is related to changes in the cornea.
Aged↗
Optic nerve oxygen tension: effects of intraocular pressure and dorzolamide.
AIM: To investigate the influence of acute changes in intraocular pressure on the oxygen tension in the vicinity of the optic nerve head under control conditions and after intravenous administration of 500 mg of the carbonic anhydrase inhibitor dorzolamide. METHODS: Domestic pigs were used as experimental animals. Oxygen tension was measured by means of a polarographic electrode in the vitreous 0.5 mm anterior to the optic disc. This entity is called the optic nerve oxygen tension. Intraocular pressure was controlled by a hypodermic needle inserted into the anterior chamber and connected to a saline reservoir. RESULTS: When the intraocular pressure was clamped at 20 cm H2O optic nerve oxygen tension was 20 (5) mm Hg (n=8). Intravenous administration of dorzolamide caused an increase in optic nerve oxygen tension of 43 (8)% (n=6). Both before and after administration of dorzolamide optic nerve oxygen tension was unaffected by changes in intraocular pressure, as long as this pressure remained below 60 cm H2O. At intraocular pressures of 60 cm H(2)O and below, dorzolamide significantly increased optic nerve oxygen tension. CONCLUSION: Intravenous administration of 500 mg dorzolamide increases the oxygen tension at the optic nerve head during acute increases in intraocular pressure.
Animals↗
Laser treatment and the mechanism of edema reduction in branch retinal vein occlusion.
PURPOSE: To test a hypothesis on the physiological mechanism of the disappearance of macular edema after laser treatment. The hypothesis is based on the effect grid laser treatment has on retinal oxygenation and hemodynamics. It predicts that laser-induced reduction of macular edema is associated with shortening and narrowing of retinal vessels in patients with branch retinal vein occlusion (BRVO). METHODS: The study included 12 subjects, treated with argon laser photocoagulation for BRVO and macular edema. Fundus photographs taken at the time of diagnosis and again after laser treatment, were digitized, and diameter and segment length of retinal vessels was measured using NIH-Image program. RESULTS: Macular edema disappeared or was dramatically reduced in all cases after laser treatment. The diameter of occluded venules constricted to 0.81+/-0.02 (mean +/- SD, P = 0.019) of the prelaser diameter and adjacent arterioles constricted to 0.78+/-0.01 (P = 0.008). The laser treatment also led to shortening of the affected vessels. The final segment length of the occluded venules was 0.95+/-0.17 (P = 0.005) of the length before treatment. The corresponding value for the adjacent arterioles is 0.95+/-0.14 (P = 0.008). Control arterioles and venules in the same fundus did not change in either length or width. CONCLUSIONS: These results do not reject the authors' hypothesis that the disappearance of macular edema in BRVO can be explained by the effect the laser photocoagulation has on retinal oxygenation. Increased oxygenation causes vessel constriction and shortening and lower intravascular pressure, which reduces edema formation according to Starling's law.
Aged↗
Methazolamide 1% in cyclodextrin solution lowers IOP in human ocular hypertension.
PURPOSE: To formulate aqueous eye drops containing methazolamide 1% in cyclodextrin solution and to evaluate their effect on intraocular pressure (IOP) in a double-blind randomized trial in humans. Methazolamide, a carbonic anhydrase inhibitor (CAI), has been used in oral doses in the treatment of glaucoma but hitherto has not been successfully formulated in eye drops. In this study the effects of methazolamide are compared with those of dorzolamide (Trusopt). METHODS: Methazolamide 1% was formulated in a 2-hydroxypropyl-beta-cyclodextrin with hydroxypropyl methylcellulose in aqueous solution. Eight persons with ocular hypertension were treated with the methazolamide-cyclodextrin eye drops and eight persons with dorzolamide (Trusopt), both groups at dosages of three times a day for 1 week. IOP was measured before treatment was begun and on days 1, 3, and 8 at 9 AM (peak) and 3 PM (trough). RESULTS: After 1 week of treatment, the peak IOP in the methazolamide group had decreased from 24.4 +/- 2.1 mm Hg (mean +/- SD) to 21.0 +/- 2.0 mm Hg, which is a 14% pressure decrease (P: = 0.006). In the dorzolamide group, the peak IOP decreased from 23.3 +/- 2.1 mm Hg to 17.2 +/- 3.1 mm Hg, which is a 26% pressure decrease (P: < 0.001). On average, the IOP declined 3.4 +/- 1.8 mm Hg after methazolamide administration and 6.1 +/- 3.6 mm Hg after dorzolamide. CONCLUSIONS: Through cyclodextrin complexation, it is possible to produce topically active methazolamide eye drops that lower IOP. This is the first double-blind clinical trial that demonstrates the efficacy of the classic CAIs in eye drop formulation.
Carbonic Anhydrase Inhibitors↗
Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing.
It is well known that cyclodextrins can enhance the permeation of poorly soluble drugs through biological membranes. However, the permeability will decrease if cyclodextrin is added in excess of the concentration needed to solvate the drug. The mechanism of cyclodextrin effect on drug permeability has not been fully explained. The effect of cyclodextrins can not be explained as solely due to increased solubility of the drug in the aqueous donor phase nor can it be explained by assuming that cyclodextrins act as classical permeation enhancers, i.e. by decreasing the barrier function of the lipophilic membrane. In the present work we have modeled the effect of cyclodextrins in terms of mixed barrier consisting of both diffusion and membrane controlled diffusion, where the diffusion of the drug in the aqueous diffusion layer is significantly slower than in the bulk of the donor. This diffusion model is described by simple mathematical equation where the properties of the system are expressed in terms of two constants P(M)/Kd and M1/2. Data for the permeation of hydrocortisone through hairless mouse skin in the presence of various cyclodextrins, and cyclodextrin polymer mixtures, were fitted to obtain values for these two constants. The rise in flux with increased cyclodextrin complex concentration and fall with excess cyclodextrin was accurately predicted. Data for the permeation of drugs through semi-permeable cellophane membrane could also be fitted to the equation. It was concluded that cyclodextrins act as permeation enhancers carrying the drug through the aqueous barrier, from the bulk solution towards the lipophilic surface of biological membranes, where the drug molecules partition from the complex into the lipophilic membrane.
Animals↗
Age related macular degeneration in monozygotic twins and their spouses in Iceland.
PURPOSE: To examine the importance of genetic factors in age-related macular degeneration by using a twin study to compare the concordance of age-related macular degeneration in monozygotic twin pairs and their spouses. METHODS: This was a prospective study that included 50 twin pairs and 47 spouses. Zygosity was determined by genetic laboratory testing. Macular findings were graded based on the grading system used by the Macular Photocoagulation Study Group and the International ARM Epidemiological Study Group. RESULTS: The concordance of age-related macular degeneration was 90% in monozygotic twin pairs which significantly exceeded that of twin/spouse pairs (70.2%); p=0.0279. In the nine pairs that were concordant, fundus appearance and visual impairment were similar. Environmental factors and medical history were essentially the same in the twin pairs. CONCLUSION: The statistically significant higher concordance of age-related macular degeneration in monozygotic twins compared to their spouses strongly suggests the importance of genetic factors.
Aged↗
Diabetic maculopathy.
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Diabetic Retinopathy↗
Optic nerve oxygen tension in pigs and the effect of carbonic anhydrase inhibitors.
PURPOSE: To evaluate how the oxygen tension of the optic nerve (ONP(O)2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture. METHODS: Polarographic oxygen electrodes were placed in the vitreous humor immediately over the optic disc in 20 anesthetized pigs. Blood gasses and cardiovascular physiology were monitored. ONP(O)2 was recorded continuously with breathing gasses of 21% O2-79% N2, 100% O2, 20% O2-80% N2, and 5.19% CO2-19.9%, O2-74.9% N2. Acetazolamide (15-1000 mg) and dorzolamide (6-1000 mg) were administered intravenously. RESULTS: The mean (+/- SD) ONP(O)2 was found to be 24.1+/-11.6 mm Hg when the pigs were breathing room air and 50.7+/-29.3 mm Hg when they were breathing 100% O2 (n = 15; P < 0.001). In response to breathing 5.19% CO2, ONP(O)2 changed from 20.8+/-5.6 mm Hg (with 20.0% O2) to 28.9+/-3.6 mm Hg (n = 4; P < 0.001). Intravenous injections of 500 mg dorzolamide increased ONP(O)2 from 16.4+/-6.1 mm Hg to 26.9+/-12.2 mm Hg, or 52.5%+/-21.2% (n = 5; P = 0.017). A dose-dependent effect on ONP(O)2 was seen with intravenous dorzolamide doses of 1000, 500, 250, 125, 63, 27, 15, and 6 mg. Intravenous injections of 500 mg acetazolamide increased ONP(O)2 from 23.6+/-9.5 mm Hg to 30.9+/-10.0 mm Hg (n = 6; P < 0.001), and a dose-dependent effect was seen with doses of 1000, 500, 250, 125, 31, and 15 mg. CONCLUSIONS: ONP(O)2 is significantly increased by the carbonic anhydrase inhibition of dorzolamide and acetazolamide, and the effect is dose dependent. These data demonstrate for the first time a direct effect of carbonic anhydrase inhibitors on ONP(O)2.
Acetazolamide↗
Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in vitro degradation and absorption studies for naproxen derivatives.
Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.
Animals↗
Active prevention in diabetic eye disease. A 4-year follow-up.
Ten years after the foundation of a national diabetic eye screening program in 1980, we have established a low prevalence of blindness and partial sight in type 1 and type 2 diabetics in Iceland. We ask whether the screening program is also associated with a low incidence of blindness in diabetics. We now report the results of a prospective study on the 4-year incidence of diabetic retinopathy and visual impairment in type 1 diabetics with age at onset less than 30 years. Out of 205 patients participating at baseline, 175 patients (85.4%) participated over the full 4-year period. Patients were examined annually and received laser treatment according to Diabetic- and Early Treatment Diabetic Retinopathy Study criteria. The 4-year incidence of any retinopathy was 38.1%, of proliferative retinopathy 6.6%, and of macular edema 3.4%. Out of 174 patients, 7.4% showed improvement in visual acuity of 2 Snellen lines while 2.5% experienced worsening of visual acuity of 2 Snellen lines during the 4-year period. No diabetic suffered more than 2 lines deterioration of vision and none became legally blind. The incidence of retinopathy in Icelandic type 1 diabetics participating in our annual eye screening program is low and the visual acuity stable. Our results suggest that visual impairment in diabetics can be prevented with active regular screening and standard laser therapy.
Adolescent↗
Retinal vessel dilatation and elongation precedes diabetic macular oedema.
AIMS/BACKGROUND: Retinal vessel dilatation is a well known phenomenon in diabetes. In this study, the theory of whether excessive changes in diameter and length of retinal vessels occur in the development of diabetic macular oedema was tested, supporting a hypothesis that the development of diabetic macular oedema may be linked to hydrostatic pressure changes described in Starling's law. METHODS: From fundus photographs of diabetic patients attending a regular eye screening programme, the diameter and segment length of retinal vessels were measured in three retinopathy groups (12 patients each) with diabetic macular oedema (DMO), background retinopathy and no retinopathy, over a period of approximately 4 years, ending at the time of diagnosis of diabetic macular oedema in the DMO group. RESULTS: A statistically significant dilatation and elongation of retinal arterioles, venules, and their macular branches was found before the diagnosis of macular oedema in the DMO group. No significant changes were found in the other two groups. CONCLUSION: It is suggested that Starling's law applies to the formation of oedema in the retina as in other tissues.
Analysis of Variance↗