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Biomedical subjects

J Ben-Nun

Publications and source records attributed to J Ben-Nun.

14 recordsLinked to original sources

Capillary blood flow in acute branch retinal vein occlusion.

PURPOSE: To study retinal capillary blood flow during the acute stage of induced branch retinal vein occlusion (BRVO) in the feline retina and the effect of systemic blood pressure during this event. METHODS: Known fractions of the animal blood cells were labeled by a fluorescent marker and tracked by an electro-optical device as they flowed within the retinal microcirculation. Branch retinal vein occlusion was induced by photocoagulation of a large vein at the optic disk rim. The findings were video recorded and analyzed by computerized image processing. RESULTS: Reversed capillary blood cell flow from the blocked vein was noted immediately following occlusion of the vein. Two patterns of reversed capillary flow were identified: one from the blocked vein to a terminal arteriole and the other from a blocked vein to another vein via a junction with a terminal arteriole. Increased systemic blood pressure decreased the reversed flow in both flow patterns. CONCLUSIONS: 1) Flow deviation to nearby retinal arterioles or veins (shunting) through the normal capillary system is an immediate hemodynamic event following acute BRVO. 2) The reversed capillary flow is affected by the systemic blood pressure.

Acute Disease↗

Fluocinolone acetonide sustained drug delivery device to treat severe uveitis.

PURPOSE: Uveitis is often a chronic disease requiring long-term medical therapy. In this report, we describe a pilot safety and efficacy trial of a novel sustained drug delivery system containing fluocinolone acetonide to treat patients with severe uveitis. DESIGN: Prospective, noncomparative, interventional case series PARTICIPANTS: Patients with severe uveitis. METHODS: Sustained drug delivery devices designed to release fluocinolone acetonide for at least 2.5 years were implanted through the pars plana into the vitreous cavity of seven eyes of five patients. All patients had severe uveitis not well controlled with, or intolerant to, repeated periocular corticosteroid injections, systemic corticosteroids, nonsteroidal immunosuppressive agents, or a combination thereof at the time of device implantation. Before device implantation, patients underwent complete evaluation including history, ophthalmologic examination, fluorescein angiography, visual field testing, and electroretinography. After surgery, patients were reexamined at 1 week, 2 weeks, 4 weeks, and at 1- to 3-month intervals. Visual fields, electroretinograms, and fluorescein angiography were repeated at 3- to 6-month intervals. MAIN OUTCOME MEASURES: Preoperative and postoperative visual acuity, ocular inflammation, anti-inflammatory medication use, and intraocular pressure. RESULTS: Patients had a diagnosis of Behçet's syndrome (two eyes), or idiopathic panuveitis (five eyes, including two with necrotizing retinitis, two with progressive chorioretinitis, and one with iridocyclitis and intermediate uveitis). Patients were observed an average of 10 months (range, 5-19 months). All eyes had stabilized or improved visual acuity after device implantation, and four of seven eyes had an improvement of three lines or more. The mean initial visual acuity, measured by Snellen chart, was 20/207, and the mean final visual acuity was 20/57 (P = 0.02). After surgery, at the final visit, no eye had clinically detectable inflammation, and all seven eyes had a marked reduction in systemic, topical, and periocular anti-inflammatory medication use. Four eyes had increased intraocular pressure 6 weeks to 6 months after device implantation. Intraocular pressure has been controlled on topical medications. No patient experienced intraoperative complications. CONCLUSIONS: A fluocinolone acetonide sustained drug delivery device is a promising new therapy for the treatment of severe uveitis. Intraocular pressure must be carefully monitored long after device implantation. Based on these data, a randomized study of a larger group of patients is warranted.

Adolescent↗

Intraocular pressure and blood flow of the optic disk: a fluorescent blood cell angiography study.

The damage to disk microcirculation in glaucoma and ocular hypertension is correlated with the damage to the neuronal tissue. However, it is not clear whether the primary damage is vascular or neurogenic. We have developed a new method which allows in vivo observation of the retinal capillary blood cell flow and the plasma flow, separately. The method was used to examine the blood cell flow in the optic disks of cats' eyes. The intraocular pressure was controlled by extra-fine intraocular canula at the anterior chamber. It was found that blood cell flow became stagnant in a few capillaries at the optic disk with an intraocular pressure of 30-45% of the systemic mean blood pressure. When an induced IOP increase to 45% of systemic mean blood pressure was sustained for 30 minutes, microcirculatory blood flow recovery was complete two hours later. When this pressure was sustained for 120 minutes, the recovery was incomplete two hours later. This work represents a new tool in the research of retinal and disk hemodynamics and microvascular pathologies. The results presented in this paper support the hypothesis that early ischemic microdamage might be the basis of the pathogenesis of the chronic glaucomas.

Animals↗

A novel dialysing seton: short-term biocompatibility.

A novel dialysing seton made from haemodialysis tubes was implanted into eleven rabbit eyes to establish its biocompatibility. The animals were observed for up to 67 days after implantation. The cannulae were well tolerated clinically. Tissue obtained at seven different time periods was studied by light and electron microscopy and showed only a mild inflammatory reaction of the same grade as or less than that surrounding nylon sutures used to close the scleral trapdoors. The eye containing the seton had consistently lower intraocular pressure compared to the sham-operated fellow eye for up to 24 days. This effect declined over the ensuing five weeks.

Animals↗

The patency of the retinal vasculature to erythrocytes in retinal vascular disease.

This paper presents the first evidence that in retinas with experimentally induced vascular disease some vessels contain only plasma. This was demonstrated by a histologic technique developed specifically to test the hypothesis that at some stage in retinal vascular disease, vessel patency to erythrocytes is lost before vessels close to plasma. Using this technique, we visualized three major components of the circulation at all retinal locations: the erythrocytes; the plasma as marked by the presence of 0.2-micron fluorescent microspheres; and all functioning endothelial cell nuclei, which were marked by the fluorochrome bis-Benzimide. It was assumed that the distributions of the erythrocytes and small particles in retinal whole mounts reflected accurately the true in vivo distributions at the moment of circulation arrest. Postenucleation the retina can be viewed and photographed within 45 min of circulation arrest. The technique was used on normal rats and on rats induced with a fast-developing model of retinal vasculopathy. With this model, we demonstrated retinal vascular segments perfused by plasma but containing no erythrocytes with functioning endothelial cells in the vessel walls. This may mean that an early factor in some retinal vascular pathologies is tissue hypoxia caused by reduced erythrocyte perfusion.

Alloxan↗

PO2 profiles and oxygen consumption in cat retina with an occluded retinal circulation.

If the retinal circulation is occluded, the retina is forced to rely on the choroidal circulation for its oxygen supply. We have measured intraretinal PO2 profiles before, during, and after such an occlusion in cat. Oxygen-sensitive microelectrodes were used to measure intraretinal PO2, and the retinal circulation was occluded by means of a glass probe placed on the retinal vessels at the optic disk. Both air and 100% O2 breathing conditions were investigated. With the retinal circulation occluded, intra-retinal PO2 fell to zero within 60% of the distance through the retina, measured from the choriocapillaris to the internal limiting membrane. With the circulation occluded, but with breathing of 100% O2, PO2 rose throughout the retina so that values within the inner retina were as high or higher than for air breathing with the retinal circulation present. This meant that the whole retina could be supplied with adequate oxygen by breathing with 100% O2 in cat. From these PO2 profiles, oxygen flux and consumption were calculated as a function of distance through the retina. These calculations showed that the outer 20% of the retina had a consumption of 5.45 +/- 2.46 (SD) ml.min-1.100 ml-1 compared with a mean value for the remaining retina of 1.47 +/- 2.66 ml.min-1.100 ml-1. This difference was statistically significant (P less than 0.001) which indicates that there are at least two regions in the retina with different oxygen consumption.

Animals↗

A new method for continuous intraocular drug delivery.

A novel device for the continuous intraocular delivery of drugs is described. The active intraocular component of the device is made from hollow haemodialysis fibres. During operation, the drug to be administered diffuses from a small extraocular reservoir to the intraocular fibres, where it passes through the semipermeable walls and into the vitreous body. The delivery of gentamicin by the device into the vitreous body of the cat is compared with direct intraocular injection techniques. Characteristics of the process of drug delivery were influenced by the geometry and design of the device. A reservoir concentration of 10 g/L gentamicin sulphate in a device with four fibres, each 5 mm long, resulted in stable vitreal gentamicin levels of 104 to 128 mg/L at 10 hours. Intravitreal injection of 0.1 ml of a 10 g/L solution of gentamicin caused localised peaks of intravitreal gentamicin concentration in the range 1180 to 3296 mg/L, before falling to 356 to 665 mg/L at 10 hours. The device provides the opportunity of a more controlled and continuous drug delivery, thus avoiding the high localised concentrations that may occur with direct injection techniques in which the required dose is delivered as a bolus. Refinement of a device of this type may result in a clinically useful method of intraocular drug delivery for drugs which present a risk of localised retinal toxicity or require repetitive administration with conventional intraocular injection techniques.

Animals↗

Pharmacokinetics of intravitreal injection. Assessment of a gentamicin model by ocular dialysis.

Intravitreal drug administration is the treatment of choice for bacterial endophtalmitis, but improved knowledge of vitreal pharmacokinetics is essential for the development of optimal antibiotic regimes. We used our recently developed sampling device to estimate vitreal gentamicin concentrations for up to 30 hr after an intravitreal bolus injection of gentamicin. The device is based on the principle of dialysis, whereby a constant flow rate of dialysate through a loop of dialysis fiber in the vitreous attains a gentamicin concentration proportional to the intravitreal gentamicin level around the fiber. The dialysate is continuously recovered and the collected samples then assayed for gentamicin. Normal cat eyes and those with induced bacterial endophthalmitis formed the two groups tested. Concentration-time data fitted well to an open single compartment pharmacokinetic model that incorporated the processes of transfer of drug from the injection site to the sampling site (a function of diffusion within the vitreous), and the elimination from the sampling site (a function of elimination from the vitreous). The initial phase of transfer between the injection and sampling site was rapid and rates were comparable in the two groups. Elimination rate constants were uniformly greater in infected eyes than in controls (0.107 hr-1 compared to 0.055 hr-1). Aqueous humor gentamicin concentrations in control eyes varied between 3 and 6 times those found in fellow infected eyes at the end of each experiment. Accelerated elimination of gentamicin from the vitreous body of eyes with endophthalmitis may be explained by increased permeability of the blood-retinal barrier.

Animals↗

Ocular dialysis. A new technique for in vivo intraocular pharmacokinetic measurements.

A new technique, using the principle of dialysis, enables continuous determination of the concentration of compounds within the vitreous humor of the eye. A semipermeable catheter inserted into the cat vitreous cavity was continuously perfused with a normal saline solution. Gentamicin concentration in the dialysate, after subconjunctival or intravitreal injection, was used to calculate gentamicin concentration in the vitreous from the catheter's recovery ratio, as calibrated in vitro. After subconjunctival injection, no gentamicin was detected in the vitreous for up to eight hours. From four to eight hours after intravitreal injection of approximately 100 micrograms of gentamicin sulfate, its vitreal concentration ranged from 30 to 80 mg/L and from nine to 16 hours it fell from 26 to 22 mg/L. This method may prove useful for the study of the pharmacokinetics of many drugs and metabolites in the eye.

Animals↗

A new method for oxygen supply to acute ischemic retina.

This paper introduces a new method for supplying oxygen directly to ischemic inner retina, using an oxygen source in the vitreous. Acute retinal vascular occlusion was created in cat eyes by direct pressure on the optic disk and its margins with a glass probe. The satisfactory occlusion of the retinal vessels was documented by direct observation, and functionally by recording the ERG. The vascular occlusion caused a large decrease in the size of the ERG b wave, with no change in the a wave amplitude. The oxygen source was a catheter made of strands of an oxygen-permeable membrane which was inserted into the vitreal cavity. After successful vascular occlusion was documented, 100% gaseous oxygen was perfused through the catheter while recording the ERG. In response to the perfused oxygen the b wave partially recovered. Ventilating the animal with 100% oxygen when the retinal vessels were occluded also caused recovery of the b wave amplitude. Termination of the vitreal oxygen source caused a decrease in b wave amplitude to the level previously observed after the occlusion of the retinal vessels. When the retinal circulation was restored by removal of the glass probe the b wave recovered. The results show that it is possible to supply adequate oxygen to the inner retina via the vitreous to replace the oxygen normally supplied by the retinal circulation. Modification of this method may be useful for the treatment of recent and incomplete retinal vascular occlusion.

Acute Disease↗

The effects of induced acute hyperglycemia in the cat on the retinal capillary blood flow.

PURPOSE: To study the effect of acute hyperglycemia on the erythrocyte flow in specific retinal capillary paths. METHODS: A technique for fluorescent labeling of a known fraction of the erythrocyte moiety of systemic blood was combined with fluorescence viewing of the retinal capillary network in live cats. This technique was developed to enable visualization of the erythrocyte flow in the retinal capillary network and used to acquire video recording of the retinal capillary erythrocyte flow in normal feline eyes. The pattern of capillary erythrocyte flow under normal blood glucose levels and normal systemic blood pressure served as baseline. Acute hyperglycemia was induced by intravenous injection of glucose while monitoring the systemic blood pressure. Two subsets of functional capillary pathways previously defined as S (simple) and C (complex) were identified in the recorded data. The relationship between erythrocyte flux in random selections of these two pathways and the level of hyperglycemia and systemic blood pressure was determined. RESULTS: Induction of acute hyperglycemia led to acute elevation of the systemic blood pressure that returned to baseline levels within few minutes, while blood glucose remained high. The capillary erythrocyte flux in S paths was significantly higher than in C paths at all values of systemic blood pressure. The capillary erythrocyte flux in the S paths was directly proportional to the systemic blood pressure whereas the flux in C paths was minimally affected by acute hyperglycemia for the systemic blood pressure range between 110 and 160 mm Hg. CONCLUSIONS: The erythrocyte flux in S paths is affected by the changes of the systemic blood pressure and these paths act as 'shunt vessels' when acute elevation of the systemic blood pressure occurs. C paths maintain stable perfusion under changing conditions, most probably in an effort to minimally alter the basic metabolic needs of the retinal tissue. Hyperglycemia per se was not responsible for changes of the cell flux in these capillary paths.

Acute Disease↗