Permeability Of Blood-aqueous Barrier Research Articles

Study of the Permeability of Blood-Aqueous Barrier with Tetracycline Group Drugs in Normal and Pathological Conditions

Study of the Permeability of Blood-Aqueous Barrier with Tetracycline Group Drugs in Normal and Pathological Conditions

Evaluation of Aqueous Flare Intensity in Eyes Undergoing Intravitreal Bevacizumab Therapy to Treat Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the effect of repeated intravitreal bevacizumab injections on blood-aqueous barrier permeability in eyes with neovascular age-related macular degeneration (AMD). Patients and Methods: Forty-eight consecutive patients with neovascular AMD received 3 intravitreal bevacizumab injections (1 mg) every 30–40 days. Subjects were followed for a period of 4 months and were examined at baseline, 1 day and 1 month after each injection. A control group comprised of 19 neovascular AMD patients waiting to begin anti-vascular endothelial growth factor (VEGF) therapy. Anterior chamber (AC) inflammation was evaluated with biomicroscopy and laser flare photometry. Results: None of the subjects treated with bevacizumab had detectable ocular inflammation during follow-up. An analysis for variance (ANOVA) of the mixed-effects model has shown neither an effect between treatment and control group (p = 0.921), nor over the time course of the follow-up (p = 0.773). Before treatment, median AC inflammation was 6.7 photons/ms (range: 3.5–18.2 photons/ms). One month after the first, second, and third injections, median laser flare was 6.4, 6.8, and 6.6 photons/ms, respectively, none of which were significantly different from baseline (all p > 0.05). Blood-aqueous barrier permeability did not change between injections and was not different from the control group. Conclusion: Inflammation induced by intravitreal bevacizumab was not detected by examination or flare photometry. This suggests that monthly bevacizumab dosing seems to be safe. The absence of AC inflammation could also reflect the known anti-inflammatory properties of anti-VEGF agents.

Selective permeability of mouse blood-aqueous barrier as determined by 15N-heavy isotope tracing and mass spectrometry

The blood-aqueous barrier plays a key role in regulating aqueous humor homeostasis by selectively restricting passage of proteins into the eye. The kinetics of aqueous flow are traditionally measured using artificial markers; however, these marker molecules do not address the barrier's selective permeability to plasma proteins. Here we applied stable isotope labeling of all serum proteins with nitrogen-15 (15N) atoms. Following systemic injection of this "heavy" serum in mice, the 15N-to-endogenous nitrogen-14 (14N) ratio of each protein in aqueous was measured by mass spectrometry. By monitoring the kinetic changes in these ratios, we determined the permeability profiles of hundreds of serum proteins. Meanwhile, we subjected one of the eyes to neoangiogenic wound healing by inflicting injury to the corneal limbus and compared the 15N proteomes between the normal eyes and the recovering eyes at 2 weeks after injury. In the injured eye, we detected markedly enhanced permeability to inhibitory complement regulator proteins, such as Cfh, Cfhr, Cfb, Cfi, Cfd, and Vtn. Many of the proteins in this group are implicated in age-related macular degeneration associated with leakage of the blood-retinal barrier due to inflammation. To rule out the possibility that the observed leakage was due simply to physical damage of the blood vessels, we separately created a neovascularization model using an alkali burn of the avascular cornea. In this latter model, elevated levels of Cfh and Cfb were evident. These findings suggest that ocular neovascularization is associated with enhanced permeability to serum complement regulators.

Clinical application of the ocular fluorophotometer

The purpose of this article is to discuss the literature on the clinical role of the ocular fluorophotometer in different ocular conditions. The ocular fluorophotometer measures the fluorescent compounds present in the cornea, lens, vitreous body and retinal pigment epithelium. These compounds can be present naturally, known as autofluorescent, or fluorescent after application of fluorescein either topically or systemically. The fluorophotometer measures the changes in barrier function in both corneal epithelium and endothelium. It is a quantitative method of detecting a breakdown in the blood–ocular barriers. It helps to measure the inward and outward movements of fluorescein across the blood–retinal barrier as well as blood–aqueous barrier permeability. The measurement of ocular barrier permeability by the fluorophotometer helps to improve our understanding of ocular conditions. It is also useful to assess the effect specific therapeutic approaches in some diseases and clinical research.

Evaluation of Therapeutic Effectiveness Using MR Imaging in a Rabbit Model of Anterior Uveitis

Magnetic resonance imaging (MRI) has been used to examine conditions that alter the permeability of the blood–retinal barrier. Our goal was to determine if blood-aqueous barrier permeability could be similarly assessed, because MRI offers the theoretical advantage of providing quantitative data directly from inflamed uveal tissues rather than from the aqueous humor into which the inflammatory reaction spills. As an additional challenge, we sought to use MRI to measure differences between the inflamed uveal tissues of corticosteroid-treated and placebo-treated uveitic eyes. Anterior uveitis was induced in one eye of eight rabbits by subcutaneous injection of Mycobacterium tuberculosis, followed after 10 days with intravitreal challenge. One rabbit of each pair was treated with topical 1% prednisolone acetate while control rabbits were treated with artificial tears. Contrast-enhanced MRI studies were performed prior to uveitis induction, one day after induction and then weekly for at least 2 weeks. MR image data were analyzed to determine percent change in peak enhancement of the ciliary body and anterior chamber. The initial rate of change of enhancement of the anterior chamber was also measured. Extensive contrast agent-induced MR image enhancement of both the anterior chamber and the ciliary processes was measured following the induction of uveitis. More rapid improvement was measured for the 1% prednisolone acetate-treated rabbit eyes (P<0.001). MR signal enhancement data obtained from the ciliary processes proved to be the most reliable indicator of disease activity in this rabbit model of uveitis. Such data can only be obtained using MRI.

Effects of Topical Prostaglandin Analogues on the Aqueous Flare Intensity in Rabbit Eyes at an Early Phase of Endotoxin-induced Uveitis

We examined the effects of prostaglandin analogues on the blood-aqueous barrier(BAB) permeability in rabbit eyes at an early phase of endotoxin-induced uveitis(EIU). One drop of 0.005% latanoprost or 0.12% unoprostone were applied to rabbit eyes. Escherichia coli lipopolysaccharides were injected to induce uveitis. The changes in flare intensity in normal eyes and EIU eyes after application of eye drops were evaluated. The effect of cyclooxygenase inhibitor on the flare intensity changes caused by the application of unoprostone was also examined. Flare intensity increased significantly after a single instillation of unoprostone, and the increase was not prevented by pretreatment with cyclooxygenase inhibitor. In eyes with EIU, unoprostone caused an additional increase of flare intensity to uveitis induced flare change. Latanoprost had no effects on BAB in eyes with normal and with uveitic conditions. Latanoprost and unoprostone did not cause an excessive inflammatory reaction in rabbit eyes at an early phase of EIU.

Effect of ifenprodil on aqueous humor dynamics and optic nerve head circulation in rabbits.

The purpose of this study was to study the effects of ifenprodil, a cerebral vasodilator with alpha and N-methyl-D-aspartate (NMDA) receptor antagonistic activities, on aqueous humor dynamics and optic nerve head (ONH) circulation in rabbits. Experiments were performed during the dark phase in rabbits conditioned to a schedule of alternating 12-hr periods of light and dark. Effects on blood-aqueous barrier permeability (K(d)), aqueous flow rate (F), outflow facility to general blood circulation (C(gen)), and uveoscleral outflow (F(u) were determined fluorophotometrically. Effects on ONH tissue circulation were estimated using the laser speckle method. Unilateral topical administration of 0.5% ifenprodil solution decreased intraocular pressure (IOP) with a maximum reduction of 3.4 mmHg and an effect duration of 3 hr without effects on the contralateral eye. A single instillation of 0.5% ifenprodil had no significant effect on K(d), F, or C(gen), whereas it substantially increased F(u). Twenty-day, twice-daily unilateral 0.5% ifenprodil instillation significantly increased tissue blood velocity in the ONH only in the treated eye.

Sulfasalazine in the prevention of anterior uveitis associated with ankylosing spondylitis

To assess the effects of sulfasalazine in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis and chronic intestinal inflammation. Twenty-two patients with anterior uveitis associated with ankylosing spondylitis were studied. Ten patients were randomised to receive oral sulfasalazine (group 1) and 12 patients randomised to no treatment (group 2); all were followed for 3 years. Blood-aqueous barrier permeability was determined by fluorophotometry and bowel biopsies were taken. A statistically significant difference was observed between the two groups regarding the number of recurrences of uveitis (p = 0.016). The blood-aqueous barrier permeability was significantly higher during acute attacks in group 2 (group 1: 31.3 +/- 26.4 x 10(-4) min-1 vs group 2: 66.2 +/- 28.5 x 10(-4) min-1; p = 0.019) but not during the disease-free period. We observed a higher incidence of chronic intestinal inflammation at the end of the study in group 2 (group 1: 3/8 vs group 2: 7/9, p = 0.153). No relation was observed between blood-aqueous barrier permeability and the number of recurrences. The number of patients with severe persistent posterior synechiae at the end of the study was higher in group 2 (group 1: 4 patients before and 4 patients at the end; group 2: 4 patients before and 8 patients at the end; p = 0.65). Sulfasalazine may be beneficial in preventing recurrences and reducing the severity of anterior uveitis associated with ankylosing spondylitis.

Intraocular lidocaine in phacoemulsification: An endothelium and blood–aqueous barrier permeability study

Objective To evaluate the effects of intraocular lidocaine hydrochloride (HCl) on the corneal endothelium and of blood–aqueous barrier (BAB) permeability in ultrasound phacoemulsification. Design Nonrandomized, comparative trial. Participants Sixty patients who underwent uneventful, single-surgeon, clear cornea phacoemulsification were studied prospectively. Methods Sub-Tenon’s anesthesia was administered to 30 patients (group 1), and intraocular lidocaine hydrochloride was administered to an additional 30 patients (group 2). An endothelial study of at least 120 cells per patient, using a noncontact specular microscope and a digital image analysis system, was performed before surgery and 1 month after surgery. Blood–aqueous barrier permeability was evaluated preoperatively and postoperatively (48 hours, 1 week and 1 month) using a laser flare meter. Main outcome measures Endothelial parameters (cell density, hexagonality, and coefficient of variation in cell area) and BAB permeability. Results No significant differences were found between groups when comparing the postoperative changes produced in endothelial cell density (95% confidence interval [CI], 0.46, 4.7; P = 0.10), hexagonality (95% CI, −2.5, 3.5; P = 0.72), and coefficient of variation in cell area (95% CI, −8.3, 4.6; P = 0.57). A multivariate study detected no significant differences in mean flare values between groups during follow-up ( P = 0.40). No clinically significant differences were found between mean preoperative and 1 month postoperative flare values in either group. Conclusions The recovery of BAB permeability 1 month after surgery seems to suggest that no additional inflammation was induced by intraocular lidocaine HCl. The fact that no differences in postoperative changes in endothelial parameters were found between groups indicates that no further corneal endothelial damage (other than that caused by surgical manipulation) was incurred. According to our results, intracameral lidocaine HCl appears to be safe for the average phacoemulsification patient in the absence of ocular pathologic conditions.

Effects of latanoprost and dipivefrin, alone or combined, on intraocular pressure and on blood-aqueous barrier permeability

AIMTo investigate the effect on intraocular pressure (IOP) and aqueous flare of topical applications of latanoprost and dipivefrin alone or combined.METHODS22 patients with open angle glaucoma or ocular hypertension were...

Clinical dose-regimen studies with latanoprost, a new ocular hypotensive PGF 2α analogue

This review summarizes recent short-term clinical studies evaluating the ocular hypotensive efficacy of different dose-regimens of latanoprost. When tested in ocular hypertensive and glaucoma patients concomitantly treated with timolol, 0.006% latanoprost given only in the evening, was found to be more effective than the same concentration given in the morning and evening. In patients with open angle, pseudoexfoliation and normal tension glaucoma not receiving other treatment, once-daily 0.005% latanoprost monotherapy was more effective than twice-daily 0.0015% latanoprost treatment. No significant differences were found in conjunctival hyperemia, sensory irritation or blood-aqueous barrier permeability between these two treatment regimens. Although the ocular hypotensive efficacy of once-daily application of the lower concentration (0.0015%) latanoprost was not investigated, we would conclude, based on the studies reviewed here, that at a concentration of 0.005%, once-a-day dosing of latanoprost is highly effective in significantly reducing intraocular pressure, causing only minimal, clinically acceptable short-term ocular side effects.

Blood-aqueous barrier permeability determination in HLA B27-positive acute anterior uveitis patients.

The blood-aqueous barrier (BAB) permeability was studied by fluorophotometry in 17 healthy control subjects and in 27 eyes from 27 patients with HLA-B27-positive acute anterior uveitis (HLA-B27 AAU). Twenty of these patients had an associated spondyloarthropathy. BAB permeability was studied during the ocular inflammatory crisis and in the disease-free periods in the same patients. Anterior chamber fluorophotometric scans were performed before and 30 minutes after the intravenous injection of 14 mg/kg of sodium fluorescein. The diffusion coefficient (Kd) was obtained from the ratio between the fluorescein concentration in the anterior chamber and the NPBF. Data were analyzed using the Student's t test and analysis of variance. A statistically significant difference (P < 0.001) was found between the Kd of active HLA-B27 AAU (61.4 +/- 16.8 x 10(-4) min-1) and the Kd of inactive HLA-B27 AAU (4.8 +/- 1.6 x 10(-4) min-1). No statistically significant differences were found between the Kd of inactive HLA-B27 AAU and the Kd of the control subjects (4.3 +/- 1.0 x 10(-4) min-1). We also failed to detect significant differences between patients with and without spondyloarthropathy either during the acute attack or during the disease-free period. On the basis of these results we conclude that the permeability of the BAB remains intact in inactive HLA-B27-positive AAU. The parallel fluorophotometric behaviour of HLA-B27-positive AAU with spondyloarthropathy and without spondyloarthropathy suggests that both share a common pathogenetic mechanism.

The Blood-Ocular Barrier in Type I Diabetes without Diabetic Retinopathy: Permeability Measurements Using Fluorophotometry

For the evaluation of a possible malfunction of the blood-retinal (BRB) and the blood-aqueous barrier (BAB) in type I diabetes without manifest angiopathy, after i.v. injection of sodium fluorescein, the permeability of BRB (P) and the diffusion coefficient of BAB [P(a)] were studied simultaneously by fluorophotometry in 34 eyes of 34 type I diabetics (HbA1c = 6.6 +/- 0.9%) without retinopathy whose ages ranged from 19 to 38 years (30.5 +/- 5); diabetes' duration was between 5 and 18 years. Fluorescein angiography was performed to exclude nonperfused areas. In all, 34 eyes of 34 healthy volunteers whose ages ranged between 23 and 34 years (28.5 +/- 3.3) served as controls; in this group, fluorophotometry was performed twice to evaluate reproducibility. The mean BAB diffusion coefficient in diabetics [P(a) = 5.3 +/- 1.8/min] was significantly increased (p = 0.00003) as compared to controls [P(a) = 3.7 +/- 0.7/min]; BRB permeability in diabetes (P = 3.2 +/- 1.4 x 10(-7) cm/s) was raised with this elevation being of lower significance (p = 0.019; controls: P = 2.6 +/- 0.7 x 10(-7) cm/s). We found a decrease in BRB permeability depending on diabetes' duration (r = -0.15; p = 0.007) that was not significant in BAB (r = -0.1; p = 0.24). No correlation was found to exist between permeability and HbA1c values either in BAB or in BRB. The reproducibility in controls was 9% in BRB determinations and 12% in BAB measurements. These results may suggest that early structural alterations without the manifestation of retinopathy possibly cause elevation in BRB permeability and are even more obvious in BAB permeability. Whereas the reliability of vitreous fluorophotometry in detecting early BRB malfunction has to be judged critically, anterior segment fluorophotometry is a reliable procedure for the monitoring of BAB affection in type I diabetes without retinopathy.

Permeability of the blood-retinal and blood-aqueous barriers in galactose-fed rats.

Blood-retinal barrier (BRB) and blood-aqueous barrier (BAB) permeability were assessed by various methods to clarify conflicting reports on whether blood-retinal barrier permeability changes occur in diabetic and galactose-fed rats and to assess the potential role of aldose reductase in this process. Different molecular weight probes were utilized in rats fed for 7-11 months either a normal diet or a diet containing 50% galactose with/without the aldose reductase inhibitor AI1576 or Ponalrestat. BRB and BAB were assessed through radiolabelled sucrose permeability studies in eyes where the anterior segment was frozen during dissection compared to eyes where the anterior segments were not frozen and by quantitative autoradiography. In addition, histological studies using Evans Blue dye, microperoxidase and horseradish peroxidase were conducted. In untreated galactose-fed rats a 4-fold increase in the mean permeability surface area product (PA) to sucrose at the BRB was observed when the aqueous humor was not frozen during retinal dissection. However, no increase in the mean PA to sucrose was observed when the aqueous humor of similar eyes was frozen during dissection. Similarly, no retinal vessel permeability increase was observed by either quantitative autoradiography of [3H]-sucrose after 15 minutes of circulation or histological studies with microperoxidase, horseradish peroxidase or Evans Blue dye. Examination of the BAB revealed an increase in the permeability of iris vessels but not the ciliary body in galactose-fed rats which was reduced by treatment with the aldose reductase inhibitor AI1576. These data indicate that while BRB permeability is not increased in galactose-fed rats, BRB permeability measurements with isotopes are subject to possible contamination from the aqueous humor in untreated galactose-fed rats, which can result in false observations of increased BRB permeability.

Effect of topically applied 2% pilocarpine and 0.25% demecarium bromide on blood-aqueous barrier permeability in dogs

Summary The effect of topically applied 2% pilocarpine and 0.25% demecarium bromide on aqueous humor flare was evaluated while treating normal eyes of dogs 3 times daily for 8 days. Fifteen clinically normal Beagles were allotted to 2 drug treatment groups, and flare was measured/using laser flaremetry. Pilocarpine caused an increase of flare to 167 photon counts (pc)/ms at 7 hours, compared with the nontreated control eye mean value 3.7 pc/ms. By 31 hours, flare had decreased to 70 pc/ms with 3 daily topical treatments. By 55 hours, the flare measurement was in the normal range. Intraocular pressure (iop) decreased in the treated eyes, compared with the non-treated eyes, and maximal decrease in iop was observed at the same time as maximal flare. Demecarium induced a similar increase in flare and decrease in iop, with peak effect seen at 31 hours. At that time, the flaremetry result was 28 pc/ms, compared with 3.4 pc/ms in the nontreated control eyes. After 8 days of 3 times daily treatment, flare values had returned to normal in eyes of dogs in both treatment groups. The transient increase in aqueous humor protein concentration did not result in ocular or visual damage, and long-term changes were not seen. The amount of flare increase attributable to topical application of pilocarpine was greater than the increase in human eyes when measured by use of laser flaremetry.

Heparin-surface-modified intraocular lens implantation in eyes with pseudoexfoliation syndrome

Eyes with pseudoexfoliation syndrome have a greater risk of intraoperative and postoperative complications. Clinical and histopathological studies indicate that heparin-surface-modified intraocular lenses (HSM IOLs) can reduce postoperative anterior segment inflammation. Our study evaluated the blood-aqueous barrier permeability in eyes with pseudoexfoliation syndrome and implanted with an HSM IOL. We examined two groups of 20 patients, one comprising patients with pseudoexfoliation syndrome and one a sex- and age-matched control group with senile cataracts. Each group was divided into two subgroups of ten patients each. In one subgroup, an HSM IOL was implanted; in the other, a conventional poly(methyl methacrylate) IOL. We performed a complete ophthalmologic examination and iris angiography preoperatively and at 30, 90, and 180 days after surgery. Fluorophotometry was performed at the 90-day and 180-day postoperative examinations. The patients with pseudoexfoliation syndrome had a higher blood-aqueous barrier permeability than did the control group. Permeability decreased significantly three and six months after surgery, especially in the HSM IOL group.

The Effects on Aqueous Dynamics of PhXA41, a New Prostaglandin F2α Analogue, After Topical Application in Normal and Ocular Hypertensive Human Eyes

To study the effects of a topically applied prostaglandin F2 alpha analogue, PhXA41 (Latanoprost; 13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-isopropyl ester), on aqueous dynamics in the human eye. A randomized, double-masked study was carried out on 20 normal and 20 ocular hypertensive humans. One eye of each subject was treated with 0.006% PhXA41, while the contralateral eye received placebo twice daily for 5 days. Compared with placebo, PhXA41 reduced intraocular pressure in both groups by approximately 20%. Tonographic facility of outflow was increased 24% in the normal group and 30% in the ocular hypertensive group; no changes were observed in the rates of aqueous humor flow in either group. The changes in tonographic facility were insufficient to fully explain the ocular hypotensive effect of the drug, suggesting that PhXA41 enhances outflow via the uveoscleral pathway. The suitability of fluorophotometry as a measure of flow was confirmed by three methods of comparing blood-aqueous barrier permeability: polarization of cameral fluorescence, intensity of backscattered light from the anterior chamber (flare), and cameral fluorescence after oral administration of fluorescein sodium. All of these measured parameters were normal, suggesting that this compound has no clinically significant effects on the blood-aqueous barrier or on the accuracy of fluorophotometry. PhXA41 was well tolerated in both groups. Only four of 40 subjects reported a transient foreign-body sensation, and only one of 40 subjects was observed to have greater than moderate conjunctival hyperemia. Most subjects had no symptoms and no measurable hyperemia. These results suggest that PhXA41 is a potentially useful ocular hypotensive agent that enhances the egress of aqueous humor via both major outflow pathways. The relative lack of ocular side effects in this study further suggests that this agent has promise for the treatment of chronic glaucoma.

Fluorophotometry in phakic eyes with anterior chamber intraocular lens implantation to correct myopia

In this longitudinal study, we implanted 16 angle-fixated anterior chamber intraocular lenses in phakic eyes of 13 patients to correct high myopia. Using fluorophotometry, we discovered a statistically significant decrease (P < .01) in lens transmittance. Blood-aqueous barrier permeability tended to remain increased six months after surgery.

Effects of Apraclonidine on Intraocular Pressure and Blood-aqueous Barrier Permeability After Phacoemulsification and Intraocular Lens Implantation

To evaluate the effect of topical apraclonidine on early postoperative intraocular pressure and blood-aqueous barrier permeability, we conducted a double-masked clinical trial in which 37 patients undergoing uncomplicated phacoemulsification and posterior chamber intraocular lens implantation were randomly assigned to treatment with 1% apraclonidine or its vehicle. One drop of 1% apraclonidine or its vehicle was instilled 1/2 hour preoperatively and immediately postoperatively. In addition to intraocular pressure, aqueous flare intensity was also determined before and after the operation by using a laser flare-cell meter. In the apraclonidine group, intraocular pressure showed no significant postoperative increase, whereas it showed a significant increase at six hours in the vehicle group (P < .01). Difference between intraocular pressure recorded at the end of the operation with the Tono-Pen II and that measured postoperatively was significantly greater in the vehicle group by 3.5 to 7.0 mm Hg (P < .05 to .01). In the apraclonidine group, the aqueous flare intensity was about half that in the vehicle group with significant differences at six (P < .05) and 24 (P < .01) hours.

Permeability of the blood-ocular barrier in adolescent and adult diabetic patients.

The permeability of the blood-ocular barrier was examined by fluorophotometry in adolescent and adult diabetic patients before the onset of retinopathy. The adolescent group consisted of 52 eyes of 52 insulin dependent diabetic patients aged 11 to 19 years and a control group of 10 eyes of 10 normal adolescents. The adult group consisted of 74 eyes of 74 non-insulin dependent diabetics and a control group of 30 eyes of 30 normal adults. The increase in lens autofluorescence in the adolescent diabetic patients compared with the controls was striking and showed a significant positive correlation (r = 0.79, p < 0.0001) with the duration of diabetes. Anterior chamber (AQ) values, an index of the permeability of the blood-aqueous barrier (BAB), increased in the adolescent diabetic patients compared with the controls and showed a significant positive correlation with glycosylated haemoglobin levels. No significant differences from the controls were observed regarding the permeability of the blood-retinal barrier (BRB). In the adult group there was no significant difference in either the permeability of the BRB or the AQ values between the diabetic and the control groups. Our results suggest that adolescent diabetic patients differ from adults in that BAB permeability is increased before the onset of retinopathy, suggesting that this is the cause of the striking increase in lens autofluorescence.