Safety and Tolerability of KIO-101 Eye Drops in Healthy Volunteers and Patients with Ocular Surface Disease-A Phase I Study.

PURPOSE: Inhibitors of dihydroorotate dehydrogenase (DHODH) have been found to be potent anti-inflammatory agents. Recently, a topical formulation (KIO-101 eye drops) of a DHODH inhibitor has been developed. The aim of the present study was to evaluate the safety and tolerability of KIO-101 eye drops in Healthy Volunteers (HVs) and patients with conjunctival hyperemia. METHODS: The study was carried out in a double-masked, placebo-controlled, randomized, parallel-group design with two parts. In part I, HVs received single and multiple instillations (four times daily for 12 consecutive days) of KIO-101 eye drops in ascending doses of 0.05%, 0.15%, and 0.30%, respectively. Part II was conducted in patients with conjunctival hyperemia who received 0.15% KIO-101 eye drops twice daily for 12 consecutive days. Ophthalmic and systemic safety examinations were performed on all participants. In part II, ocular hyperemia grading and an ocular surface disease index (OSDI) questionnaire were performed. RESULTS: 24 HVs participated in part I and 21 patients in part II. KIO-101 eye drops were well tolerated in all subjects. No serious adverse events (SAEs) occurred, and all AEs that were reported were transient and considered mild to moderate. In the highest dose cohort (0.30%), epistaxis occurred in two subjects after multiple instillations. In part II, after 12 days treatment with 0.15% KIO-101, conjunctival hyperemia decreased by -1.1 ± 0.27 points in the treatment and -0.6 ± 0.79 points in the placebo group (p = 0.0385). OSDI decreased from 47.9 ± 18.7 to 27.6 ± 19.13 points in the treatment group, while in the placebo group, a change from 41.3 ± 12.08 to 27.3 ± 18.63 points occurred. CONCLUSIONS: A 12-day treatment regimen with topical KIO-101 eye drops at low and mid doses was safe and well tolerated in both HVs and patients with conjunctival hyperemia. The obtained results point towards an early sign of reduction in conjunctival hyperemia.

Bleb vessel density as a predictive factor for surgical revisions after Preserflo Microshunt implantation.

PURPOSE: Bleb failure is a common complication after glaucoma filtration surgery. Different bleb classification schemes incorporating filtration bleb vascularization have been proposed, but the reported correlation with intraocular pressure (IOP) has been variable, possibly because of subjective vascularization grading. The purpose of the present study was to evaluate bleb vascularization after Preserflo Microshunt (PM) implantation using anterior segment OCT-angiography (AS-OCTA) as a biomarker for bleb failure. METHODS: Twenty-three eyes of twenty-three patients underwent PM implantation. Up to 12 months after surgery PM scleral passage-centred AS-OCTA measurements (PLEX Elite 9000) for bleb-vessel density (BVD) determination were performed and IOP as well as necessity for surgical revisions (needling and open revision) were documented. After multi-step image analysis (region of interest definition, artefact removal, binarization, BVD calculation), the predictive value of early postoperative BVD for surgical revisions was assessed using logistic regression modelling. RESULTS: Baseline IOP (23.57 ± 7.75 mmHg) decreased significantly to 8.30 ± 2.12, 9.17 ± 2.33 and 11.70 ± 4.40 mmHg after 1, 2 and 4 week(s), and 13.48 ± 5.83, 11.87 ± 4.49, 12.30 ± 6.65, 11.87 ± 3.11 and 13.05 ± 4.12 mmHg after 2, 3, 6, 9 and 12 month(s), respectively (p < 0.001). Nine patients (39%) needed surgical revisions after a median time of 2 months. Bleb vessel densities at 2 and 4 weeks were significantly associated with future surgical revisions upon logistic regression analysis (2 W/4 W likelihood-ratio test p-value: 0.0244/0.0098; 2 W/4 W area under the receiver operating characteristics curve: 0.796/0.909). CONCLUSION: Filtration bleb vessel density can be determined using AS-OCTA in the early postoperative period and is predictive for bleb failure after PM implantation.

Effect of Treatment with Topical Azithromycin or Oral Doxycycline on Tear Film Thickness in Patients with Meibomian Gland Dysfunction: A Randomized Controlled Trial.

Purpose: This prospective, randomized, observer-masked, parallel-group study aimed to compare the effect of topical azithromycin and oral doxycycline on tear film thickness (TFT) and signs and symptoms of ocular surface disease (OSD) in patients with meibomian gland dysfunction (MGD). Methods: Patients were randomized to either receive topical azithromycin or oral doxycycline. After a baseline visit, three follow-up visits at intervals of 2 weeks were scheduled. Main outcome of the study was change in TFT as measured with ultrahigh resolution optical coherence tomography. Results: Twenty patients were included in the analysis. TFT significantly increased in both groups (P = 0.028 vs. baseline) with no difference between the groups (P = 0.096). As secondary outcomes, ocular surface disease index (OSDI) score and composite signs of OSD significantly decreased in both groups (P = 0.023 for OSDI and P = 0.016 for OSD signs vs. baseline). While eye-related adverse events (AEs) occurred more frequently in the azithromycin group, systemic AEs were more common in the doxycycline group. Conclusions: Both treatments improved signs and symptoms of OSD in patients with MGD with no difference between the groups. Due to the higher frequency of systemic side effects of doxycycline, azithromycin eye drops seem to be an alternative with comparable efficacy. Clinical Trial Registration number: NCT03162497.

Effect of Antibiotic Eye Drops on the Nasal Microbiome in Healthy Subjects-A Pilot Study.

BACKGROUND: Antibiotic eye drops are frequently used in clinical practice. Due to the anatomical connection via the nasolacrimal duct, it seems possible that they have an influence on the nasal/pharyngeal microbiome. This was investigated by using two different commonly used antibiotic eye drops. METHODS: 20 subjects were randomized to four groups of five subjects receiving eye drops containing gentamicin, ciprofloxacin, or, as controls, unpreserved povidone or benzalkonium chloride-preserved povidone. Nasal and pharyngeal swabs were performed before and after the instillation period. Swabs were analyzed by Illumina next-generation sequencing (NGS)-based 16S rRNA analysis. Bacterial culture was performed on solid media, and bacterial isolates were identified to the species level by MALDI-TOF MS. Species-dependent antimicrobial susceptibility testing was performed using single isolates and pools of isolates. RESULTS: Bacterial richness in the nose increased numerically from 163 ± 30 to 243 ± 100 OTUs (gentamicin) and from 114 ± 17 to 144 ± 45 OTUs (ciprofloxacin). Phylogenetic diversity index (pd) of different bacterial strains in the nasal microbiome increased from 12.4 ± 1.0 to 16.9 ± 5.6 pd (gentamicin) and from 10.2 ± 1.4 to 11.8 ± 3.1 pd (ciprofloxacin). Unpreserved povidone eye drops resulted in minimal changes in bacterial counts. Preservative-containing povidone eye drops resulted in no change. A minor increase (1-2-fold) in the minimal inhibitory concentration (MIC) was observed in single streptococcal isolates. CONCLUSIONS: Antibiotic eye drops could affect the nasal microbiome. After an instillation period of seven days, an increase in the diversity and richness of bacterial strains in the nasal microbiome was observed.

Neuro-vascular coupling and heart rate variability in patients with type II diabetes at different stages of diabetic retinopathy.

Aims/Hypothesis: There is evidence that diabetes is accompanied by a break-down of functional hyperemia, an intrinsic mechanism of neural tissues to adapt blood flow to changing metabolic demands. However, to what extent functional hyperemia is altered in different stages of diabetic retinopathy (DR) in patients with type II diabetes is largely unknown. The current study set out to investigate flicker-induced retinal blood flow changes in patients with type II diabetes at different stages of DR. Materials and methods: A total of 76 subjects were included in the present parallel-group study, of which 56 had diabetes with either no DR or different stages of non-proliferative DR (n = 29 no DR, 12 mild DR, 15 moderate to severe DR). In addition, 20 healthy subjects were included as controls. Retinal blood flow was assessed before and during visual stimulation using a combined measurement of retinal vessel calibers and blood velocity by the means of Doppler optical coherence tomography (OCT). To measure systemic autonomic nervous system function, heart rate variability (HRV) was assessed using a short-term orthostatic challenge test. Results: In healthy controls, retinal blood flow increased by 40.4 ± 27.2% during flicker stimulation. Flicker responses in patients with DR were significantly decreased depending on the stage of the disease (no DR 37.7 ± 26.0%, mild DR 26.2 ± 28.2%, moderate to severe DR 22.3 ± 13.9%; p = 0.035, ANOVA). When assessing systemic autonomous neural function using HRV, normalized low frequency (LF) spectral power showed a significantly different response to the orthostatic maneuver in diabetic patients compared to healthy controls (p < 0.001). Conclusion/Interpretation: Our study indicates that flicker induced hyperemia is reduced in patients with DR compared to healthy subjects. Further, this impairment is more pronounced with increasing severity of DR. Further studies are needed to elucidate mechanisms behind the reduced hyperemic response in patients with type II diabetes. Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT03 552562].

Retinal Oxygen Metabolism in Patients With Type 2 Diabetes and Different Stages of Diabetic Retinopathy.

The aim of this cross-sectional study was to assess retinal oxygen metabolism in patients with type 2 diabetes and different stages of nonproliferative diabetic retinopathy (DR) (n = 67) compared with healthy control subjects (n = 20). Thirty-four patients had no DR, 15 had mild DR, and 18 had moderate to severe DR. Retinal oxygen saturation in arteries and veins was measured using the oxygen module of a retinal vessel analyzer. Total retinal blood flow (TRBF) was measured using a custom-built Doppler optical coherence tomography system. Retinal oxygen extraction was calculated from retinal oxygen saturation and TRBF. Arteriovenous difference in oxygen saturation was highest in healthy subjects (34.9 ± 7.5%), followed by patients with no DR (32.5 ± 6.3%) and moderate to severe DR (30.3 ± 6.5%). The lowest values were found in patients with mild DR (27.3 ± 8.0%, P = 0.010 vs. healthy subjects). TRBF tended to be higher in patients with no DR (40.1 ± 9.2 µL/min) and mild DR (41.8 ± 15.0 µL/min) than in healthy subjects (37.2 ± 5.7 µL/min) and patients with moderate to severe DR (34.6 ± 10.4 µL/min). Retinal oxygen extraction was the highest in healthy subjects (2.24 ± 0.57 µL O2/min), followed by patients with no DR (2.14 ± 0.6 µL O2/min), mild DR (1.90 ± 0.77 µL O2/min), and moderate to severe DR (1.78 ± 0.57 µL O2/min, P = 0.040 vs. healthy subjects). These results indicate that retinal oxygen metabolism is altered in patients with type 2 diabetes. Furthermore, retinal oxygen extraction decreases with increasing severity of DR.

Combining vascular and nerve fiber layer thickness measurements to model glaucomatous focal visual field loss.

We compare the focal structure-function correlation of structural measurements of peripapillary retinal nerve fiber layer thickness (RNFL-T) using optical coherence tomography (OCT), capillary density (CD) measurements using OCT-angiography (OCT-A), or a combination of both, with visual field deviation (VFD) in early to advanced glaucoma. Primary open angle glaucoma patients (n = 46, mean ± SD age: 67 ± 10 years; VF mean deviation: -10.41 ± 6.76 dB) were included in this cross-sectional study. We performed 30-2 standard automated perimetry OCT (3.5-mm diameter ring scan) and 15°×15° OCT-A (superficial vascular complex slab). Based on a nerve fiber trajectory model, each VF test spot was assigned to an OCT-A wedge and an OCT ring-sector. Two univariate linear models (Mv and Mt ) using either CD-based vascular (Mv ) or RNFL-T-based thickness information (Mt ) and one multivariate model using both (Mv:t ) were compared in their associations with measured focal VFD, which were higher for the multivariate model Mv:t (mean ± SD correlation coefficient: 0.710 ± 0.086) than for either nested model (0.627 ± 0.078 for Mv and 0.578 ± 0.095 for Mt ). Using a focal visual field approach, the combination of RNFL-T and CD showed better structure-function correlations than thickness or vascular information only.

Effect of hyperoxia and hypoxia on retinal vascular parameters assessed with optical coherence tomography angiography.

PURPOSE: To investigate the response of the superficial and deep capillary plexuses to hyperoxia and hypoxia using optical coherence tomography angiography (OCT-A) and retinal vessel analyzer. METHODS: Twenty-four healthy volunteers participated in this randomized, double-masked, cross-over study. For each subject, two study days were scheduled: on one study day, hyperoxia was induced by breathing 100% oxygen whereas on the other study day, hypoxia was induced by breathing a mixture of 88% nitrogen and 12% oxygen. Perfusion density was calculated in the superficial vascular plexus (SVP) and the deep capillary plexus (DCP), using OCT-A before (normal breathing) and during breathing of the gas mixtures. Retinal vessel calibres in major retinal vessels were measured using a dynamic vessel analyzer. RESULTS: During 100% oxygen breathing, a significant decrease in DCP perfusion density from 41.7 ± 2.4 a.u to 35.6 ± 3.1 a.u. (p < 0.001) was observed, which was accompanied by a significant decrease in vessel diameters in major retinal arteries and veins (p < 0.001 each). No significant change in perfusion density in the SVP occurred (p = 0.33). In contrast, during hypoxia, perfusion density in the SVP significantly increased from 34.4 ± 3.0 a.u. to 37.1 ± 2.2 a.u. (p < 0.001), while it remained stable in the DCP (p = 0.25). A significant increase in retinal vessel diameters was found (p < 0.01). Systemic oxygen saturation correlated negatively with perfusion density in the SVP and the DCP and retinal vessel diameters (p < 0.005 each). CONCLUSION: Our results show that systemic hyperoxia induces a significant decrease in vessel density in the DCP, while hypoxia leads to increased vessel density limited to the SVP. These results indicate that the retinal circulation shows the ability to adapt its blood flow to metabolic changes with high local resolution dependent on the capillary plexus.

Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis.

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 µl O2/min), higher in MS-ON (2.1 ± 0.5 µl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 µl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 µl/min) compared to MS-ON (38.3 ± 4.6 µl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 µl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation. Clinical Trial Registration: ClinicalTrials.gov registry, NCT03401879.

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit's eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

The Effect of Orally Administered Low-Dose Dronabinol on Retinal Blood Flow and Oxygen Metabolism in Healthy Subjects.

Purpose: The present study was performed to investigate the effect of oral dronabinol, a synthetic tetrahydrocannabinol derivate, on retinal hemodynamics in healthy subjects in a randomized, double-masked, placebo-controlled, 2-way crossover design. Methods: Twenty-four subjects received 5 mg dronabinol on 1 study day and placebo on the other study day. Total retinal blood flow (TRBF) was measured using a custom-built Doppler Optical Coherence Tomography system. Oxygen saturation of major retinal vessels was measured with a commercially available Dynamic Vessel Analyzer. Based on these parameters, retinal oxygen extraction was calculated. Measurements were performed before and after drug administration on both study days. Results: Placebo had no effect on TRBF, retinal arterial or venous oxygen content, and retinal oxygen extraction (P > 0.1 each). In contrast, dronabinol induced a significant increase in TRBF from 38.9 ± 6.1 to 40.7 ± 6.7 µL/min (P < 0.001), which was accompanied by a significant increase in retinal venous oxygen content (from 0.129 ± 0.008 to 0.132 ± 0.009 mL O2/mL, P = 0.02). As no change in retinal arterial oxygen content occurred (P = 0.12), retinal oxygen extraction remained stable (2.2 ± 0.4 µL vs. 2.2 ± 0.4 µL O2/min, P = 0.29). Conclusions: These results indicate that orally administered dronabinol increases TRBF in healthy subjects without altering retinal oxygen extraction. The drug may therefore be a candidate for improving perfusion in patients with ocular vascular disease.

Plexus-specific effect of flicker-light stimulation on the retinal microvasculature assessed with optical coherence tomography angiography.

In neural tissues, the coupling between neural activity and blood flow is a physiological key principle in blood flow regulation. We used optical coherence tomography angiography to investigate stimulus-evoked hemodynamic responses in different microvascular layers of the human retina. Twenty-two healthy subjects were included. Vessel density before and during light stimulation was measured using optical coherence tomography angiography and assessed for the superficial, intermediate, and deep capillary plexus of the retinal circulation. Volumetric blood flow was measured using a custom-built Doppler optical coherence tomography system. Our results show that flicker stimulation induced a significant increase in the vessel density of +9.9 ± 6.7% in the superficial capillary plexus, +6.6 ± 1.7% in the intermediate capillary plexus, and +4.9 ± 2.3% in the deep capillary plexus. The hyperemic response of the superficial capillary plexus was significantly higher compared to the intermediate capillary plexus (P = 0.02) and deep capillary plexus (P = 0.002). Volumetric retinal blood flow increased by +39.9 ± 34.9% in arteries and by +29.8 ± 16.8% in veins. In conclusion, we showed a strong increase in the retinal microvascular density in response to light stimulation, with the most pronounced effect in the superficial capillary plexus. This is compatible with the hypothesis that the microvasculature exerts an important function in mediating functional hyperemia in humans.NEW & NOTEWORTHY We present vessel density alterations in response to flicker stimulation using optical coherence tomography angiography and identified the superficial capillary plexus as the layer with the most pronounced effect. This points out the physiological importance of the microvasculature in mediating functional hyperemia and suggests a fine-tuned plexus-specific mechanism to meet cellular metabolic demands.

Repeatability and Reproducibility of Total Retinal Blood Flow Measurements Using Bi-Directional Doppler OCT.

Purpose: To investigate the repeatability and reproducibility of total retinal blood flow measurements using a custom-built dual-beam bidirectional Doppler optical coherence tomography (OCT) system in healthy subjects. Methods: Repeatability and reproducibility were analyzed in 10 and 34 healthy subjects, respectively. For repeatability, measurements were taken twice within 30 minutes, for reproducibility, twice within two to five weeks. Two analysis approaches were compared for calculation of absolute blood velocities: a previously published approach resulting in values for total arterial (QA,abs) and total venous blood flow (QV,abs) and a novel approach taking into account that there is a fixed relation between the phase shift in the two OCT channels (QA,new, QV,new). Repeatability and reproducibility were quantified using intraclass correlation coefficients (ICCs). Results: For QA,abs and QV,abs, ICC values between 0.78 and 0.84 were obtained. QA,new and QV,new values revealed better repeatability and reproducibility as compared to the convential appoach. Repeatability ICCs for QA,new and QV,new were between 0.91 and 0.93, and reproducibility ICCs were between 0.87 and 0.91 indicating excellent reproducibility. Good agreement was observed between total retinal blood flow values as measured from retinal arteries and retinal veins. Conclusions: Measurement of total retinal blood flow using dual-beam Doppler OCT shows excellent reproducibility, which can further be improved by using a novel algorithm for calculating blood velocities in retinal vessels. Translational Relevance: Our data indicate that dual-beam Doppler OCT can be used for longitudinal studies. Hence, quantitative retinal blood flow may be established as a biomarker for progression vascular eye diseases.

Changes in Retinal Blood Flow in Response to an Experimental Increase in IOP in Healthy Participants as Assessed With Doppler Optical Coherence Tomography.

Purpose: Blood flow autoregulation is an intrinsic mechanism of the healthy retinal vasculature to keep blood flow constant when ocular perfusion pressure (OPP) is changed. In the present study, we set out to investigate retinal blood flow in response to an experimental decrease in OPP in healthy participants using Doppler optical coherence tomography. Methods: Fifteen healthy participants aged between 22 and 31 years (mean, 27 ± 3 years) were included in the present open study. IOP was increased stepwise via the suction cup method to induce a decrease in OPP. Retinal blood flow in arteries and veins was assessed using a custom-built Doppler optical coherence tomography system and pressure-flow relationships were calculated to assess autoregulation. Results: Suction cup application induced a pronounced increase in IOP with a maximum value of 50.5 ± 8.0 mm Hg at the highest level of suction. Pressure-flow relationships revealed that blood flow was autoregulated until the OPP was decreased by approximately 21 mm Hg and started to decrease significantly when the OPP was reduced by 30 mm Hg. Retinal blood flow at the last suction period decreased at a maximum of -57.0 ± 22.3% and 65.2 ± 15.4% in retinal arteries and retinal veins, respectively. These changes in retinal blood flow were less pronounced than the decrease in OPP (-75.2 ± 19.2%), indicating retinal autoregulation. Conclusions: The results of the present study confirm that retinal blood flow is autoregulated in response to changes in the OPP. Doppler optical coherence tomography has the potential to become a clinical tool for the investigation of retinal blood flow autoregulation in the future, because of its ability to assess the blood velocities and diameter of the retinal vessels parallel and therefore also their blood flow in absolute values. (Clinicaltrials.gov number NCT03398616).

The Effect of Orally Administered Dronabinol on Optic Nerve Head Blood Flow in Healthy Subjects-A Randomized Clinical Trial.

It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics. The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects. The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in 24 healthy subjects. For each study participant, 2 study days were scheduled, on which they either received capsules containing 5 mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for 6 minutes to increase mean arterial blood pressure (MAP). This was repeated 1 hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP. Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported. Neither administration of dronabinol nor placebo had an effect on IOP, MAP, or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5 ± 8.1%, whereas placebo did not show a change in ONHBF (0.3 ± 7.4% vs. baseline, P < 0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise. In conclusion, the present data indicate that low-dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP, or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in patients with glaucoma.

Topical Low Dose Preservative-Free Hydrocortisone Reduces Signs and Symptoms in Patients with Chronic Dry Eye: A Randomized Clinical Trial.

PURPOSE: Dry eye disease (DED) is a highly prevalent ocular condition with a significant burden on affected patients. Regardless of the underlying etiology, DED is associated with increased ocular surface inflammation. We investigated the safety and efficacy of a short-term treatment with topical low dose hydrocortisone in patients with chronic DED and ocular surface inflammation. METHODS: A total of 60 patients (mean age 51 ± 14 years) with chronic DED and conjunctival hyperemia greater than grade 2 on the Efron scale were included. Patients were randomized to receive either preservative-free hydrocortisone 0.335% (Softacort, Laboratories Thea, France) for 12 days four times daily followed by 2 days twice daily instillation (intense treatment group) or 8 days three times daily followed by 3 days twice daily treatment (standard treatment group). Ocular redness was assessed at baseline, day 14, and day 28. Measurement of intraocular pressure (IOP) and clinical tests to assess signs and symptoms of DED were performed. RESULTS: Conjunctival hyperemia and Ocular Surface Disease Index (OSDI) significantly decreased in both treatment groups (p < 0.001 each) after hydrocortisone treatment. A significant increase in tear film thickness was seen 4 weeks after treatment start (p = 0.03 and p = 0.04, respectively). IOP did not change in either of the two treatment groups (p = 0.45). CONCLUSION: Treatment with low dose hydrocortisone 0.335% reduced ocular inflammation and decreased OSDI score. No change in IOP was observed in either of the two treatment schedules. Because of its good safety profile, low dose hydrocortisone may be an interesting alternative to standard corticosteroid treatment in DED. FUNDING: Laboratories Thea. TRIAL REGISTRATION: Clinicaltrials.gov registry: NCT03907865.

Correction to: Topical Low Dose Preservative-Free Hydrocortisone Reduces Signs and Symptoms in Patients with Chronic Dry Eye: A Randomized Clinical Trial.

The article "Topical Low Dose Preservative-Free Hydrocortisone Reduces Signs and Symptoms in Patients with Chronic Dry Eye: A Randomized Clinical Trial", written by Martin Kallab, Stephan Szegedi, Nikolaus Hommer, Hannes Stegmann, Semira Kaya, René M. Werkmeister, Doreen Schmidl, Leopold Schmetterer, Gerhard Garhöfer was originally published electronically on the publisher's internet portal (currently SpringerLink) on November 19, 2019 without open access.

The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy.

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder that has no cure and very limited treatment options. MSA is characterized by deposition of fibrillar α-synuclein (α-syn) in glial cytoplasmic inclusions in oligodendrocytes. Similar to other synucleinopathies, α-syn self-assembly is thought to be a key pathologic event and a prominent target for disease modification in MSA. Molecular tweezers are broad-spectrum nanochaperones that prevent formation of toxic protein assemblies and enhance their clearance. The current lead compound, CLR01, has been shown to inhibit α-syn aggregation but has not yet been tested in the context of MSA. To fill this gap, here, we conducted a proof-of-concept study to assess the efficacy of CLR01 in remodeling MSA-like α-syn pathology in the PLP-α-syn mouse model of MSA. Six-month-old mice received intracerebroventricular CLR01 (0.3 or 1 mg/kg per day) or vehicle for 32 days. Open-field test revealed a significant, dose-dependent amelioration of an anxiety-like phenotype. Subsequently, immunohistochemical and biochemical analyses showed dose-dependent reduction of pathological and seeding-competent forms of α-syn, which correlated with the behavioral phenotype. CLR01 treatment also promoted dopaminergic neuron survival in the substantia nigra. To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development.

Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy.

Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated α-synuclein. α-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting α-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting α-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial α-synucleinopathy. We used PLP-α-synuclein mice overexpressing human α-synuclein in oligodendrocytes. The animals received either antibodies that recognize α-synuclein or vehicle. Passive immunization mitigated α-synuclein pathology and resulted in reduction of total α-synuclein in the hippocampus, reduction of intracellular accumulation of aggregated α-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric α-synuclein was associated with reduction of the density of activated iba1-positive microglia profiles. However, a shift toward phagocytic microglia was seen after passive immunization of PLP-α-synuclein mice. Lowering of intracellular α-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-α-synuclein mice. In summary, the study provides evidence for the biological efficacy of immunotherapy in a transgenic mouse model of oligodendroglial synucleinopathy. The different availability of the therapeutic antibodies and the variable load of α-synuclein pathology in selected brain regions resulted in differential effects of the immunotherapy that allowed us to propose a model of the underlying mechanisms of antibody-aided α-synuclein clearance.