Plasma Instead of Serum Avoids Critical Confounding of Clinical Metabolomics Studies by Platelets.

Metabolomics is an emerging and powerful bioanalytical method supporting clinical investigations. Serum and plasma are commonly used without rational prioritization. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may affect the metabolome and increase the variance, as platelet counts and function may vary substantially in individuals. A multiomics approach systematically investigating the suitability of serum and plasma for clinical studies demonstrated that metabolites correlated well (n = 461, R2 = 0.991), whereas lipid mediators (n = 83, R2 = 0.906) and proteins (n = 322, R2 = 0.860) differed substantially between specimen. Independently, analysis of platelet releasates identified most biomolecules significantly enriched in serum compared to plasma. A prospective, randomized, controlled parallel group metabolomics trial with acetylsalicylic acid administered for 7 days demonstrated that the apparent drug effects significantly differ depending on the analyzed specimen. Only serum analyses of healthy individuals suggested a significant downregulation of TXB2 and 12-HETE, which were specifically formed during coagulation in vitro. Plasma analyses reliably identified acetylsalicylic acid effects on metabolites and lipids occurring in vivo such as an increase in serotonin, 15-deoxy-PGJ2 and sphingosine-1-phosphate and a decrease in polyunsaturated fatty acids. The present data suggest that plasma should be preferred above serum for clinical metabolomics studies as the serum metabolome may be substantially confounded by platelets.

Associations of retinal neurovascular dysfunction with inner retinal layer thickness in non-proliferative diabetic retinopathy.

PURPOSE: Neurovascular coupling impairment and inner retinal layer thinning are early detectable retinal changes in diabetes, and both worsen during progression of diabetic retinopathy (DR). However, direct interactions between these features have not been investigated so far. Therefore, we aimed to analyze associations between the retinal functional hyperemic response to light stimulation and the thickness of individual neuroretinal layers in eyes with early non-proliferative DR. METHODS: Thirty patients with type 1 diabetes featuring mild (n = 15) or moderate (n = 15) non-proliferative DR and 14 healthy subjects were included in this cross-sectional study. Retinal vessel diameters were measured before and during illumination with flickering light using a dynamic vessel analyzer. Individual layer thickness in the macula was analyzed from spectral domain optical coherence tomography. RESULTS: Flicker light-induced vessel dilation was significantly reduced in patients compared to healthy controls (veins: 3.0% vs. 6.1%, p < 0.001; arteries: 1.3% vs. 5.1%, p = 0.005). Univariately, the response in retinal veins of diabetes patients correlated significantly with ganglion cell layer (GCL) thickness (r = 0.46, p = 0.010), and negatively with hemoglobin A1c (HbA1c) levels (r=-0.41, p = 0.023) and age (r=-0.38, p = 0.037), but not with baseline diameters, glucose levels, or diabetes duration. In a multiple regression model only GCL thickness (p = 0.017, ß = 0.42) and HbA1c (p = 0.045, ß=-0.35) remained significantly associated with the vascular flicker light response. CONCLUSION: The results indicate that thinner GCL and worse glycemic control both contribute to reduced retinal neurovascular coupling in patients with clinical signs of DR. Progression of neurovascular dysfunction in DR might be related to structural degeneration of the neurovascular complex in the inner retina.

An Exploratory Retrospective Data Analysis Comparing the Outcomes of Selective Laser Trabeculoplasty and Argon Laser Trabeculoplasty in Patients with Open-Angle Glaucoma or Ocular Hypertension in Vienna, Austria, from the Year 2012 to 2022.

Background and Objectives: The aim of the present study was to compare the short-term outcomes of selective laser trabeculoplasty (SLT) with argon laser trabeculoplasty (ALT) in patients with glaucoma in a real-world setting. Materials and Methods: The present study was conducted as a retrospective case-control study. The main outcome was the change in intraocular pressure (IOP) three months after laser surgery. In addition, the number of substances used for lowering of IOP and adverse events (AEs) were assessed. Results: Charts from 25 patients were included in the present study, of which 12 had received ALT and 13 SLT. In both groups, IOP significantly decreased from baseline values 6 weeks and 3 months after laser treatment (p < 0.01 vs. baseline at each timepoint for both groups). While after 6 weeks, no difference between groups was found, after 3 months, the decrease in IOP was significantly more pronounced in the SLT group (-26 ± 21% in the ALT group vs. -41 ± 14% in the SLT group, p = 0.018 between groups, ANOVA). Three months after laser treatment, the number of IOP-lowering substances used by each patient had decreased with no difference between groups (ALT: from 2.7 ± 0.8 to 2.3 ± 0.9 substances; SLT: from 1.8 ± 1.2 to 1.3 ± 1.1 substances, p = 0.386). Only a few AEs were observed. Two patients in the ALT and one patient in the SLT group required trabeculectomy within 1 year after laser treatment due to IOP decompensation. Conclusions: In the present study, SLT was at least as effective as ALT with fewer AEs and a similar reduction in concomitant IOP-lowering medication.

Retinal Oxygen Extraction in Patients with Primary Open-Angle Glaucoma.

Objective: To compare total retinal oxygen extraction between patients with primary open-angle glaucoma (POAG) and healthy control subjects. Design: A prospective, single-center, cross-sectional, case−control study performed at the Medical University of Vienna. Subjects: Forty patients with POAG and 40 age- and sex-matched control subjects. Methods: Total retinal blood flow was measured using Doppler optical coherence tomography (OCT). Retinal arterial and venous oxygen saturation was measured using reflectance spectroscopy. From these parameters, oxygen content in the retinal arterial and venous circulation as well as total retinal oxygen extraction were calculated. Results: Total retinal blood flow was lower in POAG (25.2 ± 6.7 µL/min) as compared to healthy control subjects (35.6 ± 8.3 µL/min, p < 0.001). Retinal arterial oxygen content was not different between the two groups (0.18 ± 0.01 mL(O2)/mL in both groups, p < 0.761), but retinal venous oxygen content was higher in POAG (0.15 ± 0.01 mL(O2)/mL) than in healthy controls (0.14 ± 0.01 mL(O2)/mL p < 0.001). Accordingly, retinal oxygen extraction was reduced in POAG (0.8 ± 0.3 µL(O2)/min as compared to healthy controls: 1.4 ± 0.4 µL(O2)/min, p < 0.001). There was a significant association between total retinal blood flow and total retinal oxygen extraction with measures of structural and functional damage (p < 0.001 each). Conclusions: This study indicates that POAG is associated with a reduction in total retinal oxygen extraction linked to structural and functional damage of the disease. Since the technology is non-invasive, it allows for longitudinal studies investigating to which degree low retinal oxygen extraction is linked to the progression of the 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.

A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes.

Purpose: The aim of the present study was to investigate the effect of a three-month dietary supplementation with a methylfolate formulation on homocysteine plasma concentrations and ocular blood flow parameters in patients with diabetes. Methods: Twenty-four patients with diabetes received a dietary supplement (Oculofolin, Aprofol AG, Switzerland) containing 900 µg L­methylfolate (levomefolate calcium or [6S]-5-methyltetrahydrofolic acid, calcium salt), methylcobalamin, and other ingredients for three consecutive months. The patients' plasma homocysteine concentration and retinal blood flow were assessed at baseline and after three months of folate intake. Retinal blood flow was measured using a custom-built dual-beam Doppler optical coherence tomography (OCT) system. In addition, flicker-induced retinal vasodilatation was assessed by means of a commercially available dynamic vessel analyzer (IMEDOS, Jena, Germany). Results: Supplementation was well tolerated by all patients. After three months, plasma homocysteine concentration significantly decreased from 14.2 ± 9.3 to 9.6 ± 6.6 µmol/L (p < 0.001). In addition, a tendency toward an increased total retinal blood flow from 36.8 ± 12.9 to 39.2 ± 10.8 µl/min was observed, but this effect did not reach the level of significance (p = 0.11). Supplementation had no effect on retinal vessel diameter or flicker-induced vasodilatation. Conclusions: The present data show that a three-month intake of a dietary supplement containing methylfolate can significantly reduce blood homocysteine levels in patients with diabetes. This is of importance because higher homocysteine plasma levels have been found to be associated with an increased risk of vascular associated systemic diseases and eye diseases. Whether systemic methylfolate supplementation affects retinal perfusion must be studied in a larger population.

[Cornea Imaging by Optical Coherence Tomography - Historical Aspects and Most Recent Technical Developments]. / Bildgebung in der Kornea mittels optischer Kohärenztomografie ­ historische Entwicklung und neueste technische Fortschritte.

Since its introduction for retinal imaging in the early 1990s, optical coherence tomography (OCT) has undergone rapid development and has revolutionised ophthalmology. Although OCT was initially used mainly for the examination of the retina, numerous systems for the assessment of the anterior segment of the eye have now been developed. OCT is based on the detection and processing of the light back-scattered and back-reflected by the tissue, and provides completely new possibilities for the ophthalmologist to examine the structures of the anterior eye segment. Depending on the technical implementation, OCT systems for the anterior eye allow precise measurement of individual layers of the cornea and the chamber angle or - in the form of ultrahigh resolution OCT - the detailed visualisation of corneal morphology with near histological resolution. Through further technical developments, especially with respect to an increase in acquisition speeds, OCT has become an essential tool in the differential diagnosis and follow-up of various diseases of the cornea and might also provide new insights into their pathophysiology.

Retinal oxygen extraction in individuals with type 1 diabetes with no or mild diabetic retinopathy.

AIMS/HYPOTHESIS: The aim of this study was to compare retinal oxygen extraction in individuals with diabetes with no or mild non-proliferative diabetic retinopathy and healthy age- and sex-matched volunteers. METHODS: A total of 24 participants with type 1 diabetes and 24 healthy age- and sex-matched volunteers were included in this cross-sectional study. Retinal oxygen extraction was measured by combining total retinal blood flow measurements using a custom-built bi-directional Doppler optical coherence tomography system with measurements of oxygen saturation using spectroscopic reflectometry. Based on previously published mathematical modelling, the oxygen content in retinal vessels and total retinal oxygen extraction were calculated. RESULTS: Total retinal blood flow was higher in diabetic participants (46.4 ± 7.4 µl/min) than in healthy volunteers (40.4 ± 5.3 µl/min, p = 0.002 between groups). Oxygen content in retinal arteries was comparable between the two groups, but oxygen content in retinal veins was higher in participants with diabetes (0.15 ± 0.02 ml O2/ml) compared with healthy control participants (0.13 ± 0.02 ml O2/ml, p < 0.001). As such, the arteriovenous oxygen difference and total retinal oxygen extraction were reduced in participants with diabetes compared with healthy volunteers (total retinal oxygen extraction 1.40 ± 0.44 vs 1.70 ± 0.47 µl O2/min, respectively, p = 0.03). CONCLUSIONS/INTERPRETATION: Our data indicate early retinal hypoxia in individuals with type 1 diabetes with no or mild diabetic retinopathy as compared with healthy control individuals. Further studies are required to fully understand the potential of the technique in risk stratification and treatment monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT01843114.

In vivo tear film thickness measurement and tear film dynamics visualization using spectral domain optical coherence tomography.

Dry eye syndrome is a highly prevalent disease of the ocular surface characterized by an instability of the tear film. Traditional methods used for the evaluation of tear film stability are invasive or show limited repeatability. Here we propose a new non-invasive fully automated approach to measure tear film thickness based on spectral domain optical coherence tomography and on an efficient delay estimator. Silicon wafer phantom were used to validate the thickness measurement. The technique was applied in vivo in healthy subjects. Series of tear film thickness maps were generated, allowing for the visualization of tear film dynamics. Our results show that the in vivo central tear film thickness measurements are precise and repeatable with a coefficient of variation of about 0.65% and that repeatable tear film dynamics can be observed. The presented approach could be used in clinical setting to study patients with dry eye disease and monitor their treatments.

Regulation of retinal oxygen metabolism in humans during graded hypoxia.

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O2 in 88% N2 as well as breathing 15% O2 in 85% N2. Oxygen saturation in a retinal artery (SO2art) and an adjacent retinal vein (SO2vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% (P < 0.001) and 30.0 ± 20.9% (P < 0.001) during 12% and 15% O2 breathing, respectively. SO2art as well as SO2vein decreased during both 12% O2 breathing (SO2art: -11.2 ± 4.3%, P < 0.001; SO2vein: -3.9 ± 8.5%, P = 0.012) and 15% O2 breathing (SO2art: -7.9 ± 3.6%, P < 0.001; SO2vein: -4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: -28.9 ± 18.7%; 15% O2: -19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O2: -2.8 ± 18.9%, P = 0.65; 15% O2: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.

Repeatability of biometry in patients with meibomian gland dysfunction before and after vectored thermal pulsation therapy: A randomized, controlled trial.

PURPOSE: To evaluate the effect of vectored thermal pulsation therapy (VTPT) on the repeatability of biometry readings of two different optical biometers in patients with meibomian gland dysfunction (MGD). METHODS: Patients affected by MGD were included in this prospective, randomized, controlled, investigator-masked study. One eye was randomized to VTPT (LipiFlow®, Johnson & Johnson), and the contralateral eye served as a control. Three visits were scheduled at baseline, 2 weeks and 3 months after the treatment. The main outcome parameter of the study was the repeatability of three calculations of emmetropic intraocular lens power (EIOLP) at the 3 months visit as compared to baseline using an optical biometer (IOLMaster® 700, Carl Zeiss Meditec AG). Repeatability of different keratometry values obtained by the optical biometer and a Placido-disc topographer (MS-39®, CSO) served as secondary outcome parameters. RESULTS: Twenty-nine patients were included in the final analysis. While tear film parameters improved in the study eyes, there were no significant differences regarding the repeatability of three EIOLP measurements between baseline and 3-months-visit in both eyes (p > 0.05) and keratometry measurements in both the optical biometer and the Placido-disc topographer. Remarkably, throughout all study visits, there were some outliers regarding the repeatability of measurements. CONCLUSION: While both devices showed high repeatability regarding EIOLP and keratometry, future studies are needed to detect high-risk patients for poor repeatability.

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.

The Impact of Photopigment Bleaching on the Human Rod Photoreceptor Subretinal Space Measured Via Optical Coherence Tomography.

Purpose: The purpose of this study was to investigate rod photopigment bleaching-driven intrinsic optical signals (IOS) in the human outer retina and its measurement repeatability based on a commercial optical coherence tomography (OCT) platform. Methods: The optical path length of the rod photoreceptor subretinal space (SRS), that is, the distance between signal bands of rod outer segment tips and retinal pigment epithelium, was measured in 15 healthy subjects in ambient light and during a long-duration bleaching white-light exposure. Results: On 2 identical study days (day 1 and day 2 [D1 and D2]), light stimulation resulted in a significant decrease in rod SRS by 21.3 ± 7.6% and 19.8 ± 8.5% (both P < 0.001), respectively. The test-retest reliability of the SRS maximum change of an individual subject was moderate for single measures (intraclass correlation coefficient [ICC] = 0.730, 95% confidence interval [CI] = 0.376, 0.900, P < 0.001) and good for average measures (ICC = 0.844, 95% CI = 0.546, 0.947, P < 0.001). The mean area under the stimulus response curve with values of 14.8 ± 9.4 and 15.5 ± 7.5 µm × minutes (P = 0.782) showed excellent agreement between the stimulus response on D1 and D2. Intermittent dark adaptation of the retina led to an initial increase of the SRS by 6.1% (P = 0.018) and thereafter showed a decrease toward baseline, despite continued dark adaptation. Conclusions: The data indicate the potential of commercial OCT in measuring slow IOS in the outer retina suggesting that the rod SRS could serve as a biomarker for photoreceptor function. The presented approach could provide an easily implementable clinical tool for the early detection of diseases affecting photoreceptor health.

Impaired retinal oxygen metabolism and perfusion are accompanied by plasma protein and lipid alterations in recovered COVID-19 patients.

The aim of the present study was to investigate retinal microcirculatory and functional metabolic changes in patients after they had recovered from a moderate to severe acute COVID-19 infection. Retinal perfusion was quantified using laser speckle flowgraphy. Oxygen saturation and retinal calibers were assessed with a dynamic vessel analyzer. Arterio-venous ratio (AVR) was calculated based on retinal vessel diameter data. Blood plasma samples underwent mass spectrometry-based multi-omics profiling, including proteomics, metabolomics and eicosadomics. A total of 40 subjects were included in the present study, of which 29 had recovered from moderate to severe COVID-19 within 2 to 23 weeks before inclusion and 11 had never had COVID-19, as confirmed by antibody testing. Perfusion in retinal vessels was significantly lower in patients (60.6 ± 16.0 a.u.) than in control subjects (76.2 ± 12.1 a.u., p = 0.006). Arterio-venous (AV) difference in oxygen saturation and AVR was significantly lower in patients compared to healthy controls (p = 0.021 for AVR and p = 0.023 for AV difference in oxygen saturation). Molecular profiles demonstrated down-regulation of cell adhesion molecules, NOTCH3 and fatty acids, and suggested a bisphasic dysregulation of nitric oxide synthesis after COVID-19 infection. The results of this study imply that retinal perfusion and oxygen metabolism is still significantly altered in patients well beyond the acute phase of COVID-19. This is also reflected in the molecular profiling analysis of blood plasma, indicating a down-regulation of nitric oxide-related endothelial and immunological cell functions.Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT05650905.

Role of endothelin-A receptors in optic nerve head red cell flux regulation during isometric exercise in healthy humans.

Endothelin-1 (ET-1) is an important regulator of vascular tone in the eye. It appears to play a role in ocular disease because of its strong vasoconstrictor action, its role in intraocular pressure homeostasis, and its neurotoxic potential. We have previously shown that ET-1 is involved in choroidal red cell flux (RCF) regulation during isometric exercise in healthy humans. In the present study we hypothesized that ET-1 also plays a role in optic nerve head (ONH) RCF regulation during isometric exercise. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, two-way crossover study in 15 healthy volunteers. Subjects were randomized to receive intravenous infusions of the specific endothelin type A receptor antagonist BQ-123 and placebo on two different study days. During these infusion periods, subjects performed squatting for 6 min to increase ocular perfusion pressure (OPP). ONH RCF was assessed with laser-Doppler flowmetry, and OPP was calculated from mean arterial pressure and intraocular pressure. BQ-123 did not change OPP or ONH RCF at baseline. The relative increase in OPP during isometric exercise was comparable between both groups (between 84 and 88%, P = 0.76 between groups; P < 0.001 vs. baseline). Isometric exercise increased ONH RCF during placebo and BQ-123, but the increase was more pronounced when the endothelin type-A receptor antagonist was administered (placebo, 27.3 ± 5.4%; and BQ-123, 39.2 ± 4.4%; P = 0.007 between groups). The present data indicate that ET-1 regulates red cell flux in the ONH beyond the autoregulatory range.

Role of nitric oxide in optic nerve head blood flow regulation during an experimental increase in intraocular pressure in healthy humans.

The present study set out to investigate whether nitric oxide, a potent vasodilator, is involved in the regulatory processes in optic nerve head blood flow during an experimental increase in intraocular pressure (IOP). The study was conducted in a randomized, double-masked, placebo-controlled, three way cross-over design. 12 healthy subjects were scheduled to receive either L-NMMA (an unspecific nitric oxide synthase inhibitor), phenylephrine (an α-adrenoceptor agonist) or placebo on three different study days. Optic nerve head blood flow was measured using laser Doppler flowmetry and IOP was increased stepwise with a suction cup. Mean arterial pressure (MAP) and IOP were measured non-invasively and ocular perfusion pressure (OPP) was calculated as OPP = 2/3 MAP-IOP. Administration of L-NMMA and phenylephrine significantly increased MAP and therefore OPP at rest (p < 0.01). L-NMMA significantly reduced baseline blood flow in the optic nerve head (p < 0.01). Application of the suction cup induced a significant increase in IOP and a decrease in OPP (p < 0.01). During the stepwise increase in IOP, some autoregulatory potential was observed until OPP decreased approximately -30% below baseline. None of the administered substances had an effect on this autoregulatory behavior (p = 0.49). The results of the present study confirm that the human optic nerve head shows some regulatory capacity during a decrease in OPP. Nitric oxide is involved in the regulation of basal vascular tone in the optic nerve head but does not seem to be involved in the regulatory mechanisms during an acute increase in IOP in young healthy subjects.

Effects of orally administered moxaverine on ocular blood flow in healthy subjects.

BACKGROUND: To investigate the effect of orally administered moxaverine (Kollateral forte®) on ocular blood flow in young healthy subjects. METHODS: Sixteen healthy subjects (eight male/eight female) aged between 20 and 32 years were included in this placebo-controlled, double-masked, two-way crossover study. Volunteers received 900 mg moxaverine-hydrochloride administered orally in three equal doses or placebo identical in appearance on 2 study days. Outcome variables were measured at baseline and 5 h after first drug administration. Laser Doppler flowmetry was used to assess choroidal and optic nerve head blood flow. Blood velocities in the retrobulbar vessels were measured with color Doppler imaging. RESULTS: Neither moxaverine nor placebo changed mean arterial pressure or intraocular pressure. Neither moxaverine nor placebo had an effect on choroidal (moxaverine: by 9.5 ± 17.2 %, placebo 3.8 ± 18.8 %, p = 0.54 between groups) or optic nerve head blood flow (moxaverine: 4.8 ± 10.4 %, placebo: 1.8 ± 10.9 %, p = 0.52 between groups). Similarly, administration of moxaverine did not change blood flow velocities or calculated resistance index in the retrobulbar vessels compared to placebo. CONCLUSION: The data of the present study indicate that orally administered moxaverine does not increase ocular blood flow. This is in contrast to previous findings, where parenteral administration of moxaverine lead to a significant increase in choroidal blood flow and blood flow velocities in the retrobulbar vessels. The reason for these differing results is unclear, but may be related to the low bioavailability after oral administration.

Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route.

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC(0-t) geometric means ratios were within the pre-specified 80-125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.

Classification of Tear Film Lipid Layer En Face Maps Obtained Using Optical Coherence Tomography and Their Correlation With Clinical Parameters.

PURPOSE: The purpose of this study was to investigate the correlation between the pattern of optical coherence tomography (OCT) en face maps of the tear film lipid layer (TFLL) and lipid layer thickness (LLT), fluorescein breakup time (FBUT), and Schirmer I test values in healthy subjects. METHODS: Measurements from four clinical data sets were retrospectively analyzed, and TFLL patterns were classified into 3 categories: homogeneous (HOM), wavy (WAV), or dotted (DOT) appearance. Linear mixed model analyses were performed. Intraclass correlation coefficients and index of qualitative variation were computed to investigate interrater and intrasubject variabilities. RESULTS: For the LLT, a significant difference between HOM and DOT ( P < 0.001, ß HOMvsDOT = -6.42 nm) and WAV and DOT ( P = 0.002, ß WAVvsDOT = -4.04 nm) was found. Furthermore, the difference between WAV and DOT regarding FBUT ( P < 0.001, ß WAVvsDOT = -3.065 seconds) was significant, while no significant differences between any of the classes with respect to the Schirmer I test values were found. An intraclass correlation coefficient of 89.0% reveals a good interrater reliability, and an index of qualitative variation of 60.0% shows, on average, a considerable variability in TFLL pattern class for repeated measurements over 1 hour. CONCLUSIONS: A new classification method for OCT en face maps of the TFLL is presented. Significant differences between patterns were found with respect to LLT and FBUT. A dotted pattern on dark background appears to be the most stable type of TFLL. The analysis of OCT en face maps of the TFLL provides complimentary information to conventional imaging methods and might give new insights into the characteristics of the TFLL.

Therapeutic Potential of Cannabinoids in Glaucoma.

Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB1 and CB2, knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.