Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK.

PURPOSE: To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution. METHODS: Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B). RESULTS: TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect. CONCLUSIONS: Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

EXTENT AND LOCATION OF INTRARETINAL AND SUBRETINAL FLUID AS PROGNOSTIC FACTORS FOR THE OUTCOME OF PATIENTS WITH OPTIC DISK PIT MACULOPATHY.

PURPOSE: To determine if baseline fundoscopic and optical coherence tomography (OCT) features influence the clinical course of optic disk pit maculopathy. METHODS: A multicenter retrospective case note review was undertaken, using standardized OCT and clinical data collection. Visual success was defined as at least a two-line visual acuity improvement, anatomical success as full resolution of OCT foveal fluid with restoration of the normal foveal contour, and partial anatomical success as incomplete resolution of the OCT foveal fluid. Outcomes were compared with a synthesis of the literature, using similar eligibility criteria. RESULTS: Of 36 patients (36 eyes), 2 spontaneously improved and 34 underwent surgery. Visual success was achieved in 64% of surgical cases, anatomical success in 36%, and partial anatomical success in 47%. Cases with multilayer intraretinal and subretinal fluid were less likely to have visual success (P = 0.003). Cases where the fluid did not extend to the macular arcade vessels also had better visual and anatomical outcomes (P = 0.004 and 0.005, respectively). CONCLUSION: Fundoscopic and OCT features can help predict surgical outcome in optic disk pit maculopathy.

Outcomes of suprachoroidal haemorrhage drainage with and without vitrectomy: a 10-year study.

PURPOSE: The management of suprachoroidal haemorrhage (SCH) remains a challenge. We aimed to analyse and discuss the safety and efficacy outcomes of SCH drainage surgery over a 10-year period in one of the largest tertiary centres in the UK. METHODS: Retrospective observational study of consecutive patients who underwent SCH drainage in Manchester Royal Eye Hospital over a 10-year period (from 2008 to 2018). Safety and efficacy were assessed by analysing surgery-related complications and functional and anatomical success. Outcomes of those who underwent external drainage alone versus combined drainage and vitrectomy were compared. RESULTS: Twenty consecutive patients with a mean age of 70 ± 19 years were studied. Age over 70 years, hypertension, cardiovascular disease, and glaucoma were the most common risk factors for SCH. Eleven patients underwent external drainage alone and nine patients had combined vitrectomy and drainage. Overall, mean pre-operative BCVA improved from 2.22 ± 0.26 logMAR (20/3319 Snellen) to 1.42 ± 1.02 LogMAR (20/526 Snellen) at last follow-up visit (p = 0.002). Severe hypotony occurred in 4 patients. Overall anatomical and functional success rates were both 75%. CONCLUSIONS: Drainage of SCH with or without vitrectomy is a valuable approach in the management of extensive SCH, a condition generally associated with poor prognosis.

The management of macular hole retinal detachment and macular retinoschisis in pathological myopia; a UK collaborative study.

PURPOSE: To study UK practice patterns for the management of retinal detachment secondary to macular hole (MHRD) and macular retinoschisis (MRS) in pathological myopia (PM). To review the anatomical and visual outcomes of the surgically managed cases. METHODS: A prospective observational case series for the management of MHRD was undertaken in association with the British Ophthalmological Surveillance Unit (BOSU). The results were combined with retrospective data, collected by the COllaboration of British RetinAl Surgeons (COBRA), on the management of both MHRD and MRS in PM in the UK. A total of 20 cases of MHRD and 53 cases of MRS (27 surgical cases and 26 cases managed conservatively) are reported in this combined study. RESULTS: MHRD: Mean baseline best corrected visual acuity (BCVA) was 1.60 logMAR. All cases underwent pars plana vitrectomy (PPV). Mean post-operative BCVA was 1.49 logMAR (p = 0.674). The macular hole was closed in 5/20 (25%) cases, open/flat in 10/20 (50%) cases and open/elevated in 4/20 cases (20%). MRS: Mean baseline BCVA was 0.87 logMAR in the surgical group and 0.45 logMAR in the conservatively managed group (p = 0.002). All eyes that had surgical intervention underwent PPV. Mean post-operative BCVA was 0.68 logMAR (p = 0.183). Anatomical outcomes demonstrated a persistent MRS in 2/27 (7.4%) cases, partial resolution in 7/27 (25.9%) cases and complete resolution in 16/27 (59.2%) cases. CONCLUSIONS: PPV is the only surgical procedure performed for the management of MHRD and MRS amongst the study participants. Success rates and visual outcomes are limited for MHRD and consistent with the current literature for MRS.

Incidence, mechanism and outcomes of schisis retinal detachments revealed through a prospective population-based study.

AIM: To determine the incidence, presentation and outcomes of progressive sight-threatening retinal detachment (RD) complicating degenerative retinoschisis. METHODS: We conducted the first prospective population-based epidemiological study of progressive schisis detachment over a 1-year period (2014-2015) in the UK. Case ascertainment was via monthly British Ophthalmological Surveillance Unit reporting cards sent to all ophthalmologists in the UK. For each reported case, data were collected using incident and 6 months follow-up questionnaires gathering information including demographic, presenting symptoms, retinal findings, primary management, primary outcome, secondary management and secondary outcome. RESULTS: Fifty-five cases of progressive schisis RD were identified with similar age distribution to conventional rhegmatogenous RD (mean age 64.0 years, range 20-88), and male-to-female ratio of 2.3:1. The locations of schisis detachments were predominantly supratemporal (46.7%) and infratemporal (35.6%). At least 70% of schisis RD were associated with posterior vitreous detachment (PVD) at presentation and 21% with grade B-C proliferative vitreoretinopathy. Primary management consisted of pars plana vitrectomy (82%), scleral buckle (9%), observation (4%), laser (2%) and combined vitrectomy-buckle (2%). Primary reattachment rate was 70%. Final reattachment rate was 87% with mean best-corrected visual acuity of 0.49 Decimal (SD 0.34) for fovea-on and 0.42 Decimal (SD 0.29) for fovea-off schisis detachments at mean follow-up of 8.7 months (SE 1.0). CONCLUSIONS: The estimated annual incidence of progressive schisis RD was 0.85 per million population (95% CI 0.64 to 1.11), equivalent to around 0.66% of all rhegmatogenous RD. PVD may play a key pathogenic role in the development of progressive schisis detachments. Surgical outcomes are inferior to those of conventional rhegmatogenous RD.

In vivo imaging of cortical vitreous using 1050-nm swept-source deep range imaging optical coherence tomography.

PURPOSE: To image the cortical vitreous, determine the prevalence of the bursa premacularis and space of Martegiani, and measure the dimensions of the bursa using the new 1050-nm swept-source deep range imaging optical coherence tomography (DRI OCT-1 Atlantis). DESIGN: Retrospective cross-sectional study. METHODS: One hundred and nineteen consecutive patients (5-100 years) underwent an OCT scan using 1050-nm swept-source deep range imaging optical coherence tomography. Prevalence of the bursa premacularis and space of Martegiani and the stage of posterior vitreous detachment (PVD) were determined. The horizontal (width) and anteroposterior (depth) dimensions of the bursa were recorded along with the patient's age. RESULTS: A bursa was detected in 57.1% (136/238) of eyes. The bursa and space of Martegiani coexisted in 97.8% of eyes. Prevalence of detected bursa was 84.5% in eyes with either no PVD or perifoveal PVD only; the prevalence fell with further increases in the extent of PVD. Prevalence of detected bursa was 75.4% in patient group aged 0-60 years and 38% in the group aged 60-100 years. Mean width was 7001 µm (range: 3354-10 316 µm, SD: 1412 µm). Mean depth was 416 µm (range: 31-1189 µm, SD: 187 µm). Width and depth of the bursa did not correlate with age (R(2) width = 0.0316; R(2) depth = 0.0108). Bilateral bursa tended to be symmetrical in width but less so in depth (R(2) width = 0.63, P < .001; R(2) depth = 0.33, P < .001). CONCLUSION: Swept-source OCT has allowed us to demonstrate the almost invariable coexistence of the bursa premacularis and space of Martegiani. Swept-source OCT can image both in patients from as early as the first to as late as the tenth decade of life.

Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy.

PURPOSE: To investigate the clinical effects and safety of targeted pattern scan laser (Pascal) retinal photocoagulation (TRP) in proliferative diabetic retinopathy (PDR). METHODS: Prospective and non-randomized study of 28 eyes with treatment-naive proliferative diabetic retinopathy (PDR). Single-session 20-ms-Pascal TRP strategy applied 1500 burns to zones of retinal capillary non-perfusion and intermediate retinal ischaemia guided by wide-field fluorescein angiography (Optos). Main outcome measures at 12 and 24 weeks included; PDR grade (assessed by two masked retina specialists); central retinal thickness (CRT); mean deviation (MD) using 24-2 Swedish interactive threshold algorithm (SITA)-standard visual fields (VF); and ETDRS visual acuity (VA). RESULTS: Following primary TRP, there was PDR regression in 76% of patients at 12 weeks (κ = 0.70; p < 0.001). No laser re-treatment was required at 4 weeks, and 10 eyes underwent repeat TRP at 12 weeks. Wide-field Optos angiography at 24 weeks showed complete disease regression in 37% and partial regression in 33%. Additional panretinal laser photocoagulation (PRP) was planned for active PDR in 30%. There were significant reductions in CRT over time (10.4 µm at 12-weeks, p = 0.007; 12.1 µm at 24-weeks, p = 0.0003). The MD on VFs improved after 12 weeks (+1.25 dB; p = 0.015) and 24 weeks (+1.26 dB, p = 0.01). The VA increased by +3 letters at 24 weeks (95% CI, 1.74-5.01; p < 0.0001). CONCLUSIONS: This pilot study reports that Optos-guided Pascal 20-ms TRP using 1500 burns for treatment-naive PDR is a promising procedure with favourable safety profile.

Study of clinical applications and safety for Pascal® laser photocoagulation in retinal vascular disorders.

PURPOSE: To establish safe laser parameter standards for 10-30 ms Pascal(®) laser in clinical practice and to evaluate clinical and visual outcomes using this 532-nm multi-spot photocoagulation system. METHODS: Retrospective observational case series of 313 patients treated between 2006 and 2008. Evaluation of eight groups: A - panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR); B - focal laser treatment for clinically significant diabetic macular oedema; C - grid laser for diffuse diabetic macular oedema; D - sector PRP for ischaemic branch retinal vein occlusions (I-BRVO); E - full PRP for ischaemic central retinal vein occlusions (I-CRVO); F - macular laser treatment for macular oedema secondary to non-ischaemic BRVO; G - full PRP for rubeosis iridis and/or neovascular glaucoma (NVG) secondary to I-BRVO, I - CRVO or PDR; H - laser retinopexy for retinal breaks/degenerations. RESULTS: Mean LogMAR visual acuity for all procedures improved postlaser (p = 0.065), and laser prevented visual loss in 85% eyes. Topical anaesthesia was only required. At mean follow-up of 5 months, 72% procedures had a successful clinical outcome. Significantly higher powers were required for PRP using Pascal(®) compared to conventional laser (p = 0.001) in PDR, I-BRVO, I-CRVO and NVG. Sixty-seven per cent of patients (15/20) were successfully treated with single-session 20-ms PRP using a mean 1952 burns. There were no laser-associated adverse effects or ocular complications associated with multi-spot PRP or macular Pascal(®) arrays. CONCLUSIONS: The clinical efficacy using 10- to 30-ms pulse duration Pascal(®) laser is comparable to conventional standard protocols used for the treatment of vascular retinal disorders. Higher power, 10- to 30-ms pulse duration laser may be safely and effectively used in clinical practice.

Single-session vs multiple-session pattern scanning laser panretinal photocoagulation in proliferative diabetic retinopathy: The Manchester Pascal Study.

OBJECTIVE: To investigate the effects of pattern scanning laser (Pascal; OptiMedica, Santa Clara, California) multispot panretinal photocoagulation given in a single-session (SS-PRP) vs single-spot multiple-session PRP (MS-PRP) on proliferative diabetic retinopathy (PDR). METHODS: Single-center, randomized clinical trial of 40 eyes. Proliferative diabetic retinopathy was treated with a 400-mum spot size in 1500 burns given either as Pascal in 20-millisecond SS-PRP or in 3 sessions (100-millisecond MS-PRP) during a 4-week period. Visual acuity, central subfield retinal thickness (CRT), and 24-2 Swedish interactive thresholding algorithm visual fields were recorded at baseline and 4 and 12 weeks. MAIN OUTCOME MEASURES: Central subfield retinal thickness, mean deviation, and PDR grade at 12 weeks. RESULTS: There was a significant increase in mean CRT with MS-PRP (22 mum at 4 weeks, 95% CI, -32.25 to -10.75; 20 mum at 12 weeks, 95% CI, -28.75 to -10.82; P < .001) and no significant increase in the SS-PRP group. The mean deviation increased significantly in the SS-PRP group after 4 weeks (0.73 dB, P = .048), with no significant changes in either group at other points. A positive effect on PDR was observed in 74% of eyes in the SS-PRP group vs 53% in the MS-PRP group (P = .31). Mean treatment time for SS-PRP was 5.04 minutes (SD, 1.5 minutes) compared with 59.3 (SD, 12.7 minutes) in the MS-PRP group (P < .001). CONCLUSIONS: There were no adverse outcomes (CRT, visual acuity, or visual field) from using multispot SS-PRP vs single-spot MS-PRP at 12 weeks postlaser, and treatment times were significantly shorter for multispot SS-PRP. Pascal SS-PRP was as effective as MS-PRP in the treatment of PDR. APPLICATION TO CLINICAL PRACTICE: Twenty-millisecond Pascal SS-PRP may be safely and rapidly performed in 1500 burns with a similar efficacy to conventional MS-PRP. TRIAL IDENTIFIER: Research and Development Office PIN R00037, Central Manchester University Hospitals Foundation Trust.

In vivo laser-tissue interactions and healing responses from 20- vs 100-millisecond pulse Pascal photocoagulation burns.

OBJECTIVES: To compare in vivo burn morphologic features and healing responses of Pascal 20- and 100-millisecond panretinal photocoagulation (PRP) burns in proliferative diabetic retinopathy. DESIGN: Prospective randomized controlled trial with 24 eyes assigned to either 20- or 100-millisecond Pascal PRP. Fundus autofluorescence and Fourier domain optical coherence tomography (FD-OCT) were performed 1 hour and 2 and 4 weeks after treatment. Main outcome measures included burn morphologic features on FD-OCT and greatest linear diameter (GLD) of laser burns as evaluated in 6 standard Early Treatment of Diabetic Retinopathy Study photographic fields using autofluorescence. RESULTS: The contemporaneous increase in autofluorescence is observed with increasing pulse duration. Differences in mean GLD between 100- and 20-millisecond burns were 63 mum at 1 hour and 198 mum at 4 weeks (P < .001 for both). At 4 weeks, all burns corresponded to defects at the junction of inner and outer segments of photoreceptors (JI/OSP) and apical retinal pigment epithelium. After 4 weeks, the GLD of 20-millisecond burns reduced significantly by 35% (P < .001), with no change in 100-millisecond burns. CONCLUSIONS: All burns initially appear as equivalent square-edged, columnar foci of hyperreflectivity in the outer retina. Pascal 20-millisecond burns progressively reduce in size, and this suggests a novel healing response localized to the JI/OSP and apical retinal pigment epithelium. The higher-fluence 100-millisecond burns develop larger defects due to thermal blooming and collateral damage.

Barely visible 10-millisecond pascal laser photocoagulation for diabetic macular edema: observations of clinical effect and burn localization.

PURPOSE: To investigate the morphologic features and clinical efficacy of barely visible Pascal (Optimedica Corporation) photocoagulation burns in diabetic macular edema (DME) using Fourier-domain optical coherence tomography (FD OCT) and fundus autofluorescence (AF). DESIGN: Interventional case series. METHODS: Retrospective evaluation of 10 eyes with newly diagnosed DME that underwent barely visible Pascal photocoagulation using an array of 10-microm, 10-millisecond photocoagulation burns. FD OCT and camera-based AF was performed at baseline and at 1 hour, 2 weeks, 4 weeks, and 12 weeks after laser. Changes in retinal thickening after laser treatment were measured using retinal thickness maps within the treated sector and the central foveal subfield. RESULTS: At 1 hour after treatment, burns were visualized partially with clinical biomicroscopy. AF demonstrated spots lacking autofluorescence that confirmed effective laser uptake within the Pascal arrays. Sequential changes in hyperreflectivity on FD OCT correlated with morphologic alterations seen on AF. Burns became increasingly hyperautofluorescent between 2 and 4 weeks. There were significant reductions in the retinal thickness within treated sectors on FD OCT at 2 weeks (26 +/- 32 microm; P = .012) and 3 months after laser (20 +/- 21 microm; P = .02) compared with baseline. Clinical biomicroscopic reduction of DME was the most common finding in 80%. CONCLUSIONS: Barely visible 10-millisecond Pascal laser seems to produce an effect at the level of the inner and outer photoreceptor segments and apical retinal pigment epithelium, with minimal axial and lateral spread of burns. FD OCT confirmed spatial localization of AF signal changes that correlated with laser burn-tissue interactions over 3 months. The technique of lower-fluence barely visible 10-millisecond laser may reduce retinal edema within affected sectors and effectively treat DME with minimization of scar formation.

Chronic intraocular copper foreign body and candida: a unique combination.

PURPOSE: To describe a case of unilateral intermediate uveitis, retained copper intraocular foreign body (IOFB) and fungus. METHODS: Interventional case report. RESULTS: Brown-orange discoloration of the iris, lens and opacified vitreous was observed. Computed tomography revealed a retained IOFB, which was composed of copper. IOFB was removed during vitrectomy and cataract surgery. Copper deposition was demonstrated on the anterior capsule. Incidentally, dimorphic fungus were found in the vitreous. CONCLUSIONS: The presence of intraocular copper might have reduced the virulence of the fungus preventing endophthalmitis.

Scleral hydraulic conductivity and macromolecular diffusion in patients with uveal effusion syndrome.

PURPOSE: To determine whether uveal effusion syndrome (UES) is caused by altered scleral permeability to water and large molecules. METHODS: Transscleral water movement was measured using surgically removed sclera clamped in a modified Ussing chamber and connected to a water column set at intraocular pressure. Sclera was also clamped between two hemichambers, and transscleral diffusion of FITC-dextrans (4.4-77 kDa) was measured with a spectrophotometer. Clinical data were prospectively collected using postal questionnaires. RESULTS: Ten patients (mean age, 63 years; mean spherical equivalent, +4.7 D) had a median preoperative visual acuity of 0.20 that improved to 0.33 after surgery. Nine eyes showed visual improvement, three worsened, and two were unchanged. Histology showed disorganization of collagen fibrils, with amorphous deposits expanding the interfibrillary spaces. The mean thickness (+/-1 SD) of the excised scleral specimens was 585 +/- 309 microm, and the mean specific hydraulic conductivity was 23.9 +/- 27.5 x 10(-14) cm(2), compared with 5.8 +/- 3.9 x 10(-14) cm(2) in age-matched control specimens (P = 0.068). Three specimens had hydraulic conductivity above the 95% CI of the controls. Control eyes showed a significant reduction in diffusion coefficient (D) with age. Eyes had a mean D of 5.69 +/- 5.35 x 10(-8) cm(2) x s(-1), similar to control eyes (6.14 +/- 2.40 x 10(-8) cm(2) x s(-1), 20 kDa dextran). In one eye, the result was higher than the 95% CI of the control; in three, it was lower. CONCLUSIONS: UES is not caused by reduced scleral hydraulic conductivity, which tends to be higher than expected. Reduced macromolecular diffusion may impede the normal transscleral egress of albumin with subsequent osmotic fluid retention in some, but not all eyes.

Triamcinolone pseudo-cataract.

This is an interventional case report of a pseudo-cataract formation by the adherence of triamcinolone particles to the posterior surface of the lens following a 2-mg intravitreal injection for treatment of macular edema associated with non-ischemic central retinal vein occlusion. These deposits unusually persisted beyond 6 months.

Telangiectasis as a cause of intra-schitic haemorrhage in optic disc pit maculopathy.

PURPOSE: To present a patient with the novel finding of vascular telangiectasis as a cause of intra-schitic haemorrhage, occurring in optic disc pit-associated maculopathy. METHODS: A clinical history was detailed. Clinical examination included visual acuity assessment and slit-lamp microscopy. Fluorescein angiography was performed. RESULTS: A temporal optic disc pit, macular retinoschisis and a circumscribed detachment of the outer retinal layer and inner leaf holes were noted. A retinal haemorrhage extending into the schitic cavity was present, along with an associated vitreous haemorrhage. Fluorescein angiography showed telangiectatic vessels in association with the haemorrhage. CONCLUSION: This is the first reported case of vascular telangiectasis as a cause of intra-schitic haemorrhage occurring in optic disc pit-associated maculopathy.

Assessment of delays in presentation of patients with retinal detachment to a tertiary referral centre.

The referral pathway of patients with retinal detachment from primary care providers to a tertiary care ophthalmic unit was examined, in order to determine the length and source of any delays between the onset of symptoms and arrival at the hospital. A prospective survey of all symptomatic patients (n = 60) admitted for primary rhegmatogenous retinal detachment surgery was carried out over an 8 week period. Twenty-one patients were referred by their optometrists and 18 by their general practitioners. The remainder were referred by local accident and emergency and ophthalmic departments or presented directly to the tertiary referral centre. Patients who presented to their optometrists were symptomatic for an average of four times longer. More than half the patients thought that the time to initial presentation was the most significant delay. Referral from optometrists via general practitioners and local ophthalmic clinics was considerably longer. Increased awareness of symptoms, necessity of urgent referral and knowledge of available services locally may reduce delay for those who require emergency sight-saving surgery.