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Jay S Pepose,1,2 Paul J Hartman,3 Harvey B DuBiner,4 Marc A Abrams,5 Robert J Smyth-Medina,6 Sayoko E Moroi,7 Alan R Meyer,8 Mina P Sooch,8 Reda M Jaber,8 Konstantinos Charizanis,8 Seth A Klapman,8 Arin T Amin,8 Jonah E Yousif,8 Eliot S Lazar,9 Paul M Karpecki,10 Charles B Slonim,11 Marguerite B McDonald12 1Pepose Vision Institute, St. Louis, MO, USA; 2Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; 3Department of Ophthalmology, University of Rochester, Rochester, NY, USA; 4Clayton Eye Center, Morrow, GA, USA; 5Case Western Reserve University, Cleveland, OH, USA; 6North Valley Eye Medical Group, Mission Hills, CA, USA; 7The Ohio State University Wexner Medical Center, Columbus, OH, USA; 8Ocuphire Pharma Inc, Farmington Hills, MI, USA; 9elCON Medical, Buffalo, NY, USA; 10Kentucky College of Optometry, University of Pikeville, Pikeville, KY, USA; 11Oculos Development Services, LLC, Tampa, FL, USA; 12Department of Ophthalmology, New York University Langone Medical Center, New York, NY, USACorrespondence: Konstantinos CharizanisOcuphire Pharma, Inc., 37000 Grand River Ave, Farmington, MI 48335, USATel +1 (352) 328 9117Email kcharizanis@ocuphire.comPurpose: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population.Patients and Methods: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia.Results: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥ 1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo.Conclusion: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.Keywords: IOP, presbyopia, night vision disturbances, dim light vision disturbances, pupil diameter, ORION-1

Significance: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations., Purpose: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication., Methods: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points., Results: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours., Conclusions: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile., Competing Interests: Conflict of Interest Disclosure: The publication of this article was sponsored by Ocuphire Pharma, Inc. ARM, MPS, RMJ, KC, JEY, SAK, and ATA are or were employees, directors/officers, or paid consultants for Ocuphire Pharma. PMK, MBM, ESL, JSP, and GDH are on the medical advisory board for Ocuphire Pharma. PMK, SAF, SMM, and SRK were principal investigators for this clinical trial funded by Ocuphire Pharma. CBS serves as Chief Medical Officer of Oculos Development Services, LLC, which was the contract research organization for this clinical trial. The authors indicated that they have no other conflicts of interest with regard to the content of this article. The authors listed report a financial conflict of interest (PMK, SAF, SMM, SRK, CBS, ARM, MPS, RMJ, KC, JEY, SAK, ATA, MBM, GDH, ESL, and JSP). The sponsor (Ocuphire) provided financial and material support and participated in study design, analysis, and interpretation. The authors were responsible for the preparation of this article and the decision to submit this article for publication. Each of the authors had (full/limited) access to the study data and takes full responsibility for their presentation in this article., (Copyright © 2021 American Academy of Optometry.)

Cinacalcet is a type II calcimimetic approved for treatment of secondary hyperparathyroidism in patients with end-stage renal disease. It is generally well tolerated with the most common side effects being nausea and vomiting. Symptomatic hypocalcemia is rare, and persistent hypocalcemia has not been reported to date. We present a case of a 66-year-old woman on chronic outpatient hemodialysis who was initiated on cinacalcet when her intact parathyroid hormone was 1091 pg/mL (normal 15-75 pg/dL). Two weeks later she developed diffuse muscle twitching. The patient required a 72-hour hospitalization and treatment with a continuous intravenous calcium infusion for symptomatic hypocalcemia. The intact parathyroid hormone level at this time was 176 pg/mL. This case is the first report of cinacalcet-induced prolonged and symptomatic hypocalcemia, closely resembling the hungry bone syndrome described in some patients with secondary hyperparathyroidism following surgical parathyroidectomy.

A posterior segment approach for cell transplantation or injection into the subretinal space of the dog has been developed. Controlled penetration to the subretinal space was achieved using a 29-gauge injection cannula, either blunted or with a 30° sharpened bevel, and partially ensheathed with moveable plastic tubing. Depending on the injection volume used, the retina detached, and the fluid was reabsorbed within 1 - 3 weeks, although for smaller volumes the retina reattached within a matter of days. The optimal injection volume used was between 100 and 150 μl, or two injections of 55 μl each. By ophthalmoscopy following the surgery, it was possible to serially monitor the injection site and retinal bleb through fundus photography. Light microscopy demonstrates the distribution of stable, viable RPE cells in the subretinal space up to 6 months. The transplantation technique developed for the dog is atraumatic and free from any major surgical or clinical complications. It can be readily used to deliver cells or fluids to localized regions of the subretinal space.

In recent months, neural fetal retina has been transplanted into blind human patients affected by Retinitis Pigmentosa. Initial success, as documented by improved visual activity, has been reported (del Cerro et al., Neuroscience Abstract, 1996). With the rapid progress in human patients, additional questions are arising concerning transplantation issues. Additional answers and further success in treating clinical disease will necessarily come from new laboratory research in animal models as well as in vitro systems. This increases the need for evaluation of the data already gathered over the first decade of retinal transplantation. The extensive experimental background work that preceded the current wave of human retinal transplants is reviewed in this paper, with particular emphasis given to the work dealing with the transplantation of neural retina.

We have previously reported that Optisol, a commercially available medium (Chiron Vision, Irvine, CA), is a favorable fluid for the storage of neural retina. We now characterize the cell survival and histologic integrity of the tissue following storage and then transplantation. Neural retinas from human fetal eyes obtained within 1 h or pregnancy termination were stored in Optisol-GS medium (containing TC-199 and MEM medium, 2.5% chondroitin sulfate, 1% dextran, HEPES buffer, gentamicin sulfate, 0.1 mmol/L nonessential amino acids, sodium bicarbonate, 1 mmol/L sodium pyruvate, and additional antioxidants), at 4 degrees C for the following time periods: 0, 1, 2, and 7 days, and then tested for viability. Retinas stored for 2 and 7 days were mechanically dissociated and grafted into the eyes of light-damaged Fischer 344 rats (17 animals, 28 eyes). Nontransplanted eyes received injections of vehicle only (5 animals, 6 eyes). All animals were immunosuppressed daily with cyclosporine (10 mg/kg). All experiments were conducted in strict accordance with institutional, federal, and ARVO guidelines. Cell viability averaged 94.8%, 90.2%, 83.2%, and 76.8% at 0, 1, 2, and 7 days storage, respectively. Light microscopy demonstrated that the fetal retina was preserved without evident changes for up to 48 h. Up to 7 days there was a good to very good preservation of the cells in the outer neuroblastic layer. One month after transplantation subretinal grafts of retinal tissue stored for 2 and 7 days in Optisol showed good integration with host retina and initial photoreceptor differentiation. Optisol is a widely used medium for the preservation of human corneas prior to transplantation. Our results show that this medium is also highly suitable for preserving human fetal retinas prior to transplantation.

Previously we have observed that fetal retinal cells grafted to the subretinal space of blind rats produced a functional recovery as determined by testing the visual inhibition of the startle response. Following those studies, we performed experiments to test whether the injection itself, cell by-products, or unrelated neural cells could also produce an effect. Visual function was tested by examining the inhibitory effect of a brief light flash (300 lx) on the acoustic startle response to an immediately following intense noise burst in light blinded Fischer 344 rats. Animals were tested before and after grafts of fetal retinal cell homogenates, dissociated perinatal cerebellar cells, and sham injections in the subretinal space. Behavioral testing continued every 2 wk for 14 wk after the graft. In the pretests, the light flash inhibited the startle response, maximal at intervals of 40-70 ms with recovery thereafter. In contrast, after exposure for 4 wk to fluorescent light (300 lx) and a rest in a normal 12/12 h light/dark environment the rats showed reflex facilitation to the light, maximal at an interval of 110 ms, followed by a late period of reflex inhibition. The light flash had no effect on other rats that had been blinded by bilateral enucleation. Light blinded animals receiving either cerebellar grafts or retinal cell homogenates were no different in performance from their sham injected control animals. The present data suggest that neither subretinal injections of neural cells nor non-specific neurochemical factors are able to elicit a positive behavioral response in visually impaired animals.

Background: Cytomegalovirus (CMV) retinitis is a common, devastating complication of AIDS. Strict host specificity of human CMV (HCMV), has limited the study of the virus. The purpose of this research was to create a model that allowed the in vivo infection of human retinal tissue with HCMV., Experimental Design: Small fragments of 13-week human fetal retina were transplanted into the anterior chambers of immune-deficient mice. One week later, 15 of 30 grafts were inoculated with HCMV. Infected and noninfected specimens were compared for histopathologic changes at 14, 30, and 60 days at light and electron microscopic levels. Histochemistry was performed to characterize: level of graft differentiation, range of viral replication cycle, and effects on neuronal, glial, and monocytic elements of the retina., Results: At 30 and 60 days, grafts were well differentiated histologically and histochemically. The infected grafts showed numerous large cells containing intranuclear and intracytoplasmic inclusions. Ultrastructural examination revealed viral particles within cytoplasm and nuclei. Infected cells expressed proteins representative of all phases of the HCMV replication cycle. Most HCMV-infected cells expressed the neuronal marker, protein gene product 9.5. In a second series of experiments, tissue from one graft harvested at 45 days postinfection was used to recover HCMV in fibroblast cultures and also used successfully to passage the virus to two control grafts., Conclusions: This model allows HCMV to actively infect and replicate within highly differentiated human neural tissue. It produces pathology characteristic of CMV-infected neural tissue in a time course suitable for long-term study. The nature of this model will allow the study of: the replication properties of HCMV in nervous tissue, the specific effects of HCMV on the human retina, the interaction of HCMV with other viruses, e.g., HIV, and various anti-viral therapies.

Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11-17.5 weeks) human fetal brain or neural retina is transplanted into the anterior chamber of the eye of immunosuppressed adult rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more recently in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistochemistry with PGP 9.5 identified neuronal cell bodies and neuritic processes. Electron microscopy revealed axonal growth cones and synaptic junctions. Infection of these xenografts with cell-free HIV-1 proved difficult, however co-engraftment with HIV-1-infected human monocytes resulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation, supporting the hypothesis that these cells can mediate neurotoxicity. In other studies, xenografts of human fetal retinal tissue were readily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear inclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultures, and by serial passage of virus to additional retinal xenografts (DiLoreto et al., 1994).(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the in vivo differentiation potential of Y79 human retinoblastoma cells following pre-treatment with two novel neurotrophic agents: PEDF (human recombinant pigmented-epithelial derived factor) or IPM (interphotoreceptor matrix) wash. These agents were able to induce a significant degree of morphological differentiation in vitro. However, 48 days after subretinal transplantation of pre-treated cells, massive tumor formation was apparent. In contrast, Y79 cells pre-treated with retinoic acid/sodium butyrate, which attain a lesser degree of morphological differentiation, did not produce tumors over a 30 to 60 day-survival time (del Cerro et al., Brain Research, 12-22, 1992). We conclude that for PEDF and IPM, the degree of in vitro differentiation and the degree of mitotic arrest are independent features.