Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles.

PURPOSE: To identify current challenges facing ophthalmic pharmaceutical start-ups in developing new products. METHODS: Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. RESULTS: The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. CONCLUSION: The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs.

Density Functional Theory Insights into the Role of the Methionine-Tyrosine-Tryptophan Adduct Radical in the KatG Catalase Reaction: O2 Release from the Oxyheme Intermediate.

Density functional theory was employed for a comprehensive study that provided electronic and structural insights into the KatG catalase reaction that involves oxyheme. The catalytic role of a unique amino acid cofactor Met-Tyr-Trp (MYW) in its radical form found in KatG was thereby elucidated. It was established that the MYW-radical is flexible such that a "hinge-like opening" rotation of the Trp-107 ring with respect to the Tyr-229 ring along their covalent C-C bond is an inherent feature of its catalytic properties. Also, an H-bond between the Tyr-229 and the mobile side chain of Arg-418 further enables the catalytic events. The opening process breaks an H-bond between the N-H of Trp-107 and the inner oxygen of the Fe-O2 (oxyheme) complex present in the closed conformation of the MYW-radical. This motion lowers the spin-crossing energy barrier between the ground state and the catalytically active high-spin states and enables electron transfer from the oxyheme group to the MYW-radical. The release of molecular oxygen is thereby catalyzed and leaves ferric-heme poised for another catalytic cycle. The energy barrier for the oxyheme state to complete the catalytic event, when assisted by the radical opening process, is thereby reduced and estimated to be 5.6 kcal/mol.

Description of Ophthalmic Pharmaceutical and Device Start-Up Companies.

AIMS: To describe the number, type and location of ophthalmic companies and their associated product areas and indications. METHODS: A retrospective, non-patient-based, observational review of ophthalmic pharmaceutical and device companies with a new product in development. Data was compiled by Internet searches. RESULTS: We identified 190 companies currently developing ophthalmic products: 134 (71%) were privately held and 56 (29%) publicly held, while 136 (72%) were in the United States and 53 (28%) were outside the United States. There were 436 total products of which 338 (78%) were pharmaceuticals and 98 (22%) devices. With pharmaceuticals we identified 46 separate indications with age-related macular degeneration (n = 75), glaucoma (n = 52) and dry eye (n = 46) as most common; anti-vascular endothelial growth factor, hormone therapy and anti-inflammatory products were also common classes. With devices there were 30 indications with glaucoma (n = 26), age-related macular degeneration (n = 19) and dry eye (n = 6) as most common; drug delivery, ocular implants and prostheses were less common classes. CONCLUSIONS: Ophthalmology as a specialty is benefited by a wide effort in new medicine and device development. However, a concentration of effort into relatively few indications suggests a potential lack of market analysis and possible difficulty for many companies in commercializing their product.

Quantum mechanical investigation of aqueous desferrioxamine B metal complexes: trends in structure, binding, and infrared spectroscopy.

A systematic density functional theory study supported by extended X-ray absorption fine structure (EXAFS) and infrared spectroscopic data was conducted to elucidate how structure and vibrational spectra of aqueous desferrioxamine B (DFOB) metal complexes vary with the metal ion identity. Structural parameters derived from EXAFS analyses and trends in metal binding constants are well reproduced and validated by the applied computational model. Vibrational mode analysis guides determination and recognition of crucial structure- and metal-sensitive infrared marker bands. The key marker bands, CO and CN stretching modes, dominate the infrared spectra in the 1400-1650cm(-1) region. The modes are sensitive to the stability and size of the metal core (first coordination shell) and indicative of its deformation from the octahedral symmetry. The results shed light on the fundamental structural and electronic factors that control metal binding by siderophores, and drive their potentially rich and largely unexplored interactions with trace metals.

Photosensitization reactions in vitro and in vivo.

This review of Photochemistry and Photobiology summarizes articles published in 2010, and highlights progress in the area of photosensitization. The synthesis of conjugated photosensitizers is an area of interest where increasing water solubility has been a goal. Targeting infrared sensitizer absorption has been another goal, and relates to the practical need of deep tissue absorption of light. Photodynamic techniques for inactivating microbes and destroying tumors have been particularly successful. Biologically, singlet oxygen [(1)O(2)((1)Δ(g))] is an integral species in many of these reactions, although photosensitized oxidations tuned to electron and hydrogen transfer (Type I) give rise to other reactive species, such as superoxide and hydrogen peroxide. How photoprotection against yellowing, oxygenation and degradation occurs was also an area of topical interest.

A hand-held fiber-optic implement for the site-specific delivery of photosensitizer and singlet oxygen.

We have constructed a fiber optic device that internally flows triplet oxygen and externally produces singlet oxygen, causing a reaction at the (Z)-1,2-dialkoxyethene spacer group, freeing a pheophorbide sensitizer upon the fragmentation of a reactive dioxetane intermediate. The device can be operated and sensitizer photorelease observed using absorption and fluorescence spectroscopy. We demonstrate the preference of sensitizer photorelease when the probe tip is in contact with octanol or lipophilic media. A first-order photocleavage rate constant of 1.13 h(-1) was measured in octanol where dye desorption was not accompanied by readsorption. When the probe tip contacts aqueous solution, the photorelease was inefficient because most of the dye adsorbed on the probe tip, even after the covalent ethene spacer bonds have been broken. The observed stability of the free sensitizer in lipophilic media is reasonable even though it is a pyropheophorbide-a derivative that carries a p-formylbenzylic alcohol substituent at the carboxylic acid group. In octanol or lipid systems, we found that the dye was not susceptible to hydrolysis to pyropheophorbide-a, otherwise a pH effect was observed in a binary methanol-water system (9:1) at pH below 2 or above 8.

Photosensitizer drug delivery via an optical fiber.

An optical fiber has been developed with a maneuverable mini-probe tip that sparges O(2) gas and photodetaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene spacer group releasing sensitizer upon fragmentation of a dioxetane intermediate. Optimal sensitizer photorelease occurred when the probe tip was loaded with 60 nmol sensitizer, where crowding of the pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic tip delivered pheophorbide molecules and singlet oxygen to discrete locations. The 60 nmol sensitizer was delivered into petrolatum; however, sensitizer release was less efficient in toluene-d(8) (3.6 nmol) where most had remained adsorbed on the probe tip, even after the covalent alkene spacer bond had been broken. The results open the door to a new area of fiber optic-guided sensitizer delivery for the potential photodynamic therapy of hypoxic structures requiring cytotoxic control.

Meta-analysis of 24-h intraocular pressure fluctuation studies and the efficacy of glaucoma medicines.

PURPOSE: To compare the change in 24-h fluctuation of the intraocular pressure (IOP) from various medical therapies in patients with ocular hypertension, primary open-angle (POAG), or exfoliative glaucoma (XFG). METHODS: A meta-analysis of published studies that were controlled, prospective, and comparative trials. Based on study requirements for an objective fluctuation analysis, only studies from the authors' work met the criteria for this analysis and contained: > or = 4-week treatment period, > or = 20 patients per treatment arm, and > or = 6 time points measured with Goldmann applanation over 24 h, not spaced >5 h apart. Fluctuations were defined by the mean of the difference between the highest and lowest measured IOP for each individual patient (Sigma[maximum - minimum IOP]/number of patients). RESULTS: Thirteen articles were included evaluating 28 treatment arms in 1,017 patients. Among all individual treatments, bimatoprost demonstrated the greatest reduction in fluctuation (P = 0.03, 3.4 mm Hg). In contrast, 2-drug therapy did not reduce fluctuations from monotherapy (P = 0.09). Among prostaglandin therapies, no statistical difference existed between evening and morning dosing (P = 0.20). In XFG, a greater reduction in fluctuations was observed progressing from 1 to 2 medicines (P = 0.01), but not increasing from 2 to 3 drug therapy (P = 0.14). In general, XFG patients demonstrated a greater decrease in fluctuations than POAG patients (P = 0.003). CONCLUSIONS: In POAG differences exist in fluctuations among monotherapy treatments with bimatoprost showing the greatest effect. However, POAG patients generally demonstrate less decrease in fluctuations with treatment than compared with XFG.

Ophthalmologist attitudes regarding fixed combination treatment for glaucoma in the European Union.

PURPOSE: To survey ophthalmologists in the European Union to determine their fixed combination (FC) preferences. METHODS: A multiple-choice survey was sent to randomly chosen ophthalmologists throughout the European Union and bordering countries by electronic mail delivery. Ophthalmologists were resent the survey on two more occasions if no response was obtained. RESULTS: In total, 50 surveys were received from 530 distributed (9.4% response) from 16 countries. More ophthalmologists prescribed an FC as second (80%) or third choice (64%) therapy than first choice (30%, p=0.0036). As first (p<0.0001) and third choice (p=0.011), the dorzolamide/timolol FC was most commonly prescribed, while as second choice the latanoprost/timolol FC (p<0.0001) was most popular. Overall, 98% (49/50) of doctors believed FC therapy improved patient care most often by better compliance (n=49) and quality of life(n=48, p<0.0001). Most ophthalmologists believed that there was a difference in efficacy between the FC products (32/50, 64%) with the most effective being the bimatoprost/timolol FC (n=12, 24%, p=0.029). However, fewer ophthalmologists perceived safety differences between the products (34/50, 68%). For prostaglandins, dosing time was suggested in the morning by 18 (36%) ophthalmologists and in the evening by 24 (48%) (p=0.35). CONCLUSIONS: FCs in the European Union are a potentially popular method to reduce intraocular pressure, being prescribed most commonly as second or third choice therapy. The perceived advantages to FC therapy are greater adherence to the medicine and improved patient quality of life.

Potential benefit of intraocular pressure reduction in normal-tension glaucoma in South Korea.

PURPOSE: The aim of this study was to evaluate the potential benefit of intraocular pressure (IOP) reduction in normal tension glaucoma (NTG) Asian adult patients in South Korea. METHODS: This was a retrospective, multicenter analysis of 166 NTG Asian adult patients in South Korea. The patient population consisted of Korean patients with NTG with at least 5 years of records available for evaluation. Patients all had typical glaucomatous optic-disc and/or visual-field changes but had never had a recorded IOP >21 mmHg. RESULTS: Overall, 48 (29%) patients were progressed and 116 (71%) were stable over the follow-up period. Of patients with IOPs or=15 mmHg (27/73) 37% progressed (P = 0.041). The mean IOP for the stable group was 14.0 +/- 1.8 mmHg, whereas with the progressed group the average mean IOP was 14.4 +/- 1.6 mmHg (P = 0.20). The mean peak IOP was 17.4 +/- 2.2 mmHg in the stable group and 17.8 +/- 2.0 mmHg in the progressed group (P = 0.26). Multivariate linear regression analysis did not any identify independent risk factors for progression, including age, gender, or mean and peak IOP. CONCLUSIONS: This study provides initial evidence that Korean patients with normal-tension glaucoma, treated to lower IOPs, may have a decreased incidence of progression over 5 years than those patients with higher IOPs. More research is required to confirm this finding.

Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines.

PURPOSE: To evaluate efficacy and safety data of currently available ocular hypotensive medicines derived from 24-hour studies, of similar design, in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma, or ocular hypertension (OH). DESIGN: Meta-analysis of published articles evaluating patients with POAG, exfoliative glaucoma, or OH. METHODS: We included articles that were randomized, prospective, single- or double-masked, comparative studies of ocular hypotensive therapies over 24 hours. Each article selected contained an untreated baseline, >or=4-week treatment period, >/=20 patients per treatment arm, and >or=6 time points not spaced >5 hours apart and used Goldmann applanation or Tonopen tonometry (supine measurements) to measure intraocular pressure (IOP). MAIN OUTCOME MEASURE: Twenty-four-hour IOP efficacy. RESULTS: This analysis included 864 separate 24-hour treatment curves from 386 patients in 28 treatment arms from 11 studies. A statistical difference in the mean diurnal pressure decrease existed between monotherapy treatments for POAG/OH patients, with bimatoprost (29%) and travoprost (27%) showing the greatest 24-hour reduction (P = 0.026). Timolol 0.5% was less effective than latanoprost (24% vs. 19% reduction) but decreased the pressure at each night time point (P = 0.0003). Dorzolamide showed a 19% 24-hour pressure reduction and brimonidine 0.2% a 14% one. In exfoliative glaucoma patients, latanoprost and travoprost showed higher baseline and treatment pressures, although the pressure reductions (29% and 31%, respectively) were greater generally than observed with POAG/OH. An evening-dosed latanoprost/timolol fixed combination reduced the pressure 33%, and the dorzolamide/timolol fixed combination (DTFC), 26%. However, the power to detect a difference for this specific comparison was probably low, due to the limited number of patients (n = 20) in the DTFC group. A statistical difference between evening-dosed (24%) and morning-dosed (18%) latanoprost (P<0.0001) was noted, but not between evening (27%) and morning (26%) travoprost (P = 0.074). The mean reduction of night time points was statistically lower than day time points for latanoprost (P = 0.031), timolol (P = 0.032), and brimonidine (P = 0.050), but not for dorzolamide. Dorzolamide (P = 0.60), travoprost (P = 0.064), and bimatoprost (P = 0.057) did not demonstrate nighttime pressures lower than daytime ones. The mean reduction of night time points was statistically lower than that of day time points for latanoprost (P = 0.031), timolol (P = 0.032), and brimonidine (P = 0.050), but not for dorzolamide (P = 0.60), bimatoprost (P = 0.057), travoprost (P = 0.064). CONCLUSIONS: Similar relative efficacies generally exist in various classes of ocular hypotensive agents during night and day hours.

Epidemiology of glaucoma in central Ethiopia / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To evaluate the prevalence of glaucoma.treatment patterns and patient attitudes in Ethiopia.METHODS:A survey was administered to glaucoma patients in hospitals in Addis Ababa,Ethiopia.RESULTS:Of the 415 qualified patients,exfoliative glaucoma(17%)was most commonly found in the Gurage population(33%),whereas chronic angle-closure glaucoma(5%)was found in the Amhara/Tigre(6%)population(P=0.006).Patients were treated with an average of 1.4±0.8 medications:52% admitted recent noncompliance and 36% had undergone filtering surgery.Patients believed their physician was trying to help them(93%).God wanted them to receive treatment(89%)and their spouse was sympathetic to their disease(82%).Patients noted their community was unaware of their condition(87%)with Muslims[most common in the Gurage population(31%,P＜0.0001)]reporting this the most(25%,P=0.01).Amhara/Tigre patients strongly believed their doctors were concerned about them(94%.P=0.04).CONCLUSION:The prevalence of glaucoma type varies among ethnic groups in Ethiopia with exfoliation more common in the Gurage population and chronic angle-closure glaucoma more frequent in the Amhara/Tigre population.