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Patricia Muñoz-Villegas,1,2 Gisela García-Sánchez,1 Ricardo O Jauregui-Franco,1 Sebastian Quirarte-Justo,1 Alejandra Sánchez-Ríos,1 Oscar Olvera-Montaño1 1Regional Medical Affairs Department, Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, Mexico; 2Centro de Investigación en Matemáticas, A.C., Unidad Aguascalientes (CIMAT), Aguascalientes, Aguascalientes, MexicoCorrespondence: Patricia Muñoz-Villegas, Laboratorios Sophia, S.A. de C.V., Paseo del Norte 5255, Technology Park, Zapopan, Jalisco, 45010, México, Tel +52 33 3001 4200, Email patricia.munoz@sophia.com.mxBackground: This research aims to investigate the influence of environmental factors on the treatment efficacy of ocular lubricants in patients from urban areas with dry eye disease (DED).Methods: A phase IV clinical trial, which included 173 patients from major cities in Mexico, was randomly assigned to use ocular lubricants four times a day for 30 days. Ocular Surface Disease Index (OSDI), noninvasive tear film break-up time (NIBUT), ocular staining, and conjunctival hyperemia (CH) among other factors like weather, and air pollution as covariates were analysed.Results: After 30 days, OSDI score decreased by 14.8 points (p< 0.001), and NIBUT increased by 2.9 seconds (p< 0.001), with longer values observed in patients recruited in autumn and winter (additional 1.8 seconds, p< 0.05) compared to those recruited in spring. Patients living in cities with cooler weather and high humidity, but low air quality had higher OSDI and conjunctival stain scores of up to 4.4 and 0.3 points, respectively, as compared to those living in cities with similar pollution and humidity levels but with higher temperatures (p-values= 0.019 and 0.050). Patients with moderate CH had an increase of up to 0.8 points in their corneal stain score (p< 0.010). We also found that ozone levels were related to the predicted changes in OSDI and NIBUT.Conclusion: This study demonstrated the impact of environmental factors on the signs and symptoms of DED and suggests that patients residing in cities with inadequately controlled air pollution can benefit from using ocular lubricants to alleviate their symptoms.Trial Registration: Trial is registered at clinicaltrials.gov (NCT04702776).Keywords: Dry eye disease, dry eye symptoms, dry eye signs, environmental factors, ocular lubricants

Patricia del Carmen Muñoz-Villegas,1,2 Alejandra Sánchez-Ríos,1 Oscar Olvera-Montaño1 1Regional Medical Affairs Department, Laboratorios Sophia, S.A. de C.V, Zapopan, Jalisco, Mexico; 2Centro de Investigación en Matemáticas A.C. (CIMAT), Unidad Aguascalientes, Aguascalientes, MexicoCorrespondence: Patricia del Carmen Muñoz-Villegas, Regional Medical Affairs Department, Laboratorios Sophia, S.A. de C.V, Paseo del Norte 5255, Guadalajara Technology Park, Zapopan, Jalisco, 45010, Mexico, Tel +52 (33) 3301 4200, Email patricia.munoz@sophia.com.mxPurpose: A randomized clinical trial was run to evaluate the effectiveness of a preservative-free 0.4% sodium hyaluronate eye drop (LOF) in different dosage schemes to alleviate signs and symptoms of dry eye disease (DED).Methods: A total of 116 subjects with mild-to-moderate DED were included, and 111 completed the study (from which 67.6% were female and 65.3% were users of oral contraceptives). Patients were randomly assigned to instill a drop of LOF either 2 (BID), 4 (QID) or 6 (6TD) times a day (at least 3 hours apart) for 30 days. The clinical parameters and symptom endpoints were Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), ocular surface staining, and conjunctival hyperemia. Other parameters evaluated were chemosis, best corrected visual acuity, and the incidence of adverse events (AE).Results: There was a significant reduction in OSDI scores by day 30 in all groups. The recovery of the OSDI score back to normal values was observed in 51.4% of patients treated (50%, 48.6%, and 55.6% in BID, QID, and 6TD, respectively, p = 0.822). Similar improvement was observed for TBUT, 50.5% of patients increased this variable to > 10 seconds (39.5%, 51.4%, and 61.1%, p = 0.175), and for ocular surface staining, ≥ 72% showed Grade 0. There were no significant differences among posology groups regarding ocular surface staining, conjunctival hyperemia, or any safety parameters. No overall improvement in OSDI and TBUT to normal values was noted for 31 patients (21 were female and 71.4% users of contraceptive drugs).Conclusion: The ophthalmic use of preservative free LOF, 2, 4 or 6 times a day, may alleviate clinical parameters and symptoms in 50% of patients with mild-to-moderate DED after a one-month treatment. This improvement seemed to be less ubiquitous in patients within reproductive age and using oral contraceptives.Trial Registration: This trial is registered at clinicaltrials.gov (NCT0704531).Keywords: contraceptives, dry eye disease, ocular surface disease index, sodium hyaluronate, tear break-up time

Claudia Palacio-Pastrana,1 Patricia Muñoz-Villegas,2 Fernando Dániel-Dorantes,3 Alejandra Sánchez-Ríos,2 Oscar Olvera-Montaño,2 Yareni I Martínez-Montoya,1 Juan D Quintana-Hau,3 Leopoldo M Baiza-Durán2 1SalaUno Salud, SAPI de CV, México City, México; 2Regional Medical Affairs Department, Laboratorios Sophia SA de CV, Zapopan, Jalisco, México; 3Research and Development Department (CIS), Zapopan, Jalisco, MéxicoCorrespondence: Patricia Muñoz-Villegas, Laboratorios Sophia, SA de CV, Paseo del Norte 5255, Guadalajara Technology Park, Zapopan, Jalisco, 45010, México, Tel +52 3301 4200, Ext: 1018, Email patricia.munoz@sophia.com.mxPurpose: To evaluate the rheological properties of the ophthalmic viscoelastic device (OVD) PRO-149, its preclinical safety, and its effectiveness when used during cataract surgery in patients with age-related cataract.Material and Methods: Control (HEC) and test (PRO-149) OVDs were compared through rheological measures, by two preclinical safety studies in rabbits, and under normal-use conditions during cataract removal and lens implantation in a parallel randomized clinical trial.Results: Rheological properties were determined. Preclinical studies did not find any evidence of safety issues or toxicity. In the clinical trial, 36 subjects were included. After 29 days, there were no statistically significant differences in mean percentage of endothelial cell count change or in the postoperative intraocular pressure between groups. There were no significant differences between OVDs for any safety parameter studied. Finally, PRO-149 showed a statistically significant improvement in surgeon rating for ease of use during extraction (p < 0.05).Conclusion: PRO-149 is a dispersive OVD. The rabbit models did not find evidence of clinical alterations or toxicity. The results of the clinical study support that the two studied OVDs were clinically similar in terms of safety and effectiveness for cataract surgery.Trial Registration: The trial is registered at Clinical Trials.gov at NCT04702802 (21– 01-11).Keywords: rheology, sodium hyaluronate, surgical procedure, viscoadaptative, viscosity

Patricia Muñoz-Villegas, Andrea A Navarro-Sánchez, Alejandra Sánchez-Ríos, Oscar Olvera-Montaño, Leopoldo M Baiza-Durán Medical Affairs Department, Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, MéxicoCorrespondence: Patricia Muñoz-VillegasLaboratorios Sophia, S.A. de C.V., Paseo del Norte 5255, Guadalajara Technology Park, Zapopan, 45010, Jalisco, MéxicoTel +52 33 3001 4200, Ext: 1018Email patricia.munoz@sophia.com.mxPurpose: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHVs) as explored in phase 1 trials.Subjects and Methods: A total of 166 NHVs were identified in six phase 1 trials, examined in a retrospective analysis. The primary endpoints were visual comfort (by ocular comfort index, OCI) and safety (laboratory evaluations, vital signs (VS), visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and adverse events’ incidence (AE)).Results: Compared to baseline, 75.9%, 40.4% and 73.7% of NHV (for lubricant, hypotensive and antibiotic treatments, respectively) improved their OCI score by their final visit. Laboratory evaluations and VS were within normal ranges in 88% of NHV. Similar results were found for VA, corneal and conjunctival staining, and chemosis. IOP decreased significantly in the hypotensive agents’ group, trace to mild hyperemia was reported in 32.1%, 27.1%, and 6.8%, respectively. Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (OR 0.856, 95% CI [0.365, 1.999] and 0.636, 95% CI [0.096, 4.197], respectively). Meanwhile, on antibiotic drugs, the risk for ID-related AE was higher (OR 1.313, 95% CI [0.309, 5.583]).Conclusion: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHVs do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared.Trial Registration: This is a retrospective study of six previously conducted clinical trials, registered on clinicaltrials.gov with the following registration IDs: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.Keywords: healthy volunteer, phase 1 trial, safety, tolerability, ophthalmic drug

Patricia Muñoz-Villegas,1 Alejandra Sanchez-Rios,1 Mayra G Quinonez-Alvarado,2 Oscar Olvera-Montaño,1 Juan D Quintana-Hau,2 Leopoldo Baiza-Duran1 1Medical Affairs Department, Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, México; 2Research and Development Department (CIS), Zapopan, Jalisco, MéxicoCorrespondence: Patricia Muñoz-VillegasMedical Affairs Department, Laboratorios Sophia, S.A. de C.V., Paseo del Norte 5255, Guadalajara Technology Park. Zapopan, 45010, Jalisco, MéxicoEmail patricia.munoz@sophia.com.mxBackground: PRO-169 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that inhibits vascular endothelial growth factor-A (VEGF-A) developed for intravitreal use. The current study demonstrates the intraocular pharmacokinetics (PK) of PRO-169 and its safety using New Zealand white (NZW) rabbits.Methods: Intraocular concentration was evaluated in thirty-six rabbits at 1h, 1, 2, 5, 14 and 30 days after a single bilateral injection of PRO-169 or BEV (1.25 mg/0.05 mL). In a secondary experiment, safety was evaluated after three consecutive unilateral injections at 30-day intervals in twenty-four rabbits (PRO-169: 1.25 mg/0.05 mL or ranibizumab [RZB]: 0.5 mg/0.05 mL), by liver-associated enzymes (LAE), ophthalmological examination and adverse event (AE) incidence. Primary endpoints were vitreous maximum concentration (Cmax), time to attain maximum concentration (tmax), area under curve (AUC0-t), half-life (t1/2) and LAE. Secondary endpoints included aqueous humor (AH) and plasma pharmacokinetics, clinical examination and AEs.Results: The Cmax in the vitreous was 593.75 ± 45.63 (PRO-169) vs 644.79 ± 62.65 μg/mL (BEV) (p= 0.136). Tmax was 0.53 ± 0.82 vs 0.85 ± 0.73 days (p= 0.330). The AUC0-t was 3837.72 ± 465.91 vs 4247.31 ± 93.99 days*μg/mL (p= 0.052) and the half-life was 4.99 ± 0.89 vs 5.18 ± 0.88 days (p= 0.711). LAEs were normal in 92% of NZW rabbits; no differences between groups were observed (p> 0.05). The AH and plasma PKs were also similar. Finally, clinical examinations found no alterations. AEs were observed in 25% of PRO-169 rabbits, without differences vs RZB (p=0.399).Conclusion: PRO-169 can be efficiently diffused and distributed in ocular compartments, showing vitreous pharmacokinetics analogous to BEV. The safety experiment did not find evidence of clinical alterations from a repeated injection of PRO-169. These results provide scientific justification supporting that PRO-169 should be evaluated in future clinical trials to confirm its safety and efficacy.Keywords: bevacizumab, pharmacokinetics, ranibizumab, safety, vascular endothelial growth factor

Claudia Palacio-Pastrana,1 Eduardo Chávez-Mondragón,2 Abraham Soto-Gómez,3 Rubén Suárez-Velasco,4 Miguel Montes-Salcedo,5 Lourdes Fernández de Ortega,6 Linda Nasser-Nasser,7 Leopoldo Baiza-Durán,8 Oscar Olvera-Montaño,8 Patricia Muñoz-Villegas8 1Fundación Hospital Nuestra Señora de la Luz, IAP, CDMX, Mexico; 2Fundación de Asistencia Privada Conde de Valenciana, IAP, CDMX, Mexico; 3Catarata y Glaucoma de Occidente SA de CV, Guadalajara, Jalisco, Mexico; 4Private Office, Guadalajara, Jalisco, Mexico; 5Aris Vision Institute, Guadalajara, Jalisco, Mexico; 6Asociación Para Evitar la Ceguera en México, IAP, CDMX, Mexico; 7Visión Cirugía Ambulatoria, Monterrey, Nuevo Leon, Mexico; 8Medical Affairs, Laboratorios Sophia, SA de CV, Zapopan, Jalisco, MexicoCorrespondence: Patricia Muñoz-Villegas Tel +52 3001 4200 ext 1018Email patricia.munoz@sophia.com.mxBackground: The purpose of this study was to compare the efficacy and safety of difluprednate 0.05% (PRO-145) versus prednisolone acetate 1% (Prednefrin® SF), for management of postoperative inflammation and pain, after cataract surgery.Methods: This was a Phase III, multicenter, prospective, double-blind, clinical trial. Intent-to-treat population included 178 post-phacoemulsification patients that were assigned to receive either PRO-145, or prednisolone. One day after unilateral eye surgery, patients instilled a drop 4 times a day for 14 days (then tapering the dose downward for 14 days). The primary efficacy endpoints were anterior chamber (AC) cell grade and flare. Other parameters measured included: retinal central thickness (measured via OCT), conjunctival hyperemia, edema, pain and photophobia. Tolerability and safety were assessed through burning, itching, foreign body sensation, visual acuity (VA), intraocular pressure (IOP) and incidence of adverse events (AE).Results: A total of 171 subjects were randomized (1:1) and completed the study. Compared to day 1, there was a significant improvement in the AC cell count and flare in both groups by the final visit (80.2% vs 88.4%, p=1.000). Conjunctival hyperemia improved in a similar fashion (81.2% vs 79%, p=0.234) in both PRO-145 and prednisolone groups, without differences between them. This was also observed for edema (82.4% vs 82.5%, p=0.246), pain (15.3% vs 7%, p=0.497) and photophobia (16.4% vs 15.1%, p=0.246), respectively. There was no significant difference between treatments for any tolerability parameter studied. Finally, at the 4-week postoperative visit, there were no significant differences between treatments for VA, IOP and AE results (p-values; 0.095, 0.053 and 0.099, respectively).Conclusion: The results of this study suggest that PRO-145 is as effective and safe as prednisolone acetate in treating postoperative inflammation and pain in patients undergoing phacoemulsification. The study was registered at ClinicalTrials.gov as NCT03693989.Keywords: difluprednate, dose-reduction, cataract surgery, ophthalmic corticosteroids

Oscar Olvera-Montaño,1 Leopoldo Baiza-Duran,1 Juan D Quintana-Hau,2 Mayra G Quiñonez-Alvarado,2 Wen Zeng,3 Li Gong,3 Patricia Muñoz-Villegas1 1Clinical Research Department, Laboratorios Sophia, SA De CV, Zapopan, Jalisco, Mexico; 2Research and Development Department (CIS), Zapopan, Jalisco, Mexico; 3Sichuan Primed Shines Bio-Tech Co, Ltd, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Patricia Muñoz-VillegasLaboratorios Sophia, SA de CV, Paseo del Norte 5255, Guadalajara Technology Park, Zapopan 45010, Jalisco, MexicoTel +52 3301 4200, Ext: 1018Fax +52 3301 4200Email patricia.munoz@sophia.com.mxPurpose: To evaluate the efficacy of a therapy on improving characteristics of laser-induced choroidal neovascularization (CNV) via single intravitreal injection of a humanized anti-human VEGF monoclonal antibody (PRO-169) versus bevacizumab in a rhesus monkey model.Methods: To induce experimental CNV, small high-energy laser spots were used to treat several areas, around the macula in the retinas of monkeys at Day −21. Eighteen rhesus monkeys were used for CNV induction. The efficacy endpoints were fluorescein leakage by FFA and retinal thickness by OCT. FFA examinations were performed 19 days after induction. Appropriate animals were enrolled for treatment and randomly divided into 3 groups: bevacizumab (n=5, 7 eyes), PRO-169 (n=5, 7 eyes), and vehicle controls (n=4, 7 eyes).Results: In 25 of 36 (69.4%) eyes, CNV lesions were identified. The average percent change of retinal thickness in the eyes of bevacizumab group was −159.3±62.2% and −154.0±45.1% (p

Eduardo Chávez-Mondragón,1 Claudia Palacio,2 Abraham Soto-Gómez,3 Miguel Villanueva-Nájera,4 Guillermo De Wit-Carter,5 Ruben Suárez-Velasco,6 Leopoldo Baiza-Duran,7 Oscar Olvera-Montaño,7 Patricia Muñoz-Villegas71Fundación de Asistencia Privada Conde de Valenciana, IAP, CDMX, Mexico; 2Fundación Hospital Nuestra Señora de la Luz, IAP, CDMX, Mexico; 3Catarata y Glaucoma de Occidente, SA de CV, Guadalajara, Jalisco, Mexico; 4Private Office, CDMX, Mexico; 5Asociación para Evitar la Ceguera en Mexico IAP, CDMX, Mexico; 6Novam y Vita, Guadalajara, Jalisco, Mexico; 7Clinical Research Department, Laboratorios Sophia, SA de CV, Zapopan, Jalisco, MexicoPurpose: This study evaluated the clinical efficacy and safety of bromfenac 0.09%, sodium hyaluronate 0.4% (SH) combination therapy, versus placebo and SH in a clinical model of pterygium I–III.Methods: A total of 166 eyes (99 patients) with pterygium grade I–III were randomized to bromfenac 0.09% ophthalmic solution+SH 0.4% or placebo+SH 0.4%. This was a Phase IV, prospective, parallel, double-masked, multicenter clinical trial. One drop of bromfenac or placebo was instilled two times a day (BID) for 20 days, both groups accompanied treatments with one drop of SH three times a day (TID). The primary efficacy endpoints were the conjunctival hyperemia and the Ocular Surface Disease Index (OSDI) score. Other results measured included burning, foreign body sensation, and photophobia. The safety was assessed by the tear break-up time (TBUT), visual acuity (VA), IOP, lissamine green, fluorescein stains, and the incidence of adverse events (AEs).Results: Compared with baseline, there was a significant reduction in the conjunctival hyperemia (p=0.0001) and OSDI score in both groups (p=0.0001). There was a significant improvement in ocular symptomatology for both, placebo/SH and bromfenac/SH groups (p=0.0001), the decrement in the ocular burning was 41.1% vs 24.6%, the foreign body sensation was 31.5% vs 36.2% and, for photophobia was 23.3% vs 30.5%, respectively. A statistically significant difference was observed in TBUT for bromfenac/SH (p=0.045), at day 20. There were no significant alterations in IOP (p=0.068) or VA (p=0.632). Similar improvements were observed in the fluorescein and green lissamine staining. Finally, the incidence of AE was similar between groups.Conclusion: The treatment with bromfenac 0.09% ophthalmic solution and SH 0.4% combination therapy for 3 weeks reduced clinical signs, in patients with pterygium I–III. The results suggest that bromfenac 0.09% can improve the symptomatology, reduce the presentation of clinical signs associated with superficial ocular inflammation.Keywords: nonsteroidal anti-inflammatory drug, Ocular Surface Disease Index, conjunctival hyperemia, ocular lubricant

Abstract Introduction Diabetic macular edema (DME) is one of the leading causes of vision impairment. The relationship between DME and estimated glomerular filtration rate (eGFR) has not been clearly evaluated in Hispanic or Latino populations. The objective of this study was to evaluate the eGFR in a Latino population with DME. Methods A cross-sectional, observational, and descriptive study was carried out on the basis of a multicenter phase III clinical trial. Results A total of 82 subjects diagnosed with DME (36 women and 46 men) were included in the study. The mean age was 61.93 ± 6.71 years. Mean values of the blood chemistry parameters glycated hemoglobin and eGFR were 7.20 ± 0.95% and 74.42 ± 26.82 mL/min/1.73 m2, respectively. The time elapsed since diagnosis of diabetes mellitus was 15.30 ± 7.35 years, while the duration of DME was 1.41 ± 1.75 years. Mean values for central macular thickness (CMT) and total macular volume (TMV) were 440.99 ± 132.22 µm and 11.97 ± 2.11 mm3, respectively. DME duration had a negative correlation with TMV (Rho − 0.26, p 0.05). Chronic kidney disease (CKD) was associated with hypertension (OR 9.32, p = 0.035), elevated intraocular pressure (IOP) (OR 0.03, p = 0.011), and advanced age (OR 0.45, p = 0.011). CMT was significantly associated with TMV (β = 27.69, p

Introducción: la infección del tracto urinario es la segunda causa de compromiso bacteriano en niños, genera altos costos para el sistema de salud, puede ser la primera manifestación de una anomalía en la vía urinaria y es un factor de riesgo para múltiples patologías. Objetivo: caracterizar el perfil epidemiológico y microbiológico de la primera infección del tracto urinario en la población pediátrica de un centro de referencia en Pereira, Colombia. Métodos: estudio de corte transversal que incluyó pacientes entre 2 meses y 10 años de edad, con la primera infección urinaria según los criterios de la Academia Americana de Pediatría, entre 2016 y 2017. Las resistencias bacterianas fueron definidas según las guías CLSI vigentes (Clinical and Laboratory Standards Institute). Se utilizó estadística descriptiva y las guías STROBE para el reporte del estudio. Resultados: se incluyeron 81 pacientes, 28% de sexo masculino, la mayor parte estaban entre 2 y 12 meses de vida (40%), 49% cursaron con nitritos positivos, 39% hematuria y 37% proteinuria, 87% el gram de orina fue positivo, 18% presentaron anomalías ecográficas; los uropatógenos más frecuentes fueron Escherichia coli (86%), Proteus mirabilis (5%) y Klebsiella pneumoniae (5%). La E. coli fue resistente en 51,4%, 32,8% y 17,1% a trimetoprim-sulfametoxazol, ampicilina-sulbactam y cefalotina. La presencia de betalactamasas de espectro extendido fue de 2,8%, la mediana de tratamiento empírico fue de 3 días y el tratamiento total de 10 días. Discusión: se observó alta prevalencia de resistencia antibiótica a ampicilina, ampicilina-sulbactam y trimetoprim-sulfametoxazol, lo que desaconseja su empleo. La buena sensibilidad del E coli reportada en este estudio a la cefalotina y la amikacina, favorecen su uso como primeras elecciones terapéuticas empíricas en nuestro medio. Conclusión: se recomienda la ecografía urinaria en los pacientes con primera infección urinaria febril, debido a la alta prevalencia de anomalías urinarias identificadas.

Abstract Background The objective of this study was to validate an animal model for dry eye during and after the administration of 1% ophthalmic atropine sulfate (OAS) in New Zealand white (NZW) rabbits. Methods OAS (1%) was applied three times per day to 30 eyes of 15 healthy NZW rabbits. Sacrifice, enucleation, and lacrimal gland removal took place on days 15, 21, and 30 (OAS group). A second group (n = 5) was used as control. Clinical evaluations took place on days 3, 10, 15, 18, 21, 24 and 30. The primary endpoints were: Schirmer I test, tear break‐up time (TBUT), and corneal fluorescein staining. As secondary endpoints, clinical changes including intraocular pressure, and histopathology were evaluated. Results While OAS was administered, the Schirmer I test showed a statistically significant reduction for OAS group versus control (p

Purpose. The goals of this study were to evaluate the safety and efficacy of an ophthalmic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based nanoemulsion (Nanodrop®) in patients with dry eye disease (DED). Methods. This was a randomized phase I/II multicentric, prospective, double-blind clinical trial. Patients (phase I: n = 25 and phase II: n = 101) were assigned to receive either PRO-176 (Nanodrop®) or Systane Balance® (control) for 29 days. Once the visits of the first 25 subjects were completed, if there were less than 20% of unexpected adverse events (AEs), related to PRO-176, recruitment was continued until the sample was completed for noninferiority (efficacy) analysis (phase II, n = 126). Efficacy endpoints were the ocular surface disease index (OSDI), tear break-up time (TBUT), epithelial defects, best corrected visual acuity (BCVA), and the incidence of expected AE. Results. For the phase I portion of the study, there were no differences between groups regarding the incidence of AE. All related-AE symptoms in both groups were mild and expected. For the phase II subset, there was a significant reduction in OSDI scores at day 29 and noninferiority between treatments was confirmed (p=0.650, CI 95% [−8.7, 5.5]). Similar improvement was observed for TBUT although no significant intergroup differences were found (p=0.518, CI 95% [−0.08, 1.6]). There were no significant differences between treatments for epithelial staining or safety parameters. Conclusions. Topical application of PRO-176 is as safe and effective as the controls. Both groups were clinically similar in terms of efficacy and safety. The results support the hypothesis that ophthalmic DMPC-based nanoemulsion may improve clinical parameters and symptoms in patients with DED. This trial is registered with NCT04111965.

Abstract Background To evaluate the retinal toxicity after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white (NZW) rabbit eyes. Methods NZW rabbits were injected intravitreally with PRO-169 (n = 12), 1.25 mg/0.05 ml or ranibizumab (n = 12), 0.5 mg/0.05 ml into the right eye (OD), whereas the left eye (OS) of each rabbit was used as control. Three consecutive injections were administered at 30-days intervals. An electroretinogram (ERG) was recorded 30 days after each injection. Clinical examination was conducted before and after injections, including intraocular pressure determination and eye fundus exploration. Eyes were enucleated and retina, cornea, conjunctiva, ciliary body and optic nerve were prepared for histopathology assessment. Results ERG of the experimental and control eyes in PRO-169 and ranibizumab groups were similar in amplitude and pattern throughout the follow-up period. Clinical examination found no alterations of intraocular pressure (IOP). No retinal damage was observed in both, the experimental and control eyes, of all the rabbits. The histopathologic studies showed similar results in both groups, showing no signs of structural damage. Conclusions Our study did not find evidence of retinal toxicity from a repeated intravitreal injection of PRO-169 or ranibizumab (Lucentis®) in NZW rabbits. These findings support intravitreal PRO-169 as a safe candidate to develop as a future alternative for the treatment of retinal neovascularization diseases.

Objetivo: En este estudio se determinó el efecto de la implementación de la factura electrónica sobre la competitividad en las empresas PyMes en la comercialización de bienes y servicios. Método: el tipo de investigación es de carácter cuantitativo–explicativo, se realizó encuestas a los representantes legales de las empresas PyMes, aplicando la matriz de lado a lado de análisis de datos, para medirla e interpretarla. Resultados: Se evidencia el impacto positivo en la innovación de la organización al utilizar la factura electrónica; mejora el canal de comunicación y el servicio al cliente; incrementa la productividad; su utilización proporciona ventaja competitiva al disminuir los costos y al aumentar la competitividad, producto de la innovación, servicio, rapidez y productividad. Conclusión: Tanto la investigación como los autores teóricos coinciden en que la utilización de la factura electrónica permite a las empresas un servicio ágil; reduce reprocesos administrativos aumenta la productividad de los empleados; mejora e incrementa los servicios con la tecnología¸ y trae muchos efectos positivos a la organización.

En la práctica profesional, el psicólogo clínico tiene la obligación de comunicar los resultados de su actividad mediante un informe claro y preciso. Este informe es conocido en la literatura como Informe Psicológico Clínico (IPC), para su correcta redacción y presentación, el psicólogo debe conocer su estructura, y una serie de pautas, así como tener un estricto conocimiento de la bioética. Algunos documentos que el psicólogo debe tener presente dado que en estos se encuentran las pautas generales y consideraciones éticas son los siguientes: the Psychologist Ethical Code (2010), Ley General de Salud (2006), the American Psychological Association's Ethical Code (Asociación Americana de Psicología, 2010), Lineamientos para el Proceso de Evaluación Psicológica (GPEP, Fernández-Ballesteros y Calero, 2013), entre otros. En el presente trabajo se muestran 10 recomendaciones básicas para la elaboración de IPC en México: tener capacidad o calificación profesional, respetar la intimidad, dignidad, autonomía y libertad del paciente, respetar y hacer cumplir el derecho de informar al cliente, organizar el contenido, describir los instrumentos y evaluaciones realizadas, solicitar el consentimiento informado, justificar conclusiones, guardar la confidencialidad y el secreto profesional.

Antecedentes.La hipertensión arterial (HTA) se define como una presión arterial sistólica (PAS) mayor o igual a 140 mmHg o una presión arterial diastólica (PAD) mayor o igual a 90 mmHg medida en el paciente, siendo este uno de los principales motivos de consulta al médico. Objetivo. Obtener una mejor comprensión de los factores de riesgo comprometidos con la presentación de hipertensión arterial, en los empleados de los centros urbanos de Atención en Seguridad Social, Bienestar y Salud, empresa social de Estado (ASSBASALUD E.S.E) Manizales. Material y métodos. El estudio de tipo descriptivo transversal fue realizado mediante la aplicación de una encuesta a 241 funcionarios de la salud hombres y mujeres, con edades comprendidas entre los 20 y 69 años. Se determinaron variables como: información demográfica, antecedentes familiares y personales de hipertensión arterial, tabaquismo, índice de masa corporal, índice cintura cadera, cifras de presión arterial sistólica y diastólica. Resultados. Según la prueba de c2, las variables asociadas con hipertensión arterial fueron: individuos casados (29.6%) y solteros (29.6%), que ingieren licor (40.7%), con antecedentes patológicos relacionados con la hipertensión, que consumen medicamentos con prescripción médica y con antecedentes de exposición al cigarrillo (25.9%). La población femenina presentó la mayor proporción de factores de riesgo, siendo la hipertensión arterial y la dislipidemia los de más alto impacto con un 81.5 por ciento respectivamente. Conclusiones. Conocido el perfil epidemiológico de hipertensión arterial en la población estudiada, la institución ha de priorizar acciones en el campo de la prevención de la hipertensión arterial con una orientación multifactorial, esto con el fin de disminuir de esta manera las enfermedades cardiovasculares de sus empleados. Estos datos demuestran la importancia del índice cintura cadera como parámetro para establecer el riesgo de presentación de hipertensión arterial en estudios epidemiológicos.

PRO-169 is an anti-VEGF monoclonal antibody developed by Laboratorios Sophia that shares its sequence with Bevacizumab (BVZ); though, PRO-169 is intended for intravitreal administration. In this study, analytical characterization showed that PRO-169 had glycosylation differences in comparison to BVZ reference product (RP); since it had more content of G1F, G2F, sialic acid and high mannose. Further investigation was performed to evaluate if differences between both products would affect the efficacy and safety profile of PRO-169. PRO-169 had no alteration in its in vitro biological activity; moreover, no cytotoxicity or immunogenicity concerns should be expected as demonstrated by different orthogonal methods at analytical, in vitro and in vivo assays. These results support moving to the clinical testing of PRO-169 since no major complications will be expected with its clinical use for the treatment of ophthalmic diseases., Competing Interests: Declaration of competing interest All authors are employees of Centro de Investigación de Sophia S.A. de C.V. or Laboratorios Sophia S.A. de C.V. which are developing PRO-169. The authors declare no proprietary interest in PRO-169. Patent application MX/a/2017/003667 was submitted on 2017-03-17, by Laboratorios Sophia SA de CV. Publication date: 2018-10-19. IMPI., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The objective of this study was to identify and determine factors associated with patients' ophthalmic adherence in common ocular conditions from randomized clinical trials (RCT)., Research Design Methods: A univariate analysis with proportions, a bivariate analysis using polychoric correlations, and logistic regression (LR) models were used. The collected dataset was made up of records from RCT. Using three validated LR models, factors were identified and ranked based on their adjusted odds ratio and their statistical significance to adherence., Results: A total of 1,087 valid patients were included in this analysis, of which 88.96% presented adherence. All models were calibrated, had a good performance, were well specified and cost-effective using the Hosmer-Lemeshow test, metrics for class imbalance, link test approach and Akaike's criteriums, respectively., Conclusion: We identified as determinants for encouraging good ophthalmic adherence the adverse events presented, duration of the study, female sex, and older age; other determinants such as medical condition, protocol treatment, type of treatment and disease are all risk factors for adherence. Improvements in ophthalmic adherence may be achieved by focused attention to young male patients with chronic degenerative diseases such as glaucoma or ocular hypertension (especially those who need combination therapy) and developing medications with reduced side effects.

Purpose: The goals of this study were to evaluate the safety and efficacy of an ophthalmic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based nanoemulsion (Nanodrop®) in patients with dry eye disease (DED)., Methods: This was a randomized phase I/II multicentric, prospective, double-blind clinical trial. Patients (phase I: n  = 25 and phase II: n  = 101) were assigned to receive either PRO-176 (Nanodrop®) or Systane Balance® (control) for 29 days. Once the visits of the first 25 subjects were completed, if there were less than 20% of unexpected adverse events (AEs), related to PRO-176, recruitment was continued until the sample was completed for noninferiority (efficacy) analysis (phase II, n  = 126). Efficacy endpoints were the ocular surface disease index (OSDI), tear break-up time (TBUT), epithelial defects, best corrected visual acuity (BCVA), and the incidence of expected AE., Results: For the phase I portion of the study, there were no differences between groups regarding the incidence of AE. All related-AE symptoms in both groups were mild and expected. For the phase II subset, there was a significant reduction in OSDI scores at day 29 and noninferiority between treatments was confirmed ( p =0.650, CI 95% [-8.7, 5.5]). Similar improvement was observed for TBUT although no significant intergroup differences were found ( p =0.518, CI 95% [-0.08, 1.6]). There were no significant differences between treatments for epithelial staining or safety parameters., Conclusions: Topical application of PRO-176 is as safe and effective as the controls. Both groups were clinically similar in terms of efficacy and safety. The results support the hypothesis that ophthalmic DMPC-based nanoemulsion may improve clinical parameters and symptoms in patients with DED. This trial is registered with NCT04111965., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Leopoldo M. Baiza-Durán et al.)

Background: The objective of this study was to validate an animal model for dry eye during and after the administration of 1% ophthalmic atropine sulfate (OAS) in New Zealand white (NZW) rabbits., Methods: OAS (1%) was applied three times per day to 30 eyes of 15 healthy NZW rabbits. Sacrifice, enucleation, and lacrimal gland removal took place on days 15, 21, and 30 (OAS group). A second group (n = 5) was used as control. Clinical evaluations took place on days 3, 10, 15, 18, 21, 24 and 30. The primary endpoints were: Schirmer I test, tear break-up time (TBUT), and corneal fluorescein staining. As secondary endpoints, clinical changes including intraocular pressure, and histopathology were evaluated., Results: While OAS was administered, the Schirmer I test showed a statistically significant reduction for OAS group versus control (p < 0.001), and versus basal production (p < 0.001). TBUT showed statistically significant differences between groups (days 3 and 10; p = 0.001) and versus basal values (day 3; p < 0.001). Fluorescein staining showed a statistically significant difference (day 3; p = 0.001). The most frequent clinical finding was conjunctival hyperemia (76.9% OAS vs. 20% control). For histopathology, all OAS subjects presented some degree of inflammation (86.7% minimal; 13.3% mild) whereas the control presented only 30% minimal inflammation. Goblet cell density showed no difference., Conclusions: The effectiveness of the OAS dry eye model in NZW rabbits as reported in previous studies was confirmed, provided that the application of the drug is maintained throughout the intervention; it is not a viable model after OAS administration is suspended., (© 2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Purpose : To evaluate the efficacy of a preservative free sodium hyaluronate/chondroitin sulfate ophthalmic solution (SH/CS-PF) in patients with dry eye disease (DED). Methods : This was a randomized phase IV, multicentric, prospective, double-blind clinical trial. Intent-to-treat (ITT) and per-protocol (PP) analyses were performed. Patients were assigned to receive either SH/CS-PF, Systane® Ultra (PEG/PG) or Systane® Ultra PF (PEG/PG-PF) for 90 days. A total of 326 patients were included in the ITT, and 217 in the PP analysis. Efficacy endpoints were goblet cell density, Nelson's grades (conjunctival impression cytology), tear break-up time (TBUT), Ocular Surface Disease Index (OSDI), and Schirmer's test. Other parameters included were tolerability, measured by the ocular symptomatology; and safety, measured through corneal staining, intraocular pressure, visual acuity and adverse events. Results : In the ITT, there was a significant increase in mean goblet cell density in all treatments compared with their baseline (28.4% vs 21.4% and 30.8%), without difference between arms ( p = .159). Eyes exposed to SH/CS-PF, PEG/PG and PEG/PG-PF showed Grade 0-I squamous metaplasia (85.5%, 87.9% and 93.2%, respectively). Similar improvements were observed for TBUT (1.24 ± 2.3s vs 1.27 ± 2.4s and 1.39 ± 2.3s) and OSDI scores at day 90 (-8.81 ± 8.6 vs -7.95 ± 9.2 and -8.78 ± 9.8), although no significant intergroup difference was found. Schirmer's test also presented improvement compared to baseline (1.38 ± 4.9 vs 1.50 ± 4.7 and 2.63 ± 5.9), with a significantly higher variation for PEG/PG-PF. There were no significant differences between treatments for any tolerability and safety parameter, nor between ITT and PP analyses for any outcome. Conclusions : The topical application of SH/CS-PF is as effective, safe and well tolerated as that of PEG/PG or PEG/PG-PF. The results suggest that SH/CS-PF may lead to normalization of clinical parameters and symptom alleviation in patients treated for DED.

Background: To evaluate the retinal toxicity after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white (NZW) rabbit eyes., Methods: NZW rabbits were injected intravitreally with PRO-169 (n = 12), 1.25 mg/0.05 ml or ranibizumab (n = 12), 0.5 mg/0.05 ml into the right eye (OD), whereas the left eye (OS) of each rabbit was used as control. Three consecutive injections were administered at 30-days intervals. An electroretinogram (ERG) was recorded 30 days after each injection. Clinical examination was conducted before and after injections, including intraocular pressure determination and eye fundus exploration. Eyes were enucleated and retina, cornea, conjunctiva, ciliary body and optic nerve were prepared for histopathology assessment., Results: ERG of the experimental and control eyes in PRO-169 and ranibizumab groups were similar in amplitude and pattern throughout the follow-up period. Clinical examination found no alterations of intraocular pressure (IOP). No retinal damage was observed in both, the experimental and control eyes, of all the rabbits. The histopathologic studies showed similar results in both groups, showing no signs of structural damage., Conclusions: Our study did not find evidence of retinal toxicity from a repeated intravitreal injection of PRO-169 or ranibizumab (Lucentis ® ) in NZW rabbits. These findings support intravitreal PRO-169 as a safe candidate to develop as a future alternative for the treatment of retinal neovascularization diseases., Competing Interests: Competing interestsThe authors declare that they have no other competing interest in this work., (© The Author(s) 2020.)

Background: Prenatal alcohol exposure (PA) restricted to days 8-20 of rat gestation reduces the activity of the dopaminergic neurons (DA) in the ventral tegmental area (VTA). Hyperactivity and impulsivity have been observed under this treatment; however, it is unknown whether DA levels are affected. Decision-making in risk situations, meanwhile, has been associated with impulsive behavior, but because studies of this phenomenon in animal models are limited, we do not yet know whether PA has any effect. The present study investigated the effects of PA on risk-taking behavior and locomotor activity in pre-pubertal male rats. In addition, DA levels in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) in response to methylphenidate (MP) were assessed., Methods: Dams were treated with either two daily 3.0-g/kg doses of alcohol or an isocaloric solution, from days 8-20 of gestation. Locomotor activity and risk-taking in pre-pubertal male rats after PA, and DA levels in the NAcc and mPFC after a single dose of MP (5mg/kg), were analyzed., Results: Hyperactivity and increased risk-taking behavior were observed in the rats treated prenatally with alcohol compared to controls. Methylphenidate increased DA levels in the NAcc regardless of prenatal treatment, but significantly higher DA levels were found in the PA group regardless of postnatal treatment with saline or MP., Conclusion: The presence of hyperactivity and increased risk-taking behavior after prenatal alcohol treatment is supported. Results suggest that higher DA levels in the rats with PA could be due to a down-regulation of postsynaptic receptors, the desensitization of presynaptic receptors, or a compensatory over-activity of DA neurons in the VTA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone which has recently emerged as a designer drug of abuse. The objective of this study was to investigate the locomotor sensitization induced by MDPV in adolescent mice, and associated neuroplastic changes in the nucleus accumbens and striatum through deltaFosB and CREB expression. Behavioural testing consisted of three phases: Phase I: conditioning regimen with MDPV (0.3 mg/kg/day for five days) or saline; Phase II: resting (11 days); Phase III: challenged with MDPV (0.3 mg/kg), cocaine (10 mg/kg) or saline on day 16 for both groups. Mice repeatedly exposed to MDPV increased locomotor activity by 165-200% following acute MDPV or cocaine administration after an 11-day resting period, showing a MDPV-induced sensitization to itself and to cocaine. An explanation for this phenomenon could be the common mechanism of action between these two psychostimulants. Furthermore, the MDPV challenge resulted in higher levels of phospho-CREB in MDPV-conditioned mice compared with MDPV-naive mice, probably due to an up-regulation of the cAMP pathway. Likewise, MDPV exposure induced a persistent increase in the striatal expression of deltaFosB; the priming dose of MDPV also produced a significant increase in the accumbal expression of this transcription factor. This study constitutes the first evidence that an exposure to a low dose of MDPV during adolescence induces behavioural sensitization and provides a neurobiological basis for a relationship between MDPV and cocaine. We hypothesize that, similar to cocaine, both CREB and deltaFosB play a role in the induction of this behavioural sensitization., (© The Author(s) 2016.)