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INTRODUCTION: Patients with dry eye disease (DED) complain of a multitude of symptoms that affect their visual function and quality of life (QoL). This clinical investigation assessed the performance, tolerance, and safety of a novel preservative-free ophthalmic solution containing xanthan gum 0.2% and desonide sodium phosphate 0.025%. METHODS: This was an observational, prospective, multicentric, and post-market clinical investigation to assess the effect of three times a day instillation of the study formulation in patients suffering from DED. The primary objective was to achieve a 50% reduction in conjunctival hyperemia index as assessed with the OCULUS Keratograph after 1 month of treatment compared to baseline values. The secondary objectives included patient-reported outcomes, clinical performance, and safety. RESULTS: Thirty patients were enrolled (21 women, 9 men) with a mean age of 61.10 ± 14.53 years. The instillation of the study formulation was associated with a significant reduction in redness scores after 1 month of treatment compared to baseline (mean - 0.51 ± 0.51; p ≤ 0.0001). Although the primary endpoint was not completely met, a 50% reduction in the conjunctival hyperemia index was achieved in 23% of the participants, and 77% showed a reduction of 26% of the same index. In addition, the ophthalmic solution significantly increased tear film break-up time, and a significant reduction of corneal and conjunctival staining with fluorescein was achieved. It also reduced DED symptoms and had a very good safety profile. CONCLUSIONS: the study formulation produced a significant improvement in the signs, symptoms, and QoL of patients with mild to moderate DED with a good safety profile after 1 month of treatment.
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INTRODUCTION: To demonstrate efficacy and safety of an ophthalmic hydrogel formulation of netilmicin/dexamethasone, containing xanthan gum twice a day (b.i.d.) versus netilmicin/dexamethasone eye drops four times a day (q.i.d) to treat inflammation and prevention of infection after cataract surgery. METHODS: Patients undergoing phacoemulsification with intraocular lens implantation (IOL) were randomised in two groups: group 1, twice daily (b.i.d.) dexamethasone 0.1%/netilmicin 0.3% (Netildex) ophthalmic gel; group 2, four times daily (q.i.d.) dexamethasone 0.1%/netilmicin 0.3% (Netildex) eye drops. Both treatments were administered for 14 days after surgery. Patients were evaluated before surgery, on the day of surgery and at 1, 7, 15 and 60 postoperative days. The primary efficacy endpoint was evaluation of cellularity and flare in the anterior chamber through slit-lamp biomicroscopy 7 days after surgery. Secondary endpoints included: presence of signs/symptoms of postoperative ocular inflammation and incidence of infection. RESULTS: One hundred seventy-three patients were randomised and 168 were evaluable. Flare and cellularity were resolved at day 7 in 92.5% of patients and almost completely by day 15. In both intent to treat (ITT) and per-protocol (PP) populations, the efficacy analysis demonstrated that the gel formulation administered twice a day was non-inferior to the eye drops administered four times a day. For ITT analysis, the lower limit of the 97.5% confidence interval (- 0.0535) was greater than the non-inferiority limit of -0.10. For the PP analysis, the lower limit of the 97.5% confidence interval (- 0.0526) was greater than the non-inferiority limit of - 0.10. The patient's global tolerability and reported symptoms were similar between treatment groups. No microbial load and no safety events were observed. CONCLUSIONS: Efficacy of the gel reduced posology (twice a day) is not inferior to four times a day eye drops. Both treatments were well tolerated and efficacious. The new reduced posology hydrogel formulation may improve patient compliance and quality of life. TRIAL REGISTRATION: Eudract: 2016-0021138-63; ClinicalTrial.gov: NCT029738880.
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Catarata , Netilmicina , Humanos , Netilmicina/uso terapéutico , Implantación de Lentes Intraoculares/efectos adversos , Dexametasona/efectos adversos , Hidrogeles/efectos adversos , Calidad de Vida , Inflamación/tratamiento farmacológico , Inflamación/etiología , Soluciones Oftálmicas/uso terapéutico , Método Doble Ciego , Catarata/complicaciones , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/prevención & control , Resultado del TratamientoRESUMEN
A rapid, selective and sensitive method for quantification of latanoprost free acid in rabbit aqueous humor (AH) and ciliary body (CB) using reverse phase-high performance liquid chromatography coupled with electrospray ionization (ESI)-mass spectrometry/mass spectrometry has been developed and validated. Quantification in AH and CB was achieved by stable isotope dilution employing tetra-deuterated analog of latanoprost free acid, used as internal standard. Sample preparation was based on protein precipitation with methanol in AH, and on liquid extraction with a mixture of ethyl acetate and isopropanol 60:40 (v/v) in CB. Elution was achieved on an octylsilica (C8) column, using an isocratic elution method. Detection was performed on a triple quadrupole mass spectrometer, using ESI in positive ion selected reaction monitoring mode. Calibration curves were linear in the validated concentration ranges of 10-160 ng/mL in AH and 80-1280 ng/g in CB. The accuracy and precision values, obtained from three different sets of quality control samples, each analyzed in triplicate on three different days, were within the generally accepted criteria for analytical methods (< 15%). The limit of detection was 30.66 pg/mL in AH and 237.75 pg/g in CB. The assay proved to be accurate and precise when applied to the in vivo study of latanoprost free acid in rabbit AH and CB after single administration of an eye drops containing latanoprost.
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Humor Acuoso/química , Cromatografía Liquida/métodos , Cuerpo Ciliar/química , Prostaglandinas F Sintéticas/análisis , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Estabilidad de Medicamentos , Latanoprost , Análisis de los Mínimos Cuadrados , Masculino , Conejos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodosRESUMEN
A rapid, sensitive and selective method for the simultaneous quantification of carteolol and dorzolamide in rabbit aqueous humor (AH) and ciliary body (CB) has been developed and validated using reversed phase-high performance liquid chromatography (RP-HPLC) with isocratic elution coupled with atmospheric pressure chemical ionization mass spectrometry/mass spectrometry (APCI-MS/MS). The analytes and nadolol (used as internal standard, IS) were purified from AH by protein precipitation. The sample preparation from CB was based on a two steps extraction procedure at different pH, utilizing a liquid-liquid extraction with a mixture of ethyl acetate, toluene and isopropanol 50:40:10 (v/v) at pH 8, followed by a second extraction with ethyl acetate at pH 11. The combined organic extracts were then back extracted into 0.1% aqueous trifluoroacetic acid (TFA). The accuracy and precision values, calculated from three different sets of quality control samples analyzed in sestuplicate on three different days, were within the generally accepted criteria for analytical methods (<15%). The assay proved to be accurate and precise when applied to the in vivo study of carteolol and dorzolamide in rabbit AH and CB after single administration of an eye drops containing both drugs.
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Antihipertensivos/análisis , Humor Acuoso/química , Carteolol/análisis , Cromatografía Líquida de Alta Presión/métodos , Cuerpo Ciliar/química , Espectrometría de Masa por Ionización de Electrospray/métodos , Sulfonamidas/análisis , Tiofenos/análisis , Animales , Antihipertensivos/uso terapéutico , Carteolol/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Masculino , Hipertensión Ocular/tratamiento farmacológico , Conejos , Sulfonamidas/uso terapéutico , Tiofenos/uso terapéuticoRESUMEN
Dexamethasone transport across ocular epithelium was evaluated by means of permeability studies on a series of ester prodrugs with the aim of identifying the most promising candidates for the treatment of the ocular surface. Organotypic conjunctival bovine epithelial cell cultures were assumed representative of an average ocular epithelium and used to describe the mechanism of permeation. Permeability coefficients were also determined in excised rabbit corneas set up and in vivo pharmacokinetic experiments. All dexamethasone esters permeated through the transcellular route and their permeability coefficient rose with the increase of the molecules lipophilicity until a maximum was reached in correspondence of dexamethasone butyrate (Log P = 3.95). It was found that esters hydrolysis occurring in various extent along the transport process, affected the overall permeability rate. There was evidence that the permeation process can be confined at the ocular epithelium layer if the ester is highly hydrophobic and not susceptible of fast hydrolysis.
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Humor Acuoso/metabolismo , Conjuntiva/metabolismo , Córnea/metabolismo , Dexametasona/farmacocinética , Células Epiteliales/metabolismo , Animales , Transporte Biológico , Bovinos , Células Cultivadas , Conjuntiva/citología , Dexametasona/química , Ésteres , Masculino , Permeabilidad , Conejos , Distribución TisularRESUMEN
OBJECTIVE: The purpose of this study was to obtain a primary cell culture of bovine origin similar to the conjunctiva in terms of morphology and cell types, which could be of use for in vitro toxicity studies. METHODS: After separation from the stroma by enzymatic treatment, conjunctival epithelial cells were dissociated and plated onto collagen-coated Transwell filters (1.13 cm(2) area). One group of plates was maintained in immersion and another was cultured under air-lifted conditions. Anti-epithelial keratin antibodies (AE1/AE3, K4) and antidesmoplakin 1 and 2 were used to characterize the cells by indirect immunofluorescence. The cell layer was examined after histological processing of the Transwell filter. Ultrastructural analysis was carried out by scanning electron microscopy (SEM). The bioelectric parameters transepithelial electrical resistance (TEER), potential difference (PD), short circuit current and paracellular permeability profile of carboxyfluorescein were monitored as indices of the functional characteristics of these cultures. Cytotoxicity was evaluated on morphological and functional (TEER) grounds after treating the cultures with several test substances. RESULTS: Morphological studies showed pure and homogeneous cell cultures. In the SEM analysis, we observed contiguous polygonal cells with numerous short microvilli, a characteristic proportion of light, medium and dark cells and a sparse population of rounded PAS-positive cells, i.e. resembling goblet cells. Air-lifted cultures also showed a tissue-like cellular organization (8-9 layers). Immersion cultures reached a maximum TEER value of around 2.95 kOmega x cm(2) 7 days after plating while in air-lifted cultures TEER peaked up to 5.59 komega x cm(2) 11 days after plating. With regard to the use of bovine conjunctival epithelial cells (BCECs) for cytotoxicity screening, the system responded finely to the insults and yielded morphological and functional results in accordance with data obtained in vivo. CONCLUSIONS: BCECs reproduce cell morphology and differentiation of the original tissue and should prove a useful tool for initial studies of drug toxicity.