In Vivo Effects of Preservative-free and Preserved Prostaglandin Analogs: Mouse Ocular Surface Study

PURPOSE: Chronic use of topical hypotensive agents induces several side effects caused by preservatives. The purpose of this study was to evaluate the effects of prostaglandin analogs with varying concentrations of benzalkonium chloride (BAC), preservative-free (PF), and alternative preservatives on mouse corneal tissue. METHODS: Thirty-five, 8- to 10-week-old female C57BL/6 mice (five mice for each group) were used for this study. To the control group, we applied normal saline, and to each drug-treated group we applied 0.02% BAC, bimatoprost 0.01% (with BAC 0.02%), latanoprost 0.005% (with BAC 0.02%), travoprost 0.004% (with 0.001% polyquad) or tafluprost 0.0015% with/without 0.001% BAC, once a day (9 p.m.) for 4 weeks. Corneal fluorescein staining was evaluated in all groups. After harvest, the corneal tissues were embedded in paraffin and then Hematoxylin-Eosin stain was performed for histopathological examination. Immunofluorescence staining was done against TNF-alpha, IL-6, HLA DR, pJNK, and pAkt. RESULTS: In corneal fluorescein staining, severe punctate epithelial keratitis was seen in the groups of 0.02% BAC, 0.02% BAC containing bimatoprost 0.01% and latanoprost 0.005%. The surface desquamation, irregular surface, loss of cell borders, anisocytosis and stromal shrinkage were observed in the groups of BAC-containing eye drops. Moreover, the groups treated with BAC-containing eye drops have high inflammatory markers, significantly decreased cell viability-related signal, pAkt, and higher apoptosis-inducing signal, pJNK, than the control group. On the other hand, travoprost 0.004% and PF tafluprost 0.0015% have less cellular morphologic changes, lower inflammation, and higher cellular viability than BAC-containing formulations. CONCLUSIONS: Corneal damage, increased inflammation and apoptosis and low cell viability were observed in BAC-containing groups. PF or alternatively preserved glaucoma medications seem to be a reasonable and viable alternative to those preserved with BAC.

Topical Prostaglandin Analogue Drugs Inhibit Adipocyte Differentiation

PURPOSE: To investigate the effects of topical prostaglandin analogue drugs on the differentiation of adipocytes. METHODS: Differentiation of 3T3-L1 preadipocytes was induced with isobutylmethylxanthine, dexamethasone, and insulin. 3T3-L1 cells were exposed to 0.008, 0.08, 0.2 microM of latanoprost and travoprost. Reverse transcription polymerase chain reaction for mRNA expression of lipoprotein lipase and peroxisome proliferator-activated receptor gamma 2 (PPARgamma2), and glycerol-3-phosphate dehydrogenase (G3PDH) assays were performed to examine the effects on early and late differentiation, respectively. Also, glycerol assays were done to evaluate the effect of prostaglandin analogues on lipolysis after differentiation. RESULTS: Both prostaglandin analogues inhibited differentiation of preadipocytes. Topical prostaglandin analogues significantly decreased G3PDH activity, a marker of late differentiation. However, topical prostaglandin analogues did not change mRNA expressions of lipoprotein lipase and PPARgamma2, markers of early differentiation. The activities of the early markers of differentiation were not changed significantly before and after growth arrest. Compared to latanoprost, travoprost decreased G3PDH activity more significantly (p 0.05). CONCLUSIONS: Prostaglandin analogues display an inhibitory effect on the differentiation of adipocytes when the cells start to differentiate especially in the late stage of differentiation. Thus, commercial topical prostaglandin analogues may decrease the fat contents of eyelids.

Ocular surface evaluation in patients treated with a fixed combination of prostaglandin analogues with 0.5% timolol maleate topical monotherapy: a randomized clinical trial

OBJECTIVES: To compare ocular surface changes induced via glaucoma treatment in patients using fixed combinations of prostaglandin analogues (travoprost, latanoprost and bimatoprost) with 0.5% timolol maleate METHODS: A prospective, multicenter, randomized, parallel group, single-blind clinical trial was performed in 33 patients with ocular hypertension or open angle glaucoma who had not been previously treated. The ocular surface was evaluated prior to and three months after treatment, with a daily drop instillation of one of the three medications. The main outcome measurements included the tear film break-up time, Schirmer's test, Lissamine green staining, the Ocular Surface Disease Index questionnaire, impression cytology using HE and PAS and immunocytochemistry for interleukin-6 and HLA-DR. Ensaiosclinicos.gov.br: UTN - U1111-1129-2872 RESULTS: All of the drugs induced a significant reduction in intraocular pressure. Decreases in the Schirmer's test results were observed with all of the drugs. Decreases in tear-film break-up time were noted with travoprost/timolol and latanoprost/timolol. An increase in the Lissamine green score was noted with travoprost/timolol and bimatoprost/timolol. The Ocular Surface Disease Index score increased after treatment in the travoprost/timolol group. Impression cytology revealed a significant difference in cell-to-cell contact in the same group, an increase in cellularity in all of the groups and an increase in the number of goblet cells in all of the groups. The fixed combinations induced an increase in IL-6 expression in the travoprost/timolol group, in which there was also an increase in HLA-DR expression. CONCLUSIONS: All of the fixed combinations induced a significant reduction in intraocular pressure, and the travoprost/timolol group showed increased expression of the inflammatory markers HLA-DR and interleukin-6. All three tested medications resulted in some degree of deterioration in ...

Conjunctival changes induced by prostaglandin analogues and timolol maleate: a histomorphometric study

PURPOSE: To compare histological changes induced by antiglaucoma medications in the rabbit conjunctiva. METHODS: Fifty New Zealand rabbits were divided in 5 groups of 10 animals. The left eyes were treated daily with one drop of bimatoprost 0.03 percent, travoprost 0.004 percent, latanoprost 0.005 percent, timolol maleate 0.5 percent or artificial tears containing benzalkonium chloride (BAK) for 30 days. The right eyes served as controls. Superior limbic conjunctival biopsies were performed at the 8th and 30th day in 5 rabbits of each group. The conjunctiva was fixed with 10 percent formaldehyde, followed by HE and PAS staining. Morphohistometric quantitative analyses were performed to evaluate the following parameters: inflammatory infiltrate, epithelial thickness, number of goblet cells, diameter and number of blood vessels. RESULTS: At the 8th and 30th posttreatment days, all groups, except one that received artificial tears, exhibited a diffuse inflammatory infiltrate, composed by lymphocytes and neutrophils, which was denser in the timolol group than in the prostaglandin (PG) analogues groups. At the 30th day, the timolol group also showed an increased subepithelial collagen density and a significant increase in epithelial thickness (p=0.0035). The goblet cell density was significantly increased at the 8th day in the group treated with travoprost (p=0.0006), and at the 30th day in those treated with bimatoprost (p=0.0021) and latanoprost (p=0.009). CONCLUSIONS: Although a moderate, diffuse inflammatory infiltrate was observed in PG-treated eyes, no changes in conjunctival epithelial thickness or subconjunctival collagen density were observed with these medications, suggesting that these drugs induce fewer changes than timolol maleate in the rabbit conjunctiva.

OBJETIVOS: Comparar alterações histológicas induzidas por medicação anti-glaucomatosa na conjuntiva de coelhos. MÉTODOS: Cinqüenta coelhos da raça Nova Zelândia foram divididos em 5 grupos de 10 animais. Os olhos esquerdos foram tratados com uma gota diária de bimatoprosta 0,03 por cento, travoprosta 0,004 por cento, latanoprosta 0,005 por cento, maleato de timolol 0,5 por cento ou lágrimas artificiais contendo cloreto de benzalcônio (BAK) por 30 dias. Os olhos direitos serviram como controles. Foram realizadas biópsias conjuntivais límbicas superiores no 8º e 30º dias em 5 coelhos de cada grupo. A conjuntiva foi fixada com formaldeído 10 por cento, seguido por coloração de HE e PAS. Foi realizada análise quantitativa morfohistométrica para avaliar os seguintes parâmetros: infiltrado inflamatório, espessura epitelial, número de células caliciformes, diâmetro e número de vasos sanguíneos. RESULTADOS: No 8º e 30º dias de tratamento, todos os grupos, exceto aquele que recebeu lágrimas artificiais, exibiram infiltrado inflamatório difuso, composto por linfócitos e neutrófilos, sendo mais denso no grupo timolol do que nos grupos dos análogos de prostaglandinas. No 30º dia, o grupo timolol apresentou um aumento na densidade de colágeno subepitelial e um aumento significativo da espessura epitelial (p=0,0035). A densidade de células caliciformes aumentou significativamente no 8º dia no grupo tratado com travoprosta (p=0,0006), e no 30º dia nos grupos tratados com bimatoprosta (p=0,0021) e latanoprosta (p=0,009). CONCLUSÕES: Embora tenha sido observado um infiltrado inflamatório difuso e moderado nos olhos tratados com análogos de prostaglandinas, não houve alterações na espessura epitelial conjuntival ou densidade colágena subepitelial com essas medicações, sugerindo que essas drogas induzem menores alterações que o maleato de timolol na conjuntiva de coelhos.

Efecto de la dosis reducida de un análogo de la prostanglandina (luprostiol) por vía submucosa intravulvar en la luteólisis y la manifestación en vacas Suizo Pardo / Effect of reduce dose of prostaglandin via intravulva submucosal on the luteolytic effect and the estrous cycle in brown swiss cows

El objetivo del estudio fue evaluar si la dosis reducida de un análogo de la prostaglandina (Luprostiol) (LP) por vía submucosa intravulvar (SMIV) e ipsilateral al cuerpo lúteo (IPL) inducen la luteólisis y la manifestación del estro. Se utilizaron 39 vacas de la raza Suizo Pardo en producción con ciclos estrales regulares, las cuales fueron asignadas a los siguientes tratamientos: 15 mg de LP por vía intramuscular (n=13); T1, 11.2 mg de LP por vía SMIV e IPL (n=13); T2, 7.5 mg de LP por vía SMIV e IPL (n=13). Se tomaron muestras sanguíneas para medir la concentración plasmática de progesterona (P4) a la 0 h y posteriormente cada 12 h, hasta las 72 h postratamiento. Se consideró la luteólisis (LUT) cuando las concentraciones de P4 fueron menores de 1 ng/ml y se mantuvieron hasta las 72 h postratamiento. A las 0 h, inicio de los tratamientos, la concentración de P4 fue de 3.22 ng/ml, después de las 24 h los niveles de P4 fueron menores de 1 ng/ml y se mantuvieron hasta las 72 h postratamiento, sin mostrar diferencia entre los grupos tratados (P>0.05). El porcentaje total del estro (PTE) (84.1 por ciento) y el intervalo tratamiento-manifestación del estro (ITE) (86.4 h) fueron similares entre tratamientos (P>0.05). El peso corporal, el nivel de producción láctea, el número de parto y el intervalo parto-tratamiento no fueron determinantes para efectuar la LUT, el ITE y el PTE (P>0.05). Las vacas que recibieron dosis reducidas de LP por vía SMIV e IPL tuvieron LUT, ITE y PTE similares a los observados en vacas con una dosis completa y por vía intramuscular