Efficacy of timolol in the treatment of facial hemangioma and its effect on the proliferation and apoptosis of hemangioma stem cells.

To investigate the efficacy of timolol in the treatment of facial hemangioma and the effect on the proliferation and apoptosis of hemangioma stem cells, 60 cases of children with IHs admitted to our hospital between 2020 and 2021 were selected and divided into two groups. The grouping was according to the lottery method, with 30 cases in each group. In the observation group, 0.5% timolol maleate eye drops were applied topically, and in the control group, propranolol hydrochloride tablets were administered orally to observe the efficacy of hemangioma, changes in hemangioma stem cells and the incidence of adverse reactions in both groups. Results showed that combined with the four-level score and ultrasound results, the number of effective treatment cases in the observation group was 28, which was higher than that in the control group, (P<0.05). The total number of adverse reactions in the observation group was 2, with an incidence rate. Under the intervention conditions of timolol, the proliferation level of hemangioma stem cells was inhibited, and the apoptosis rate of hemangioma stem cells increased with the increase of culture time (P<0.05). Among them, the apoptosis rate of the timolol group was higher than that of the blank control group at the same time point (P<0.05), and the difference was most significant at 48h (P<0.001). In conclusion, Timolol can effectively treat facial hemangioma in children, inhibit the proliferation of hemangioma stem cells and promote their apoptosis, with good curative effect, short treatment time and no obvious adverse reactions and it is economical and easy to accept.

Timolol maleate, a ß blocker eye drop, improved edema in a retinal vein occlusion model.

Purpose: To investigate the therapeutic effects of eye drops, namely, timolol maleate, a ß-adrenergic receptor antagonist, and latanoprost, a prostaglandin F2α analog, on retinal edema in a murine retinal vein occlusion (RVO) model. Methods: An RVO model was established using laser-induced RVO in mice, which were administered timolol maleate and latanoprost eye drops several times after venous occlusion. Subsequently, the thickness of the inner nuclear layer (INL) and the expression levels of such genes as Vegf and Atf4, which are stress markers of the endoplasmic reticulum, were examined. Primary human cultured retinal microvascular endothelial cells (HRMECs) were treated with timolol under hypoxic conditions, after which the gene expression pattern was investigated. Importantly, an integrated stress response inhibitor (ISRIB) was used in the RVO model, he known ISRIB, which suppresses the expression of ATF4 in retinal edema. Results: Increased INL thickness was suppressed by timolol eye drops, as were the expressions of Vegf and Atf4, in the RVO model. However, latanoprost eye drops did not induce any change in INL thickness. In HRMECs, hypoxic stress and serum deprivation increased the Vegf and Atf4 expressions; in response, treatment with timolol suppressed the Vegf expression. Furthermore, the ISRIB decreased the Vegf expression pattern and edema formation, which are associated with RVO. Conclusions: These results indicate that timolol eye drops may be a potential option for RVO treatment.

Activation of ADRB2/PKA Signaling Pathway Facilitates Lipid Synthesis in Meibocytes, and Beta-Blocker Glaucoma Drug Impedes PKA-Induced Lipid Synthesis by Inhibiting ADRB2.

Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs.

Timolol 0.5% ophthalmic solution influences cardiac function in healthy cats.

OBJECTIVES: The aim of this study was to ascertain the effect of a drop of timolol 0.5% ophthalmic solution on the systolic function of the left ventricle (LV) and left atrium (LA), and to confirm if timolol helped appraisal of diastolic function by reducing heart rate (HR) and separating the transmitral outflow waves from tissue Doppler imaging (TDI). METHODS: A total of 41 client-owned healthy cats underwent two echocardiograms 20 mins apart. The timolol group (33 cats) received a drop of timolol solution after the first examination. Standard and speckle-tracking echocardiography evaluated the LV and LA function of both groups at the two time points evaluated. RESULTS: Timolol reduced HR (19%), and fractional shortening from LV (20.3%) and LA (16.6%). Septal S' decreased by 51% (from 7.7 to 5.2 cm/s) and lateral S' dropped by 43.1% (7.3 to 5.1 cm/s). Most longitudinal techniques did not change after timolol, including the mitral annular plane systolic excursion from the interventricular annulus, tricuspid annular plane systolic excursion, LV longitudinal strain and LV tissue motion annular displacement. The isovolumic relaxation time increased by 15.2% (from 54 to 64.6 ms), with most cats presenting this variable above the reference (>60 ms). Timolol did not support diastolic assessment, enabling evaluation in only 2/11 cats when using lateral TDI and 1/9 cats using septal TDI. Regarding side effects, miosis occurred in 18 cats (54.5%). CONCLUSIONS AND RELEVANCE: Timolol reduced systolic function, decreasing standard echocardiographic variables. Regarding diastolic evaluation, although timolol decreased HR, it did not separate the mitral diastolic waves, as expected.

Combination product of dermal matrix, preconditioned human mesenchymal stem cells and timolol promotes wound healing in the porcine wound model.

A combination product of human mesenchymal stem/stromal cells (MSCs) embedded in an extracellular matrix scaffold and preconditioned with hypoxia and the beta-adrenergic receptor antagonist, timolol, combined with sustained timolol application post implantation, has shown promising results for improving wound healing in a diabetic mouse model. In the present study, we extend those findings to the more translatable large animal porcine wound model and show that the combined treatment promotes wound reepithelialization in these excisional wounds by 40.2% and increases the CD31 immunostaining marker of angiogenesis compared with the matrix control, while maintaining an accumulated timolol plasma concentration below the clinically safe level of 0.3 ng/mL after the 15-day course of topical application. Human GAPDH was not elevated in the day 15 wounds treated with MSC-containing device relative to wounds treated with matrix alone, indicating that the xenografted human MSCs in the treatment do not persist in these immune-competent animals after 15 days. The work demonstrates the efficacy and safety of the combined treatment for improving healing in the clinically relevant porcine wound model.

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice.

Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 µM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 105 cells/cm2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro-inflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti-inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.

[Successful Treatment of Refractory Ischemic Diabetic Foot Ulcers by Combination Therapy of Autologous Platelet-rich Gel and Topical ß Adrenergic Receptor Blocker: a Case Report].

HISTORY AND CLINICAL FINDINGS: A 76 year-old woman with 8-year history of diabetes mellitus and hypertension was admitted with gangrene of left great toe, 3rd, 4th and 5th toes. Twenty months ago, She started to receive hemodialysis due to end-stage renal disease. She did not have any history of reactive airway disease nor bradycardia that would contraindicate the use of topical beta-blocker. The X-ray of left lower limb and foot showed calcification of left superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, dorsal foot artery and digital artery, as well as osteolytic destruction at distal end of metatarsal bone, and lateral dislocation of the 4th and 5th toes. Color Doppler ultrasound of bilateral lower extremity arteries showed obvious calcification of bilateral superficial femoral arteries, thrombosis of left popliteal artery, severe stenosis of left anterior tibial artery, occlusion of left posterior tibial artery, right anterior tibial artery and posterior tibial artery. Computed tomographic angiography (CTA) of bilateral lower limb arteries revealed moderate stenosis of left superficial femoral artery, occlusion of left popliteal artery, left posterior tibial artery and dorsal pedal artery, occulusion of right posterior tibial artery, but right dorsal pedal artery was visible. DIAGNOSIS, TREATMENT AND FOLLOW-UP: Diagnosis of diabetic foot (left, grade 4) and diabetic lower extremity arterial occlusion (left, stage 4) was made. Based on multidisciplinary team (MDT) discussion, the patient was unable to undergo vascular bypass surgery, and left lower extermity amputation also was not suitable because of right atrial thrombosis. Therefore, conservative treatment was recommended. The specific scheme used clopidogrel for antiplatelet agglutination, Low Molecular Weight Heparin (Clexane) and warfarin for anticoagulation, lipo-alprostadil for vasodilation, as well as local debridement and ultrasonic debridement. The treatments were given for up to 9 weeks, but with no significant clinical response. So the patient was treated with vacuum-assisted closure and autologous platelet-rich gel therapy for the next 7 weeks, then applied with 1 drop of timolol maleate 0.5% ophthalmic solution per cm 2 wound area every other day for another 6 weeks, the wound rapidly healed and re-epithelialized basically. The follow-up for 5 weeks showed that the wound healed completely without any discomfort. No side effect was found.

Are topical beta-blockers really effective "in real life" for targeted therapy-induced paronychia.

Paronychia and periungual pyogenic granuloma represent one of the most common and bothersome dermatologic toxicities observed with ErbB inhibitors. There is no standardized treatment, and management remains challenging. Moreover, conservative management with noninvasive treatment should be promoted for fragile patients in a metastatic setting. Over the last few years, the efficacy of topical blocking agents has been considered for managing cutaneous or mucosal pyogenic granulomas. Very recently, the use of topical propranolol or of timolol has been reported in several patients undergoing treatment with EGFR inhibitors and developing pyogenic granulomas of the nail. We performed a retrospective single-center review of patients with targeted therapy-related paronychia/periungual pyogenic granulomas who had been treated with topical timolol, either alone or in combination with other topical treatments. Nearly two thirds of patients showed at least a partial response after 1 month of therapy, and the use of a topical beta-blocker in our population was associated with a favorable safety profile. Finally, topical timolol may represent a promising treatment option for the management of cancer patients suffering from painful periungual lesions. Comparative clinical trials, however, are still needed.

An in vitro study of scarring formation mediated by human Tenon fibroblasts: Effect of Y-27632, a Rho kinase inhibitor.

Scar formation is the most common cause for failure of glaucoma filtration surgery because of increased fibroblast proliferation and activation. We have now examined the effect of Y-27632, a Rho-associated protein kinase (ROCK) inhibitor, on postsurgical scarring formation in human Tenon fibroblasts (HTFs). Collagen gel contraction assay was used to compare contractility activity of Y-27632 with several antiglaucoma drugs. Immunofluorescence and western blotting were used to examine expression of scar formation-related factors. We found that Y-27632 inhibited collagen gel contraction, as well as α-smooth muscle actin and vimentin expression; these were promoted by treatment with latanoprost, timolol, or transforming growth factor (TGF)-ß. To investigate the effect of Y-27632 in postsurgical scarring, we mimicked TGF-ß secretion by stimulating HTFs with TGF-ß prior to Y-27632 treatment. HTFs cultured in the presence of TGF-ß significantly increased gel contraction. In contrast, when HTFs were treated with 10µM Y-27632, contraction was significantly inhibited. Furthermore, Y-27632 reduced TGF-ß-induced phosphorylation of mitogen-activated protein kinase signalling. These results suggest that ROCK inhibitors may inhibit fibrosis by inhibiting transdifferentiation of Tenon fibroblasts into myofibroblasts and by inhibiting TGF-ß signalling after surgery through mitogen-activated protein kinase pathway suppression. These results implicate that ROCK inhibitors may improve outcomes after filtering surgery with a potential antiscarring effect, while latanoprost and timolol may induce fibrosis. SIGNIFICANCE OF THE STUDY: Scar formation is the primary cause of failure after glaucoma filtration surgery. A ROCK inhibitor, Y-27632, has been introduced as a novel potential antiglaucoma treatment to reduce intraocular pressure. The aim of our study was to elucidate the effect of Y-27632 on scarring formation after glaucoma filtration surgery, in direct comparison with other antiglaucoma drugs. Our findings thus suggested that Y-27632 may inhibit fibrosis and improve outcome after glaucoma filtration surgery through inhibition of transdifferentiation of Tenon fibroblasts into myofibroblasts, and the TGF-ß and MAPK signalling after surgery, while latanoprost and timolol may induce fibrosis.

Melanin targeting for intracellular drug delivery: Quantification of bound and free drug in retinal pigment epithelial cells.

Melanin binding affects drug distribution and retention in pigmented ocular tissues, thereby affecting drug response, duration of activity and toxicity. Therefore, it is a promising possibility for drug targeting and controlled release in the pigmented cells and tissues. Intracellular unbound drug concentrations determine pharmacological and toxicological actions, but analyses of unbound vs. total drug concentrations in pigmented cells are lacking. We studied intracellular binding and cellular drug uptake in pigmented retinal pigment epithelial cells and in non-pigmented ARPE-19 cells with five model drugs (chloroquine, propranolol, timolol, diclofenac, methotrexate). The unbound drug fractions in pigmented cells were 0.00016-0.73 and in non-pigmented cells 0.017-1.0. Cellular uptake (i.e. distribution ratio Kp), ranged from 1.3 to 6300 in pigmented cells and from 1.0 to 25 in non-pigmented cells. Values for intracellular bioavailability, Fic, were similar in both cells types (although larger variation in pigmented cells). In vitro melanin binding parameters were used to predict intracellular unbound drug fraction and cell uptake. Comparison of predictions with experimental data indicates that other factors (e.g. ion-trapping, lipophilicity-related binding to other cell components) also play a role. Melanin binding is a major factor that leads to cellular uptake and unbound drug fractions of a range of 3-4 orders of magnitude indicating that large reservoirs of melanin bound drug can be generated in the cells. Understanding melanin binding has important implications on retinal drug targeting, efficacy and toxicity.

The Beta 2 Adrenergic Receptor Antagonist Timolol Improves Healing of Combined Burn and Radiation Wounds.

In a scenario involving a nuclear detonation during war or a terrorist attack, acute radiation exposure combined with thermal and blast effects results in severe skin injury. Although the cutaneous injury in such a scenario may not be lethal, it may lead to inflammation, delayed wound healing and loss of the skin barrier, resulting in an increased risk of infection. In this study, we tested the potential use of timolol, a beta-adrenergic receptor antagonist, to improve epidermal wound closure after combined burn and radiation injury using an ex vivo human skin culture model. Daily application of 10 µ M timolol after combined injury (burn and 10 Gy ex vivo irradiation) increased wound epithelialization by 5-20%. In addition, exposure to 10 Gy significantly suppressed epidermal keratinocyte proliferation by 46% at 48 h postirradiation. Similar to what has been observed in a thermal burn injury, the enzyme phenylethanolamine N-methyltransferase (PNMT), which generates epinephrine, was elevated in the combined thermal burn and radiation wounds. This likely resulted in elevated tissue levels of this catecholamine, which has been shown to delay healing. Thus, with the addition of timolol to the wound to block the binding of locally generated epinephrine to the beta-adrenergic receptor, healing is improved. This work suggests that by antagonizing local epinephrine action within the wound, a beta-adrenergic receptor antagonist such as timolol may be a useful adjunctive treatment to improve healing in the combined burn and radiation injury.

Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds.

Chronic venous leg ulcers are profoundly debilitating and result in billions in health care expenditure. Thus, there is a quest for engineered and innovative approaches. Herein we present a 63-year-old patient with a 30 year history of venous stasis and left lower extremity ulcers, which have been refractory to standard of care, anticoagulation and venous stripping. The medial ulcer was treated with transplantation of autologous adipose mesenchymal stem cell (AMSC)-enriched, high-density lipoaspirate (HDL) on OASIS wound matrix and compression therapy. The lateral ulcer was treated as a control with standard debridement and compression therapy. Four weeks later, both ulcers received daily topical timolol. Three months later, the test ulcer was completely epithelized and remains healed for over 15 months. However, the control showed minimal signs of improvement. In companion studies in our laboratory, human AMSC were cultured in Minimum Essential Medium Eagle Alpha Modifications (MEMα) with fetal bovine serum (FBS). Timolol was administered to AMSC prior to treatment with epinephrine and 104 bacteria/ml heat-killed Staphylococcus aureus. The MEMα with FBS devoid of AMSC served as a background control. After 24 h, cell culture supernatants and protein lysates were collected to determine cytokine production. There was a statistical significant decrease in pro-inflammatory interleukin-6 and -8 induced by the bacteria (to model the wound environment) in AMSC in the presence of timolol compared with control (p < 0.5). This is the first case of a successful combination of autologous AMSC-enriched, HDL with topical timolol for the healing of chronic venous leg ulcers. Copyright © 2016 John Wiley & Sons, Ltd.

Evaluation of the anti-Acanthamoeba activity of two commercial eye drops commonly used to lower eye pressure.

Efficient treatments against Acanthamoeba Keratitis (AK), remains until the moment, as an issue to be solved due to the existence of a cyst stage which is highly resistant to most chemical and physical agents. In this study, two antiglaucoma eye drops were tested for their activity against Acanthamoeba. Moreover, this study was based on previous data which gave us evidence of a possible link between the absences of Acanthamoeba at the ocular surface in patients treated with beta blockers for high eye pressure both containing timolol as active principle. The amoebicidal activity of the tested eye drops was evaluated against four strains of Acanthamoeba using Alamar blue method. For the most active drug the cysticidal activity against A. castellanii Neff cysts and further experiments studying changes in chromatin condensation levels, in the permeability of the plasmatic membrane, the mitochondrial membrane potential and the ATP levels in the treated amoebic strains were done. Even though both eye drops were active against the different tested strains of Acanthamoeba, statistical analysis revealed that one of them (Timolol Sandoz) was the most effective one against all the tested strains presenting IC50s ranging from 0.529% ± 0.206 for the CLC 16 strain to 3.962% ± 0.150 for the type strain Acanthamoeba castellanii Neff. Timolol Sandoz 0.50% seems to induce amoebic cell death by damaging the amoebae at the mitochondrial level. Considering its effect, Timolol Sandoz 0.50% could be used in the case of contact lens wearers and patients with glaucoma.

Effects of perioperative topical dorzolamide hydrochloride-timolol maleate administration on incidence and severity of postoperative ocular hypertension in dogs undergoing cataract extraction by phacoemulsification.

OBJECTIVE To assess the effects of topically applied 2% dorzolamide hydrochloride-0.5% timolol maleate ophthalmic solution (DHTM) on incidence and severity of postoperative ocular hypertension (POH; ie, intraocular pressure [IOP] > 25 mm Hg) in dogs undergoing cataract extraction by phacoemulsification. DESIGN Randomized, masked, controlled study. ANIMALS 103 dogs (180 eyes). PROCEDURES Pertinent history, signalment, and ophthalmic examination findings were recorded. Dogs received 1 drop of DHTM or sham treatment solution (sterile, buffered, isotonic eye drops) in both eyes 14 hours and 2 hours before anesthetic induction and at the time of corneal incision closure (ie, end of surgery); IOPs were assessed by rebound tonometry 2, 4, 6, and 8 hours after surgery and between 7:30 and 8:00 am on the following day. Dogs with IOPs of 26 to 45 mm Hg received 1 drop of 0.005% latanoprost solution topically; the surgeon's treatment of choice was used for dogs with IOPs > 45 mm Hg. Incidence of POH and postoperative IOPs were compared between treatment groups. RESULTS DHTM treatment resulted in significantly lower incidence of POH than did sham treatment at the level of the dog (18/53 [34%] vs 31/50 [62%]) and the eye (24/94 [26%] vs 42/86 [48%]). Mean IOP did not differ between groups at the time of POH detection. The DHTM-treated eyes that developed POH were significantly more likely to have a 1-hour follow-up IOP < 25 mm Hg after latanoprost administration than were sham-treated eyes (19/25 [76%] vs 18/35 [51%]; OR, 3.87). CONCLUSIONS AND CLINICAL RELEVANCE Multidose perioperative administration of DHTM in dogs undergoing phacoemulsification reduced the incidence of POH and improved responsiveness of POH to latanoprost treatment.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function.

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic ß2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs.

Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects.

Effect of topical aqueous suppression on intraocular gas duration after pure perfluoropropane injection in nonvitrectomized eyes with retinal detachment.

PURPOSE: To determine whether topical aqueous suppressants affect the duration of pure expansile intraocular gas in nonvitrectomized eyes. METHODS: A prospective randomized controlled trial was performed on nonvitrectomized patients undergoing retinal detachment repair with scleral buckle or pneumatic retinopexy using 0.3 mL of 100% perfluoropropane (C3F8) gas tamponade. Eyes were randomly assigned to receive topical dorzolamide 2% and timolol 0.5% twice daily postoperatively until gas dissolution or to observation. RESULTS: Twenty-one patients met all inclusion and exclusion criteria. Twelve were randomized to the control group and nine to the dorzolamide-timolol group. In the dorzolamide-timolol group, mean intraocular pressure was 17.4 on postoperative Day 1 and 12.5 on postoperative Week 1 (P = 0.03). In the control group, mean intraocular pressure was 14.5 on postoperative Day 1 and 15.1 on postoperative Week 1 (P = 0.73). The mean duration of C3F8 was 37.8 days in the dorzolamide-timolol group and 40.4 days in the control group (P = 0.70). CONCLUSION: Topical aqueous suppression does not seem to have a significant effect on the duration of pure expansile intraocular C3F8 in nonvitrectomized eyes after pneumatic retinopexy or scleral buckling.

Novel usage of intraocular pressure-lowering drugs as wound-healing inhibitors after trabeculectomy with cell culture and animal models.

Inhibiting the healing of wounds to ensure that the aqueous humor can drain into the scleral space unimpeded and form a filtering bleb plays a crucial role in determining the success rate of glaucoma surgery. The aim of this study was to investigate the novel use, with cell culture and animal models, of some commercial intraocular pressure (IOP)-lowering drugs in inhibiting the healing of fibroblast wounds. The Tenon's fibroblasts of rabbits were cultured to evaluate 13 IOP-lowering drugs for cellular proliferation, collagen formation, and migration. These were measured using [(3)H]thymidine and [(3)H]proline uptake, and Transwell chambers. A preservative of benzalkonium chloride (BAK) was initially used, with 0.02% as a maximal original concentration. All of the drugs and the BAK were diluted from original commercial concentrations to 1/10, 1/100, and 1/1000. The more inhibitive drugs screened from the cell cultures were then selected for further short-term application during and after trabeculectomy surgeries had been performed on the rabbits. Expression of the proliferative cell nuclear antigen was immunohistochemically examined 3 and 7 days after surgery. The results revealed that the inhibitive effects of BAK in cellular [(3)H]thymidine and [(3)H]proline uptake, and cellular migration were only evident at 0.002% concentrations. Based on the results of the cell cultures, timolol, latanoprost, and unoprostone exhibited a greater inhibitory effect than the other drugs. Moreover, the animal studies showed that latanoprost and unoprostone significantly suppressed the positive expression of proliferative cell nuclear antigen around the operative excision area 7 days after the trabeculectomy surgeries. The results indicate that short-term use of some IOP-lowering drugs, such as latanoprost and unoprostone, may inhibit postoperative wound healing after glaucoma surgery.

Eficácia da combinação fixa de timolol 0, 5% e brinzolamida 1% no tratamento do glaucoma primário de ângulo aberto e na hipertensão ocular / Efficacy of fixed combination of timolol 10% and Brinzolamide 1% for primary open angle glaucoma and ocular hypertension

OBJETIVO: Avaliar a eficácia e conforto dos pacientes portadores de glaucoma primário de ângulo aberto (GPAA) ou hipertensão ocular (HO) em uso da combinação fixa de timolol 0,5% e brinzolamida 1%. MÉTODOS: Foram acompanhados prospectivamente 26 pacientes portadores de GPAA ou HO, num total de 50 olhos que foram instituídos a utilizarem a combinação fixa de timolol 0,5% e brinzolamida 1%. As avaliações foram feitas por um único examinador por tonometria de aplanação (Goldman) em 7 e 30 dias. Os possíveis efeitos colaterais e intolerância foram descritos pelos próprios pacientes através da pergunta: "Você sentiu alguma alteração ao pingar a medicação prescrita?" Os dados foram coletados e analisados estatisticamente. RESULTADOS: Os valores de pressão intraocular (PIO) foram significativamente menores nas avaliações de 7 e 30 dias (p<0,001). A média da redução da PIO foi de 38%, variando de uma média inicial de 23,8 mmHg para 14,6 e 14,4 mmHg nos dias 7 e 30, respectivamente. Dos 26 pacientes incluídos apenas 4 relataram alguma queixa ao pingar o colírio, sendo que as queixas variaram de ardência, leve queimação e embaçamento. CONCLUSÃO: A combinação fixa de timolol 0,5% e brinzolamida 1% mostrou-se eficaz no tratamento de pacientes com GPAA e HO com eficácia semelhante a da literatura e apresentou um baixo índice de efeitos desconfortáveis relatados pelos usuários da medicação.

OBJETICVE: To evaluate the efficacy and side effects of timolol 0,5% and brinzolamide 1% fixed combination in patients with primary open angle glaucoma (POAG) and ocular hypertension (OH). METHODS: 50 eyes of 26 patients with POAG or OH were evaluated with topical therapy with fixed combination of timolol 0.5% and brinzolamide 1%.The measurements with Goldmann tonometry were applied by only one ophthalmologist after 7 and 30 days on medication. The side effects were described by the patient based on the following question: "Did you feel any alteration with the prescribed drops?" The data were collected and analized statistically. RESULTS: The intraocular pressure (IOP) was lower in 7 and 30 days (p<0.001).The mean reduction in IOP was 38% with a variation from 23,8 mmhg to 14.6 and 14.4 mmhg in 7 and 30 days. Four patients had side effects: burning and blurring vision were related. CONCLUSION: the fixed combination of timolol 0.5% and brinzolamide 1% had good results with lower IOP in the treatment of patients with POAG and OH just like in the literature and had few side effects.