Female offspring of mice perinatally exposed to benzophenone-3 showed early subfertility linked to a poor oocyte stockpile.

Previously, we found that the ultraviolet filter benzophenone-3 (BP3) causes fetal growth restriction in mice when is applied when implantation occurs (first week of gestation). However, whether BP3 can affect gestation and fertility after implantation period is unknown. We aimed to study the effects on reproductive physiology of the offspring caused by perinatal exposure to BP3. C57BL/6 pregnant mice were dermally exposed to 50 mg BP3/kg bw.day or olive oil (vehicle) from gestation day 9 (gd9) to postnatal day 21 (pnd1). We observed no differences in mother's weights, duration of gestation, number of pups per mother, onset of puberty or sex ratio. The weights of the pups exposed to benzophenone-3 were transiently lower than those of the control. Estrous cycle was not affected by perinatal exposure to BP3. Besides, we performed a fertility assessment by continuous breeding protocol: at 10 weeks of age, one F1 female and one F1 male mouse from each group was randomly chosen from each litter and housed together for a period of 6 months. We noticed a reduction in the number of deliveries per mother among dams exposed to BP3 during the perinatal period. To see if this decreased fertility could be associated to an early onset of oocytes depletion, we estimated the ovarian reserve of germ cells. We found reduced number of oocytes and primordial follicles in BP3. In conclusion, perinatal exposure to BP3 leads to a decline in the reproductive capacity of female mice in a continuous breeding protocol linked to oocyte depletion.

COMPARISON OF THE EFFECTS OF EIGHT DIFFERENT TOPICAL NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ON REDUCING INTRAVITREAL INJECTION-INDUCED PAIN.

PURPOSE: To compare topical nonsteroidal anti-inflammatory drug (NSAID) efficacy on intravitreal injection-induced pain reduction and determine the most efficient topical NSAID. METHODS: This randomized-controlled study included 662 eyes of 662 patients. Based on the types of NSAID administered before intravitreal injection, eight subgroups were formed. In the control group, a sterile saline solution was applied instead of NSAIDs. The visual analog scale was used to assess pain scores after intravitreal injection. The visual analog scale scores were noted immediately and 6 hours following injection (sixth hour). RESULTS: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% had the lowest scores, immediately after and after 6 hours, with no significant differences. Diclofenac and ketorolac had higher visual analog scale scores than the first trio but lower scores than the control group. Flurbiprofen, pranoprofen, and indomethacin did not significantly affect immediate pain; however, at the sixth hour, the visual analog scale scores were significantly reduced. CONCLUSION: Nepafenac 0.3%, nepafenac 0.1%, and bromfenac 0.09% were the most effective NSAIDs for pain reduction. Although some NSAIDs did not have a significant effect on immediate pain, they all provided significant benefits at the sixth hour.

Topical bromfenac in VEGF-driven maculopathies: topical review and meta-analysis.

BACKGROUND: Topical non-steroidal anti-inflammatory drugs have the potential to reduce treatment burden and improve outcomes of anti-VEGF therapy for a number of retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. In this review, we focused on the advantages of topical bromfenac as an adjunct to intravitreal anti-VEGF therapy in VEGF-driven maculopathies. METHODS: Cochrane Library, PubMed, and EMBASE were systematically reviewed to identify the relevant studies of neovascular age-related macular degeneration, diabetic macular edema, macular edema associated with retinal vein occlusion, myopic choroidal neovascularization, and radiation maculopathy which reported changes in central retinal thickness, visual acuity, and the number of anti-VEGF injections needed when anti-VEGF therapy was combined with topical bromfenac. RESULTS: In total, ten studies evaluating bromfenac as an adjunct to anti-VEGF therapy were identified. Five studies were included in meta-analysis of the number of injections and five studies were included in the analysis of changes in central retinal thickness. A statistically significantly lower number of intravitreal injections (p = 0.005) was required when bromfenac was used as an adjunct to anti-VEGF therapy compared to anti-VEGF monotherapy with pro re nata regimen. At the same time, eyes receiving bromfenac as an adjunct to anti-VEGF therapy demonstrated non-inferior outcomes in central retinal thickness (p = 0.07). Except for one study which reported better visual outcomes with combined treatment, no difference in visual acuity or clinically significant adverse effects were reported. CONCLUSIONS: This literature review and meta-analysis showed that topical bromfenac can be considered as a safe adjunct to anti-VEGF therapy with a potential to reduce the treatment burden with anti-VEGF drugs requiring frequent injections without compromising improvement of central retinal thickness or visual acuity.

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate.

PURPOSE: Diazepam is utilized as a convulsion antidote following nerve gas attacks. As an emergency medicine, it requires storage at ambient temperatures which often doesn't meet manufacturers' requirements, leading to an early invalidation of the product. Current work investigated this issue. METHODS: Long-term stability of diazepam ampoules for injection stored in an ambient temperature of the Mediterranean climate for ~10 years vs storage at room temperature was studied. RESULTS: Diazepam assay and pH remained within pharmacopeial specifications irrespective of storage conditions. A major degradation product 2-methylamino-5-chlorobenzophenone (MACB) showed a clear trend of accumulation as a function of storage time, exceeding the permitted limit at ~2 years, irrespective of storage conditions. A strong correlation between the discoloration of the solutions and the concentration of MACB was obtained. Intravenous administration of MACB to rats at doses ~2200-fold higher than permissible specification levels caused neither mortality nor any toxicological nor post-mortem findings. CONCLUSIONS: Regarding the parameters tested: diazepam assay, MACB assay, and pH, storing ampoules of diazepam solution for injection in field conditions of high temperatures of the Mediterranean climate did not cause accelerated degradation as compared to room temperature. These findings open an option for the usage of expired ampoules in special scenarios.

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma.

BACKGROUND: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study. METHODS: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining. RESULTS: Short-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046). CONCLUSIONS: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.

Intravitreal bromfenac liposomal suspension (100 µg / 0.1 ml). A safety study in rabbit eyes.

INTRODUCTION: There is a need to find alternative treatments for MEe. Bromfenac has shown promise in inhibiting the COX-2 enzymatic pathway that partially causes the inflammatory cascade which contributes to the precipitation of ME. However, like other NSAID's, its intraocular half-life is limited. We hypothesize that a delayed-release liposome formulation containing bromfenac might provide a similar anti-inflammatory effect as long-lasting steroid release systems without the well-known steroidal side-effects. We introduced a novel formulation with these characteristics into the vitreous cavity of rabbit eyes in order to evaluate its safety profile. MATERIAL AND METHODS: 10 left eyes of rabbits were injected with the liposome-encapsulated bromfenac suspension (100 µg/0.1 ml). Basal ERG's were recorded. Total follow-up time was 3 months, at which point ERG's were repeated and eyes were enucleated for histopathological study. Total amplitude and implicit times were recorded. A difference of 25% in either recording was considered significant. Significance was assessed using the paired-t test and Wilcoxon matched-pairs signed-rank test. A p-value of <0.05 was considered significant. RESULTS: No significant changes were recorded in ERG measurements after 3 months when compared to basal measurements. Histopathological analysis of retinal specimens found no traces of liposome-induced toxicity. CONCLUSION: The liposome-encapsulated bromfenac suspension (100 µg/0.1 ml) is not toxic and has been proven safe to use in an animal model. Therefore, this formulation shows promise as a possible future alternative treatment for ME and should be further studied to show its biological effect and efficacy.

Characterization of the metabolites of GW1929 in rat by liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

RATIONALE: GW1929 is a potent PPAR-γ activator. To fully understand its mechanism of action, it is necessary to study the in vitro and in vivo metabolism. METHODS: For in vitro metabolism, GW1929 was incubated with rat hepatocytes at 37°C for 2 h. For in vivo metabolism, rats were orally administered with GW1929 at a single dose of 10 mg/kg and plasma, urinary and fecal samples were collected at defined time points. All the samples were analyzed by the developed ultra-high-performance liquid chromatography combined with tandem mass spectrometry. The structures of metabolites were proposed according to their accurate masses and product ions. RESULTS: A total of 17 metabolites, including seven glucuronide conjugates, were detected and structurally identified. M4 (hydroxylation), M13 (demethylation) and M14 (hydroxylation) were the most abundant metabolites. The metabolic pathways of GW1929 referred to hydroxylation, demethylation, deamination and glucuronidation. CONCLUSIONS: The present study provided new information on the in vitro and in vivo metabolic profiles of GW1929 which will be helpful for a better understanding of the mechanism of the elimination of GW1929.

Dermal exposure to the UV filter benzophenone-3 during early pregnancy affects fetal growth and sex ratio of the progeny in mice.

The aim of this study was to analyze whether dermal exposure to benzophenone 3 (BP-3) during pregnancy affects critical parameters of pregnancy, and whether this exposure may affect the outcome of a second pregnancy in mice. Pregnant mice were exposed to 50-mg BP-3/kg body weight/day or olive oil (vehicle) from gestation day (gd) 0 to gd6 by dermal exposure. High-frequency ultrasound imaging was used to follow up fetal and placental growth in vivo. Blood flow parameters in uterine and umbilical arteries were analyzed by Doppler measurements. Mice were killed at gd5, gd10, and gd14 on the first pregnancy, and at gd10 and 14 on the second pregnancy. The weight of the first and second progenies was recorded, and sex ratio was analyzed. BP-3 levels were analyzed in serum and amniotic fluid. BP-3 reduced the fetal weight at gd14 and feto-placenta index of first pregnancy, with 16.13% of fetuses under the 5th percentile; arteria uterina parameters showed altered pattern at gd10. BP-3 was detected in serum 4 h after the exposure at gd6, and in amniotic fluid at gd14. Offspring weight of first progeny was lower in BP-3 group. Placenta weights of BP-3 group were decreased in second pregnancy. First and second progenies of mothers exposed to BP-3 showed a higher percentage of females (female sex ratio). Dermal exposure to low dose of BP-3 during early pregnancy resulted in an intrauterine growth restriction (IUGR) phenotype, disturbed sex ratio and alterations in the growth curve of the offspring in mouse model.

VITREOUS PROSTAGLANDIN E2 CHANGES AFTER TOPICAL ADMINISTRATION OF DICLOFENAC 0.1%, INDOMETHACIN 0.5%, NEPAFENAC 0.3%, AND BROMFENAC 0.09.

PURPOSE: To evaluate the vitreous concentration of different nonsteroidal anti-inflammatory drugs (NSAIDs) after topical administration and the related prostaglandin E2 (PGE2) levels in patients undergoing pars plana vitrectomy. METHODS: A prospective, randomized, investigator-masked study was performed. One hundred four patients scheduled for a pars plana vitrectomy for an epiretinal membrane or a macular hole were randomized to receive topical diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, bromfenac 0.09%, or placebo 3 days before surgery. At the beginning of surgery, a sample of undiluted vitreous was collected in each patient to assess NSAIDs concentration and PGE2 levels. RESULTS: The median vitreous concentrations were 203.35 (interquartile range 146.54-264.18) pg/mL for diclofenac, 243.45 (interquartile range 156.96-365.37) pg/mL for nepafenac, 438.21 pg/mL (interquartile range, 282.52-645.87) for its active metabolite amfenac, 350.14 (interquartile range, 290.88-481.95) pg/mL for indomethacin, and 274.59 (245.43-358.25) pg/mL for bromfenac. Vitreous PGE2 levels were significantly lower for all the NSAIDs groups compared with the control group (P < 0.001). A statistically significant higher vitreous PGE2 level was found in the diclofenac group compared with the other NSAIDs groups (P < 0.05). CONCLUSION: Topical NSAIDs achieve sufficient vitreous concentration to decrease vitreous PGE2 levels compared with the control group. The different efficacy in reducing PGE2 concentration may affect the management of posterior segment inflammation.

Phototoxic risk assessment of dermally-applied chemicals with structural variety based on photoreactivity and skin deposition.

Combined use of photochemical and pharmacokinetic (PK) data for phototoxic risk assessment was previously proposed, and the system provided reliable phototoxic risk predictions of chemicals in same chemical series. This study aimed to verify the feasibility of the screening system for phototoxic risk assessment on dermally-applied chemicals with wide structural diversity, as a first attempt. Photochemical properties of test chemicals, 2-acetonaphthalene, 4'-methylbenzylidene camphor, 6-methylcoumarin, methyl N-methylanthranilate, and sulisobenzone, were evaluated in terms of UV absorption and reactive oxygen species (ROS) generation, and PK profiles of the test chemicals in rat skin were characterized after dermal co-application. All test chemicals showed strong UVA/B absorption with molar extinction coefficients of over 3000 M-1⋅cm-1, and irradiated 2-acetonaphthalene, 6-methylcoumarin, and methyl N-methylanthranilate exhibited significant ROS generation. Dermally-applied 2-acetonaphthalene and 4'-methylbenzylidene camphor indicated high and long-lasting skin deposition compared with the other test chemicals. Based on the photochemical and PK data, 2-acetonaphthalene was predicted to have potent phototoxic risk. The predicted phototoxic risk of the test chemicals by integration of obtained data was mostly consistent with their in vivo phototoxicity observed in rat skin. The screening strategy employing photochemical and PK data would have high prediction capacity and wide applicability for photosafety evaluation of chemicals.

Topical bromfenac transiently delays axotomy-induced retinal ganglion cell loss.

Optic nerve axotomy in rodents allows detailed studies of the effect of different treatments on the survival of central nervous system neurons, the retinal ganglion cells (RGCs). Here we have analyzed the neuroprotective effect of topical bromfenac treatment, a nonsteroidal anti-inflammatory drug (NSAID) used in clinic to ameliorate post-operative inflammation, on axotomized rat RGCs. The left optic nerve of adult rats was subjected to optic nerve crush (ONC). Half of the rats were treated with a topical instillation of saline. On the other half, immediately after the surgery, 2 drops of bromfenac (0.09% Yellox; Bausch & Lomb) were instilled, and then every 12 h until analysis. Retinas in both groups were dissected 3, 5, 7, 9 and 14 days after ONC (n = 4-8/time point/group). Toxicity of bromfenac was assessed in intact retinas treated during 14 days (n = 6). Intact untreated retinas were used as control of the RGC population. RGCs were identified by Brn3a immunodetection and automatically quantified. Our results show that bromfenac does not cause RGC loss in intact retinas. In the injured groups, the number of RGCs at 7, 9 and 14 days after the lesion was significantly higher in treated vs. untreated retinas. To our knowledge this is the first report showing that a topical treatment with a NSAIDs delays axotomy-induced RGC loss and indicates that treatment with NSAIDs could be used as conjunctive therapy in diseases that proceed with optic nerve damage.

Sunscreen bans: Coral reefs and skin cancer.

WHAT IS KNOWN AND OBJECTIVE: Hawaii will ban two major ingredients of sunscreens. This article reviews the reasons and future directions. Hawaii recently enacted legislation that will ban the use of two major ingredients of the majority of commonly used sunscreens. The reason for the ban is the ingredients' putative deleterious impact on marine ecosystems, particularly coral reefs. But sunscreens also save lives by decreasing the risk of UV-induced skin cancers. We review both sides of the issue and potential implications for the healthcare system. COMMENT: Coral reefs consist of organisms in delicate equilibria that are susceptible to small changes in their surroundings. Recent natural and man-made disruptions, direct or indirect, such as changes in ocean temperature and chemistry, ingress of invasive species, pathogens, pollution and deleterious fishing practices, have been blamed for the poor health, or even the outright destruction, of some coral reefs. The most popular sunscreen products contain two ingredients-oxybenzone and octinoxate-that have also been implicated in coral toxicity and will be banned. This creates a healthcare dilemma: Will the protection of coral reefs result in an increase in human skin cancers? WHAT IS NEW AND CONCLUSION: Concentration estimates and mechanism studies support an association-direct or indirect (via promotion of viral infection)-of sunscreens with bleaching of coral reefs. A ban on the two most common sunscreen ingredients goes into effect in Hawaii on January 1, 2021. Proponents suggest that this is a trend, just the first of many such bans worldwide; opponents warn of a dire increase in human skin cancers. As a result, alternative sunscreen compounds are being sought.

A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation.

The objective of the present study is to demonstrate that a newly developed selective c-Fos/activator protein (AP)-1 inhibitor, T-5224, inhibits the expression of matrix metalloproteinases (MMPs) in human articular chondrocytes, and prevents cartilage destruction in an osteoarthritis (OA)-induced mouse model. First, we examined the effect of T-5224 on MMP and inflammatory cytokine expression by real-time polymerase chain reaction in human articular chondrocytes. We created an OA model by destabilization of the medial meniscus (DMM) in mice. T-5224 was orally administered once a day and the OA pathology was assessed by histological, immunohistochemical, and micro-computed tomography (CT) analyses. T-5224 inhibited the mRNA expression levels of MMP-1, 3, and 13, and interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6 in IL-1-stimulated human chondrocytes. Oral administration of T-5224 to OA-induced mice prevented cartilage destruction. The histological scores for OA were significantly better in the T-5224-treated group than the vehicle-treated group. Type X collagen and MMP-13 were not increased in the T-5224-treated group by immunohistochemical staining. Micro-CT analysis showed mild but apparent osteophyte development in the femoral condyle and antero-medial aspect of the tibia in the vehicle-treated group but not in the T-5224-treated group. Taken together, specific inhibition of c-Fos/AP-1 and the resulting inhibition of the transactivation of a broad spectrum of downstream MMPs, along with inflammatory cytokines, effectively prevented cartilage destruction and osteophyte formation.

Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model Study.

PURPOSE: To assess feasibility and efficacy of CKD-516, a vascular disrupting agent, in transarterial chemoembolization in a liver tumor model. MATERIALS AND METHODS: A VX2 carcinoma strain was implanted in rabbit liver (n = 40) and incubated for 2 weeks. After confirmation of tumor growth using computed tomography, transarterial chemoembolization was performed. CKD-516 was dissolved in ethiodized oil, and animals were allocated to 4 treatment groups (n = 10 in each): group A, ethiodized oil; group B, ethiodized oil/CKD-516; group C, ethiodized oil + doxorubicin; group D, ethiodized oil/CKD-516 + doxorubicin. To assess hepatic damage, serum aspartate transaminase and alanine transaminase levels were measured on day 1, 3, and 7 after delivery. To assess tumor necrosis, animals were euthanized on day 7, and explanted tumors were stained with hematoxylin and eosin and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Percentage areas of viable tumors were calculated using digitalized histopathologic specimen images. RESULTS: Tumor viability rates were 47.1% ± 11.4%, 27.5% ± 13.6%, 14.4% ± 12.5%, and 0.7% ± 1.0% in groups A, B, C, and D (P < .001). Liver enzyme levels were elevated after drug delivery but recovered during follow-up. Significant between-group differences were observed on days 1, 3, and 7 (aspartate transaminase and alanine transaminase: P = .0135 and P = .0134, P = .0390 and P = .0084, and P = .8260 and P = .0440). CONCLUSIONS: Treatment with a combination of CKD-516 and conventional transarterial chemoembolization showed therapeutic benefit in a liver tumor model.

Anti-Hyperuricemic Effect of 2-Hydroxy-4-methoxy-benzophenone-5-sulfonic Acid in Hyperuricemic Mice through XOD.

Conventionally, benzophenone-type molecules are beneficial for alleviating the UV exposure of humans. More importantly, various compounds with this skeleton have demonstrated various biological activities. In this paper, we report the anti-hyperuricemic effect of the benzophenone compound 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (HMS). Preliminarily, its molecular docking score and xanthine oxidase (XOD) inhibition suggested a good anti-hyperuricemic effect. Then, its anti-hyperuricemic effect, primary mechanisms and general toxicity were examined on a hyperuricemic mouse model which was established using potassium oxonate and hypoxanthine together. HMS demonstrated a remarkable anti- hyperuricemic effect which was near to that of the control drugs, showing promising perspective. General toxicity was assessed and it showed no negative effects on body weight growth and kidney function. Moreover, anti-inflammatory action was observed for HMS via spleen and thymus changes. Its anti-hyperuricemic mechanisms may be ascribed to its inhibition of XOD and its up-regulation of organic anion transporter 1 (OAT1) and down-regulation of glucose transporter 9 (GLUT9).

Physicochemical and In Vitro Evaluation of Drug Delivery of an Antibacterial Synthetic Benzophenone in Biodegradable PLGA Nanoparticles.

Due to the increasing incidents of antimicrobial-resistant pathogens, the development of new antibiotics and their efficient formulation for suitable administration is crucial. Currently, one group of promising antimicrobial compounds are the benzophenone tetra-amides which show good activity even against gram-positive, drug-resistant pathogens. These compounds suffer from poor water solubility and bioavailability. It is therefore important to develop dosage forms which can address this disadvantage while also maintaining efficacy and potentially generating long-term exposures to minimize frequent dosing. Biodegradable nanoparticles provide one solution, and we describe here the encapsulation of the experimental benzophenone-based antibiotic, SV7. Poly-lactic-co-glycolic-acid (PLGA) nanoparticles were optimized for their physicochemical properties, their encapsulation efficiency, sustained drug release as well as antimicrobial activity. The optimized formulation contained particles smaller than 200 nm with a slightly negative zeta potential which released 39% of their drug load over 30 days. This formulation maintains the antibacterial activity of SV7 while minimizing the impact on mammalian cells.

Comparison of topically applied flurbiprofen or bromfenac ophthalmic solution on post-operative ocular hypertension in canine patients following cataract surgery.

OBJECTIVE: To compare the prevalence and kinetics of ocular hypertension after routine cataract extraction when using a predominately COX-2 inhibitor (bromfenac) versus a predominately COX-1 inhibitor (flurbiprofen) in combination with a topical corticosteroid. PROCEDURES: Patients undergoing unilateral or bilateral cataract surgery were randomly assigned to receive flurbiprofen or bromfenac at the day of surgery and continued for 6 weeks postoperatively, along with topical neo poly dexamethasone. No systemic nonsteroidal anti-inflammatory medications were administered before or after surgery. Intraocular pressure was monitored pre and postoperatively. When an IOP of >25 mmHg was detected, therapeutic intervention was performed. RESULTS: Eyes in both treatment groups showed a similar IOP profile with the highest mean IOP occurring two hours postsurgery and slowly declining during the next 6 weeks. However, eyes receiving bromfenac had a higher mean IOP at 2 h post-op (22.1 mmHg) than eyes receiving flurbiprofen (18.8 mmHg) and a slower decrease in IOP in the weeks after surgery. Over the course of the study, a higher percentage of eyes receiving bromfenac had therapy discontinued over concerns of elevated IOP compared to eyes receiving flurbiprofen (bromfenac 23.1% and flurbiprofen 9.8%). On average, the risk of having elevated intraocular pressure with bromfenac is 1.04 times higher than with flurbiprofen. CONCLUSION: Elevated postoperative IOP was observed in both treatment groups; however, bromfenac-treated eyes were more likely to require intervention for elevated IOP.

Bromfenac ophthalmic solution 0.09 %: human aqueous humor concentration detected by high-performance liquid chromatography.

The purpose of this study was to evaluate the aqueous humor concentrations of bromfenac ophthalmic solution 0.09 % in patients undergoing phacoemulsification. Patients requiring cataract extraction received one drop (50 µL) of bromfenac 0.09 % solution in the eye to be operated, before bedtime the day before surgery or the morning of the surgery. The last administration was recorded. At the time of paracentesis, an aqueous humor sample was collected with a 30-gauge needle attached to a TB syringe and was later analyzed by high-performance liquid chromatography for drug concentration. 188 treated volunteers and 48 control, untreated, subjects were included in the study. The mean aqueous concentration of bromfenac in the treated group was 37.60 ± 68.86 and 0 nM (nmol/L) in the control group (p < 0.0001). Correlation coefficient in bromfenac group between time elapsed from instillation and drug concentration was -0.16 (p not significant). Bromfenac showed properties of good penetration and stable concentration in aqueous humor up to about 12 h after instillation.

[Effect of medicinal treatment on epithelial wound healing after phacoemulsification]. / . Vliianie medikamentoznoi terapii na épitelizatsiiu rogovichnogo razreza posle fakoémul'sifikatsii.

AIM: to compare the dynamics of epithelial wound healing under two different post-op treatments in patients after uncomplicated phacoemulsification. MATERIAL AND METHODS: This prospective randomized clinical trial included 40 eyes of 40 patients aged 66.4±8.2 years who underwent uncomplicated phacoemulsification with flexible intraocular lens implantation through a 2.2-mm corneal incision. Patients were randomized to receive either dexamethasone 0.1% and diclofenac 0.1% (n=20 eyes, Group I), or bromfenac 0.09% (n=20 eyes, Group II). Also, all patients instilled levofloxacin 0.5%. The dynamics of epithelial wound healing was assessed with the RTVue-100 spectral domain optical coherence tomograph with CAM-L corneal module in the 3D CORNEA mode 2 hours after surgery and on days 1, 3, 5, and 10. RESULTS: The postoperative period was uneventful in all cases. Two hours after surgery, epithelial defects were found in all eyes and their length did not differ statistically p=0.47. On the first day after surgery, complete epithelization was observed in 30% of cases from Group I and 60% of cases from Group II. The average length of epithelial defects was reliably smaller in Group II than in Group I (p=0.04 respectively). On postoperative day 3, 20% eyes from Group I still had epithelial defects with the average length of 0.45±0.13 mm, while there was only one eye with a 0.2-mm epithelial defect in Group II. Finally, on postoperative day 5, there was a single 0.3-mm epithelial defect in one eye from Group I. On day 10, none of the patients had epithelial defects in either group. CONCLUSION: Epithelial wound healing at the site of corneal incision after non-complicated phacoemulsification was found to be faster in patients instilled with bromfenac twice daily than in patients receiving dexamethasone and diclofenac four times daily as anti-inflammatory therapy and given topical fluoroquinolones for antibacterial purpose.