RESUMO
To develop novel norepinephrine transporter (NET)-targeting positron emission tomography (PET) probes with optimal pharmacokinetic properties, a series of meta-bromobenzylguanidine derivatives was synthesized. 4-Fluorodiethoxyethane-3-bromobenzylguanidine (compound 12) showed relatively good affinity for the NET (IC50 = 1.00 ± 0.04 µM). The corresponding radiotracer 18F-12 was prepared in high radiochemical purity (>98%) via a three-step method. The in vitro cellular uptake results demonstrated that 18F-12 was specifically taken up by NET-expressing SK-N-SH cells by the uptake-1 mechanism. Biodistribution studies in mice showed that 18F-12 exhibited high cardiac uptake (10.45 ± 0.66 %ID/g at 5 min p.i. and 6.44 ± 0.40 %ID/g at 120 min p.i.), faster liver clearance, and a lower dose of absorbed radiation than [123I]-labeled meta-iodobenzylguanidine ([123I]MIBG). Small animal PET imaging confirmed the high heart-to-background ratio of 18F-12 and the uptake-1 mechanism specific for the NET in rats, indicating its potential as a promising PET radiotracer for cardiac sympathetic nerve imaging.
Assuntos
Bromobenzenos/metabolismo , Guanidinas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Bromobenzenos/farmacocinética , Linhagem Celular Tumoral , Radioisótopos de Flúor/farmacocinética , Guanidinas/farmacocinética , Humanos , Camundongos Endogâmicos ICR , Tomografia por Emissão de Pósitrons/métodosRESUMO
The impact of organic anion-transporting polypeptide (OATP) inhibition on systemic and liver exposures of three OATP substrates was investigated in cynomolgus monkeys. A monkey physiologically-based pharmacokinetic (PBPK) model was constructed to describe the exposure changes followed by OATP functional attenuation. Rosuvastatin, bromfenac, and carotegrast were administered as a single intravenous cassette dose (0.5 mg/kg each) in monkeys with and without predosing with rifampin (RIF; 20 mg/kg) orally. The plasma exposure of rosuvastatin, bromfenac, carotegrast, and OATP biomarkers, coproporphyrin I (CP-I) and CP-III were increased 2.3, 2.1, 9.1, 5.4, and 8.8-fold, respectively, when compared to the vehicle group. The liver to plasma ratios of rosuvastatin and bromfenac were reduced but the liver concentration of the drugs remained unchanged by RIF treatment. The liver concentrations of carotegrast, CP-I, and CP-III were unchanged at 1 h but increased at 6 h in the RIF-treated group. The passive permeability, active uptake, and biliary excretion were characterized in suspended and sandwich-cultured monkey hepatocytes and then incorporated into the monkey PBPK model. As demonstrated by the PBPK model, the plasma exposure is increased through OATP inhibition while liver exposure is maintained by passive permeability driven from an elevated plasma level. Liver exposure is sensitive to the changes of metabolism and biliary clearances. The model further suggested the involvement of additional mechanisms for hepatic uptakes of rosuvastatin and bromfenac, and of the inhibition of biliary excretion for carotegrast, CP-I, and CP-III by RIF. Collectively, impaired OATP function would not reduce the liver exposure of its substrates in monkeys.
Assuntos
Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Modelos Biológicos , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Fenilalanina/análogos & derivados , Quinazolinonas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Animais , Área Sob a Curva , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Interações Medicamentosas , Eliminação Hepatobiliar , Fígado/metabolismo , Macaca fascicularis , Masculino , Modelos Animais , Transportadores de Ânions Orgânicos/metabolismo , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Quinazolinonas/administração & dosagem , Rosuvastatina Cálcica/administração & dosagemRESUMO
Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150-250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.
Assuntos
Bromobenzenos/farmacocinética , Modelos Animais de Doenças , Modelos Biológicos , Administração Oral , Animais , Bromobenzenos/análise , Bromobenzenos/toxicidade , Masculino , Camundongos , Camundongos TransgênicosRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Dinoprostona/metabolismo , Corpo Vítreo/metabolismo , Administração Oftálmica , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacocinética , Benzofenonas/administração & dosagem , Benzofenonas/farmacocinética , Bromobenzenos/administração & dosagem , Bromobenzenos/farmacocinética , Cromatografia Líquida de Alta Pressão , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Membrana Epirretiniana/metabolismo , Membrana Epirretiniana/cirurgia , Feminino , Humanos , Indometacina/administração & dosagem , Indometacina/farmacocinética , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Fenilacetatos/administração & dosagem , Fenilacetatos/farmacocinética , Estudos Prospectivos , Perfurações Retinianas/metabolismo , Perfurações Retinianas/cirurgia , VitrectomiaRESUMO
Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75⯱â¯12.54-234.68⯱â¯46.76â¯nM against hCA I, 42.84⯱â¯9.36 and 200.54⯱â¯57.25â¯nM against hCA II, 0.84⯱â¯0.12-14.63⯱â¯3.06â¯nM against AChE and 0.93⯱â¯0.20-18.53⯱â¯5.06â¯nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.
Assuntos
Produtos Biológicos/síntese química , Bromobenzenos/síntese química , Inibidores da Anidrase Carbônica/síntese química , Antagonistas Colinérgicos/síntese química , Fenóis/síntese química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacocinética , Bromobenzenos/metabolismo , Bromobenzenos/farmacocinética , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Anidrase Carbônica I/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Antagonistas Colinérgicos/metabolismo , Antagonistas Colinérgicos/farmacocinética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Humanos , Simulação de Acoplamento Molecular , Fenóis/metabolismo , Fenóis/farmacocinética , Ligação ProteicaRESUMO
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.
Assuntos
Humor Aquoso/química , Benzofenonas/análise , Bromobenzenos/análise , Cromatografia Líquida de Alta Pressão/métodos , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/farmacocinética , Benzofenonas/administração & dosagem , Benzofenonas/farmacocinética , Bromobenzenos/administração & dosagem , Bromobenzenos/farmacocinética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/farmacocinética , Facoemulsificação , Cuidados Pré-Operatórios , Estudos Prospectivos , Fatores de TempoRESUMO
PURPOSE: To assess vitreous concentrations of nonsteroidal anti-inflammatory drugs (NSAIDs) and prostaglandin E2 (PGE2) in patients treated with NSAIDs before vitrectomy for macular pucker. METHODS: A prospective, investigator-masked, randomized study was performed in 64 patients scheduled to undergo vitrectomy. The patients were randomized 1:1:1:1 to receive indomethacin 0.5%, bromfenac 0.09%, nepafenac 0.1%, or placebo three times a day. NSAIDs and PGE2 levels were evaluated in vitreous samples collected at the beginning of surgery. RESULTS: Mean (SD) vitreous concentrations of the study drugs were 503.13 (241.1) pg/mL for indomethacin, 302.5 (91.03) pg/mL for bromfenac, and 284.38 (128.2) pg/mL for nepafenac. Mean (SD) vitreous PGE2 levels were 247.9 (140.9) pg/mL for indomethacin, 322.12 (228.1) pg/mL for bromfenac, 448.8 (261.1) pg/mL for nepafenac, and 1,133 (323.9) pg/mL for placebo. All three NSAIDs reduced vitreous PGE2 levels to a statistically significant extent, without a significant difference among them. CONCLUSION: All assessed NSAIDs penetrated the vitreous and lowered basal PGE2 levels. A greater penetration was associated with pseudophakic eyes. The important inhibition of prostaglandins in the retina may have a clinical effect on the management of inflammatory retina diseases.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Dinoprostona/metabolismo , Corpo Vítreo/metabolismo , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacocinética , Benzofenonas/administração & dosagem , Benzofenonas/farmacocinética , Disponibilidade Biológica , Bromobenzenos/administração & dosagem , Bromobenzenos/farmacocinética , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Feminino , Humanos , Indometacina/administração & dosagem , Indometacina/farmacocinética , Masculino , Soluções Oftálmicas , Fenilacetatos/administração & dosagem , Fenilacetatos/farmacocinética , Estudos Prospectivos , Doenças Retinianas/tratamento farmacológico , Distribuição Tecidual , VitrectomiaRESUMO
PURPOSE: To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. METHODS: The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. RESULTS: The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (Pâ=â0.026) but not the other two NSAIDs. CONCLUSIONS: Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacocinética , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Benzofenonas/administração & dosagem , Benzofenonas/química , Benzofenonas/farmacocinética , Bromobenzenos/administração & dosagem , Bromobenzenos/química , Bromobenzenos/farmacocinética , Corioide/efeitos dos fármacos , Corioide/metabolismo , Cromatografia Líquida , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/química , Diclofenaco/administração & dosagem , Diclofenaco/química , Diclofenaco/farmacocinética , Humanos , Masculino , Fenilacetatos/administração & dosagem , Fenilacetatos/química , Fenilacetatos/farmacocinética , Coelhos , Espectrometria de Massas em TandemRESUMO
The extensive use of polybrominated diphenyl ethers (PBDEs) and decabromodiphenyl ethane (DBDPE) has made them widespread contaminants in abiotic environments, but data regarding their bioavailability to benthic organisms are sparse. The bioaccumulation potential of PBDEs and DBDPE from field-collected sediment was evaluated in the oligochaete Lumbriculus variegatus using a 49-d exposure, including a 28-d uptake and a 21-d elimination phase. All PBDEs and DBDPE were bioavailable to the worms with biota-sediment accumulation factors (BSAFs) ranging from 0.0210 g organic carbon/g lipid to 4.09 g organic carbon/g lipid. However, the bioavailability of highly brominated compounds (BDE-209 and DBDPE) was poor compared with that of other PBDEs, and this was confirmed by their relatively low freely dissolved concentrations (C(free)) measured by solid-phase microextraction. The inverse correlation between BSAFs and hydrophobicity was explained by their uptake (k(s)) and elimination (k(e)) rate constants. While ke changed little for PBDEs, ks decreased significantly when chemical hydrophobicity increased. The difference in bioaccumulation kinetics of brominated flame retardants in fish and the worms was explained by their physiological difference and the presence of multiple elimination routes. The appropriateness of 28-d bioaccumulation testing for BSAF estimation was validated for PBDEs and DBDPE. In addition, C(free) was shown to be a good indicator of bioavailability.
Assuntos
Bromobenzenos/farmacocinética , Retardadores de Chama/farmacocinética , Sedimentos Geológicos/química , Éteres Difenil Halogenados/farmacocinética , Oligoquetos/metabolismo , Poluentes Químicos da Água/farmacocinética , Animais , China , Interações Hidrofóbicas e Hidrofílicas , Cinética , Microextração em Fase Sólida , Instalações de Eliminação de ResíduosRESUMO
Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight. Liver weight increases were dose and exposure time related and statistically significant at ≥10 mg/kg per d. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were dose and time related. The 75 mg/kg per d group had minimally increased mitoses within hepatocytes (5 days only). Hepatocyte vacuolation was observed (13 weeks) and was considered TBB exposure related at ≥25 mg/kg per d. Concentrations of blood TBB increased linearly with dose and at 13 weeks, ranged from 0.5 to 17 µg/mL (2.5-75 mg/kg per d). In conclusion, rats administered TBB doses of 10-75 mg/kg per d for 13 weeks had mild liver effects. A no observed adverse effect level of 5 mg/kg per d was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥10 mg/kg per d.
Assuntos
Bromobenzenos/toxicidade , Fígado/efeitos dos fármacos , Animais , Bromobenzenos/sangue , Bromobenzenos/farmacocinética , Fígado/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade SubcrônicaRESUMO
OBJECTIVE: To compare the peak to-aqueous penetration of three nonsteroidal anti-inflammatory drugs: ketorolac tromethamine 0.45%, bromfenac 0.09%, nepafenac 0.1%, and amfenac (the active metabolite of nepafenac) in patients undergoing phacoemulsification. METHODS: A single center, double-masked study randomized 122 patients to receive one of three treatment arms. On-label dosing of ketorolac (BID), bromfenac (BID), and nepafenac (TID) was instructed for 1 day prior to surgery. Patients were instructed to instill one drop the morning of surgery. The patients received four additional doses 1 hour prior to phacoemulsification. After completion of the paracentesis site with a superblade, aqueous humor (0.15 cc) was collected through the peripheral clear cornea with a 30-gauge needle attached to a TB syringe. Following collection, aqueous samples were stored at -40°C prior to analysis. Drug concentrations were analyzed by liquid chromatography tandem mass spectrometry using positive turbo-ion spray ionization and multiple reaction monitoring mode for quantification. An independent sample Student's t-test was used to detect between-group differences. RESULTS: The peak aqueous concentration of ketorolac 0.45% was 10 times the concentration of bromfenac 0.09%, and five times the concentration of and 54% greater than the metabolically inactive nepafenac 0.1%. The mean peak aqueous concentration of ketorolac 0.45% was 688.87 ± 749.6 ng/ml. Bromfenac achieved a mean peak aqueous concentration of 67.64 ± 62.4 ng/ml. The mean peak aqueous concentrations of nepafenac and amfenac were 447.10 ± 225.7 ng/ml and 140.37 ± 56.6 ng/ml, respectively. The peak concentration of ketorolac was statistically significantly greater than bromfenac (P ≤ 0.0005), nepafenac (P ≤ 0.05), and amfenac (P ≤ 0.005). A limitation of this study is that aqueous samples were collected just prior to surgery and not during the postoperative period due to ethical considerations. CONCLUSIONS: Ketorolac 0.45% achieved significantly greater aqueous concentrations when compared to bromfenac 0.09% and the active metabolite of nepafenac 0.1% (amfenac) in patients undergoing phacoemulsification.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/farmacocinética , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Catarata/tratamento farmacológico , Cetorolaco/farmacocinética , Fenilacetatos/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzenoacetamidas/administração & dosagem , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Catarata/metabolismo , Método Duplo-Cego , Feminino , Humanos , Cetorolaco/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fenilacetatos/administração & dosagemRESUMO
PURPOSE: Anti-inflammatory activity of topical nonsteroidal anti-inflammatory drugs is mediated by suppression of cyclooxygenase (COX) isoenzymes. This study compared ocular penetration and inflammation suppression of topical ketorolac 0.45% and bromfenac 0.09% ophthalmic solutions in a rabbit model. METHODS: At hour 0, 36 rabbits received ketorolac 0.45%, bromfenac 0.09%, or an artificial tear 3 times once every 20 min. Half of the rabbits in each group then received intravenous injections of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran at hour 1, and the other half at hour 10. Aqueous and iris-ciliary body (ICB) samples were collected in the former group at hour 2 (peak) and in the latter group at hour 11 (trough) An additional group of 6 animals received only FITC-dextran, and samples were collected 1 h later. Peak and trough nonsteroidal anti-inflammatory drug concentrations were compared with previously determined half-maximal inhibitory concentrations (IC(50)) for COX isoenzymes. RESULTS: Peak and trough aqueous and ICB concentrations of ketorolac were at least 7-fold or greater than those of bromfenac. At peak levels, both ketorolac 0.45% and bromfenac 0.09% significantly inhibited LPS-induced aqueous prostaglandin E(2) and FITC-dextran elevation (P < 0.01). At trough, both study drugs significantly inhibited LPS-induced aqueous prostaglandin E(2) elevation (P < 0.05), but only ketorolac 0.45% significantly reduced LPS-induced aqueous FITC-dextran elevation (P < 0.01). Aqueous and ICB ketorolac concentrations exceeded its IC(50) for COX-1 and COX-2 at peak and trough. Aqueous and ICB bromfenac levels exceeded its IC(50) for COX-2 at peak and trough, but not for COX-1 at trough aqueous levels and peak and trough ICB levels. CONCLUSIONS: Both ketorolac 0.45% and bromfenac 0.09% effectively suppressed inflammation at peak. At trough, only ketorolac 0.45% effectively suppressed inflammation as measured by FITC-dextran leakage. The difference in inflammation suppression may be due to differences in tissue concentrations and/or greater COX-1 suppression by ketorolac 0.45%.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzofenonas/farmacologia , Bromobenzenos/farmacologia , Endoftalmite/tratamento farmacológico , Olho/metabolismo , Cetorolaco/farmacologia , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Dextranos/metabolismo , Dinoprostona/análise , Feminino , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Cetorolaco/farmacocinética , Lipopolissacarídeos , Prostaglandina-Endoperóxido Sintases/metabolismo , CoelhosRESUMO
PURPOSE: The purpose of this study was to compare the ocular pharmacokinetics of experimental solutions of bromfenac in DuraSite(®) to Xibrom™ (bromfenac ophthalmic solution) 0.09%. METHODS: The bromfenac content was measured in the aqueous humor of 84 Dutch Belted rabbits after a single dose of either 0.045% or 0.09% bromfenac in DuraSite in the left eye and the commercial preparation in the right eye. The drug content in the aqueous humor was measured at 0.5, 1, 2, 4, 8, 12, and 24 h after instillation. In a separate multi-dose study, rabbits received one drop of the 0.09% experimental or commercial preparation, 3 times daily for 14 days. For both experiments the drug content in ocular tissues was analyzed using liquid chromatography atmospheric pressure ionization tandem mass spectrometry. RESULTS: In single-dose experiments, the concentration of bromfenac in the aqueous humor was higher with the experimental preparations than with the commercial solution. The area under the concentration-time curve of 0.045% and 0.09% bromfenac in DuraSite was â¼2 and 4-fold higher than that of commercial bromfenac ophthalmic solution, 0.09%. After multi-dose experiments, ocular tissue concentrations of bromfenac were â¼3 times higher for the experimental than for the commercial formulation. CONCLUSIONS: The study demonstrates that the DuraSite topical drug delivery system can deliver bromfenac to various ocular tissues and attain considerably higher concentrations than the commercially available eye drop formulation. The higher aqueous concentration sustained with these experimental formulations could broaden the utility of bromfenac and/or reduce the currently approved dosing frequency of this drug.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Olho/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Feminino , Masculino , Soluções Oftálmicas , Concentração Osmolar , Coelhos , Distribuição TecidualRESUMO
UNLABELLED: Meta-iodobenzylguanidine (MIBG) labeled with (123)I or (131)I has been widely used for the diagnosis and radiotherapy of norepinephrine transporter (NET)-expressing tumors. However, (123)I/(131)I-MIBG has limitations for detecting small lesions because of its lower spatial resolution than PET tracers. In this study, meta-bromobenzylguanidine (MBBG) labeled with (76)Br (half-life, 16.1 h), an attractive positron emitter, was prepared and evaluated as a potential PET tracer for imaging NET-expressing tumors. METHODS: (76)Br-MBBG was prepared by a halogen-exchange reaction between the (76)Br and iodine of nonradioactive MIBG. The stability of MBBG was evaluated in vitro and in vivo by high-performance liquid chromatography analysis. Cellular uptake studies with or without NET inhibitors were performed in NET-positive PC-12 cell lines. Biodistribution studies were performed in PC-12 tumor-bearing nude mice by administration of a mixed solution of MBBG, MIBG, and (18)F-FDG. The tumor was imaged using (76)Br-MBBG and (18)F-FDG with a small-animal PET scanner. RESULTS: MBBG was stable in vitro, but some time-dependent dehalogenation was observed after administration in mice. MBBG showed high uptake in PC-12 tumor cells that was significantly decreased by the addition of NET inhibitors. In biodistribution studies, MBBG showed high tumor accumulation (32.0 +/- 18.6 percentage injected dose per gram at 3 h after administration), and the tumor-to-blood ratio reached as high as 54.4 +/- 31.9 at 3 h after administration. The tumor uptake of MBBG correlated well with that of MIBG (r = 0.997) but not with that of (18)F-FDG. (76)Br-MBBG PET showed a clear image of the transplanted tumor, with high sensitivity, which was different from the lesion shown by (18)F-FDG PET. CONCLUSION: (76)Br-MBBG showed high tumor accumulation, which correlated well with that of MIBG, and provided a clear PET image. These results indicated that (76)Br-MBBG would be a potential PET tracer for imaging NET-expressing neuroendocrine tumors and could provide useful information for determining the indications for (131)I-MIBG therapy.
Assuntos
Bromobenzenos , Regulação Neoplásica da Expressão Gênica , Guanidinas , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Tomografia por Emissão de Pósitrons/métodos , Receptores Adrenérgicos/metabolismo , Animais , Transporte Biológico , Bromobenzenos/síntese química , Bromobenzenos/metabolismo , Bromobenzenos/farmacocinética , Fluordesoxiglucose F18 , Guanidinas/síntese química , Guanidinas/metabolismo , Guanidinas/farmacocinética , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Células PC12 , RatosRESUMO
PURPOSE: To assess vitreous concentrations of nonsteroidal antiinflammatory drugs (NSAIDs) and prostaglandin E(2) in patients treated with NSAIDs before vitrectomy. METHODS: This was an investigator-masked, randomized, multicenter study. Patients received ketorolac 0.4% 4 times a day, bromfenac 0.09% 2 times a day, nepafenac 0.1% 3 times a day, or no NSAID for 3 days before surgery. Nonsteroidal antiinflammatory drugs and prostaglandin E(2) levels were determined in vitreous samples collected at the beginning of surgery. RESULTS: Thirty-one patients were included in the analyses. The mean (SD) vitreous concentrations were as follows: ketorolac 2.8 (3.2) ng/mL, bromfenac 0.96 (0.31) ng/mL, nepafenac 1.1 (0.6) ng/mL, and amfenac 2.0 (0.8) ng/mL aligned with the initial concentrations of the topical NSAIDs. Mean (SD) vitreous prostaglandin E(2) levels of the control patients and those treated with ketorolac 0.4%, bromfenac 0.09%, or nepafenac 0.1% were 270.6 (91.7) pg/mL, 189.6 (50.2) pg/mL, 247.2 (38.3) pg/mL, and 267.7 (99.7) pg/mL, respectively. Patients treated with ketorolac 0.4% had significantly lower prostaglandin E(2) levels than those treated with no NSAID (P = 0.047) or nepafenac 0.1% (P = 0.028). CONCLUSION: All three NSAIDs penetrated into the vitreous cavity. Topical therapy with ketorolac may lower preoperative vitreous prostaglandin E(2) levels, which may have a clinical impact on the management of prostaglandin-mediated diseases, including cystoid macular edema.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/farmacocinética , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Dinoprostona/farmacocinética , Cetorolaco/farmacocinética , Fenilacetatos/farmacocinética , Vitrectomia , Corpo Vítreo/metabolismo , Administração Tópica , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzenoacetamidas/administração & dosagem , Benzofenonas/administração & dosagem , Disponibilidade Biológica , Bromobenzenos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Cetorolaco/administração & dosagem , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Soluções Oftálmicas , Fenilacetatos/administração & dosagem , Doenças Retinianas/cirurgia , Distribuição TecidualRESUMO
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the formation of prostaglandin by cyclooxygenases. Several agents in this class have been approved for the treatment of postoperative pain and inflammation following cataract surgery. Bromfenac 0.09% (Xibrom, ISTA Pharmaceuticals, USA) is a relatively new topical NSAID that exhibits ocular penetration and duration of action sufficient to permit twice-daily dosing. Bromfenac dosed twice-daily was clearly superior to placebo for postoperative pain and inflammation in a large, controlled trial and compares favorably with other NSAIDs in smaller studies. Adverse events associated with use have been minimal in large studies, although there are reports of corneal compromise with bromfenac use in cases of preexisting corneal disease. The comfort and reduced frequency of use offered by bromfenac would be expected to improve patient compliance, which would in turn be expected to result in adoption of bromfenac over other NSAIDs by many physicians. However, head-to-head trials comparing bromfenac with other NSAIDs using a twice-daily dosing schedule have not been undertaken. Bromfenac and other NSAIDs are seeing expanded use for the treatment and prevention of cystoid macular edema, and could have clinical utility in other diseases of vascular permeability.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Oftalmopatias/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Extração de Catarata , Células Cultivadas , Conjuntivite Alérgica/tratamento farmacológico , Oftalmopatias/cirurgia , Humanos , Edema Macular/tratamento farmacológico , Miose/tratamento farmacológico , Soluções Oftálmicas/administração & dosagem , Testes de Toxicidade , Resultado do Tratamento , Uveíte Anterior/tratamento farmacológicoAssuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Humor Aquoso/metabolismo , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Cetorolaco/farmacocinética , Absorção , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Dinoprostona/metabolismo , Humanos , Técnicas Imunoenzimáticas , Cetorolaco/administração & dosagem , Espectrometria de Massas , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/farmacocinética , FacoemulsificaçãoRESUMO
PURPOSE: The aim of this study was to evaluate the ocular pharmacokinetics of a single dose of bromfenac sodium ophthalmic solution 0.1% in subjects undergoing routine cataract surgery with intraocular lens implantation. METHODS: An open-label, phase II confirmatory study of 54 subjects undergoing cataract surgery with intraocular lens implantation. A single drop of bromfenac sodium ophthalmic solution 0.1% was administered at 30, 60, 90, 120, 180, or 240 min prior to the initiation of cataract surgery. Samples of aqueous humor were aspirated through a paracentesis and analyzed by using high-performance liquid chromatography. Based upon these data, predicted concentrations of bromfenac in the aqueous humor over 24 h were generated by using computer simulation and compared with the IC(50) for bromfenac as a measure of anti-inflammatory efficacy. RESULTS: Peak aqueous-humor concentrations of bromfenac occurred between 150 and 180 min following ophthalmic dosing, with a mean concentration of 78.7 ng/mL. The level of bromfenac decreased in a log-linear fashion with an elimination-rate constant of 1.4. Bromfenac remained above the IC(50) value of cyclo-oxygenase-2 (COX-2) during the evaluated time points and over the 12-h dosing interval, using a computer model of extrapolated time points and assuming first-order elimination. CONCLUSIONS: Pharmacokinetic modeling, based upon samples collected over 240 min after a single dose of bromfenac sodium ophthalmic solution 0.1% suggests that aqueous-humor concentrations remain at clinically effective levels (above its IC(50) value for COX-2) for over 12 h. Based upon this rationale, these results supported clinical trials that demonstrated the efficacy of twice-daily dosing of bromfenac sodium ophthalmic solution 0.1% to manage patients with postoperative ocular pain and inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Humor Aquoso/metabolismo , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To compare aqueous drug concentrations and prostaglandin E(2) (PGE(2)) levels in patients treated with ketorolac 0.4% and bromfenac 0.09% at trough dosing. SETTING: Private practice, Wilkes-Barre, Pennsylvania, USA. METHODS: This single-center randomized investigator-masked clinical study comprised 56 patients having cataract surgery. Patients received 1 drop of ketorolac 0.4% or bromfenac 0.09% 6 hours and 12 hours preoperatively consistent with on-label dosing schedules. Aqueous humor was collected at the start of surgery and analyzed for concentrations of ketorolac and bromfenac using a reverse-phase high-performance liquid chromatography-mass spectroscopy system and for PGE(2) levels by competitive enzyme immunoassay. RESULTS: The mean aqueous PGE(2) level was 204.2 pg/mL +/- 95.5 (SD) in patients treated with ketorolac 0.4% and 263.7 +/- 90.0 pg/mL in patients treated with bromfenac 0.09%, (P = .020). The mean aqueous concentration of ketorolac and bromfenac at trough dosing was 130.5 +/- 37.8 ng/mL and 6.2 +/- 3.1 ng/mL, respectively (P = .004). CONCLUSIONS: Higher aqueous levels and greater PGE(2) inhibition were observed in cataract surgery patients treated with ketorolac 0.4% than in patients treated with bromfenac 0.09% at trough dosing. These findings suggest that ketorolac 0.4% administered 4 times a day may provide better control of prostaglandin-mediated inflammation than bromfenac 0.09% administered twice a day.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Humor Aquoso/metabolismo , Benzofenonas/farmacocinética , Bromobenzenos/farmacocinética , Dinoprostona/metabolismo , Cetorolaco/farmacocinética , Absorção , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzofenonas/administração & dosagem , Bromobenzenos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Feminino , Humanos , Técnicas Imunoenzimáticas , Cetorolaco/administração & dosagem , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/farmacocinética , FacoemulsificaçãoRESUMO
PURPOSE: The aim of this study was to determine the distribution and concentrations of bromfenac ophthalmic solution in ocular tissues following topical instillation in New Zealand White (NZW) rabbits. DESIGN: Two animal studies were conducted. METHODS: A single 50-muL (14)C-bromfenac ophthalmic solution (20-25 muCi or 0.09%) was administered into the right eyes of 14-18 randomly assigned NZW rabbits. At various time points, ocular tissues were collected and analyzed for (14)C-bromfenac contents. Ocular tissues were combusted and the amount of radioactivity was determined by liquid scintillation counting (LSC). Aqueous-humor samples were directly transferred to LSC vials. RESULTS: Peak concentrations of (14)C-bromfenac were observed in the aqueous humor and most ocular tissues at or before 2-hours. The highest concentrations were in the cornea, conjunctiva, and sclera. Similar amounts were detected in the aqueous humor, iris-ciliary body, choroid, and, to a slightly lesser degree, in the retina. Measurable amounts of bromfenac were detected in all samples at the 24-hours time point (> or =0.001 mug equivalent/g). CONCLUSIONS: Significant penetration and measurable amounts of (14)C-bromfenac were detected in all ocular tissues over 24 h, including the sclera, choroid, and retina. These results strongly suggest the utility of bromfenac ophthalmic solution 0.09% in treating inflammation of both the anterior and posterior ocular segments.