The selegiline transdermal system (STS) is being developed to treat major depressive disorder. In a Phase I clinical study, the STS (20 mg/20 cm2) produced mild dermal irritability and demonstrated a low potential for contact allergenicity. In Phase III multicenter studies in major depression, over 1800 patients have been evaluated for dermal safety to reveal an overall rate of application site reactions (ASRs) with STS of 21.8% compared with a placebo rate of 9.7%. Discontinuation rates due to dermal adverse events in clinical studies were low (3.5%). Overall, the STS demonstrated good tolerability regarding ASRs and the potential for delayed contact hypersensitivity.
{"title":"Selegiline Transdermal System (STS): Assessments of Dermal Safety in Human","authors":"M. Pauporte, A. Azzaro, G. Moonsammy, H. Maibach","doi":"10.1081/CUS-200035366","DOIUrl":"https://doi.org/10.1081/CUS-200035366","url":null,"abstract":"The selegiline transdermal system (STS) is being developed to treat major depressive disorder. In a Phase I clinical study, the STS (20 mg/20 cm2) produced mild dermal irritability and demonstrated a low potential for contact allergenicity. In Phase III multicenter studies in major depression, over 1800 patients have been evaluated for dermal safety to reveal an overall rate of application site reactions (ASRs) with STS of 21.8% compared with a placebo rate of 9.7%. Discontinuation rates due to dermal adverse events in clinical studies were low (3.5%). Overall, the STS demonstrated good tolerability regarding ASRs and the potential for delayed contact hypersensitivity.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"14 1","pages":"179 - 187"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83859934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mercury poisoning is becoming a health concern due to the extensive pollution of water and fish and the increasing consumption of fish in the human diet. Mercury is extremely toxic to the body, especially the central nervous system, but diagnosis is difficult due to the lack of specific signs. We report four patients with persistent palmar plaques that correlated with blood mercury levels and cleared upon the elimination of mercury from the body.
{"title":"Persistent Palmar Plaques—Another Possible Cutaneous Sign of Mercury Poisoning","authors":"P. Dantzig","doi":"10.1081/CUS-120029761","DOIUrl":"https://doi.org/10.1081/CUS-120029761","url":null,"abstract":"Mercury poisoning is becoming a health concern due to the extensive pollution of water and fish and the increasing consumption of fish in the human diet. Mercury is extremely toxic to the body, especially the central nervous system, but diagnosis is difficult due to the lack of specific signs. We report four patients with persistent palmar plaques that correlated with blood mercury levels and cleared upon the elimination of mercury from the body.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"23 1","pages":"77 - 81"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72853366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Bezwada, L. Clark, S. Adams, T. O'brien, G. Schultz
Levofloxacin and ofloxacin are fluoroquinolone antibacterial agents with activity against a broad spectrum of Gram‐positive and Gram‐negative ocular pathogens. Levofloxacin is the pure S‐(−) isomer of ofloxacin, and is approximately twice as active as the R‐(+) isomer. Studies were conducted to measure the pharmacokinetics of levofloxacin and ofloxacin in the cornea and aqueous humor of the intact rabbit eye and also to determine the therapeutic efficacy of the two compounds for the treatment of experimental pseudomonas keratitis. A single ocular dose of 1.5% levofloxacin to intact rabbit eyes produced average maximum concentration (Cmax) values in both cornea and aqueous humor that were approximately five times greater than that of 0.3% ofloxacin. Furthermore, concentrations of levofloxacin in corneas were maintained above the minimum inhibitory concentration 90% (MIC90) for most ocular pathogens for more than 2 hours following a single topical dose. In a rabbit model of pseudomonas keratitis, dosing rabbits for 2 days with either 1.5% levofloxacin every 2 hours, or 0.3% ofloxacin every 30 minutes, resulted in the elimination of viable pseudomonas organisms from all treated rabbits. The results of these bioavailability and efficacy studies support the concept that a less frequent dosing regimen with 1.5% levofloxacin ophthalmic solution (every 2 hours) will be as effective as dosing 0.3% ofloxacin every 30 minutes for treatment of bacterial keratitis.
{"title":"Comparative Ocular Bioavailability and Efficacy of Topical Levofloxacin and Ofloxacin in Rabbits","authors":"P. Bezwada, L. Clark, S. Adams, T. O'brien, G. Schultz","doi":"10.1081/CUS-120029763","DOIUrl":"https://doi.org/10.1081/CUS-120029763","url":null,"abstract":"Levofloxacin and ofloxacin are fluoroquinolone antibacterial agents with activity against a broad spectrum of Gram‐positive and Gram‐negative ocular pathogens. Levofloxacin is the pure S‐(−) isomer of ofloxacin, and is approximately twice as active as the R‐(+) isomer. Studies were conducted to measure the pharmacokinetics of levofloxacin and ofloxacin in the cornea and aqueous humor of the intact rabbit eye and also to determine the therapeutic efficacy of the two compounds for the treatment of experimental pseudomonas keratitis. A single ocular dose of 1.5% levofloxacin to intact rabbit eyes produced average maximum concentration (Cmax) values in both cornea and aqueous humor that were approximately five times greater than that of 0.3% ofloxacin. Furthermore, concentrations of levofloxacin in corneas were maintained above the minimum inhibitory concentration 90% (MIC90) for most ocular pathogens for more than 2 hours following a single topical dose. In a rabbit model of pseudomonas keratitis, dosing rabbits for 2 days with either 1.5% levofloxacin every 2 hours, or 0.3% ofloxacin every 30 minutes, resulted in the elimination of viable pseudomonas organisms from all treated rabbits. The results of these bioavailability and efficacy studies support the concept that a less frequent dosing regimen with 1.5% levofloxacin ophthalmic solution (every 2 hours) will be as effective as dosing 0.3% ofloxacin every 30 minutes for treatment of bacterial keratitis.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"21 1","pages":"83 - 90"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89348458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Sarikaki, M. Rallis, H. Tanojo, I. Panteri, Y. Dotsikas, Y. Loukas, G. Papaioannou, C. Demetzos, S. Weber, H. Moini, H. Maibach, L. Packer
One promising class of antioxidant compounds is polyphenols, contained abundantly in pine bark extract (Pycnogenol®—pine bark extract). This medicinal extract is utilized for its anti‐inflammatory properties. Its pharmacological action in skin depends on the kinetics of its absorption. In this study the dermal bioavailability of pine bark extract was investigated. Viable human skin, adapted on continuously perfused Franz cells, was applied with 5% (w/v) pine bark solution. Samples were taken at 0.5, 1, 2, 4, 6, 8, 10, and 12‐hour intervals and analyzed for detection of pine bark extract constituents by high performance liquid chromatography (HPLC) (reversed phase column, isocratic conditions) coupled with an electrochemical detector (EC). Several constituents of pine bark extract such as gallic acid, protocatechuic acid, catechin, p‐hydroxybenzoic acid, vanillin, and one unidentified constituent were detected. These findings indicate that pine bark extract is readily absorbed by human skin and can be used for topical application.
{"title":"In Vitro Percutaneous Absorption of Pine Bark Extract (Pycnogenol) in Human Skin","authors":"V. Sarikaki, M. Rallis, H. Tanojo, I. Panteri, Y. Dotsikas, Y. Loukas, G. Papaioannou, C. Demetzos, S. Weber, H. Moini, H. Maibach, L. Packer","doi":"10.1081/CUS-200035353","DOIUrl":"https://doi.org/10.1081/CUS-200035353","url":null,"abstract":"One promising class of antioxidant compounds is polyphenols, contained abundantly in pine bark extract (Pycnogenol®—pine bark extract). This medicinal extract is utilized for its anti‐inflammatory properties. Its pharmacological action in skin depends on the kinetics of its absorption. In this study the dermal bioavailability of pine bark extract was investigated. Viable human skin, adapted on continuously perfused Franz cells, was applied with 5% (w/v) pine bark solution. Samples were taken at 0.5, 1, 2, 4, 6, 8, 10, and 12‐hour intervals and analyzed for detection of pine bark extract constituents by high performance liquid chromatography (HPLC) (reversed phase column, isocratic conditions) coupled with an electrochemical detector (EC). Several constituents of pine bark extract such as gallic acid, protocatechuic acid, catechin, p‐hydroxybenzoic acid, vanillin, and one unidentified constituent were detected. These findings indicate that pine bark extract is readily absorbed by human skin and can be used for topical application.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"52 1","pages":"149 - 158"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87888408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Ryan, B. Hulette, L. Gildea, R. Dearman, I. Kimber, G. Gerberick
The evaluation of the potential to induce allergic contact dermatitis is an important component of the overall safety assessment process of a new chemical entity that may be encountered through the skin. Currently, the murine local lymph node assay (LLNA) is the method of choice for assessing skin sensitization potential. However, despite the success of the LLNA as an alternative test method that results in a reduction in and refinement of animal usage, it does require the continued use of animals. Therefore, the development of an in vitro predictive test method for skin sensitization is still necessary. A number of different approaches have been taken to develop such a method including the examination of changes in cell surface marker expression in cultured human dendritic cells (DC). The purpose of this current study was to examine the effect of allergen exposure on peripheral blood mononuclear cell (PBMC)‐derived DC using a panel of cell surface markers known to be important in the development of allergic contact dermatitis; CD86, CD80, CD83, CD54, CD40, and CD1a. Changes in the expression of these markers were measured at the level of transcription and cell surface expression. The DC derived from the adherent cell fraction of human PBMC were exposed to either 1 mM or 5 mM dinitrobenzene sulfonic acid (DNBS), the water‐soluble analog of the strong contact allergen 2,4‐dinitrochlorobenzene for 24 hr. After treatment, surface markers expression was measured by flow cytometry, and total RNA was obtained for microarray analysis using Affymetrix U95Av2 Genechips®. Increases in both the cell surface expression and transcript levels of CD86 were observed for PBMC‐DC exposed to DNBS, with 5 mM DNBS inducing the greater change. Cell surface expression of CD80 and CD54 was similar for 1 mM DNBS treated and control cells, and no significant changes were seen at the transcript level. Treatment with 5 mM DNBS resulted in a decrease in cell surface expression for both of these markers. Although a significant allergen‐induced decrease in the transcript level for CD54 was noted, CD80 transcripts were increased. No marked effects on CD83 cell surface or gene expression were observed for either the 1 mM or 5 mM DNBS‐treated cells. Cell surface expression of CD40 and CD1a was somewhat variable in DC preparations treated with 1 mM DNBS, and no significant changes in transcript levels were induced. However, treatment with 5 mM DNBS induced a more marked decrease in cell surface expression of CD40 and CD1a and a significant decrease in the transcript level for CD1a. In summary, we found that changes in cell surface expression in PBMC‐DC following 24‐hr exposure to a contact allergen were reflective of the transcript levels for each of the markers examined with the exception of CD80 in cells treated with 5 mM DNBS.
诱发过敏性接触性皮炎的可能性评估是对可能通过皮肤接触的新化学实体进行整体安全性评估过程的重要组成部分。目前，小鼠局部淋巴结试验(LLNA)是评估皮肤致敏潜力的首选方法。然而，尽管LLNA作为一种替代测试方法取得了成功，导致动物使用的减少和改进，但它确实需要继续使用动物。因此，开发一种体外预测皮肤致敏试验方法仍然是必要的。已经采取了许多不同的方法来开发这种方法，包括检查培养的人类树突状细胞(DC)中细胞表面标记物表达的变化。本研究的目的是研究过敏原暴露对外周血单个核细胞(PBMC)衍生DC的影响，使用一组已知在过敏性接触性皮炎发展中重要的细胞表面标记物;CD86, CD80, CD83, CD54, CD40和CD1a。在转录水平和细胞表面表达水平上测量这些标记物表达的变化。将人PBMC贴壁细胞片段衍生的DC暴露于1 mM或5 mM的二硝基苯磺酸(DNBS)中24小时，DNBS是强接触过敏原2,4 -二硝基苯的水溶性类似物。处理后，流式细胞术检测表面标记物的表达，并使用Affymetrix U95Av2 Genechips®进行微阵列分析，获得总RNA。在暴露于DNBS的PBMC‐DC中，CD86的细胞表面表达和转录水平均有所增加，其中5mm DNBS诱导的变化更大。细胞表面CD80和CD54的表达在1 mM DNBS处理和对照细胞中相似，在转录水平上未见明显变化。5 mM DNBS处理导致这两种标记物的细胞表面表达降低。虽然注意到过敏原诱导的CD54转录水平明显下降，但CD80转录水平却增加了。1 mM或5 mM DNBS处理的细胞对CD83细胞表面或基因表达均无明显影响。CD40和CD1a的细胞表面表达在1 mM DNBS处理的DC制剂中有一定的变化，转录物水平没有显著变化。然而，5 mM DNBS处理诱导CD40和CD1a细胞表面表达更明显下降，CD1a转录物水平显著下降。总之，我们发现PBMC - DC暴露于接触性过敏原24小时后细胞表面表达的变化反映了除5 mM DNBS处理细胞中的CD80外所检测的每种标记物的转录水平。
{"title":"Examination of Phenotypic Changes in Peripheral Blood‐Derived Dendritic Cells Following Exposure to a Contact Allergen: Cell Surface Marker and Gene Expression","authors":"C. Ryan, B. Hulette, L. Gildea, R. Dearman, I. Kimber, G. Gerberick","doi":"10.1081/CUS-120030167","DOIUrl":"https://doi.org/10.1081/CUS-120030167","url":null,"abstract":"The evaluation of the potential to induce allergic contact dermatitis is an important component of the overall safety assessment process of a new chemical entity that may be encountered through the skin. Currently, the murine local lymph node assay (LLNA) is the method of choice for assessing skin sensitization potential. However, despite the success of the LLNA as an alternative test method that results in a reduction in and refinement of animal usage, it does require the continued use of animals. Therefore, the development of an in vitro predictive test method for skin sensitization is still necessary. A number of different approaches have been taken to develop such a method including the examination of changes in cell surface marker expression in cultured human dendritic cells (DC). The purpose of this current study was to examine the effect of allergen exposure on peripheral blood mononuclear cell (PBMC)‐derived DC using a panel of cell surface markers known to be important in the development of allergic contact dermatitis; CD86, CD80, CD83, CD54, CD40, and CD1a. Changes in the expression of these markers were measured at the level of transcription and cell surface expression. The DC derived from the adherent cell fraction of human PBMC were exposed to either 1 mM or 5 mM dinitrobenzene sulfonic acid (DNBS), the water‐soluble analog of the strong contact allergen 2,4‐dinitrochlorobenzene for 24 hr. After treatment, surface markers expression was measured by flow cytometry, and total RNA was obtained for microarray analysis using Affymetrix U95Av2 Genechips®. Increases in both the cell surface expression and transcript levels of CD86 were observed for PBMC‐DC exposed to DNBS, with 5 mM DNBS inducing the greater change. Cell surface expression of CD80 and CD54 was similar for 1 mM DNBS treated and control cells, and no significant changes were seen at the transcript level. Treatment with 5 mM DNBS resulted in a decrease in cell surface expression for both of these markers. Although a significant allergen‐induced decrease in the transcript level for CD54 was noted, CD80 transcripts were increased. No marked effects on CD83 cell surface or gene expression were observed for either the 1 mM or 5 mM DNBS‐treated cells. Cell surface expression of CD40 and CD1a was somewhat variable in DC preparations treated with 1 mM DNBS, and no significant changes in transcript levels were induced. However, treatment with 5 mM DNBS induced a more marked decrease in cell surface expression of CD40 and CD1a and a significant decrease in the transcript level for CD1a. In summary, we found that changes in cell surface expression in PBMC‐DC following 24‐hr exposure to a contact allergen were reflective of the transcript levels for each of the markers examined with the exception of CD80 in cells treated with 5 mM DNBS.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"27 1","pages":"104 - 91"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83344631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Graham, F. Reid, N. Niemuth, Shawn M. Shumaker, Jack D. Waugh
Background/Purpose: A weanling swine model was previously developed to study healing of cutaneous injuries induced by the blistering chemical warfare agent sulfur mustard. Noninvasive bioengineering methods are used in the model to monitor the progress of wound healing and evaluate the efficacy of treatments. It is necessary to anesthetize the animals to facilitate bioengineering data collection from ventral abdominal wound sites. As anesthetic agents affect cardiac output and deep vascular and cutaneous microcirculation in many species, there was a need to identify an anesthetic regimen with minimal effects on baseline measurements. The effects of three anesthetic regimens on reflectance colorimetry, transepidermal water loss, and laser Doppler perfusion imaging were studied in unexposed control animals. Methods: The following regimens were tested on six female Yorkshire swine (weanlings, 8–11 kg): repeated, separate intramuscular (i.m.) injections of ketamine HCl and xylazine HCl (K/X, at 20 ± 2 mg/kg and 2 ± 0.2 mg/kg, respectively), repeated i.m. injections of a tiletamine HCl/zolazepam HCl/xylazine HCl combination (T/X, at 2.2 mg/kg, 2.2 mg/kg, and 4.4 mg/kg, respectively), and the tiletamine HCl/zolazepam HCl/xylazine HCl combination as a preanesthetic and isoflurane inhalation to maintain anesthesia (T/X/Iso; dosage of tiletamine HCl/zolazepam HCl/xylazine HCl was the same as listed above, with 2.5–3.0% isoflurane in oxygen at an initial flow rate of 2 L/min, reduced to 1.0%–1.5% at 0.8–1.0 L/min for maintenance). Each regimen was administered in three iterations within a week (every other day), with a minimum 1‐week washout period between regimens. Results: The effect of the anesthetic regimens on bioengineering assessments of ventral abdominal skin was evaluated. For reflectance colorimetry, regimens T/X and K/X had a narrower range of readings over the three testing days than T/X/Iso. Either T/X or K/X was suitable, with T/X preferred because of a lesser blanching effect. T/X or T/X/Iso were preferred for transepidermal water loss readings, because overall they depressed transepidermal water loss rates less than did K/X. T/X, T/X/Iso, and K/X all affected cutaneous blood flow, with no clear preference. Conclusions: Overall, T/X produced the most consistent results with the fewest anesthetic effects.
{"title":"Effects of Three Anesthetic Regimens on Bioengineering Methods Conducted on Ventral Abdominal Skin of Weanling Swine","authors":"J. Graham, F. Reid, N. Niemuth, Shawn M. Shumaker, Jack D. Waugh","doi":"10.1081/CUS-120030168","DOIUrl":"https://doi.org/10.1081/CUS-120030168","url":null,"abstract":"Background/Purpose: A weanling swine model was previously developed to study healing of cutaneous injuries induced by the blistering chemical warfare agent sulfur mustard. Noninvasive bioengineering methods are used in the model to monitor the progress of wound healing and evaluate the efficacy of treatments. It is necessary to anesthetize the animals to facilitate bioengineering data collection from ventral abdominal wound sites. As anesthetic agents affect cardiac output and deep vascular and cutaneous microcirculation in many species, there was a need to identify an anesthetic regimen with minimal effects on baseline measurements. The effects of three anesthetic regimens on reflectance colorimetry, transepidermal water loss, and laser Doppler perfusion imaging were studied in unexposed control animals. Methods: The following regimens were tested on six female Yorkshire swine (weanlings, 8–11 kg): repeated, separate intramuscular (i.m.) injections of ketamine HCl and xylazine HCl (K/X, at 20 ± 2 mg/kg and 2 ± 0.2 mg/kg, respectively), repeated i.m. injections of a tiletamine HCl/zolazepam HCl/xylazine HCl combination (T/X, at 2.2 mg/kg, 2.2 mg/kg, and 4.4 mg/kg, respectively), and the tiletamine HCl/zolazepam HCl/xylazine HCl combination as a preanesthetic and isoflurane inhalation to maintain anesthesia (T/X/Iso; dosage of tiletamine HCl/zolazepam HCl/xylazine HCl was the same as listed above, with 2.5–3.0% isoflurane in oxygen at an initial flow rate of 2 L/min, reduced to 1.0%–1.5% at 0.8–1.0 L/min for maintenance). Each regimen was administered in three iterations within a week (every other day), with a minimum 1‐week washout period between regimens. Results: The effect of the anesthetic regimens on bioengineering assessments of ventral abdominal skin was evaluated. For reflectance colorimetry, regimens T/X and K/X had a narrower range of readings over the three testing days than T/X/Iso. Either T/X or K/X was suitable, with T/X preferred because of a lesser blanching effect. T/X or T/X/Iso were preferred for transepidermal water loss readings, because overall they depressed transepidermal water loss rates less than did K/X. T/X, T/X/Iso, and K/X all affected cutaneous blood flow, with no clear preference. Conclusions: Overall, T/X produced the most consistent results with the fewest anesthetic effects.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"25 1","pages":"105 - 118"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80107214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glutamate has been implicated in ocular development. The present study aims to characterize the physical changes that occur as a result of systemic intake of monosodium glutamate (MSG). As MSG has also been suggested to play a part in myopia, its effect on form‐deprived eyes was also investigated. Form‐deprivation myopia (FDM) was induced by placing a black goggle over one eye of each chick. Neonatal chicks were injected with daily MSG (0.1, 1 and 10 mg/day) or saline control for 14 days intraperitoncally (n = 6–7 in all cases). The results show that MSG significantly reduced the eye weight (EW), ocular length (OL), and equatorial diameter (ED) of the normal (i.e. with MSG treatment but not form‐deprived) ocular growth (mean ± s.e.m, MSG dose in parenthesis): EW, 0.90 ± 0.02 vs. 0.81 ± 0.05 (0.1), 0.78 ± 0.04 (1), 0.83 ± 0.04 (10); OL, 1.02 ± 0.03 vs. 0.94 ± 0.03 (0.1), 0.95 ± 0.01 (1), 0.97 ± 0.02 (10); ED, 1.36 ± 0.01 vs. 1.30 ± 0.02 (0.1), 1.28 ± 0.02 (1), 1.33 ± 0.03 (10). As a result of FDM, these measurements of the eye tend to increase as well as result in thinning of the retina and thickening of the sclera. However, under MSG treatment, no significant increase in these parameters with form‐deprived chicks occurred. In fact, a gradual downward trend was observed. Histological measurements show that both the normal and myopic retinal and scleral layers were thinner than the controls (i.e. no MSG or FDM) at MSG‐1 and 10 mg/day (thickness ± s.e.m, MSG dose in parenthesis): control retina: 97 ± 12 vs. 77 ± 3 (1) and 78 ± 2 (10); FDM retina: 83 ± 16 vs. 74 ± 4 (1) and 75 ± 3 (10); control sclera: 44 ± 7 vs. 29 ± 2 (1) and 36 ± 3 (10); FDM sclera; 41 ± 5 vs. 31 ± 2 (1) and 32 ± 2 (10). However, MSG # injections of 0.1 mg/day caused a significant increase in both normal and myopic retinal and scleral thickness compared to the controls stated above: MSG retina, 140 ± 14 and FDM retina, 157 ± 15; MSG sclera, 55 ± 7 and FDM sclera, 63 ± 8. The results suggest that MSG at high concentrations can cause a reduction in ocular growth probably due to its related cytotoxicity and the subsequent cellular destruction with or without inherent FDM. The increase in retinal and scleral thickness at low dose of MSG may be due to intracellular swelling as has been reported in other studies. The damaging effect of MSG to the retina of both goggled and open eyes may be sufficient to cause the eye to become myopic as images will thus be projected in front of the retina. Despite the low dosage used, it still caused significant ocular damages, which suggests that the amount of MSG intake must be viewed with caution.
谷氨酸与眼部发育有关。本研究旨在描述由于全身摄入味精(MSG)而发生的物理变化。由于味精也被认为在近视中起作用，它对形状缺失的眼睛的影响也被研究了。形式剥夺性近视(FDM)是通过在每只小鸡的一只眼睛上戴上黑色护目镜来诱导的。雏鸡分别每日腹腔注射味精(0.1、1和10 mg/d)或生理盐水对照，连续14 d (n = 6 ~ 7)。结果表明，味精显著降低正常(即味精治疗但未形成剥夺)眼生长的眼重(EW)、眼长(OL)和赤道直径(ED)(平均值±s.e.m，味精剂量在括号内):EW为0.90±0.02 vs. 0.81±0.05(0.1)、0.78±0.04(1)、0.83±0.04 (10);OL, 1.02±0.03和0.94±0.03(0.1),0.95±0.01(1),0.97±0.02 (10);艾德,1.36±0.01和1.30±0.02(0.1),1.28±0.02(1),1.33±0.03(10)。FDM的结果是，眼睛的这些测量值趋于增加，并导致视网膜变薄和巩膜增厚。然而，在味精处理下，这些参数在形态缺失的雏鸡中没有显著增加。事实上，观察到一个逐渐下降的趋势。组织学测量显示，在MSG‐1和10 mg/天(厚度±s.e.m, MSG剂量在括号内)时，正常和近视的视网膜和巩膜层都比对照组(即没有MSG或FDM)薄:对照视网膜:97±12 vs. 77±3(1)和78±2 (10);FDM视网膜:83±16 vs. 74±4(1)和75±3 (10);对照巩膜:44±7 vs. 29±2(1)和36±3 (10);FDM巩膜;41±5 vs. 31±2(1)和32±2(10)。然而，与上述对照组相比，注射0.1 mg/天的味精使正常和近视的视网膜和巩膜厚度显著增加:味精视网膜，140±14,FDM视网膜，157±15;味精巩膜，55±7;FDM巩膜，63±8。结果表明，高浓度味精可能由于其相关的细胞毒性和随后的细胞破坏而导致眼部生长减少，无论是否存在固有的FDM。低剂量味精的视网膜和巩膜厚度增加可能是由于细胞内肿胀，其他研究也有报道。味精对戴着护目镜和睁开眼睛的视网膜的破坏作用可能足以导致眼睛近视，因为图像因此会投射到视网膜前。尽管使用的剂量很低，但它仍然会造成严重的眼部损伤，这表明必须谨慎看待味精的摄入量。
{"title":"The Damaging Effect of Systemic Injection of Monosodium Glutamate (MSG) on the Development of Normal and Form‐Deprived Eyes of the Chick","authors":"C. Yeung, S. Chiang, C. Pang, D. Lam","doi":"10.1081/CUS-120027481","DOIUrl":"https://doi.org/10.1081/CUS-120027481","url":null,"abstract":"Glutamate has been implicated in ocular development. The present study aims to characterize the physical changes that occur as a result of systemic intake of monosodium glutamate (MSG). As MSG has also been suggested to play a part in myopia, its effect on form‐deprived eyes was also investigated. Form‐deprivation myopia (FDM) was induced by placing a black goggle over one eye of each chick. Neonatal chicks were injected with daily MSG (0.1, 1 and 10 mg/day) or saline control for 14 days intraperitoncally (n = 6–7 in all cases). The results show that MSG significantly reduced the eye weight (EW), ocular length (OL), and equatorial diameter (ED) of the normal (i.e. with MSG treatment but not form‐deprived) ocular growth (mean ± s.e.m, MSG dose in parenthesis): EW, 0.90 ± 0.02 vs. 0.81 ± 0.05 (0.1), 0.78 ± 0.04 (1), 0.83 ± 0.04 (10); OL, 1.02 ± 0.03 vs. 0.94 ± 0.03 (0.1), 0.95 ± 0.01 (1), 0.97 ± 0.02 (10); ED, 1.36 ± 0.01 vs. 1.30 ± 0.02 (0.1), 1.28 ± 0.02 (1), 1.33 ± 0.03 (10). As a result of FDM, these measurements of the eye tend to increase as well as result in thinning of the retina and thickening of the sclera. However, under MSG treatment, no significant increase in these parameters with form‐deprived chicks occurred. In fact, a gradual downward trend was observed. Histological measurements show that both the normal and myopic retinal and scleral layers were thinner than the controls (i.e. no MSG or FDM) at MSG‐1 and 10 mg/day (thickness ± s.e.m, MSG dose in parenthesis): control retina: 97 ± 12 vs. 77 ± 3 (1) and 78 ± 2 (10); FDM retina: 83 ± 16 vs. 74 ± 4 (1) and 75 ± 3 (10); control sclera: 44 ± 7 vs. 29 ± 2 (1) and 36 ± 3 (10); FDM sclera; 41 ± 5 vs. 31 ± 2 (1) and 32 ± 2 (10). However, MSG # injections of 0.1 mg/day caused a significant increase in both normal and myopic retinal and scleral thickness compared to the controls stated above: MSG retina, 140 ± 14 and FDM retina, 157 ± 15; MSG sclera, 55 ± 7 and FDM sclera, 63 ± 8. The results suggest that MSG at high concentrations can cause a reduction in ocular growth probably due to its related cytotoxicity and the subsequent cellular destruction with or without inherent FDM. The increase in retinal and scleral thickness at low dose of MSG may be due to intracellular swelling as has been reported in other studies. The damaging effect of MSG to the retina of both goggled and open eyes may be sufficient to cause the eye to become myopic as images will thus be projected in front of the retina. Despite the low dosage used, it still caused significant ocular damages, which suggests that the amount of MSG intake must be viewed with caution.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"29 1","pages":"41 - 52"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91205822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose. Retinoic acid (RA) has been proposed to be of value in treating myopia, as it affects scleral growth in chicks with form‐deprivation myopia. The present study aimed to test the effects of RA injection on a form‐deprivation myopia (FDM) model in chicks. Methods. The chicks were form‐deprived by having a black goggle sutured over one eye with the contralateral eye as the control. Daily intraperitoneal injection of all‐trans RA was performed for 12 days. The eye weight (EW), ocular length (OL), equatorial diameter (ED), and the thickness of retina and sclera were measured to reflect the effects of RA on ocular development under form‐deprivation myopia. Results. The effect of RA was biphasic with alleviating effect on FDM limited to a daily dose of up to 10 µg/day with relatively less myopic development than the controls. Significant differences of EW and OL, but not ED, at 10 µg/day RA (P < 0.05) were observed. The thinning of retina and the thickening of sclera as a result of FDM were reversed, albeit not significantly, in the presence of RA up to a daily dose of 10 µg/day. Conclusions. The results show that exogenously applied RA has the potential to inhibit scleral growth in form‐deprived chicks. Such findings are in line with the understanding that regulation of scleral growth is one of the key factors in myopia, and RA may be of value in its treatment.
{"title":"Retinoic Acid Reduces Ocular Elongation in Chicks with Form‐Deprivation Myopia","authors":"C. Yeung, S. Chiang, C. Pang, D. Lam","doi":"10.1081/CUS-120027482","DOIUrl":"https://doi.org/10.1081/CUS-120027482","url":null,"abstract":"Purpose. Retinoic acid (RA) has been proposed to be of value in treating myopia, as it affects scleral growth in chicks with form‐deprivation myopia. The present study aimed to test the effects of RA injection on a form‐deprivation myopia (FDM) model in chicks. Methods. The chicks were form‐deprived by having a black goggle sutured over one eye with the contralateral eye as the control. Daily intraperitoneal injection of all‐trans RA was performed for 12 days. The eye weight (EW), ocular length (OL), equatorial diameter (ED), and the thickness of retina and sclera were measured to reflect the effects of RA on ocular development under form‐deprivation myopia. Results. The effect of RA was biphasic with alleviating effect on FDM limited to a daily dose of up to 10 µg/day with relatively less myopic development than the controls. Significant differences of EW and OL, but not ED, at 10 µg/day RA (P < 0.05) were observed. The thinning of retina and the thickening of sclera as a result of FDM were reversed, albeit not significantly, in the presence of RA up to a daily dose of 10 µg/day. Conclusions. The results show that exogenously applied RA has the potential to inhibit scleral growth in form‐deprived chicks. Such findings are in line with the understanding that regulation of scleral growth is one of the key factors in myopia, and RA may be of value in its treatment.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"95 1","pages":"53 - 64"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76190643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Clark, P. Bezwada, K. Hosoi, T. Ikuse, S. Adams, G. Schultz, T. O'brien
Levofloxacin, the L‐isomer of ofloxacin and a potent quinolone with a broad spectrum of antibacterial activity, was evaluated in a series of toxicology studies including acute and chronic dosing in rabbits and primates with intact and injured eyes. No evidence of ocular toxicity was observed in rabbits with intact eyes that were topically instilled with levofloxacin ophthalmic solutions under various treatment regimens, including multiple dosing (four to six times daily) for up to 26 weeks at levofloxacin concentrations from 0.3% to 3%. When rabbits were repetitively instilled (10 times at 30 minute intervals) with 0.3%, 1%, or 3% levofloxacin ophthalmic solutions over a single day, they exhibited no increase in ocular irritation scores, whereas dosing with 10% and 25% levofloxacin produced dose‐dependent increases in ocular discharge, conjunctival injection and edema, corneal edema/fluorescein staining, iridic congestion, and behavioral abnormalities. Healing of 7.5 mm diameter epithelial wounds in rabbit eyes was not delayed by dosing four times daily (QID) with 0.5% or 1.5% levofloxacin in four different vehicles, with complete healing after 48 hours. The QID dosing with 3% or 6% levofloxacin retarded healing at 24 hours, but healing was complete in eyes treated with 3% levofloxacin by 72 hours after injury, and nearly complete in eyes treated with 6% levofloxacin by 96 hours. Using a similar model in primates, QID treatment with 1.5% levofloxacin produced no delay in healing of epithelial wounds or increased corneal thickness compared to glycerin vehicle, while QID treatment with 3% levofloxacin delayed healing at 24 and 48 hours after injury and increased corneal thickness for 11 days. Histological evaluation of the eyes confirmed that there was no detrimental effect to the corneal endothelium as a result of treatment with 1.5% levofloxacin. In conclusion, the results of these studies support the ocular safety of concentrations of levofloxacin up to 1.5% when administered topically to the intact or wounded eye.
{"title":"Comprehensive Evaluation of Ocular Toxicity of Topical Levofloxacin in Rabbit and Primate Models","authors":"L. Clark, P. Bezwada, K. Hosoi, T. Ikuse, S. Adams, G. Schultz, T. O'brien","doi":"10.1081/CUS-120029762","DOIUrl":"https://doi.org/10.1081/CUS-120029762","url":null,"abstract":"Levofloxacin, the L‐isomer of ofloxacin and a potent quinolone with a broad spectrum of antibacterial activity, was evaluated in a series of toxicology studies including acute and chronic dosing in rabbits and primates with intact and injured eyes. No evidence of ocular toxicity was observed in rabbits with intact eyes that were topically instilled with levofloxacin ophthalmic solutions under various treatment regimens, including multiple dosing (four to six times daily) for up to 26 weeks at levofloxacin concentrations from 0.3% to 3%. When rabbits were repetitively instilled (10 times at 30 minute intervals) with 0.3%, 1%, or 3% levofloxacin ophthalmic solutions over a single day, they exhibited no increase in ocular irritation scores, whereas dosing with 10% and 25% levofloxacin produced dose‐dependent increases in ocular discharge, conjunctival injection and edema, corneal edema/fluorescein staining, iridic congestion, and behavioral abnormalities. Healing of 7.5 mm diameter epithelial wounds in rabbit eyes was not delayed by dosing four times daily (QID) with 0.5% or 1.5% levofloxacin in four different vehicles, with complete healing after 48 hours. The QID dosing with 3% or 6% levofloxacin retarded healing at 24 hours, but healing was complete in eyes treated with 3% levofloxacin by 72 hours after injury, and nearly complete in eyes treated with 6% levofloxacin by 96 hours. Using a similar model in primates, QID treatment with 1.5% levofloxacin produced no delay in healing of epithelial wounds or increased corneal thickness compared to glycerin vehicle, while QID treatment with 3% levofloxacin delayed healing at 24 and 48 hours after injury and increased corneal thickness for 11 days. Histological evaluation of the eyes confirmed that there was no detrimental effect to the corneal endothelium as a result of treatment with 1.5% levofloxacin. In conclusion, the results of these studies support the ocular safety of concentrations of levofloxacin up to 1.5% when administered topically to the intact or wounded eye.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"37 1","pages":"1 - 18"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87744739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Yeung, K. Chan, S. Chiang, C. Pang, W. Ko, D. Lam
1. This study demonstrated that the modification of calcium concentrations ([Ca2 +]) could severely affect the viability of human retinal pigment epithelial (ARPE19) cells. 2. Pharmacological agents with varying mechanisms of action: verapamil (VP), diltiazem (DIL), caffeine (CF), papaverine (PA), forskolin (FSK), ryanodine (RYN), thapsigargin (THG), and cyclosporin A (CysA) were used to evaluate the effect of modifying cytosolic Ca2 + on the viability of ARPE19 cells. The difference in cell proliferations under different treatments was performed using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Ca2 +‐imaging was used to determine the changes in intracellular Ca2 + levels ([Ca2 +]i) over 5 min of drug treatments. 3. Amongst the agents tested, PA, RYN, and THG actually increased the total number of cells initially on Day 1. However, apart from PA, all caused significant reduction of cell viability by Day 5. Variable [Ca2 +]i levels in the cells were obtained with significant rises in the presence of DIL, CF, PA, FSK, and CysA. Verapamil, RYN, and THG caused a rise in [Ca2 +]i, but the effect was not significant. 4. The present study showed that the APRE19 cells were very sensitive to the Ca2 + homeostasis. It is possible that other ocular cells may also display such vulnerability. Therefore, clinically used pharmacological agents that are known to affect Ca2 + must be treated with caution.
{"title":"Alterations of Calcium Homeostasis Affect the Survival of Human Retinal Epithelial Cells","authors":"C. Yeung, K. Chan, S. Chiang, C. Pang, W. Ko, D. Lam","doi":"10.1081/CUS-120030170","DOIUrl":"https://doi.org/10.1081/CUS-120030170","url":null,"abstract":"1. This study demonstrated that the modification of calcium concentrations ([Ca2 +]) could severely affect the viability of human retinal pigment epithelial (ARPE19) cells. 2. Pharmacological agents with varying mechanisms of action: verapamil (VP), diltiazem (DIL), caffeine (CF), papaverine (PA), forskolin (FSK), ryanodine (RYN), thapsigargin (THG), and cyclosporin A (CysA) were used to evaluate the effect of modifying cytosolic Ca2 + on the viability of ARPE19 cells. The difference in cell proliferations under different treatments was performed using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Ca2 +‐imaging was used to determine the changes in intracellular Ca2 + levels ([Ca2 +]i) over 5 min of drug treatments. 3. Amongst the agents tested, PA, RYN, and THG actually increased the total number of cells initially on Day 1. However, apart from PA, all caused significant reduction of cell viability by Day 5. Variable [Ca2 +]i levels in the cells were obtained with significant rises in the presence of DIL, CF, PA, FSK, and CysA. Verapamil, RYN, and THG caused a rise in [Ca2 +]i, but the effect was not significant. 4. The present study showed that the APRE19 cells were very sensitive to the Ca2 + homeostasis. It is possible that other ocular cells may also display such vulnerability. Therefore, clinically used pharmacological agents that are known to affect Ca2 + must be treated with caution.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"22 1","pages":"135 - 147"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77532587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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