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F Jehl - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics in vivo and pharmacodynamics ex vivo in vitro of meropenem and cefpirome in the Yucatan Micropig model continuous infusion versus intermittent injection
Clinical Microbiology and Infection, 1998Co-Authors: H Elkhaili, Jeandaniel Peter, D Pompei, Dominique Levěque, Laurence Linger, Yves Salmon, Julie Salmon, H Monteil, F JehlAbstract:Objective To investigate the pharmacodynamic disposition of two recently developed β-lactam antibiotics, meropenem and cefpirome, in the Yucatan Micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo Micropig model after administration by both intermittent injection and continuous infusion. Methods Cefpirome (1 g) was given to the Micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum β-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB). Results The bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log 10 decrease of inoculum. Conclusions In the present study the Micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested β-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of β-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity.
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pharmacokinetics of three new β lactams in the Yucatan Micropig model administered by intravenous bolus injection and continuous infusion
International Journal of Antimicrobial Agents, 1997Co-Authors: H Elkhaili, D Pompei, Yves Salmon, Julie Salmon, H Monteil, Dominique Leveque, J D Peter, F JehlAbstract:Abstract The miniature pig is becoming a popular non-rodent animal model in biochemical research because of physiological similarities to humans. In addition, the Micropig presents the advantages of large animal species for experimental pharmacokinetics. However, pharmacokinetics of antimicrobial agents are poorly documented in the pig and further work is needed to establish interspecies comparisons. This prompted us to investigate the disposition of three well documented β-lactams (cefepime, cefpirome and meropenem) in this model and also to evaluate the potential to use it for pharmacodynamic studies. Each drug was given following a single dose both by direct intravenous injection (or short infusion for meropenem) and continuous infusion. Six animals were enrolled in each group. Blood samples were obtained over a 0–12 h period, using a catheter placed in the external jugular vein. All β-lactams were assayed by high performance liquid chromatography (HPLC). Pharmacokinetics of cefepime and cefpirome given by bolus injection in the microswine were close to those in man receiving equivalent dosage (i.e. 2 g). The terminal half-lives are similar (human: 1.80 h, 1.80 h; pig: 1.46 h, 1.29 h) as is the case for clearance values (human: 1.82, 1.80; pig: 1.90, 1.74 ml/min per kg) for cefepime and cefpirome, respectively. The administration by continuous infusion does not influence the elimination rate of cefepime, cefpirome and meropenem. Meropenem kinetics in the Micropig were also similar to those in man. The terminal half-lives are similar (human, 0.83 h; pig, 0.88 h) as in the case for clearance values (human, 4.0 h; pig, 4.90 ml/min per kg) after 30 min intravenous infusion of meropenem. We concluded that the Micropig is an adequate model for the study of the pharmacokinetics and probably the pertinent model for ex-vivo pharmacodynamics investigations of cefepime, cefpirome and meropenem.
Mark J Post - One of the best experts on this subject based on the ideXlab platform.
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metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty a study in the atherosclerotic Yucatan Micropig
Circulation, 2000Co-Authors: Bart J G L De Smet, Cornelius Borst, Yvonne J M Van Der Helm, Dominique P V De Kleijn, Roeland Hanemaaijer, J H Verheijen, L Robertus, Mark J PostAbstract:Background - Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation. Methods and Results - In atherosclerotic iliac arteries of 12 Yucatan Micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3±0.1 versus 0.8±0.1 mm (P=0.01) and 2.2±0.5 versus 4.9±0.7 mm2 (P=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9±0.6 mm2 in the Batimastat group compared with 3.8±0.8 mm2 in the vehicle group (P=0.003, mixed model analysis P=0.01). Neointima formation was 1.3±0.3 mm2 in the Batimastat group and 1.0±0.2 mm2 in the vehicle group (P=0.542). Conclusions - Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition. Chemicals/CAS: batimastat, 130370-60-4; Metalloendopeptidases, EC 3.4.24.-; Phenylalanine, 63-91-2; Protease Inhibitors; Thiophenes
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the relation between de novo atherosclerosis remodeling and angioplasty induced remodeling in an atherosclerotic Yucatan Micropig model
Arteriosclerosis Thrombosis and Vascular Biology, 1998Co-Authors: Bart J G L De Smet, Cornelius Borst, Gerard Pasterkamp, Yvonne J M Van Der Helm, Mark J PostAbstract:Geometric remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference that, together with plaque growth or neointima formation, determines the lumen of the artery. The heterogeneous nature of arterial obstructions raises the question of whether early and late outcomes (restenosis) of angioplasty are affected by the degree and direction of de novo atherosclerotic remodeling. This study was designed to assess the relationship between atherosclerotic remodeling and the degree and mechanism of restenosis after balloon angioplasty. Atherosclerosis was induced in 27 peripheral arteries of 18 Yucatan Micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed, with serial intravascular ultrasound and quantitative angiography before and after intervention and at 42 days' follow-up. We used the relative media-bounded area (MBA), defined as the MBA of the treated site divided by the MBA of the reference, before angioplasty as a measure of remodeling in de novo atherosclerosis and late MBA loss as a measure of remodeling after balloon angioplasty. Relative MBA before angioplasty was not correlated with angiographic and echographic acute gain after balloon angioplasty (r=.22, P=.28 and r=.14, P=.48) or with late lumen loss (r=-.05, P=.81 and r=.19, P=.33). No correlation was found between relative MBA and late MBA loss (r=.14 and P=.48). In the atherosclerotic Yucatan Micropig, remodeling during de novo atherosclerosis has no relevance for acute gain and late lumen loss after balloon angioplasty. Both the direction and the extent of remodeling after balloon angioplasty are not related to the direction and extent of remodeling during de novo atherosclerosis.
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the relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty a study in the normal rabbit and the hypercholesterolemic Yucatan Micropig
Circulation, 1994Co-Authors: Mark J Post, Cornelius Borst, R E KuntzAbstract:BACKGROUND Although arterial renarrowing after angioplasty has been attributed largely to intimal hyperplasia, there has been no systematic effort to correlate the actual hyperplastic tissue mass with angiographic lumen reduction. Using balloon angioplasty in various animal restenosis models, we quantitatively assessed the separate contributions of intimal hyperplasia and arterial remodeling to angiographic late lumen loss. METHODS AND RESULTS Data used for this study were obtained from experiments of conventional and thermal (37 degrees C or 55 degrees to 90 degrees C) balloon angioplasty-treated femoral and iliac arteries in normal rabbits and conventional balloon angioplasty-treated iliac arteries in Yucatan Micropigs fed either a normal or an atherogenic diet. Quantitative angiography was performed immediately before and after intervention and at 3 or 8 weeks thereafter, and late loss in lumen diameter was taken as the difference between arterial diameter immediately after treatment and at 3 or 8 weeks of follow-up. Intimal hyperplasia was quantified histologically as the area of tissue mass within the internal elastic lamina. We observed a consistent discrepancy between the actual late loss seen with angiography and the diameter reduction that could be explained by histological intimal thickness alone in both animal models. This discrepancy ranged from 86 +/- 3% of the late loss in the 8 weeks/37 degrees C group to 77 +/- 22% in the conventional group for rabbits and 52 +/- 23% in an atherogenic diet group (n = 10) to 89 +/- 11% in a normal diet group (n = 6) for pigs. This discrepancy appeared to be due predominantly to reduction of the area circumscribed by the internal elastic membrane, a process that is tentatively designated as arterial remodeling. In both the rabbit femoral artery and in the Yucatan iliac artery, remodeling, not intimal hyperplasia, correlated with angiographic late loss. CONCLUSIONS In both the normal rabbit and the normal and atherosclerotic pig, restenosis after angioplasty results from both intimal hyperplasia and arterial remodeling. The exact etiology of arterial renarrowing after angioplasty has important implications on the design of antirestenosis drugs and new coronary devices.
H Elkhaili - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics in vivo and pharmacodynamics ex vivo in vitro of meropenem and cefpirome in the Yucatan Micropig model continuous infusion versus intermittent injection
Clinical Microbiology and Infection, 1998Co-Authors: H Elkhaili, Jeandaniel Peter, D Pompei, Dominique Levěque, Laurence Linger, Yves Salmon, Julie Salmon, H Monteil, F JehlAbstract:Objective To investigate the pharmacodynamic disposition of two recently developed β-lactam antibiotics, meropenem and cefpirome, in the Yucatan Micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo Micropig model after administration by both intermittent injection and continuous infusion. Methods Cefpirome (1 g) was given to the Micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum β-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB). Results The bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log 10 decrease of inoculum. Conclusions In the present study the Micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested β-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of β-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity.
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pharmacokinetics of three new β lactams in the Yucatan Micropig model administered by intravenous bolus injection and continuous infusion
International Journal of Antimicrobial Agents, 1997Co-Authors: H Elkhaili, D Pompei, Yves Salmon, Julie Salmon, H Monteil, Dominique Leveque, J D Peter, F JehlAbstract:Abstract The miniature pig is becoming a popular non-rodent animal model in biochemical research because of physiological similarities to humans. In addition, the Micropig presents the advantages of large animal species for experimental pharmacokinetics. However, pharmacokinetics of antimicrobial agents are poorly documented in the pig and further work is needed to establish interspecies comparisons. This prompted us to investigate the disposition of three well documented β-lactams (cefepime, cefpirome and meropenem) in this model and also to evaluate the potential to use it for pharmacodynamic studies. Each drug was given following a single dose both by direct intravenous injection (or short infusion for meropenem) and continuous infusion. Six animals were enrolled in each group. Blood samples were obtained over a 0–12 h period, using a catheter placed in the external jugular vein. All β-lactams were assayed by high performance liquid chromatography (HPLC). Pharmacokinetics of cefepime and cefpirome given by bolus injection in the microswine were close to those in man receiving equivalent dosage (i.e. 2 g). The terminal half-lives are similar (human: 1.80 h, 1.80 h; pig: 1.46 h, 1.29 h) as is the case for clearance values (human: 1.82, 1.80; pig: 1.90, 1.74 ml/min per kg) for cefepime and cefpirome, respectively. The administration by continuous infusion does not influence the elimination rate of cefepime, cefpirome and meropenem. Meropenem kinetics in the Micropig were also similar to those in man. The terminal half-lives are similar (human, 0.83 h; pig, 0.88 h) as in the case for clearance values (human, 4.0 h; pig, 4.90 ml/min per kg) after 30 min intravenous infusion of meropenem. We concluded that the Micropig is an adequate model for the study of the pharmacokinetics and probably the pertinent model for ex-vivo pharmacodynamics investigations of cefepime, cefpirome and meropenem.
Cornelius Borst - One of the best experts on this subject based on the ideXlab platform.
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nonmuscle myosin heavy chain b expression in balloon dilated and stented arteries a study in the atherosclerotic Yucatan Micropig
Netherlands Heart Journal, 2005Co-Authors: De Leon H, Cornelius Borst, J N Wilcox, A Schoneveld, M J PostAbstract:BACKGROUND Restenosis after balloon angioplasty is in part due to remodelling, whereas restenosis after stenting is entirely due to neointima formation. Nonmuscle myosin heavy chain-B (NMMHC-B) is expressed by vascular smooth muscle cells and because of its overexpression in restenotic lesions after balloon angioplasty, NMMHC-B is proposed as a potential therapeutic target. Because the mechanisms underlying restenosis after balloon angioplasty or after stenting are different we hypothesised that the expression of NMMHC-B would differ in balloon-dilated versus stented arteries. METHODS To study the localisation and time course of expression of NMMHC-B, we performed stenting or balloon dilation in peripheral arteries of 16 atherosclerotic Yucatan Micropigs and used serial intravascular ultrasound (IVUS) and angiography to measure geometric dimensions following balloon angioplasty or stenting. In situ hybridisation techniques were used to detect NMMHC-B mRNA. 5'-bromo-2'-deoxyuridine (BrdU) was administered to detect proliferating cells. By counting the number of silver grains in the different layers of the artery, we could compare the amount of expression at the different time points between the groups. RESULTS In intima and media, NMMHC-B expression increased after balloon dilation and stenting and peaked at 7 days. In stented arteries, the expression of NMMHC-B remained high for up to 42 days after injury, whereas in balloon-dilated arteries it had normalised. In the adventitia of balloon-dilated arteries, but not of stented arteries, NMMHC-B expression peaked at 7 days. NMMHC-B expression was not limited to proliferating cells. CONCLUSION NMMHC-B is expressed near sites of active repair after arterial injury, but not limited to proliferating cells. The different pattern of NMMHC-B expression after balloon dilation compared with stenting may be related to arterial remodelling, because stented arteries that do not remodel lack this conspicuous adventitial expression at 7 days.
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metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty a study in the atherosclerotic Yucatan Micropig
Circulation, 2000Co-Authors: Bart J G L De Smet, Cornelius Borst, Yvonne J M Van Der Helm, Dominique P V De Kleijn, Roeland Hanemaaijer, J H Verheijen, L Robertus, Mark J PostAbstract:Background - Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation. Methods and Results - In atherosclerotic iliac arteries of 12 Yucatan Micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3±0.1 versus 0.8±0.1 mm (P=0.01) and 2.2±0.5 versus 4.9±0.7 mm2 (P=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9±0.6 mm2 in the Batimastat group compared with 3.8±0.8 mm2 in the vehicle group (P=0.003, mixed model analysis P=0.01). Neointima formation was 1.3±0.3 mm2 in the Batimastat group and 1.0±0.2 mm2 in the vehicle group (P=0.542). Conclusions - Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition. Chemicals/CAS: batimastat, 130370-60-4; Metalloendopeptidases, EC 3.4.24.-; Phenylalanine, 63-91-2; Protease Inhibitors; Thiophenes
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the relation between de novo atherosclerosis remodeling and angioplasty induced remodeling in an atherosclerotic Yucatan Micropig model
Arteriosclerosis Thrombosis and Vascular Biology, 1998Co-Authors: Bart J G L De Smet, Cornelius Borst, Gerard Pasterkamp, Yvonne J M Van Der Helm, Mark J PostAbstract:Geometric remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference that, together with plaque growth or neointima formation, determines the lumen of the artery. The heterogeneous nature of arterial obstructions raises the question of whether early and late outcomes (restenosis) of angioplasty are affected by the degree and direction of de novo atherosclerotic remodeling. This study was designed to assess the relationship between atherosclerotic remodeling and the degree and mechanism of restenosis after balloon angioplasty. Atherosclerosis was induced in 27 peripheral arteries of 18 Yucatan Micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed, with serial intravascular ultrasound and quantitative angiography before and after intervention and at 42 days' follow-up. We used the relative media-bounded area (MBA), defined as the MBA of the treated site divided by the MBA of the reference, before angioplasty as a measure of remodeling in de novo atherosclerosis and late MBA loss as a measure of remodeling after balloon angioplasty. Relative MBA before angioplasty was not correlated with angiographic and echographic acute gain after balloon angioplasty (r=.22, P=.28 and r=.14, P=.48) or with late lumen loss (r=-.05, P=.81 and r=.19, P=.33). No correlation was found between relative MBA and late MBA loss (r=.14 and P=.48). In the atherosclerotic Yucatan Micropig, remodeling during de novo atherosclerosis has no relevance for acute gain and late lumen loss after balloon angioplasty. Both the direction and the extent of remodeling after balloon angioplasty are not related to the direction and extent of remodeling during de novo atherosclerosis.
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the relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty a study in the normal rabbit and the hypercholesterolemic Yucatan Micropig
Circulation, 1994Co-Authors: Mark J Post, Cornelius Borst, R E KuntzAbstract:BACKGROUND Although arterial renarrowing after angioplasty has been attributed largely to intimal hyperplasia, there has been no systematic effort to correlate the actual hyperplastic tissue mass with angiographic lumen reduction. Using balloon angioplasty in various animal restenosis models, we quantitatively assessed the separate contributions of intimal hyperplasia and arterial remodeling to angiographic late lumen loss. METHODS AND RESULTS Data used for this study were obtained from experiments of conventional and thermal (37 degrees C or 55 degrees to 90 degrees C) balloon angioplasty-treated femoral and iliac arteries in normal rabbits and conventional balloon angioplasty-treated iliac arteries in Yucatan Micropigs fed either a normal or an atherogenic diet. Quantitative angiography was performed immediately before and after intervention and at 3 or 8 weeks thereafter, and late loss in lumen diameter was taken as the difference between arterial diameter immediately after treatment and at 3 or 8 weeks of follow-up. Intimal hyperplasia was quantified histologically as the area of tissue mass within the internal elastic lamina. We observed a consistent discrepancy between the actual late loss seen with angiography and the diameter reduction that could be explained by histological intimal thickness alone in both animal models. This discrepancy ranged from 86 +/- 3% of the late loss in the 8 weeks/37 degrees C group to 77 +/- 22% in the conventional group for rabbits and 52 +/- 23% in an atherogenic diet group (n = 10) to 89 +/- 11% in a normal diet group (n = 6) for pigs. This discrepancy appeared to be due predominantly to reduction of the area circumscribed by the internal elastic membrane, a process that is tentatively designated as arterial remodeling. In both the rabbit femoral artery and in the Yucatan iliac artery, remodeling, not intimal hyperplasia, correlated with angiographic late loss. CONCLUSIONS In both the normal rabbit and the normal and atherosclerotic pig, restenosis after angioplasty results from both intimal hyperplasia and arterial remodeling. The exact etiology of arterial renarrowing after angioplasty has important implications on the design of antirestenosis drugs and new coronary devices.
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therelative importance ofarterial remodeling compared withintimal hyperplasia inlumen renarrowing after balloon angioplast a studyinthenormalrabbit andthe hypercholesterolemic Yucatan Micropig
1994Co-Authors: Cornelius BorstAbstract:Summary Our experimental data indicate that arterial remod-elingcontributed moreto lumenreductionin theweeksafter balloon dilation than did intimal hyperplasia. These data are now supported by intravascular ultra-soundstudies in human coronary arteries.10"' Acknowledgments Thiswork was supported in part by the Netherlands Heart Foundation, NHSgrant 92.365. The authors thank Dr Lie-selotte van Erven and Evelyn Velema for performing therabbit experiments, Nico Attevelt for his biotechnical assis- tance, and DrTonvan Leeuwenfor his critical review ofthemanuscript. References 1. Liu MW, Roubin GS, King SB III. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation. 1989;79:1374-1387. 2. Nobuyoshi M, Kimura T, Ohishi H, Horiuchi H, Nosaka H,Hamasaki N, Yokoi H, Kim K. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. JAmCoil Cardiol. 1991;17:433-439. 3. Ellis SG, MullerDWM.Arterialinjuryandthe
Makiko Fujii - One of the best experts on this subject based on the ideXlab platform.
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the comparison of surface free energy of human Yucatan Micropig and hairless mouse skins and influence of surfactant on surface free energy of the skin
Biological & Pharmaceutical Bulletin, 2019Co-Authors: Makiko Fujii, Kaname Hashizaki, Kiku Kato, Miko Imai, Hiroki Kuwabara, Minori Awano, Hiroyuki TaguchiAbstract:Surface free energy (SFE) is an important factor for evaluation of wettability or adhesion. Thus, the SFE of a Yucatan Micropig (YMP) skin and a hairless mouse (HM) skin, which are commonly used in skin permeation studies instead of human skin, were compared with the human skin. Contact angles of water and 1-bromo naphthalene to skin were measured and the SFE was calculated using the Owens-Wendt equation. The SFE of the human abdominal skin was 40 mN/m and its polar component σsp was as low as 2 mN/m, which was similar to that of the low sebum skin reported previously. In the case of the YMP skin, σsp was high on the surface but similar to that obtained after the skin was tape-stripped twice. The HM skin showed similar SFE as that of the human skin. When the surfactant was applied on the skin, wiped, and dried, the remaining surfactant increased the SFE in σsp; however, the original SFE was obtained after rinsing with water. The YMP skin and HM skin is similar to the human abdominal skin with a low sebum level. Thus, they are also good skin models for studying wettability or adhesion of a substance.
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effect of alcohol on skin permeation and metabolism of an ester type prodrug in Yucatan Micropig skin
European Journal of Pharmaceutical Sciences, 2017Co-Authors: Makiko Fujii, Naoya Koizumi, Rieko Ohara, Azusa Matsumi, Kayoko Ohura, Teruko Imai, Yoshiteru WatanabeAbstract:We studied the effect that three alcohols, ethanol (EA), propanol (PA), and isopropanol (IPA), have on the skin permeation of p-hydroxy benzoic acid methyl ester (HBM), a model ester-type prodrug. HBM was applied to Yucatan Micropig skin in a saturated phosphate buffered solution with or without 10% alcohol, and HBM and related materials in receptor fluid and skin were determined with HPLC. In the absence of alcohol, p-hydroxy benzoic acid (HBA), a metabolite of HBM, permeated the skin the most. The three alcohols enhanced the penetration of HBM at almost the same extent. The addition of 10% EA or PA to the HBM solution led to trans-esterification into the ethyl ester or propyl ester of HBA, and these esters permeated skin as well as HBA and HBM did. In contrast, the addition of 10% IPA promoted very little trans-esterification. Both hydrolysis and trans-esterification in the skin S9 fraction were inhibited by BNPP, an inhibitor of carboxylesterase (CES). Western blot and native PAGE showed the abundant expression of CES in Micropig skin. Both hydrolysis and trans-esterification was simultaneously catalyzed by CES during skin permeation. Our data indicate that the alcohol used in dermal drug preparations should be selected not only for its ability to enhance the solubility and permeation of the drug, but also for the effect on metabolism of the drug in the skin.
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influence of characteristics of oily vehicle on skin penetration of ufenamate
Biological & Pharmaceutical Bulletin, 2017Co-Authors: Hayato Iino, Makiko Fujii, Manami Fujino, Shizuka Kohara, Kaname Hashizaki, Hitomi Kira, Naoya Koizumi, Yoshiteru Watanabe, Naoki UtoguchiAbstract:: Skin penetration amounts of a highly lipophilic drug, ufenamate, prepared in four oily vehicles, including white petrolatum (WP), liquid paraffin (LP), isopropyl myristate (IPM), and isocetyl stearate (ICS), were compared. Ufenamate was mixed in each vehicle at 5% and applied at a rate of 2 mg/cm2 to intact, stripped, and delipidized Yucatan Micropig skin. The amounts of ufenamate and IPM in the stratum corneum (SC), epidermis, and dermis were determined. The skin penetration amounts of ufenamate from liquid oils were significantly higher than those from WP; the amounts of ufenamate were in the order WP
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influence of admixture with urea ointment and white petrolatum on the penetration of corticosteroids into Yucatan Micropig skin
Japanese Journal of Pharmaceutical Health Care and Sciences, 2005Co-Authors: Keiichi Ohzeki, Makiko Fujii, Yoshiteru Watanabe, Chuji Yanagawa, Noriko Suzuki, Yasushi KanzakiAbstract:Admixtures of two primary corticosteroid ointments, Almeta® and Myser® ointments, were made with urea ointment and white petrolatum. The release rate of corticosteroids from the admixed ointments with urea ointment and white petrolatum to a buffer solution were significantly lower than those expected from a dilution ratio 0.5 for both Almeta® and Myser® ointments. Also, for the admixtures with urea ointment, the amount of corticosteroids penetrating into the model skin was larger than that expected from the dilution ratio, especially for Myser® ointment, while the amounts of corticosteroids penetrating into the skin from the admixtures with white petrolatum were smaller than those expected from the dilution ratio, for both primary ointments.An electron probe micro analyzer was used to observe the actual distribution profile of corticosteroid molecules in a cross section of the skin. In the case of the Myser®-urea ointment admixture, the distribution profile of difulprednate was quite homogeneous, probably due to the softening effect of urea on the skin and the affinity of difulprednate with skin tissue, though the urea ointment did not have much effect on the distribution profile of alclometasone released from the Almeta® ointment. On the other hand, difulprednate was concentrated at the surface for the admixture with white petrolatum.
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enhancement effect of p menthane 3 8 diol on in vitro permeation of antipyrine and indomethacin through Yucatan Micropig skin
Drug Development and Industrial Pharmacy, 2004Co-Authors: Makiko Fujii, Mitsuo Matsumoto, Yasuhiro Takeda, Minako Yoshida, Yoshiteru WatanabeAbstract:The enhancing effect of p‐menthane‐3,8‐diol (MDO) on skin permeation of antipyrine (ANP) and indomethacin (IM) through Yucatan Micropig skin in vitro was compared with l‐menthol. p‐menthane‐3,8‐diol is a metabolite of l‐menthol and has little odor. It is easy to combine the vehicle because of lower lipophilicity than l‐menthol. All formulations contained 40% (v/v) ethanol. The permeation of ANP increased with MDO about three times that without enhancer by increasing ANP concentration in the skin. However, the MDO effect was about a quarter that of l‐menthol. The permeation of IM with MDO was about 15 times that with no enhancer and it was almost the same as that with l‐menthol. The lag time of permeation was not significantly changed by MDO, which was not so in the case of l‐menthol. Skin concentration of IM increased about 11 times and six times with MDO and l‐menthol, respectively. MDO and l‐menthol partitioned to the skin relatively high concentrations, 5.9 and 2.5 mg/cm3, respectively. The solubility ...
