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Kenneth R Chapman - One of the best experts on this subject based on the ideXlab platform.

  • long term xanthine therapy of asthma Enprofylline and theophylline compared
    Chest, 1994
    Co-Authors: Kenneth R Chapman, Karin Ljungholm, Anders Kallen
    Abstract:

    Background Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of Enprofylline and theophylline given over a 1-year period to adults with asthma. Methods Patients were recruited from 18 centers and 4 countries to participate in a 1-month double-blind comparison of Enprofylline or theophylline in the treatment of asthma and were subsequently maintained on a regimen with the assigned medication for a further 11 months. The dosage of each xanthine was incremented from 150 mg twice daily at initiation to 300 and later 450 mg twice daily depending on the patient's tolerance and, in the case of theophylline, the rapidly assayed serum theophylline level. Patients kept a diary in which they recorded peak expiratory flow rate (PEFR) measured morning and evening, asthma symptom score, and the number of β 2 -agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization. Results Three-hundred forty-eight patients (174 Enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV 1 during the first month of treatment with no significant difference between drugs (0.25 L for Enprofylline vs 0.30 L for theophylline). Similarly, there were no differences in clinical outcome such as asthma exacerbations or β 2 -agonist usage between the two groups over follow-up. However, inhaled steroid dosage was more likely to have been incremented in theophylline-treated than Enprofylline-treated patients (18% vs 8%, p=0.025). Both drugs produced a modest increase in heart rate throughout the trial (approximately 5 beats/min). In 31 patients (26 Enprofylline, 5 theophylline), asymptomatic elevations in aspartate aminotransferase and/or alanine aminotransferase occurred at least once during the study. In five patients (four Enprofylline, one theophylline), the increase exceeded three times the upper limit of the normal range. In some subjects receiving Enprofylline, serum Enprofylline levels rose progressively despite constant oral dosage of the drug. Conclusions: Long-term xanthine therapy is well-tolerated by most adult asthmatics. However, long-term Enprofylline administration may be associated with elevation in liver enzyme levels and unpredictable blood levels, thereby limiting its clinical usefulness.

  • long term xanthine therapy of asthma Enprofylline and theophylline compared international Enprofylline study group
    Chest, 1994
    Co-Authors: Kenneth R Chapman, Karin Ljungholm, Anders Kallen
    Abstract:

    BACKGROUND: Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of Enprofylline and theophylline given over a 1-year period to adults with asthma. METHODS: Patients were recruited from 18 centers and 4 countries to participate in a 1-month double-blind comparison of Enprofylline or theophylline in the treatment of asthma and were subsequently maintained on a regimen with the assigned medication for a further 11 months. The dosage of each xanthine was incremented from 150 mg twice daily at initiation to 300 and later 450 mg twice daily depending on the patient's tolerance and, in the case of theophylline, the rapidly assayed serum theophylline level. Patients kept a diary in which they recorded peak expiratory flow rate (PEFR) measured morning and evening, asthma symptom score, and the number of beta 2-agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization. RESULTS: Three-hundred forty-eight patients (174 Enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV1 during the first month of treatment with no significant difference between drugs (0.25 L for Enprofylline vs 0.30 L for theophylline). Similarly, there were no differences in clinical outcome such as asthma exacerbations or beta 2-agonist usage between the two groups over follow-up. However, inhaled steroid dosage was more likely to have been incremented in theophylline-treated than Enprofylline-treated patients (18% vs 8%, p = 0.025). Both drugs produced a modest increase in heart rate throughout the trial (approximately 5 beats/min). In 31 patients (26 Enprofylline, 5 theophylline), asymptomatic elevations in aspartate aminotransferase and/or alanine aminotransferase occurred at least once during the study. In five patients (four Enprofylline, one theophylline), the increase exceeded three times the upper limit of the normal range. In some subjects receiving Enprofylline, serum Enprofylline levels rose progressively despite constant oral dosage of the drug. CONCLUSIONS: Long-term xanthine therapy is well-tolerated by most adult asthmatics. However, long-term Enprofylline administration may be associated with elevation in liver enzyme levels and unpredictable blood levels, thereby limiting its clinical usefulness.

  • A rapid monoclonal antibody blood theophylline assay; lack of cross-reactivity with Enprofylline.
    Therapeutic Drug Monitoring, 1994
    Co-Authors: Aileen David-wang, Brenda Scarth, David J. Freeman, Kenneth R Chapman
    Abstract:

    We evaluated a rapid monoclonal antibody theophylline assay for two reasons: (a) to determine its specificity with respect to the possible confounding influence of a structurally related xanthine, Enprofylline, and (b) to assess its accuracy relative to high-performance liquid chromatography (HPLC). Blood samples were taken from 233 patients who had been randomized in double-blind fashion to receive either oral theophylline (n=117) or Enprofylline (n=116) for the treatment of chronic reversible obstructive airways disease. Monoclonal antibody assays (MAAs) were performed in 10 clinical sites by 10 trained paramedical technicians. Three patients, who actually received Enprofylline but not theophylline, had MAA theophylline values of ≥3.2 μg/ml, giving a specificity of 97%

  • a rapid monoclonal antibody blood theophylline assay lack of cross reactivity with Enprofylline
    Therapeutic Drug Monitoring, 1994
    Co-Authors: Aileen Davidwang, David J. Freeman, Brenda Scarth, Kenneth R Chapman
    Abstract:

    : We evaluated a rapid monoclonal antibody theophylline assay for two reasons: (a) to determine its specificity with respect to the possible confounding influence of a structurally related xanthine, Enprofylline, and (b) to assess its accuracy relative to high-performance liquid chromatography (HPLC). Blood samples were taken from 233 patients who had been randomized in double-blind fashion to receive either oral theophylline (n = 117) or Enprofylline (n = 116) for the treatment of chronic reversible obstructive airways disease. Monoclonal antibody assays (MAAs) were performed in 10 clinical sites by 10 trained paramedical technicians. Three patients, who actually received Enprofylline but not theophylline, had MAA theophylline values of > or = 3.2 micrograms/ml, giving a specificity of 97%. HPLC determination of simultaneous blood samples confirmed that theophylline levels were in fact < 3.2 micrograms/ml and that theophylline was not being taken surreptitiously. Good correlation was observed between MAA and HPLC in patients taking theophylline (y = 1.07 x + 0.36; r = 0.93; standard error of the estimate (SEE) = 1.93). However, there was wide variability from technician to technician such that r values for individual sites ranged from 0.67 to 0.99. Based on the overall correlation, the prediction of an individual HPLC value from an individual MAA value had broad 95% confidence limits: when the MAA value was 10 micrograms/ml, the predicted HPLC value was 9.19 +/- 3.32; when MAA = 15 micrograms/ml; HPLC = 13.19 +/- 3.33; and when MAA = 20 micrograms/ml; HPLC = 17.19 +/- 3.36.(ABSTRACT TRUNCATED AT 250 WORDS)

  • a comparison of Enprofylline and theophylline in the maintenance therapy of chronic reversible obstructive airway disease
    The Journal of Allergy and Clinical Immunology, 1990
    Co-Authors: Kenneth R Chapman, S Boucher, R H Hyland, Harvey Kreisman, R N Rivington, Richard V Hodder, E L York, Raja T Abboud, S Peters, Norman Wolkove
    Abstract:

    Abstract To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease, 242 patients were assigned in randomized, double-blind fashion to receive either oral Enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens. After a week of placebo xanthine therapy, Enprofylline-treated patients received 150 mg of this drug twice daily (b.i.d.)for 3 days, 300 mg b.i.d. for 2 weeks, and 450 mg b.i.d. for 2 weeks. Theophylline was administered in identical doses, except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher. At 300 mg b.i.d., both drugs significantly increased morning peak expiratory flow rate (PEFR), the mean increase above baseline being significantly higher for theophylline-treated patients (29.9 ±37.2 L/min) than for Enprofylline-treated patients (17.4 ± 36.9 L/min) ( p = 0.023). At 450 mg b.i.d., improvement in morning PEFR was not significantly different between theophylline-treated (31.5 ± 44.4 L/min) and Enprofylline-treated groups (23.5 ± 48.4 L/min). Evening PEFR, FEV 1 , and asthma symptom scores also improved significantly, demonstrating no significant difference between groups. The incidence of side effects was also similar between groups. We conclude that both Enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma, Enprofylline, 450 mg b.i.d., being approximately equivalent to theophylline, 300 or 450 mg b.i.d.

Toshitaka Nabeshima - One of the best experts on this subject based on the ideXlab platform.

  • alterations in renal uptake kinetics of the xanthine derivative Enprofylline in endotoxaemic mice
    Journal of Pharmacy and Pharmacology, 1996
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Toshiki Okasaka, Nobuo Kato
    Abstract:

    : The pharmacokinetics and renal uptake of Enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of Enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of Enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound Enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of Enprofylline after constant infusion for 1 h. The renal uptake rate of Enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of Enprofylline by inducing a decrease in the renal uptake ability.

  • time dependent changes in the pharmacokinetics and renal excretion of xanthine derivative Enprofylline induced by bacterial endotoxin in rats
    Biological & Pharmaceutical Bulletin, 1995
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Nobuo Kato
    Abstract:

    Time-dependent changes in the pharmacokinetics and renal handling of Enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of Enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and Enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of Enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for Enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of Enprofylline was examined by a single injection of Enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of Enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for Enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of Enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.

  • Brain distribution characteristics of xanthine derivatives and relation to their locomotor activity in mice
    Journal of Pharmacy and Pharmacology, 1995
    Co-Authors: Soheila Haghgoo, Li Wang, Takaaki Hasegawa, Masayuki Nadai, Takeo Ishigaki, Ken-ichi Miyamoto, Toshitaka Nabeshima
    Abstract:

    The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, Enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, Enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg−1, MPX caused a decrease in such activity over 10 mg kg−1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > Enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, Enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of Enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.

  • alterations in the pharmacokinetics and protein binding of Enprofylline in eisai hyperbilirubinemic rats
    Drug Metabolism and Disposition, 1994
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Osamu Tagaya, Toshitaka Nabeshima
    Abstract:

    Mutant rats possessing conjugated hyperbilirubinemia have recently been established from Sprague-Dawley rats (SDRs) and are called Eisai hyperbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of Enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in 9- and 19-week-old EHBRs and compared with their age-matched normal SDRs. Enprofylline was administered intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetics. Pharmacokinetic parameters for both total and unbound Enprofylline were estimated by model-independent methods. Both systemic clearance and volume of distribution at steady state of Enprofylline significantly increased in 19-week-old EHBRs. However, there were no differences in the glomerular filtration rate estimated as inulin clearance and fraction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia in EHBRs had no effect on the pharmacokinetics and renal handling of unbound Enprofylline. These results indicate that the pharmacokinetics of Enprofylline, but not renal handling, glomerular filtration, or tubular secretion are modified in EHBRs by changes in protein binding behavior.

  • influence of age on the disposition and renal handling of Enprofylline in rats
    Journal of Pharmacy and Pharmacology, 1994
    Co-Authors: Isao Muraoka, Li Wang, Takaaki Hasegawa, Masayuki Nadai, Osamu Tagaya, Toshitaka Nabeshima
    Abstract:

    : The effects of ageing on the pharmacokinetics, renal handling and protein binding of Enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of Enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of Enprofylline or urinary recovery of unchanged Enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (Vmax)(223.33, 160.24 and 142.98 micrograms min-1 kg-1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (Vmax/Km) of Enprofylline (75.45, 51.03 and 44.13 mL min-1 kg-1, respectively), while a slight change in the Michaelis-Menten constant (Km) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of Enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.

Masayuki Nadai - One of the best experts on this subject based on the ideXlab platform.

  • possible involvement of organic anion and cation transporters in renal excretion of xanthine derivatives 3 methylxanthine and Enprofylline
    Life Sciences, 2007
    Co-Authors: Masayuki Nadai, Miki Kato, Hideo Yoshizumi, Masao Kimura, Shunsuke Kurono, Hiroko Saito, Takaaki Hasegawa
    Abstract:

    Whether organic anion and cation transporters are involved in the renal excretion of xanthine derivatives, 3-methylxanthie and Enprofylline, remains unclear. In this study, we have investigated the effects of typically predominant substrates for organic anion and cation transporters on the tubular secretion of 3-methylxanthine and Enprofylline in rats. In the renal clearance experiments using typical substrates for organic anion transporters, probenecid and p-aminohippurate, probenecid (20 mg/kg), but not p-aminohippurate (100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and Enprofylline. The typical substrates for organic cation transport systems, tetraethylammonium (30.6 mg/kg) and cimetidine (50 or 100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and Enprofylline. These results suggest that the renal secretory transport of 3-methylxanthine and Enprofylline are mediated by probenecid-, cimetidine- and tetraethylammonium-sensitive transport systems. Uric acid, an organic anion, significantly inhibited the renal secretion of 3-methylxanthine, but not Enprofylline, suggesting that the renal tubular transport of 3-methylxanthine is also mediated via uric acid-sensitive transport system. These findings suggest the possibility that both organic anion and cation transporters are, at least, involved in the renal tubular transport of 3-methylxanthine and Enprofylline in rats.

  • alterations in renal uptake kinetics of the xanthine derivative Enprofylline in endotoxaemic mice
    Journal of Pharmacy and Pharmacology, 1996
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Toshiki Okasaka, Nobuo Kato
    Abstract:

    : The pharmacokinetics and renal uptake of Enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of Enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of Enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound Enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of Enprofylline after constant infusion for 1 h. The renal uptake rate of Enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of Enprofylline by inducing a decrease in the renal uptake ability.

  • time dependent changes in the pharmacokinetics and renal excretion of xanthine derivative Enprofylline induced by bacterial endotoxin in rats
    Biological & Pharmaceutical Bulletin, 1995
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Nobuo Kato
    Abstract:

    Time-dependent changes in the pharmacokinetics and renal handling of Enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of Enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and Enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of Enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for Enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of Enprofylline was examined by a single injection of Enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of Enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for Enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of Enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.

  • Brain distribution characteristics of xanthine derivatives and relation to their locomotor activity in mice
    Journal of Pharmacy and Pharmacology, 1995
    Co-Authors: Soheila Haghgoo, Li Wang, Takaaki Hasegawa, Masayuki Nadai, Takeo Ishigaki, Ken-ichi Miyamoto, Toshitaka Nabeshima
    Abstract:

    The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, Enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, Enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg−1, MPX caused a decrease in such activity over 10 mg kg−1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > Enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, Enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of Enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.

  • alterations in the pharmacokinetics and protein binding of Enprofylline in eisai hyperbilirubinemic rats
    Drug Metabolism and Disposition, 1994
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Osamu Tagaya, Toshitaka Nabeshima
    Abstract:

    Mutant rats possessing conjugated hyperbilirubinemia have recently been established from Sprague-Dawley rats (SDRs) and are called Eisai hyperbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of Enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in 9- and 19-week-old EHBRs and compared with their age-matched normal SDRs. Enprofylline was administered intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetics. Pharmacokinetic parameters for both total and unbound Enprofylline were estimated by model-independent methods. Both systemic clearance and volume of distribution at steady state of Enprofylline significantly increased in 19-week-old EHBRs. However, there were no differences in the glomerular filtration rate estimated as inulin clearance and fraction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia in EHBRs had no effect on the pharmacokinetics and renal handling of unbound Enprofylline. These results indicate that the pharmacokinetics of Enprofylline, but not renal handling, glomerular filtration, or tubular secretion are modified in EHBRs by changes in protein binding behavior.

Takaaki Hasegawa - One of the best experts on this subject based on the ideXlab platform.

  • possible involvement of organic anion and cation transporters in renal excretion of xanthine derivatives 3 methylxanthine and Enprofylline
    Life Sciences, 2007
    Co-Authors: Masayuki Nadai, Miki Kato, Hideo Yoshizumi, Masao Kimura, Shunsuke Kurono, Hiroko Saito, Takaaki Hasegawa
    Abstract:

    Whether organic anion and cation transporters are involved in the renal excretion of xanthine derivatives, 3-methylxanthie and Enprofylline, remains unclear. In this study, we have investigated the effects of typically predominant substrates for organic anion and cation transporters on the tubular secretion of 3-methylxanthine and Enprofylline in rats. In the renal clearance experiments using typical substrates for organic anion transporters, probenecid and p-aminohippurate, probenecid (20 mg/kg), but not p-aminohippurate (100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and Enprofylline. The typical substrates for organic cation transport systems, tetraethylammonium (30.6 mg/kg) and cimetidine (50 or 100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and Enprofylline. These results suggest that the renal secretory transport of 3-methylxanthine and Enprofylline are mediated by probenecid-, cimetidine- and tetraethylammonium-sensitive transport systems. Uric acid, an organic anion, significantly inhibited the renal secretion of 3-methylxanthine, but not Enprofylline, suggesting that the renal tubular transport of 3-methylxanthine is also mediated via uric acid-sensitive transport system. These findings suggest the possibility that both organic anion and cation transporters are, at least, involved in the renal tubular transport of 3-methylxanthine and Enprofylline in rats.

  • alterations in renal uptake kinetics of the xanthine derivative Enprofylline in endotoxaemic mice
    Journal of Pharmacy and Pharmacology, 1996
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Toshiki Okasaka, Nobuo Kato
    Abstract:

    : The pharmacokinetics and renal uptake of Enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg-1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of Enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of Enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound Enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of Enprofylline after constant infusion for 1 h. The renal uptake rate of Enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (Vmax) from 17.3 to 32.2 micrograms h-1 g-1 of kidney and in the Michaelis-Menten constant (Km) from 2.7 to 21.7 micrograms mL-1 and decrease in the nonsaturable uptake rate constant (K4) from 0.87 to 0.43 mL h-1 g-1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of Enprofylline by inducing a decrease in the renal uptake ability.

  • time dependent changes in the pharmacokinetics and renal excretion of xanthine derivative Enprofylline induced by bacterial endotoxin in rats
    Biological & Pharmaceutical Bulletin, 1995
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Toshitaka Nabeshima, Soheila Haghgoo, Nobuo Kato
    Abstract:

    Time-dependent changes in the pharmacokinetics and renal handling of Enprofylline induced by bacterial endotoxin (Klebsiella pneumoniae LPS) were investigated in rats. To evaluate the early effect of LPS on kidney functions and the renal excretion of Enprofylline, which is an organic anion drug excreted primarily by an active tubular secretion, LPS (250μg/kg) was infused for 5 min under constant infusion at rates of 2.3 and 23 μg/min/kg for inulin and Enprofylline, respectively. LPS caused a drop in the glomerular filtration rate (GFR), estimated as the renal clearance of inulin, to 65-75% of that observed in the control rats within 30 min after the LPS treatment. The renal clearance (CLr) of Enprofylline decreased in conjunction with GFR, while the percentage of decrease in the CLr was slightly greater than that in GFR. LPS-induced decreases in the CLr for Enprofylline and GFR continued over the testing period of 120min. The time-dependent effect of LPS on the pharmacokinetics of Enprofylline was examined by a single injection of Enprofylline (2.5 mg/kg) to rats pretreated 2, 10 or 24h earlier with or without LPS. The pharmacokinetic parameters of Enprofylline were determined by a model-independent method. Significant changes in the systemic clearance for Enprofylline were observed in rats pretreated 2 and 10h earlier with LPS. but no such changes were observed in rats pretreated 24h earlier with LPS. These findings indicate the existence of a time-dependent effect of LPS on the pharmacokinetics of Enprofylline, and suggest that LPS at a dose of 250 μg/kg, at least, does not induce cytotoxicity to kidney cells.

  • Brain distribution characteristics of xanthine derivatives and relation to their locomotor activity in mice
    Journal of Pharmacy and Pharmacology, 1995
    Co-Authors: Soheila Haghgoo, Li Wang, Takaaki Hasegawa, Masayuki Nadai, Takeo Ishigaki, Ken-ichi Miyamoto, Toshitaka Nabeshima
    Abstract:

    The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, Enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, Enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg−1, MPX caused a decrease in such activity over 10 mg kg−1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > Enprofylline. The inhibition constants (Ki) for adenosine A1 receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, Enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of Enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A1 affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.

  • alterations in the pharmacokinetics and protein binding of Enprofylline in eisai hyperbilirubinemic rats
    Drug Metabolism and Disposition, 1994
    Co-Authors: Masayuki Nadai, Li Wang, Takaaki Hasegawa, Osamu Tagaya, Toshitaka Nabeshima
    Abstract:

    Mutant rats possessing conjugated hyperbilirubinemia have recently been established from Sprague-Dawley rats (SDRs) and are called Eisai hyperbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of Enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in 9- and 19-week-old EHBRs and compared with their age-matched normal SDRs. Enprofylline was administered intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetics. Pharmacokinetic parameters for both total and unbound Enprofylline were estimated by model-independent methods. Both systemic clearance and volume of distribution at steady state of Enprofylline significantly increased in 19-week-old EHBRs. However, there were no differences in the glomerular filtration rate estimated as inulin clearance and fraction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia in EHBRs had no effect on the pharmacokinetics and renal handling of unbound Enprofylline. These results indicate that the pharmacokinetics of Enprofylline, but not renal handling, glomerular filtration, or tubular secretion are modified in EHBRs by changes in protein binding behavior.

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  • long term xanthine therapy of asthma Enprofylline and theophylline compared
    Chest, 1994
    Co-Authors: Kenneth R Chapman, Karin Ljungholm, Anders Kallen
    Abstract:

    Background Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of Enprofylline and theophylline given over a 1-year period to adults with asthma. Methods Patients were recruited from 18 centers and 4 countries to participate in a 1-month double-blind comparison of Enprofylline or theophylline in the treatment of asthma and were subsequently maintained on a regimen with the assigned medication for a further 11 months. The dosage of each xanthine was incremented from 150 mg twice daily at initiation to 300 and later 450 mg twice daily depending on the patient's tolerance and, in the case of theophylline, the rapidly assayed serum theophylline level. Patients kept a diary in which they recorded peak expiratory flow rate (PEFR) measured morning and evening, asthma symptom score, and the number of β 2 -agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization. Results Three-hundred forty-eight patients (174 Enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV 1 during the first month of treatment with no significant difference between drugs (0.25 L for Enprofylline vs 0.30 L for theophylline). Similarly, there were no differences in clinical outcome such as asthma exacerbations or β 2 -agonist usage between the two groups over follow-up. However, inhaled steroid dosage was more likely to have been incremented in theophylline-treated than Enprofylline-treated patients (18% vs 8%, p=0.025). Both drugs produced a modest increase in heart rate throughout the trial (approximately 5 beats/min). In 31 patients (26 Enprofylline, 5 theophylline), asymptomatic elevations in aspartate aminotransferase and/or alanine aminotransferase occurred at least once during the study. In five patients (four Enprofylline, one theophylline), the increase exceeded three times the upper limit of the normal range. In some subjects receiving Enprofylline, serum Enprofylline levels rose progressively despite constant oral dosage of the drug. Conclusions: Long-term xanthine therapy is well-tolerated by most adult asthmatics. However, long-term Enprofylline administration may be associated with elevation in liver enzyme levels and unpredictable blood levels, thereby limiting its clinical usefulness.

  • long term xanthine therapy of asthma Enprofylline and theophylline compared international Enprofylline study group
    Chest, 1994
    Co-Authors: Kenneth R Chapman, Karin Ljungholm, Anders Kallen
    Abstract:

    BACKGROUND: Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of Enprofylline and theophylline given over a 1-year period to adults with asthma. METHODS: Patients were recruited from 18 centers and 4 countries to participate in a 1-month double-blind comparison of Enprofylline or theophylline in the treatment of asthma and were subsequently maintained on a regimen with the assigned medication for a further 11 months. The dosage of each xanthine was incremented from 150 mg twice daily at initiation to 300 and later 450 mg twice daily depending on the patient's tolerance and, in the case of theophylline, the rapidly assayed serum theophylline level. Patients kept a diary in which they recorded peak expiratory flow rate (PEFR) measured morning and evening, asthma symptom score, and the number of beta 2-agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization. RESULTS: Three-hundred forty-eight patients (174 Enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV1 during the first month of treatment with no significant difference between drugs (0.25 L for Enprofylline vs 0.30 L for theophylline). Similarly, there were no differences in clinical outcome such as asthma exacerbations or beta 2-agonist usage between the two groups over follow-up. However, inhaled steroid dosage was more likely to have been incremented in theophylline-treated than Enprofylline-treated patients (18% vs 8%, p = 0.025). Both drugs produced a modest increase in heart rate throughout the trial (approximately 5 beats/min). In 31 patients (26 Enprofylline, 5 theophylline), asymptomatic elevations in aspartate aminotransferase and/or alanine aminotransferase occurred at least once during the study. In five patients (four Enprofylline, one theophylline), the increase exceeded three times the upper limit of the normal range. In some subjects receiving Enprofylline, serum Enprofylline levels rose progressively despite constant oral dosage of the drug. CONCLUSIONS: Long-term xanthine therapy is well-tolerated by most adult asthmatics. However, long-term Enprofylline administration may be associated with elevation in liver enzyme levels and unpredictable blood levels, thereby limiting its clinical usefulness.