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Seiji Nishino - One of the best experts on this subject based on the ideXlab platform.
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Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice
Sleep, 2010Co-Authors: Masashi Okuro, Nobuhiro Fujiki, Nozomu Kotorii, Yuji Ishimaru, Pierre Sokoloff, Seiji NishinoAbstract:CAFFEINE, IN THE FORM OF CAFFEINE-CONTAINING BEVERAGES OR OVER-THE-COUNTER CAFFEINE TABLETS (100 MG OR 200 MG), IS A WIDELY USED WAKE-promoting substance, used to reduce sleepiness in normal people.1,2 Caffeine is also widely used for patients with primary (such as narcolepsy) and secondary hypersomnia (hypersomnia associated with neurological diseases); these patients self-medicate with caffeine before they visit the sleep clinic to receive more potent medication.2 Caffeine is a non-selective antagonist for adenosine receptors (A1 and A2a receptors), and blockade of these receptors is believed to mediate its stimulant effects.1 One of the limitations of caffeine for treating hypersomnia is its low wake-promoting potency, while high doses may induce side effects such as anxiety, tremors, headache, and gastrointestinal irritation. Caffeine is demethylated to 3 active metabolites, Paraxanthine, theobromine, and theophylline, and C-8 hydroxylated to 1,3,7-trimethyluric acid (TMU).3–5 The interspecies variations in caffeine metabolism, related to cytochrome P4501A enzyme, exist; and the percentages of the production of these 4 metabolites are reported to be 59.9%, 8.7%, 5.0%, and 26.4% in humans, and 19.1%, 10.8%, 21.7%, and 47.8% in mice.5 Like caffeine, Paraxanthine is a central nervous stimulant. In addition, caffeine and Paraxanthine have similar anti-adenosine actions, though the literature has consistently reported that Paraxanthine exhibits slightly higher binding potencies for adenosine A1 and A2a receptors6 and both lower toxicity and lesser anxiogenic effects than caffeine.7 This may be explained by the pharmacological properties of other caffeine metabolites, such as theophylline, which often induce nausea, diarrhea, tachycardia, and arrhythmias.8 A recent study demonstrated that Paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, Paraxanthine may be more effective than caffeine for wake-promotion in normal people and treatment of hypersomnia in those with cardiovascular and neurological diseases. Therefore, we evaluated the wake-promoting efficacy of Paraxanthine in wild-type (WT) and narcoleptic mice models and compared it with those of caffeine and modafinil. Effects of these compounds on locomotor activity, core body temperature and anxiety levels were also compared. Narcoleptic mice were included since narcolepsy is the prototypical primary hypersomnia, and orexin/ataxin-3 narcoleptic mice share the major pathophysiology of human narcolepsy (hypocretin cell ablation).10,11 As such, the observed efficacy in narcoleptic mice is an accurate predictor of efficacy for treatment of pathological sleepiness.
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effects of Paraxanthine and caffeine on sleep locomotor activity and body temperature in orexin ataxin 3 transgenic narcoleptic mice
Sleep, 2010Co-Authors: Masashi Okuro, Nobuhiro Fujiki, Nozomu Kotorii, Yuji Ishimaru, Pierre Sokoloff, Seiji NishinoAbstract:CAFFEINE, IN THE FORM OF CAFFEINE-CONTAINING BEVERAGES OR OVER-THE-COUNTER CAFFEINE TABLETS (100 MG OR 200 MG), IS A WIDELY USED WAKE-promoting substance, used to reduce sleepiness in normal people.1,2 Caffeine is also widely used for patients with primary (such as narcolepsy) and secondary hypersomnia (hypersomnia associated with neurological diseases); these patients self-medicate with caffeine before they visit the sleep clinic to receive more potent medication.2 Caffeine is a non-selective antagonist for adenosine receptors (A1 and A2a receptors), and blockade of these receptors is believed to mediate its stimulant effects.1 One of the limitations of caffeine for treating hypersomnia is its low wake-promoting potency, while high doses may induce side effects such as anxiety, tremors, headache, and gastrointestinal irritation. Caffeine is demethylated to 3 active metabolites, Paraxanthine, theobromine, and theophylline, and C-8 hydroxylated to 1,3,7-trimethyluric acid (TMU).3–5 The interspecies variations in caffeine metabolism, related to cytochrome P4501A enzyme, exist; and the percentages of the production of these 4 metabolites are reported to be 59.9%, 8.7%, 5.0%, and 26.4% in humans, and 19.1%, 10.8%, 21.7%, and 47.8% in mice.5 Like caffeine, Paraxanthine is a central nervous stimulant. In addition, caffeine and Paraxanthine have similar anti-adenosine actions, though the literature has consistently reported that Paraxanthine exhibits slightly higher binding potencies for adenosine A1 and A2a receptors6 and both lower toxicity and lesser anxiogenic effects than caffeine.7 This may be explained by the pharmacological properties of other caffeine metabolites, such as theophylline, which often induce nausea, diarrhea, tachycardia, and arrhythmias.8 A recent study demonstrated that Paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, Paraxanthine may be more effective than caffeine for wake-promotion in normal people and treatment of hypersomnia in those with cardiovascular and neurological diseases. Therefore, we evaluated the wake-promoting efficacy of Paraxanthine in wild-type (WT) and narcoleptic mice models and compared it with those of caffeine and modafinil. Effects of these compounds on locomotor activity, core body temperature and anxiety levels were also compared. Narcoleptic mice were included since narcolepsy is the prototypical primary hypersomnia, and orexin/ataxin-3 narcoleptic mice share the major pathophysiology of human narcolepsy (hypocretin cell ablation).10,11 As such, the observed efficacy in narcoleptic mice is an accurate predictor of efficacy for treatment of pathological sleepiness.
Michael B. Bracken - One of the best experts on this subject based on the ideXlab platform.
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Caffeine Metabolites in Umbilical Cord Blood, Cytochrome P-450 1A2 Activity, and Intrauterine Growth Restriction
American journal of epidemiology, 2006Co-Authors: Laura M. Grosso, Neal L Benowitz, Elizabeth W. Triche, Kathleen Belanger, Theodore R. Holford, Michael B. BrackenAbstract:Studies investigating antenatal caffeine consumption and reproductive outcomes show conflicting results, and most studies have used maternal self-reported caffeine consumption to estimate fetal exposure. This study (n=1,606) was specifically designed to test the association of caffeine and its primary metabolites in umbilical cord blood with intrauterine growth restriction (IUGR). Pregnant women were recruited from 56 obstetric practices and 15 clinics affiliated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000. In an adjusted model including caffeine only, levels in all quartiles were associated with reduced risk of IUGR. In adjusted analyses including Paraxanthine and caffeine, serum Paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective. These conflicting findings suggest that cytochrome P-450 1A2 (CYP1A2) metabolic activity may be associated with IUGR, so the ratio of Paraxanthine to caffeine was then modeled. The likelihood of IUGR increased 21% for every one standard deviation change in the ratio (adjusted odds ratio=1.21, 95% confidence interval: 1.07, 1.37), suggesting that CYP1A2 activity, and not the absolute levels of Paraxanthine, influences fetal growth. No associations were observed between caffeine or any metabolites and preterm delivery.
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Association of caffeine metabolites in umbilical cord blood with IUGR and preterm delivery: A prospective cohort study of 1609 pregnancies
Annals of Epidemiology, 2005Co-Authors: Laura M. Grosso, Elizabeth W. Triche, Kathleen Belanger, Theodore R. Holford, N.l. Benowitz, Michael B. BrackenAbstract:Purpose To examine the association between IUGR and preterm delivery (PTD) and fetal caffeine exposure when estimated by serum caffeine and Paraxanthine in umbilical cord. Methods Prospective cohort study conducted in Connecticut and Massachusetts specifically testing the relation of caffeine and its metabolites, measured in cord blood (ng/ml) to IUGR (N = 1606) and PTD (N = 1609). Important covariates were controlled for in logistic regression models. Ridge regression for generalized linear models was used to control for collinearity among metabolites. All metabolite analyses were done blind to consumption data and reproductive outcomes. Results We observed a 24% increase in risk for IUGR per Paraxanthine quartile change (Ridge adjusted OR 1.24; 95% CI 1.10, 1.39), while caffeine was protective for IUGR: Ridge adjusted OR 0.87 (95% CI 0.78, 0.97) per quartile change. When the ratio of Paraxanthine:caffeine was modeled, there was a 6-fold increase in risk for IUGR for every one-unit increase in the ratio (MLE adjusted OR 6.03; 95% CI 2.14, 17.03). There was an 18% increase in risk for preterm delivery per Paraxanthine quartile change (Ridge adjusted OR 1.18; 95% CI 1.05, 1.33). Caffeine was not associated with PTD nor was the Paraxanthine:caffeine ratio. Maternal self-reported caffeine consumption during the third trimester was not associated with either outcome. Conclusions Paraxanthine, rather than caffeine, may increase risk for IUGR and PTD. These findings may explain the equivocal literature evaluating reported consumption only. More research to replicate and extend these findings which have relevance to other health outcomes is warranted.
Masashi Okuro - One of the best experts on this subject based on the ideXlab platform.
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Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice
Sleep, 2010Co-Authors: Masashi Okuro, Nobuhiro Fujiki, Nozomu Kotorii, Yuji Ishimaru, Pierre Sokoloff, Seiji NishinoAbstract:CAFFEINE, IN THE FORM OF CAFFEINE-CONTAINING BEVERAGES OR OVER-THE-COUNTER CAFFEINE TABLETS (100 MG OR 200 MG), IS A WIDELY USED WAKE-promoting substance, used to reduce sleepiness in normal people.1,2 Caffeine is also widely used for patients with primary (such as narcolepsy) and secondary hypersomnia (hypersomnia associated with neurological diseases); these patients self-medicate with caffeine before they visit the sleep clinic to receive more potent medication.2 Caffeine is a non-selective antagonist for adenosine receptors (A1 and A2a receptors), and blockade of these receptors is believed to mediate its stimulant effects.1 One of the limitations of caffeine for treating hypersomnia is its low wake-promoting potency, while high doses may induce side effects such as anxiety, tremors, headache, and gastrointestinal irritation. Caffeine is demethylated to 3 active metabolites, Paraxanthine, theobromine, and theophylline, and C-8 hydroxylated to 1,3,7-trimethyluric acid (TMU).3–5 The interspecies variations in caffeine metabolism, related to cytochrome P4501A enzyme, exist; and the percentages of the production of these 4 metabolites are reported to be 59.9%, 8.7%, 5.0%, and 26.4% in humans, and 19.1%, 10.8%, 21.7%, and 47.8% in mice.5 Like caffeine, Paraxanthine is a central nervous stimulant. In addition, caffeine and Paraxanthine have similar anti-adenosine actions, though the literature has consistently reported that Paraxanthine exhibits slightly higher binding potencies for adenosine A1 and A2a receptors6 and both lower toxicity and lesser anxiogenic effects than caffeine.7 This may be explained by the pharmacological properties of other caffeine metabolites, such as theophylline, which often induce nausea, diarrhea, tachycardia, and arrhythmias.8 A recent study demonstrated that Paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, Paraxanthine may be more effective than caffeine for wake-promotion in normal people and treatment of hypersomnia in those with cardiovascular and neurological diseases. Therefore, we evaluated the wake-promoting efficacy of Paraxanthine in wild-type (WT) and narcoleptic mice models and compared it with those of caffeine and modafinil. Effects of these compounds on locomotor activity, core body temperature and anxiety levels were also compared. Narcoleptic mice were included since narcolepsy is the prototypical primary hypersomnia, and orexin/ataxin-3 narcoleptic mice share the major pathophysiology of human narcolepsy (hypocretin cell ablation).10,11 As such, the observed efficacy in narcoleptic mice is an accurate predictor of efficacy for treatment of pathological sleepiness.
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effects of Paraxanthine and caffeine on sleep locomotor activity and body temperature in orexin ataxin 3 transgenic narcoleptic mice
Sleep, 2010Co-Authors: Masashi Okuro, Nobuhiro Fujiki, Nozomu Kotorii, Yuji Ishimaru, Pierre Sokoloff, Seiji NishinoAbstract:CAFFEINE, IN THE FORM OF CAFFEINE-CONTAINING BEVERAGES OR OVER-THE-COUNTER CAFFEINE TABLETS (100 MG OR 200 MG), IS A WIDELY USED WAKE-promoting substance, used to reduce sleepiness in normal people.1,2 Caffeine is also widely used for patients with primary (such as narcolepsy) and secondary hypersomnia (hypersomnia associated with neurological diseases); these patients self-medicate with caffeine before they visit the sleep clinic to receive more potent medication.2 Caffeine is a non-selective antagonist for adenosine receptors (A1 and A2a receptors), and blockade of these receptors is believed to mediate its stimulant effects.1 One of the limitations of caffeine for treating hypersomnia is its low wake-promoting potency, while high doses may induce side effects such as anxiety, tremors, headache, and gastrointestinal irritation. Caffeine is demethylated to 3 active metabolites, Paraxanthine, theobromine, and theophylline, and C-8 hydroxylated to 1,3,7-trimethyluric acid (TMU).3–5 The interspecies variations in caffeine metabolism, related to cytochrome P4501A enzyme, exist; and the percentages of the production of these 4 metabolites are reported to be 59.9%, 8.7%, 5.0%, and 26.4% in humans, and 19.1%, 10.8%, 21.7%, and 47.8% in mice.5 Like caffeine, Paraxanthine is a central nervous stimulant. In addition, caffeine and Paraxanthine have similar anti-adenosine actions, though the literature has consistently reported that Paraxanthine exhibits slightly higher binding potencies for adenosine A1 and A2a receptors6 and both lower toxicity and lesser anxiogenic effects than caffeine.7 This may be explained by the pharmacological properties of other caffeine metabolites, such as theophylline, which often induce nausea, diarrhea, tachycardia, and arrhythmias.8 A recent study demonstrated that Paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, Paraxanthine may be more effective than caffeine for wake-promotion in normal people and treatment of hypersomnia in those with cardiovascular and neurological diseases. Therefore, we evaluated the wake-promoting efficacy of Paraxanthine in wild-type (WT) and narcoleptic mice models and compared it with those of caffeine and modafinil. Effects of these compounds on locomotor activity, core body temperature and anxiety levels were also compared. Narcoleptic mice were included since narcolepsy is the prototypical primary hypersomnia, and orexin/ataxin-3 narcoleptic mice share the major pathophysiology of human narcolepsy (hypocretin cell ablation).10,11 As such, the observed efficacy in narcoleptic mice is an accurate predictor of efficacy for treatment of pathological sleepiness.
Uwe Fuhr - One of the best experts on this subject based on the ideXlab platform.
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Differences in caffeine and Paraxanthine metabolism between human and murine CYP1A2
Biochemical pharmacology, 2002Co-Authors: Andreas Labedzki, Jeroen T.m. Buters, Wafaâ Jabrane, Uwe FuhrAbstract:For the characterisation of murine models of CYP1A2 mediated metabolism in humans we compared the metabolism of caffeine and Paraxanthine in human liver microsomes (LM) (two samples) and in LM from CYP1A2-null and wild-type mice. Inhibition experiments were carried out with the quinolones norfloxacin and pefloxacin and the substrate, caffeine. Additionally, in vivo pharmacokinetics of Paraxanthine was determined in CYP1A2-null and wild-type mice. All LM produced the primary metabolites of caffeine and Paraxanthine. In human LM, the main metabolite of caffeine was Paraxanthine (K(M) 0.4 and 0.5 mmol L(-1)). In wild-type and CYP1A2-null mice LM, the main caffeine metabolite was 1,3,7-trimethylurate, but formation was not saturable. Apparent K(M) for Paraxanthine formation from caffeine in wild-type and CYP1A2-null murine LM were 0.2 and 4.9 mmol L(-1), respectively. The main metabolite of Paraxanthine was 1-methylxanthine in human (K(M) 0.13 and 0.2 mmol L(-1)) and in wild-type mice LM (K(M) 0.53 mmol L(-1)). In CYP1A2-null murine LM, the main Paraxanthine metabolite was 7-methylxanthine. The quinolones competitively inhibited caffeine metabolism in human but not in wild-type or CYP1A2-null murine LM. No obvious differences were seen for blood pharmacokinetics and urinary metabolite excretion of Paraxanthine between CYP1A2-null and wild-type mice. Thus, for Paraxanthine, norfloxacin and pefloxacin interaction with CYP1A2 there were clear differences between mice and man. Our results suggest that an interspecies comparison is required for the metabolism of individual xenobiotics interacting with CYP1A2 prior to the use of mice models to predict its toxicity and/or pharmacological activity in man.
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simple and reliable cyp1a2 phenotyping by the Paraxanthine caffeine ratio in plasma and in saliva
Pharmacogenetics, 1994Co-Authors: Uwe Fuhr, Karl Ludwig RostAbstract:Several procedures to monitor CYP1A2 activity in vivo by the use of caffeine as a probe have been proposed. They comprise caffeine clearance, based on both plasma and saliva concentrations, urinary metabolite ratios, the 13C-caffeine breath test, and the Paraxanthine/caffeine ratio in plasma. The la
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Simple and reliable CYP1A2 phenotyping by the Paraxanthine/caffeine ratio in plasma and in saliva
Pharmacogenetics, 1994Co-Authors: Uwe Fuhr, Karl Ludwig RostAbstract:Several procedures to monitor CYP1A2 activity in vivo by the use of caffeine as a probe have been proposed. They comprise caffeine clearance, based on both plasma and saliva concentrations, urinary metabolite ratios, the 13C-caffeine breath test, and the Paraxanthine/caffeine ratio in plasma. The la
Diana G. Wilkins - One of the best experts on this subject based on the ideXlab platform.
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Maternal Serum Caffeine Metabolites and Small-for-Gestational Age Birth
American journal of epidemiology, 2002Co-Authors: Mark A. Klebanoff, Richard J. Levine, John D. Clemens, Diana G. WilkinsAbstract:To determine whether the third-trimester maternal serum concentration of Paraxanthine, caffeine's primary metabolite, is associated with delivery of a small-for-gestational age infant (birth weight less than the 10th percentile for gestational age, gender, and ethnicity) and whether this association differs by smoking, the authors studied 2,515 women who participated in the Collaborative Perinatal Project from 1959 to 1966. The women provided a third-trimester serum sample and had been controls for a nested case-control study of spontaneous abortion. The mean serum Paraxanthine concentration was greater in women who gave birth to small-for-gestational age infants (754 ng/ml) than to appropriately grown infants (653 ng/ml, p = 0.02). However, the linear trend for increasing serum Paraxanthine concentration to be associated with increasing risk of small-for-gestational age birth was confined to women who also smoked (p = 0.03). There was no association between Paraxanthine and fetal growth in nonsmokers (p = 0.48). Adjustment for maternal age, pre-pregnant weight, education, parity, ethnicity, and the number of cigarettes smoked per day did not alter the results substantially, although the p value for trend among smokers increased to 0.07. The authors conclude that maternal third-trimester serum Paraxanthine concentration, which reflects caffeine consumption, was associated with a higher risk of reduced fetal growth, particularly among women who smoked.
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Maternal Serum Paraxanthine, a Caffeine Metabolite, and the Risk of Spontaneous Abortion
The New England journal of medicine, 1999Co-Authors: Mark A. Klebanoff, Richard J. Levine, Rebecca Dersimonian, John D. Clemens, Diana G. WilkinsAbstract:Background Whether the consumption of caffeine during pregnancy increases the risk of spontaneous abortion is controversial. Prior studies have determined caffeine consumption by questionnaire. We used a biologic marker, serum Paraxanthine, a metabolite of caffeine, to measure the dose of caffeine. Methods In a nested case–control study, we measured serum Paraxanthine in 591 women who had spontaneous abortions at less than 140 days' gestation and in 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation or later and who had serum drawn on the same day of gestation as the women who had abortions. The women were enrolled in the Collaborative Perinatal Project during the period from 1959 to 1966, and serum Paraxanthine was measured over 30 years later. Results A total of 487 women who had spontaneous abortions (82 percent) and 2087 controls (82 percent) had quantifiable serum Paraxanthine concentrations. However, the mean serum Paraxanthine concentration was higher in t...
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Serum Caffeine and Paraxanthine as Markers for Reported Caffeine Intake in Pregnancy
Annals of epidemiology, 1998Co-Authors: Mark A. Klebanoff, Richard J. Levine, Rebecca Dersimonian, John D. Clemens, Diana G. WilkinsAbstract:Abstract PURPOSE: Previous studies of maternal caffeine use and pregnancy outcome have relied on self-reported use. Even if these were perfectly accurate, inter-individual differences in caffeine metabolism result in a relatively weak correlation between caffeine intake and serum concentration. The purpose of this study was to determine whether the serum concentration of caffeine or its primary metabolite, Paraxanthine, obtained at an unknown time during working hours, is useful to distinguish between pregnant women who report consuming small and large amounts of caffeine. METHODS: We selected from the Birmingham fetal growth study 60 women with normal pregnancy outcomes who reported consuming ⩽ 0.8 mg/kg/day of caffeine in a 24-hour dietary recall, 60 who consumed 0.81–2.5 mg/kg/day, 60 who consumed 2.51–5.0 mg/kg/day and 59 who consumed ⩾ 5.01 mg/kg/day. These women had serum drawn for storage during regular clinic hours on the same day as the recall interview. Caffeine and Paraxanthine were measured in the stored serum using high performance liquid chromatography. RESULTS: The weighted kappa coefficient between strata of caffeine intake and quartiles of serum Paraxanthine was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and 0.51, respectively, for quartiles of serum caffeine. The Pearson correlation coefficient between intake and Paraxanthine was 0.50 for smokers and 0.53 for nonsmokers, and 0.37 and 0.51, respectively, for serum caffeine. These values are comparable to the correlation between reported smoking and serum cotinine in pregnancy. CONCLUSIONS: The serum concentrations of Paraxanthine, and to a lesser degree, caffeine are useful to distinguish between women with varying levels of caffeine intake.
