A Prospective Randomized, Double-Blind, Two-Period Crossover Pharmacokinetic Trial Comparing Green Coffee Bean Extract-A Botanically Sourced Caffeine-With a Synthetic USP Control.

Coffee is a primary dietary source of the chlorogenic acids (CGAs) of phenolic compounds. Coffee contains caffeine and other phytonutrients, including CGAs. Caffeine on its own has been well characterized and descried pharmacokinetically in the literature, less so for CGAs. The purpose of this double-blind crossover study was to determine the comparative pharmacokinetics of CGAs with caffeine (natural extract) with synthetic caffeine (US Pharmacopeia [USP] standard). Sixteen healthy male subjects were randomly assigned to take 1 dose of product 1, 60 mg of botanically sourced caffeine from 480 mg of green coffee bean extract, or product 2, 60 mg of synthetic USP caffeine, with 5 days between. Blood analysis was done to determine the levels of CGA compounds, more specifically 3-, 4-, and 5-caffeoylquinic acid (CQA), and serum caffeine. The natural caffeine extract exhibited mean peak concentrations (Cmax ) of 3-CQA (11.4 ng/mL), 4-CQA (6.84 ng/mL), and 5-CQA (7.20 ng/mL). The mean systemic 4-hour exposure (AUC0-4 h ) was 3-CQA (27.3 ng·h/mL), 4-CQA (16.1 ng·h/mL), and 5-CQA (15.7 ng·h/mL). The median tmax was 3-CQA (1.00 hour), 4-CQA (1.00 hour), and 5-CQA (1.50 hours). The tmax of caffeine was 0.75 hours (natural extract) and 0.63 hours (synthetic caffeine). Cmax and AUC0-4 h of serum caffeine were statistically equivalent between products. The geometric least-squares mean ratios (GMRs) of Cmax and AUC0-4 h of caffeine were 97.77% (natural extract) and 98.33% (synthetic caffeine). It would appear that CGA compounds from the natural caffeine extract are bioavailable, and 3-CGA may be the compound most absorbed. In addition, caffeine sourced from natural extract versus synthetic were statistically similar for pharmacokinetic parameters. There were no adverse events or safety concerns.

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior.

Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (quicker and higher peak concentrations). We evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic clinical drug delivery. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60mg/kg/day; as well as dual-dosages of 4 and 10mg/kg/day, 20 and 30mg/kg/day, or 30 and 60mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30ng/mL), while the 4/10mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8ng/mL). Treatment with the higher dual-dosage (HD: 30/60mg/kg) resulted in hyperactivity, while the lower (LD: 4/10mg/kg) had no effect. Chronic effects of these dual-dosages were assessed throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle, decreased exploratory behavior, and increased anxiolytic behavior. Findings suggest that these dual-dosage-drinking-paradigms can be used to examine the effects of clinically relevant pharmacokinetic doses of MP and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

OBJECTIVES: Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. METHODS: Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. RESULTS: Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). DISCUSSION: The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure.

Fatal caffeine overdose: a case report and review of literature.

Caffeine is a central nervous system stimulant that is consumed by large numbers of people on a routine basis, usually in the form of coffee or tea. However, if consumed in high doses, this xanthine alkaloid is profoundly toxic and can result in death. Increasingly being sold as a dietary supplement, many people, particularly those in the health and fitness community, where it is touted as a fitness and muscle building aid, are consuming caffeine anhydrous on a daily basis. We report a case of fatal caffeine overdose in a 39-year-old man resulting from the self-administered ingestion of approximately 12 g of pure caffeine anhydrous. Autopsy blood caffeine levels were 350 mg/L. We recommend mandated labeling of pure caffeine anhydrous, highlighting the toxicity risk of ingesting this chemical; and we recommend ensuring that caffeine levels are included in the comprehensive forensic toxicology panel performed on all cases.

Effects of caffeine on the inflammatory response induced by a 15-km run competition.

PURPOSE: The objective of this study is as follows: 1) to determine the effects of caffeine supplementation on the inflammatory response (IL-6 and IL-10 levels and leukocyte numbers) induced by a 15-km run competition and 2) to examine the effect of caffeine supplementation on the energetic metabolites as well as on the exercise-induced oxidative stress. METHODS: A double-blinded study of supplementation with caffeine was performed. Athletes participating in the study (n = 33) completed a 15-km run competition. Before competition, athletes took 6 mg · kg(-1) body weight of caffeine (caffeine group, n = 17) or a placebo (placebo group, n = 16). Blood samples were taken before and after competition (immediately and after 2-h recovery). Leukocyte numbers were determined in blood. Concentrations of oxidative stress markers, antioxidants, interleukins (IL-6 and IL-10), caffeine, adrenaline, and energetic metabolites were measured in plasma or serum. RESULTS: Caffeine supplementation induced higher increases in circulating total leukocytes and neutrophils, with significant differences between groups after recovery. Adrenaline, glucose, and lactate levels increased after exercise, with higher increases in the caffeine group. Exercise induced significant increases in IL-6 and IL-10 plasma levels, with higher increases in the caffeine group. Caffeine supplementation induced higher increases in oxidative stress markers after the competition. CONCLUSION: Caffeine supplementation induced higher levels of IL-6 and IL-10 in response to exercise, enhancing the anti-inflammatory response. The caffeine-induced increase in adrenaline could be responsible for the higher increase in IL-6 levels, as well as for the increased lactate levels. Furthermore, caffeine seems to enhance oxidative stress induced by exercise.

The effect of caffeine consumption on the success rate of pregnancy as well various performance parameters of in-vitro fertilization treatment.

BACKGROUND: This study evaluated the effect of caffeine consumption on the success rate of pregnancy and various in vitro fertilization (IVF) performance parameters. MATERIAL/METHODS: Serum and follicular fluid samples were collected from 619 women undergoing IVF treatment (2002-2003). Caffeine assessment was based on measuring the levels of caffeine in serum and follicular fluid and on the number of coffee or tea or caffeinated drinks consumed per day. RESULTS: A total of 97.3% of participants reported the consumption of caffeinated drinks such as coffee, tea and soft drinks. Their average caffeine consumption was 455.82 mg/day (range: 3.71-3561 mg/day). Coffee was the primary source of caffeine intake. The average caffeine levels in serum (0.913 µg/ml) were significantly higher than in follicular fluid (0.701 µg/ml). After controlling for various potential confounding variables, no association was found between coffee or tea consumption and the success rate of pregnancy. Looking at the effect of caffeine consumption on the IVF performance parameters, we found that the number of eggs decreased as the caffeine serum levels increased (P=0.011). An increase in coffee consumption was positively associated with the number of aborted pregnancy (P=0.007), while the number of good embryo decreased with high tea consumption (P=0.015). CONCLUSIONS: Though no association was seen between coffee or tea consumption and pregnancy rate, this study is the first to report that caffeine can reach the follicular fluid and there is a suggestive evidence of its possible harmful role on the consequences of reproductive process. This clearly warrants further investigation.

SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence.

Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. Our objective was to measure caffeine effects on cerebral perfusion in humans using single photon emission computed tomography with a specific focus on areas of reinforcement and reward. Two groups of nonsmoking subjects were studied, one with a low (8 subjects) and one with a high (6 subjects) daily coffee consumption. The subjects ingested 3 mg/kg caffeine or placebo in a raspberry-tasting drink, and scans were performed 45 min after ingestion. A control group of 12 healthy volunteers receiving no drink was also studied. Caffeine consumption led to a generalized, statistically nonsignificant perfusion decrease of 6% to 8%, comparable in low and high consumers. Compared with controls, low consumers displayed neuronal activation bilaterally in inferior frontal gyrus-anterior insular cortex and uncus, left internal parietal cortex, right lingual gyrus, and cerebellum. In high consumers, brain activation occurred bilaterally only in hypothalamus. Thus, on a background of widespread low-amplitude perfusion decrease, caffeine activates a few regions mainly involved in the control of vigilance, anxiety, and cardiovascular regulation, but does not affect areas involved in reinforcing and reward.

High-dose adenosine overcomes the attenuation of myocardial perfusion reserve caused by caffeine.

OBJECTIVES: We studied whether an increase in adenosine dose overcomes caffeine antagonism on adenosine-mediated coronary vasodilation. BACKGROUND: Caffeine is a competitive antagonist at the adenosine receptors, but it is unclear whether caffeine in coffee alters the actions of exogenous adenosine, and whether the antagonism can be surmounted by increasing the adenosine dose. METHODS: Myocardial perfusion scintigraphy (MPS) was used to assess adenosine-induced hyperemia in 30 patients before (baseline) and after coffee ingestion (caffeine). At baseline, patients received 140 microg/kg/min of adenosine combined with low-level exercise. For the caffeine study, 12 patients received 140 microg/kg/min of adenosine (standard) and 18 patients received 210 microg/kg/min (high dose) after caffeine intake (200 mg). Myocardial perfusion was assessed semiquantitatively and quantitatively, and perfusion defect was characterized according to the presence of reversibility. RESULTS: Caffeine reduced the magnitude of perfusion abnormality induced by standard adenosine as measured by the summed difference score (SDS) (12.0 +/- 4.4 at baseline vs. 4.1 +/- 2.1 after caffeine, p < 0.001) as well as defect size (18% [3% to 38%] vs. 8% [0% to 22%], p < 0.01), whereas it had no effect on the abnormalities caused by high-dose adenosine (SDS, 7.7 +/- 4.0 at baseline vs. 7.8 +/- 4.2 after caffeine, p = 0.7). There was good agreement between baseline and caffeine studies for segmental defect category (kappa = 0.72, 95% confidence interval: 0.65 to 0.79) in the high-dose group. An increase in adenosine after caffeine intake was well tolerated. CONCLUSIONS: Caffeine in coffee attenuates adenosine-induced coronary hyperemia and, consequently, the detection of perfusion abnormality by adenosine MPS. This can be overcome by increasing the adenosine dose without compromising test tolerability.

[Acute caffeine intoxication after intake of 'herbal energy capsules']. / Acute coffeïne-intoxicatie na het innemen van 'herbal energy'-capsules.

Two males, 15 and 17 years old respectively, presented at the Emergency Department complaining of cramping abdominal pain, nausea and vomiting after ingestion of energy capsules. Physical examination revealed sinus tachycardia and slight abdominal pain. Laboratory examination showed substantial hypokalaemia and mild hyperglycaemia. Questioning revealed that they had taken 5 and 3 'herbal energy capsules' respectively and that these capsules supposedly contained 200 mg of caffeine each. Toxicological analysis showed a greatly increased serum caffeine concentration in both patients. The peak concentrations calculated were in the highly toxic range and could have led to severe acute complications such as convulsions. Pharmaceutical analysis demonstrated that these 'Supercap Xtreme'-capsules contained 700 mg caffeine or more. All symptoms presented were compatible with caffeine intoxication. The content of these capsules is not reliable and could lead to life-threatening intoxication.

Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Performance-enhancing dietary supplements have not been clinically tested for safety or efficacy. In clinical trials performed under resting conditions, performance-enhancing supplements raise blood pressure and affect glucose homeostasis. The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown. WHAT THIS STUDY ADDS: Supplement-induced effects on blood pressure and glucose levels are not ameliorated by exercise. Exercise does not affect the kinetics of stimulant ingredients, caffeine and synephrine. Performance-enhancing supplement use modestly improves exercise tolerance. AIMS Dietary supplements (DS) promoted to enhance athletic performance often contain herbal sympathomimetics such as Citrus aurantium (synephrine) and caffeine. We aimed to characterize the pharmacology of a performance-enhancing DS in the setting of exercise. METHODS: Ten healthy adults (three women) aged 20-31 years participated in a three-arm, double-blind, placebo-controlled, crossover study. Subjects ingested one dose of DS (Ripped Fuel Extreme Cut(R) with 21 mg synephrine and 304 mg caffeine by analysis) under resting conditions and 1 h prior to moderately intense exercise (30 min on cycle ergometer at 75-80% HR(max)), with a placebo (PLC)/exercise control. Plasma synephrine and caffeine concentrations were measured over 12 h, and vital signs, serum electrolytes, oxygen consumption and perceived exercise exertion were monitored. RESULTS: No significant adverse events occurred. Synephrine and caffeine pharmacokinetics were unaffected by exercise. Post-exercise diastolic blood pressure was higher after DS (peak mean 71.7 +/- 8.7 mmHg) than PLC (63.0 +/- 4.9 mmHg) (p = 0.007). There were no substantial treatment-related differences in post-exercise HR, systolic blood pressure, or temperature. Postprandial plasma glucose increased to 121.0 +/- 31.6 mg dl(-1) with DS and exercise vs. 103.7 +/- 25.5 mg dl(-1) with PLC and exercise (P = 0.004). No treatment differences in exercise-related oxygen consumption, serum lactate, or insulin were observed. Exercise was rated less difficult with DS than PLC (P = 0.001). CONCLUSIONS: Blood pressure and plasma glucose increased post-exercise with DS use, which could be detrimental in some people. Exercise was perceived as less strenuous after DS, presumably due to the stimulant effects of caffeine.

No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract.

We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.

Acute effects of tea on fasting and postprandial vascular function and blood pressure in humans.

BACKGROUND: Effects of regular exposure to polyphenolic compounds found in tea, leading to improved endothelial function and blood pressure, may reduce cardiovascular disease risk. Controlled trials in humans have found that ingestion of tea can improve endothelial function, but also cause a rapid onset acute increase in blood pressure. OBJECTIVE: To examine the acute effects of tea consumption on fasting and postprandial vascular function and blood pressure. METHODS: Endothelium-dependent dilatation of the brachial artery, assessed using ultrasound and blood pressure were measured in 20 participants with a history of coronary artery disease. Measurements were performed at baseline and at 3.5 h (blood pressure) and 4 h (endothelial function) after drinking three cups of black tea or hot water (consumed at time = 0, 1.5 and 3 h) with and without a high-fat (50 g) meal: a total of four treatments administered in random order. RESULTS: The high-fat meal did not impair endothelial function. In comparison to water alone, endothelium-dependent dilatation was increased by the meal with tea (1.7 (0.4, 3.0)%, P = 0.02), but was not significantly altered by the tea alone (0.7 (-0.6, 2.0)%, P = 0.32). Systolic blood pressure was significantly increased by tea alone in comparison to each of the other three groups: water alone (9.3 (4.5, 14.1) mmHg, P = 0.0003), meal with water (9.8 (5.0, 14.6) mmHg, P = 0.0001) and meal with tea (7.2 (2.4,12.0) mmHg, P = 0.004). Consumption of a meal negated the acute increase in systolic blood pressure found with tea in the fasting state. CONCLUSION: Consumption of food may alter the acute effects of tea on vascular function and blood pressure.

Limited phase I study of morphine-3-glucuronide.

The toxicity of morphine-3-glucuronide (M3G) has been investigated in an open, uncontrolled, single-blinded, single dose study over a limited range of doses. Three cohorts each of three healthy volunteers received 7.5, 15, and 30 mg/70 kg intravenous (IV) M3G. Blood sampling was undertaken for the following 24 h. Subjective toxicity was recorded on visual analogue scales and plasma M3G concentrations measured by a specific HPLC assay. Virtually no effects and no change in cardiovascular or respiratory parameters were seen. The pharmacokinetics fitted a two-compartment model. The mean elimination half-life (+/- S.D.) of M3G was 1.66 (+/- 0.47) h. Mean AUC standardized to a dose of 1 mg/70 kg was 228 (+/- 62) etamolL(-1) x h. Mean M3G clearance was 169 (+/- 48) mLmin(-1) and the mean volume of distribution was 23.1 (+/- 4.8) liters. At the doses investigated there were no clear neuroexcitatory effects, no opioid effects, and the pharmacokinetics were very similar to those of morphine-6-glucuronide (M6G).

Clinically significant pharmacokinetic interactions between dietary caffeine and medications.

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.

Metabolic and exercise endurance effects of coffee and caffeine ingestion.

Caffeine (Caf) ingestion increases plasma epinephrine (Epi) and exercise endurance; these results are frequently transferred to coffee (Cof) consumption. We examined the impact of ingestion of the same dose of Caf in Cof or in water. Nine healthy, fit, young adults performed five trials after ingesting (double blind) either a capsule (Caf or placebo) with water or Cof (decaffeinated Cof, decaffeinated with Caf added, or regular Cof). In all three Caf trials, the Caf dose was 4.45 mg/kg body wt and the volume of liquid was 7.15 ml/kg. After 1 h of rest, the subject ran at 85% of maximal O2 consumption until voluntary exhaustion (approximately 32 min in the placebo and decaffeinated Cof tests). In the three Caf trials, the plasma Caf and paraxanthine concentrations were very similar. After 1 h of rest, the plasma Epi was increased (P < 0.05) by Caf ingestion, but the increase was greater (P < 0.05) with Caf capsules than with Cof. During the exercise there were no differences in Epi among the three Caf trials, and the Epi values were all greater (P < 0.05) than in the other tests. Endurance was only increased (P < 0. 05) in the Caf capsule trial; there were no differences among the other four tests. One cannot extrapolate the effects of Caf to Cof; there must be a component(s) of Cof that moderates the actions of Caf.

Identification of a pyrovalerone metabolite in the rat by gas chromatography-mass spectrometry and determination of pyrovalerone by gas chromatography-nitrogen-phosphorus detection.

Pyrovalerone and its hydroxylated metabolite have been identified by gas chromatography-mass spectrometry in rat urine and plasma. A sensitive gas chromatographic method for the quantitative analysis of pyrovalerone in rat urine and plasma is described. The method also permits the quantitative monitoring of the urinary excretion of the drug and its metabolite. Pyrovalerone and its hydroxylated metabolite are detected up to 18 h after a single oral administration to the rat at a dose of 20 mg/kg.