OBJECTIVES: The objective of this study is to evaluate the efficacy and tolerability of theobromine in patients with upper airway cough syndrome compared to those of levocloperastine. MATERIALS AND METHOD: This was a randomized, double-blind study. One hundred sixty-five patients with upper airway cough syndrome participated in a 5 day treatment; 85 subjects were included in the theobromine treatment group and 80 in the levocloperastine control group. Cough severity score, daytime cough symptom (DCS), nighttime cough symptom (NCS) and cough quality of life questionnaire (CQLQ) were analyzed for symptom analysis, and vital signs and laboratory study were performed for safety evaluation before and after medication administration. RESULTS: The primary efficacy analysis showed that the mean change in cough grade between baseline and follow-up in the treatment group was lower than that in the control group. This led to the conclusion that theobromine has similar efficacy to control treatment. The secondary efficacy analysis of changes in DCS, NCS and CQLQ verified this conclusion. Considering safety, only one case of dyspepsia was considered to be probably related to theobromine. Other tests conducted before and after treatment confirmed the safety of treatment medications. CONCLUSION: Theobromine is a novel natural antitussive medication that has similar efficacy to levocloperastine and adequate safety.
Cough ; Double-Blind Method ; Dyspepsia ; Follow-Up Studies ; Humans ; Quality of Life ; Theobromine ; Vital Signs ; Surveys and Questionnaires

Pharmacokinetic interaction of chrysin, a flavone present in honey, propolis and herbs, with caffeine was investigated in male Sprague-Dawley rats. Because chrysin inhibited CYP1A-selective ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase activities in enriched rat liver microsomes, the pharmacokinetics of caffeine, a CYP 1A substrate, was studied following an intragastric administration with 100 mg/kg chrysin. In addition to the oral bioavailability of chrysin, its phase 2 metabolites, chrysin sulfate and chrysin glucuronide, were determined in rat plasma. As results, the pharmacokinetic parameters for caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) were not changed following chrysin treatment in vivo, despite of its inhibitory effect on CYP 1A in vitro. The bioavailability of chrysin was found to be almost zero, because chrysin was rapidly metabolized to its sulfate and glucuronide conjugates in rats. Taken together, it was concluded that the little interaction of chrysin with caffeine might be resulted from the rapid metabolism of chrysin to its phase 2 metabolites which would not have inhibitory effects on CYP enzymes responsible for caffeine metabolism.
Animals ; Biological Availability ; Caffeine* ; Cytochrome P-450 CYP1A1 ; Drug Interactions ; Honey ; Humans ; In Vitro Techniques ; Male ; Metabolism ; Microsomes, Liver ; Pharmacokinetics ; Plasma ; Propolis ; Rats* ; Rats, Sprague-Dawley ; Theobromine

To examine individual variation in drug metabolism catalyzed by flavin-containing monooxygenase (FMO), 179 Korean volunteers' urinary molar concentration ratio of theobromine (TB) and caffeine (CA) was determined. Their urine was collected for 1 hr (between 4 and 5 hrs) after they drank a cup of coffee containing 115 mg CA and analyzed by an HPLC system. The lowest TB/CA ratio obtained was 0.40, the highest ratio was 15.17 (38-fold difference), and the median ratio for all subjects was 1.87. The mean was 2.66 with 2.36 S.D.. In 134 nonsmokers, the mean ratio was 2.35 +/- 1.93, that of 51 males was 2.30 +/- 2.26 and 83 females was 2.37 +/- 1.85, respectively. There was no significant gender difference in the obtained TB/CA ratio (Mann-Whitney test; p=0.518). There were no smokers among the 83 female volunteers. In the remaining 96 male subjects, the ratio obtained in 51 nonsmokers was 2.30 +/- 2.06 and that of 45 smokers was 3.62 +/- 3.19. This indicated that the TB/CA ratio was increased significantly in smokers (p=0.007). However, when the TB/CA ratios (FMO activity) obtained in all 179 Korean volunteers are compared with the urinary concentration ratios of paraxanthine (PX) plus 1,7-dimethylurate (17U) to CA (CYP1A2 activity), there was a weak but significant correlation (Pearson's correlation coefficient test; r2=0.28, p<0.0001). This indicates that, although the urinary TB/CA ratio mostly represents FMO activity, minor contribution by CYP1A2 activity cannot be ignored. In conclusion, the FMO activity measured by taking the urinary TB/CA ratio from normal healthy Korean volunteers shows marked individual variations without significant gender differences and the increased TB/CA ratio observed in cigarette smokers may have been caused by the increased CYP1A2 activity.
Caffeine* ; Chromatography, High Pressure Liquid ; Coffee* ; Cytochrome P-450 CYP1A2 ; Drinking* ; Ethanol ; Female ; Humans ; Male ; Metabolism ; Molar ; Theobromine* ; Tobacco Products ; Volunteers

Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC50 values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.
Administration, Oral ; Animals ; Caffeine* ; Cytochrome P-450 CYP1A1 ; Cytochrome P-450 CYP2B1 ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System ; Drug Interactions ; Far East ; Herb-Drug Interactions ; Inhibitory Concentration 50 ; Microsomes, Liver ; Pharmacokinetics* ; Plasma ; Rats* ; Scutellaria baicalensis ; Theobromine

AIMTo study the effect of AMP579 and adenosine on potassium ionic (K+) or sodium ionic (Na+) channels and to elucidate ionic mechanisms underlying negative inotropic and antiarrhythmic effects of AMP579 and adenosine.

METHODSIonic channel currents of rat and guinea pig ventricular myocytes were recorded by patch clamp technique in whole-cell configuration.

RESULTSAdenosine showed a stronger activating effect on transient outward K+ current (I(to)) than AMP579, EC50 of adenosine and AMP579 were 2.33 and 8. 32 micromol x L(-1), respectively (P < 0.05). An adenosine A1 receptor blocker, 1,3-dipropyl-8-cyclopentylxanthine (PD116948), can abolish the effects of AMP579 and adenosine on I(to), demonstrating that the effect is mediated by adenosine A1 receptor. Adenosine exerted a more obvious inhibitory effect on delayed rectifier K+ current (IK) than AMP579. IC50 of adenosine and AMP579 were 1.21 and 2.31 micromol x L(-1), respectively (P < 0.05). AMP579 had a more powerful inhibitory effect on inward rectifier K+ current (IK1) than adenosine. IC50 of AMP579 and adenosine were 4.15 and 20.7 micromol x L(-1), repectively (P < 0.01). AMP579 and adenosine exerted a similar inhibitory effect on fast inward Na+ current (INA), IC50 of AMP579 and adenosine were 9.46 and 6.23 micromol x L(-1), respectively (P > 0.05).

CONCLUSIONAdenosine showed a stronger activating effect on I(to) than AMP579, however, the mechanism of AMP579 and adenosine activating I(to) was mediated by adenosine A1 receptor. AMP579 has a more powerful inhibitory effect on IK1, and less inhibitory effect on IK than adenosine. Both drugs have a similar inhibitory effect on INa. The negative inotropic and antiarrhythmic effects are related to these ionic mechanisms.

Adenosine ; chemistry ; pharmacology ; Adenosine A1 Receptor Antagonists ; Adenosine A2 Receptor Antagonists ; Animals ; Dose-Response Relationship, Drug ; Electric Stimulation ; Guinea Pigs ; Heart Ventricles ; cytology ; Imidazoles ; chemistry ; pharmacology ; Male ; Membrane Potentials ; drug effects ; Molecular Structure ; Myocytes, Cardiac ; cytology ; drug effects ; physiology ; Potassium Channels ; physiology ; Potassium Channels, Inwardly Rectifying ; physiology ; Pyridines ; chemistry ; pharmacology ; Rats ; Rats, Wistar ; Sodium Channels ; physiology ; Theobromine ; analogs & derivatives ; pharmacology ; Xanthines ; pharmacology