Showing papers on "Theobromine published in 1982"
TL;DR: The potency of xanthine derivatives as adenosine antagonists was studied in fat cells and hippocampal slices (A2-receptors) and on L-[3H]phenylisopropyladenosine (PIA) binding in membranes from rat cortex.
220 citations
TL;DR: It is imperative that a major research program be undertaken to evaluate these methylxanthines and, of course, cocoa, coffee, and tea, and it only will be through elucidating their mechanism of action that the authors will be in a position to assess their safety.
Abstract: The critical review of the literature cited on pharmacology, toxicology, metabolism, and safety assessment clearly demonstrates that cocoa per se has not attracted a great deal of scientific interest because of its long-term usage with no reported adverse effects that would be injurious to man. On the other hand, a great deal of research has been directed towards understanding the pharmacological properties of the methylxanthines--caffeine, theobromine, and theophylline. Much of the emphasis on metabolism, toxicology, teratogenic potential, and safety assessment has been on the evaluation of caffeine. In light of the serious health concerns ascribed to the effects of caffeine and the lack of basic information on theobromine and theophylline, it is imperative that a major research program be undertaken to evaluate these methylxanthines and, of course, cocoa, coffee, and tea. It only will be through elucidating their mechanism of action that we will be in a position to assess their safety. Before committing research efforts to evaluating the long-term effects of these methylxanthines and their respective foodstuffs, which serve as our primary source of exposure, it is critical to initiate more basic research on the metabolism of caffeine, theophylline, and theobromine in several animal species and man. While published reports do appear in this area, it is essential to understand fully the similarities and differences between various animals and man. The influence of dietary factors and drug interactions must also be determined. Before establishing dosage levels for a chronic toxicity study, the pharmacokinetics of the dose must be determined in the species that will be used in long-term studies. This is necessary if there is a dose-dependency in the animal above which saturation may occur and the plasma half-life kinetics change, or shifts occur either in the metabolic pathways of degradation and/or in the route of excretion from the body. The area of teratology must also be thoroughly evaluated. Studies undertaken should include identification and quantitation of the metabolites of caffeine, theophylline, and theobromine in the pregnant animal, the respective pharmacokinetics of each compound, dose-dependency (if this is the case), and their potential teratogenicity. In addition, the influence of other drugs or dietary variables must be included. In addition to teratology, a great deal of research is needed to assess and quantitate fetal and neonatal metabolism of these compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
97 citations
TL;DR: Daily caffeine injections resulted in the development of caffeine tolerance, characterized by a 6 fold shift to the right in the caffeine dose‐effect curve Saline substitution for the 32.0 mg/kg caffeine maintenance dose resulted in a substantial decrease in responding.
Abstract: 1 Rats were trained to respond under a variable interval 30 s (VI 30) schedule of food reinforcement. Caffeine (0.32-32 mg/kg), theophylline (1.0-56 mg/kg) and theobromine (10-320 mg/kg) in general produced dose-related decreases in operant responding. At relatively low doses, caffeine (1.0 mg/kg) and theophylline (3.2 mg/kg) produced slight but nonsignificant increases in VI 30 responding. 3 The rank order of potency for producing decreases in responding was caffeine greater than theophylline greater than theobromine. 4 Daily caffeine injections (32 mg/kg, i.p.) resulted in the development of caffeine tolerance. This tolerance was characterized by a 6 fold shift to the right in the caffeine dose-effect curve. Saline substitution for the 32.0 mg/kg caffeine maintenance dose resulted in a substantial decrease in responding.
90 citations
01 Jan 1982
TL;DR: Quantitative metabolic study of dimethylxanthines demonstrated that paraxanthine is the most important pathway in man and its high plasma concentration cannot be explained by a lower level of metabolism or urinary excretion compared with theobromine and theophylline.
Abstract: Because only 4 % of human urinary caffeine metabolites are trimethyl derivatives, in contrast to 42 % in the rat, demethylation of caffeine into dimethylxanthines and the metabolic pathways of these dimethylxanthines were studied in man. After oral administration of caffeine to overnight fasted volunteers, plasma kinetics of caffeine and paraxanthine, theophylline, theobromine produced by demethylation were analyzed and showed a parallel increase of caffeine and paraxanthine while theophylline and theobromine plasma concentration exhibited a small increase. Quantitative metabolic study of dimethylxanthines demonstrated that paraxanthine is the most important pathway in man and its high plasma concentration cannot be explained by a lower level of metabolism or urinary excretion compared with theobromine and theophylline. Uracil derivatives of caffeine, paraxanthine and theobromine were identified and quantified with 14 other metabolites. In addition 5-acetylamino-6-amino-3-methyluracil was also quantified after paraxanthine administration. 1-Methylxanthine was shown to be the precursor of this acetylated uracil. Quantitatively the paraxanthine pathway corresponds to 72% of the first demethylation of caffeine and half of the urinary metabolites are 1-methylxanthine and 1-methylxanthine derivatives.
58 citations
TL;DR: Screening of caffeine for its effect on the growth of a number of Aspergillus and Penicillium species indicated that caffeine may have biological activity against a variety of mycotoxigenic molds.
Abstract: The effect of caffeine and theobromine on growth and ochratoxin A production by Aspergillus ochraceus was determined using microbiological medium. Caffeine produced a small decrease in growth, while reducing ochratoxin production as much as 98%. Theobromine had relatively little effect on growth or ochratoxin production. Screening of caffeine for its effect on the growth of a number of Aspergillus and Penicillium species indicated that caffeine may have biological activity against a variety of mycotoxigenic molds.
47 citations
TL;DR: Results indicate that in mammalian cells the control of cell cycle progression and the modification of radiation-induced division delay are not simply related to intracellular levels of cyclic AMP, but there appear to be at least two competing mechanisms which are differentially affected by caffeine analogues or by direct addition of dibutyryl cyclicAMP.
Abstract: The mitotic selection procedure for cell cycle analysis was utilized to investigate the concentration-dependent modification of radiation-induced division delay in Chinese hamster ovary (CHO) cells by methyl xanthines (caffeine, theophylline, and theobromine) and by dibutyryl cyclic AMP. The methyl xanthines (concentrations from 0.5 to 1000 micrograms/ml) all reduced radiation-induced division delay with the effect being linear between approximately 100 and 1000 micrograms/ml. After doses of 100-300 rad, delay was reduced by 75, 94 or 83 per cent at 1000 micrograms/ml for each drug, respectively. However, the addition of dibutyryl cyclic AMP had an opposite effect: radiation-induced delay was increased by the concentration range of 0.3 to 300 micrograms/ml. These results indicate that in mammalian cells the control of cell cycle progression and the modification of radiation-induced division delay are not simply related to intracellular levels of cyclic AMP. Rather, there appear to be at least two competing mechanisms which are differentially affected by caffeine analogues or by direct addition of dibutyryl cyclic AMP. The direct effect of caffeine and the methyl xanthines on membrane calcium permeability is considered.
30 citations
TL;DR: Activity in ammonia-dependent carbamyl phosphate synthetase and ornithine transcarbamylase activities in rats ingesting high concentrations of caffeine and theophylline, as well as increased blood levels of urea, and their correlation with self-mutilation are studied.
26 citations
Journal Article•
TL;DR: In this article, the effects of allopurinol on the plasma clearance and metabolism of theobromine have been investigated under multiple-dosing conditions, and it was shown that the elimination of this compound is dependent on enzyme systems other than xanthine oxidase, presumably the hepatic mixed function oxidases.
Abstract: The effects of allopurinol on the plasma clearance and metabolism of theobromine have been investigated under multiple-dosing conditions. Allopurinol had no effect on the clearance of theobromine, indicating that the elimination of this compound is dependent on enzyme systems other than xanthine oxidase, presumably the hepatic mixed-function oxidases. The excretion of 3-methylxanthine, 6-amino-5-(N-methylformylamino)-1-methyluracil, and unchanged theobromine were similarly unaffected by the allopurinol treatment. Although allopurinol abolished the formation of 7-methyluric acid (7MU) and increased the excretion of 7-methylxanthine (7MX), the metabolic clearance to (7MX + 7MU) was not significantly different with and without allopurinol. It is proposed that the secondary biotransformation of 7MX to 7MU is mediated by xanthine oxidase.
24 citations
Journal Article•
TL;DR: It is proposed that the secondary biotransformation of 7MX to 7MU is mediated by xanthine oxidase, and the metabolic clearance to (7MX + 7MU) was not significantly different with and without allopurinol.
23 citations
TL;DR: Temperature is the most effective: the velocity of caffeine biosynthesis is increased by raising the temperature and vice versa and the close correlation between the theobromine content and the methylation rate is suspended when purine alkaloid formation is influenced by factors other than leaf development.
Abstract: In the leaves of Coffea arabica L., purine alkaloid formation was estimated by analyzing the theobromine and caffeine content and by measuring the methylation rate of [2-14C]theobromine to [2-14C]caffeine in short-term experiments (6–24 h). At the same time, growth (in terms of dry weight and area), net photosynthesis (NPS), and dark respiration were determined. During leaf development, which was considered to be terminated when NPS was at a maximum (60–80 μmol g-1 s-1) and dark respiration at a minimum (5–7.5 μmol g-1 s-1), the content of theobromine and the velocity of caffeine formation were both found to decrease by a factor of more than 100. The close correlation between the theobromine content and the methylation rate is suspended when purine alkaloid formation is influenced by factors other than leaf development. Among these factors, temperature is the most effective: the velocity of caffeine biosynthesis is increased by raising the temperature and vice versa. Although the plants were well irrigated, a drastic decrease of NPS in the afternoon was observed under all environmental conditions tested. Light saturation was reached between 170–360 μmol m-2 s-1. The temperature optimum of NPS was shown to be very broad (24–33°C)m provided the adaptation time was sufficiently long.
22 citations
TL;DR: Spermatogenic cell degeneration and necrosis and multinucleate cell formation were seen after 28 days in seminiferous tubular cross sections containing the early stages of spermatogenesis, but sections containing stages X to XIV were spared or were much less involved.
TL;DR: The reversed-phase mode of high-performance liquid chromatography was used to determine the intra- and inter-individual levels of UV- absorption low-molecular-weight compounds in saliva; many of the compounds known to occur in serum were also found in saliva, however, concentrations in saliva are lower.
TL;DR: Cocoa and the theobromine were negative in the Salmonella/mammalian microsome mutagenicity test both with and without metabolic activation, and Pure theOBromine increased SCE levels in a dose-dependent way.
TL;DR: Methylxanthines consumed daily by most humans were investigated for induction of sister chromatid exchanges (SCE) and effects observed in this highly sensitive in vivo system decreased in the order theophylline/theobromine>caffeine >paraxathine>monomethylxanthine.
Abstract: Methylxanthines consumed daily by most humans were investigated for induction of sister chromatid exchanges (SCE). Effects observed in this highly sensitive in vivo system decreased in the order theophylline/theobromine>caffeine >paraxathine>monomethylxanthines.
01 Jan 1982
TL;DR: The high degree of correlation observed between clearance to 1MU and clearance to 3MX suggests that the two demethylation reactions are under a common regulatory control which is distinct from that for the 8-oxidation to DMU.
Abstract: Theophylline and theobromine metabolism in man was studied after single dose intravenous administration (theophylline) and at steady-state during chronic oral administration (theophylline and theobromine). Co-administration of the xanthine oxidase inhibitor allopurinol with theophylline caused a decreased excretion of 1-methyluric acid (1MU) and an increased excretion of 1-methylxanthine (1MX). In the case of theobromine, allopurinol caused the disappearance of 7-methyluric acid (7MU) from urine and an increase in excretion of 7-methylxanthine. It is concluded that 1MU and 7MU arise by initial demethylations of theophylline and theobromine respectively, followed by xanthine oxidase mediated 8-oxidation of the monomethylxanthine. Other pathways for metabolism of the dimethylxanthines were not affected by allopurinol and are assumed to be cytochrome P-450 mediated. In children, theophylline total clearance was enhanced and all metabolic pathways were increased to approximately the same extent. In premature neonates, oxidative metabolism of theophylline was absent but 7-methylation to caffeine accounted for about 2 % of the dose. In cigarette smokers the demethylation pathways for theophylline were increased to a greater extent than 8-oxidation to 1,3-dimethyluric acid (DMU). Cimetidine inhibited the demethylation pathways but had little effect on the clearance to DMU. Inhibition of demethylation was more marked in cigarette smokers. These results, together with the high degree of correlation observed between clearance to 1MU and clearance to 3MX, suggests that the two demethylation reactions are under a common regulatory control which is distinct from that for the 8-oxidation to DMU.
TL;DR: In this paper, an HPLC method is described for the analysis of added caffeine and theobromine in animal diets using HPLC with samples extracted in CHC13 and interferences eliminated with a Sep-paktm.
Abstract: An HPLC method is described for the analysis of added caffeine and theobromine in animal diets using HPLC with samples extracted in CHC13 and interferences eliminated with a Sep-paktm. This method has good accuracy and precision but is not suitable for matrixes where the methylxanthines exist as a integral part of the matrix (e.g., foods).
TL;DR: The inverse relationship observed between cGMP and tyrosine aminotransferase degradation is consistent with a role for this cyclic nucleotide in the control of specific protein degradation.
TL;DR: In this article, it was shown that toluidine, chloroaniline and dichloroanile isomers can be separated using the normal liquid stationary phases on a non-alkali-treated support.
Abstract: It is difficult to separate toluidine, chloroaniline and dichloroaniline isomers using the normal liquid stationary phases on a non-alkali-treated support. However, toluidine isomers were completely resolved on caffeine, theobromine, theophylline, xanthine and hypoxanthine, and chloroaniline isomers were effectively separated on picolinic acid, quinolinic acid, isonicotinic acid, orotic acid, 3,5-diaminobenzoic acid, theobromine, xanthine, uracil and a mixed stationary phase of melamine and barbituric acid. Further, six dichloroaniline isomers were also effectively resolved on nicotinic acid, isonicotinic acid, picolinic acid, creatine, hydroxy-L-proline, caffeine, hydantion and mixed stationary phases consisting of nicotinamide and p-aminobenzoic acid and of silicone KF-54 and sodium hydroxide. These effective separations were obtained on non-alkali-treated supports.
TL;DR: Signals of both methyl groups of theobromine underwent significant upfield shifts when sodium benzoate was added to a theobromaine solution, which suggests that a complex is formed by vertical stacking or plane-to-plane stacking.
TL;DR: In this article, 1-(5-oxohexyl) theobromine (I) in alkaline solution was hydrolyzed by heating to give 4-(methylamino)-1-methyl-5-(5)-oxo hexyl) aminocarbonylimidazole (II) and N-[4-(5 carboxy-1-methylimidazeolyl)]-Nmethyl-N'-(5-oxide hexyl urea (III).
Abstract: 1-(5-Oxohexyl) theobromine (I) in alkaline solution was hydrolyzed by heating to give 4-(methylamino)-1-methyl-5-(5-oxohexyl) aminocarbonylimidazole (II) and N-[4-(5-carboxy-1-methylimidazolyl)]-N-methyl-N'-(5-oxohexyl) urea (III). When acidified with HCl, II and III were cyclized to 4, 4a, 5, 6, 7, 8-hexahydro-10-oxo-1, 4, 4a-trimethyl-1H-pyrido [1, 2-a]-purine (IV) and 4, 5, 7, 8, 9, 10-hexahydro-5, 12-dioxo-1, 4, 10a-trimethyl-1H-pyrido [2', 1' : 2, 3]-imidazo [4, 5-f] oxadiazocine hydrochloride (V), respectively.
01 Jan 1982
TL;DR: In this paper, it was shown that the expression methylxanthines as used for theophylline and for synthetic xanthine derivatives is misleading and that pentoxifylline exhibits different pharmacological properties in comparison to caffeine.
Abstract: It is demonstrated that the expression methylxanthines as used for theophylline and for synthetic xanthine derivatives is misleading. In publications concerning theophylline there is often no clear distinction between salts of theophylline and chemical derivatives of theophylline. The impression is thus given that all so-called bronchospasmolytic active theophylline salts and derivatives are converted to theophylline by metabolic or hydrolytic processes. This, however, is only true for salts of theophylline and not for its chemical derivatives. In the case of the synthetic xanthine derivative pentoxifylline, a vasotherapeutic agent of the caffeine type, it is shown that on chemical derivatization not only are physico-chemical parameters, for example water- und lipid-solubility changed, but also pharmacokinetic parameters, such as resorption rates, distribution volumes, and therapeutic plasma levels. The different physico-chemical properties of pentoxifylline in comparison to natural methylxanthines, result in a change in the metabolic pathway. While pentoxifylline is mainly metabolized via oxidation of the oxohexyl side chain, theophylline and caffeine are metabolized mainly by demethylation reactions. The therapeutic plasma levels for theophylline are between 10 and 20 µg/ml whereas those of pentoxifylline are below 0.5 µg/mi. Furthermore, pentoxifylline exhibits different pharmacological properties in comparison to caffeine, theophylline and theobromine and is better tolerated by the patient.
TL;DR: Results indicate that caffeine and theophylline are retardants of the myosin B superprecipitation reaction in the concentration ranges investigated.
Abstract: Myosin B was extracted from rabbit fast skeletal muscle. Caffeine (2-70 mM), theophylline (2-30 mM), and theobromine (2 mM) were examined for their effects on the rate and extent of myosin B superprecipitation at a low ionic strength (50 mM KCl) and a low concentration of ATP (40 microM) by the turbidimetric method. The rate of the superprecipitation was significantly (p less than 0.05 and p less than 0.01) reduced by 30-70 mM caffeine and 2-30 mM theophylline, while the extent was significantly (p less than 0.01) increased by 10-30 mM theophylline. The onset of the superprecipitation was also delayed and a clearing phase was even induced by 50-70 mM caffeine. Theobromine had no significant effect on the rate or extent of the superprecipitation at the concentration used. These results indicate that caffeine and theophylline are retardants of the myosin B superprecipitation reaction in the concentration ranges investigated.
01 Jan 1982
TL;DR: The hypothesis that methylation at position 3 is of highest importance for the action on chromosomes seems to be confirmed by the ineffectiveness of paraxanthine as com- pared to the other tested compounds.
Abstract: planted s.c. in the animals causes a continuous incorpora- tion of BrdU instead of thymidine into the DNA. After 2 cell cycles a special staining technique reveals differentially stained chromatids exhibiting SCEs. After administration of the test substances (dispersed in corn oil and given by stomach tube) dose relationships for caffeine, theophylline, theobromine and paraxanthine were established. In agree- ment with other investigators who use the SCE test results are considered as positive when the numbers of SCEs/cell reach at least 1~ times those of control (>5.7 SCEs/cell corresponding to p < 0.0001, t-test). The frequency of SCEs as a function of dose (mg/kg b.wt) is shown in the figure. Equal doses of theophylline and theobromine produced the same rates of SCEs in this test system. Caffeine produced a distinctly weaker effect and increased the SCE rate only when doses above a threshold of 150 mg/kg b.wt were ap- plied whereas paraxanthine induced only a very small in- crease of SCEs. The monomethylxanthines (1-methylxan- thine, 3-methylxantbine and 7-methylxanthine) showed no effects. The hypothesis that methylation at position 3 is of highest importance for the action on chromosomes seems to be confirmed by the ineffectiveness of paraxanthine as com- pared to the other tested compounds. The mentioned dif- ference in the metabolism of theobromine and theophylline is not reflected by the SCE test which indicates that the substance itself generates the mutagenic effect and not its metabolites.
01 Jan 1982
TL;DR: In this paper, a new ion pair high pressure liquid chromatographic assay was developed, allowing simultaneous quantitation of urinary concentrations of theophylline and its major metabolites, 3-methylxanthine, 1-methyluric acid and 1,3-dimethyl uric acid.
Abstract: A new ion pair high pressure liquid chromatographic assay has been developed, allowing simultaneous quantitation of urinary concentrations of theophylline and its major metabolites, 3-methylxanthine, 1-methyluric acid and 1,3-dimethyluric acid. The compounds are extracted from urine by means of a combination of a normal and an ion pair liquid-liquid extraction, using an ethylacetate/chloroform/isopropanol (45 : 45 :10) mixture as extraction solvent and tetrabutylammonium-ion as an ion pairing counter ion. (pH = 6.5). Separation of the compounds was obtained with a reversed phase HPLC method, with an Ultrasphere ODS column and an ion pairing system with tetrabutylammonium cation as the counter ion in sodium acetate buffer (pH = 4.75) with gradient elution with increasing methanol concentration. Detection occurred by measuring UV-absorbance at 280 nm. Good separation was obtained from other xanthines (xanthine, theobromine, caffeine, caffeine’s main metabolite 1,7-dimethylxanthine, 1-methylxanthine) and endogenous uric acid.
01 Jan 1982
TL;DR: Caffeine is preferred to theophylline and theobromine because of its stronger stimulating action on the respiratory centre and also because it has less side effects.
Abstract: Caffeine (1,3,7-trimethylxanthine) is used to prevent apneic spells in premature newborn infants, the possible consequences of which include hypoxia, bradycardia and cyanosis. One of the causes of apneic spells lies in the fact that the medullary respiratory centre is less sensitive to CO2. Caffeine is preferred to theophylline and theobromine because of its stronger stimulating action on the respiratory centre and also because it has less side effects. At therapeutic serum concentrations observed in this study caffeine does not increase heart rate.