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Theobromine

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Kathy Nguyen

on 5 June 2014

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Transcript of Theobromine

THEOBROMINE
<the compound of chocolate>
History
Alex Baker
Kathy Nguyen
Katie Krebs
Quyen Anh Pham
Sophie Wilson
Absorption
All routes, but mostly oral administration
Bioavailability 96% in humans
Peak plasma concentration at 2.5 hours
Distribution
90% unbound in plasma
Potential to cross BBB
Metabolism
Demethylation at 1, 3, 7 positions by CYP450
Broken down into metabolites 3-methylxanthine and 7-methylxanthine
7-methylxanthine to 7-methyluric acid by xanthine oxidase
Excretion
Urinary Excretion
Less than 10% through GI tract
Physicochemical Properties
Water soluble (logP=-0.69)
Small size (0.18kDa) so mostly freely filtered in glomerulus
Volume of Distribution = 0.62 L/kg
pKa=10 (ionized form in stomach and intestines)
Pharmacokinetics
Toxicokinetics

Pharmacodynamics
Toxicodynamics
G-coupled protein receptor
Natural, competitive, nonselective antagonist at A1 and A2
Main target is heart
Weakly affects CNS
Humans
Dogs
Other Animals
Non-human primates
Decreased thymus weight, heart rate, excitability, growth
Digestive complications
Immature Rabbits
1-1.5% administered orally for 120 days = Dead
Forensics for an Overdose
Chromatographic methods, such as thin-layer chromatography, high-performance liquid chromatography, and capillary electrophoresis
UV spectroscopy with a separation procedure
Drug-Drug Interactions
Toxicology
Theocron
Pargyline
Modern Societal Use
Culinary/Confectionery

Economic Livelihood
Potential Medical and Other Uses
Controversial Uses
Pest Coyote Control
Potential Medical & Health Uses
Adamafio, N. (2013). "Theobromine Toxicity and Remediation of Cocoa By-products: An Overview." Journal of Biological Sciences 13(7).
Agudelo, C., et al. (2013). "Chocolate ingestion-induced non-cardiogenic pulmonary oedema in a puppy: a case report." Veterinarni Medicina 58(2).
Arnaud M.J. and C. Welsch (1979). “Theophylline and caffeine metabolism in man.” Methods in Clinical Pharmacology 3:135-148.
Baggott, M. J., et al. (2013). "Psychopharmacology of theobromine in healthy volunteers." Psychopharmacology 228(1): 109-118.
Berkowitz, B.A., S. Spector, and W. Pool (1971). “The interaction of caffeine, theophylline and theobromine with monoamine oxidase inhibitors.” European Journal of Pharmacology 16(3): 315-321.
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Chou C.C. and T.W. Vickroy (2003). “Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues.” Am J Vet Res 64: 216–224.
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Hurst, W.J., R.A. Martin and S.M. Tarka (1984). “Analytical methods for quantitation of methylxanthines.” Prog Clin Biol Res 158:17-28.
Johnston, J. J. (2005). "Evaluation of cocoa-and coffee-derived methylxanthines as toxicants for the control of pest coyotes." Journal of agricultural and food chemistry 53(10): 4069-4075.
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Miller G.E. et al. (1984). “Comparative theobromine metabolism in five mammalian species.” Drug Metabolism and Disposition 12(2):154-160.
Patel, V., et al. (2012). "Chocolates as Dosages form-An Overview." Int. J. of Pharm. & Research Sci.(IJPRS) 1(6): 397-412.
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Ramli, N. et al (2000). "Caffeine and Theobromine Levels in Chocolate Couverture and Coating Products." Malaysian Journal of Nutrition 6: 55-63.
Reddy, B. S., et al. (2013). "Chocolate Poisoning in a Dog." International Journal of Veterinary Health Science & Research 1(4): 1-3.
Resman, B.H. et al. (1977). “Breast milk distribution of theobromine from chocolate.” The Journal of Pediatrics 91(3): 477-480.
Smit, H.J. (2011). “Theobromine and the Pharmacology of Cocoa.” Methylxanthines 200: 201-234.
Stavric, B. (1988). "Methylxanthines: toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines." Food and chemical toxicology 26(8): 725-733.
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Methylxanthine
Metabolite of caffeine
Comes from plants
Found in chocolate
TOXICITY IN HUMANS
Little to no accurate data on TD50 or lethality in humans
1000mg (5 dark chocolate bars) reported:
Decreased alertness & responsiveness
Headaches, nausea, vomiting
Extrapolation of toxic dose of a rat = 18g/day in humans

171 milk chocolate bars or 90 dark chocolate bars!!!

THERAPEUTIC USE
300-600mg recommended for cardiac stimulation, diuresis, & arterial dilation
Compared to humans, theobromine is:
Metabolized in liver slower
Undergoes enteroheptatic recycling
Excreted with parent compounds & metabolites
Half-life = 17.5hrs
TOXICITY IN DOGS:
More to less toxic: Cooking chocolate/Cocoa powder > Dark > Milk
Oral LD50 = 100-500mg/kg
Symptoms:
restlessness / over-stimulation, hyperacidity, vomiting, diarrhea, stiffness, muscle twitching, rapid breathing, seizures
Death caused by irregular heartbeats, hyperthermia, respiratory failure, edema, congestion

THERAPEUTIC?
20mg/kg for cardiac stimulation & diuresis
BUT reports of toxic effects at this dose (restlessness & vomiting)
ED50 not extensively researched
Mice
Increased #dead pups/litter
More abnormal sperm, smaller testicles, changes in Sertoli cells
Rats
oral LD50 = 950mg/kg
Theobromine mix as a more socially acceptable form to control coyotes and reduce loss of cattle and calves for farmers
Considered as a
doping drug
in equine sports to alter/enhance racehorse performance
Vascular dysfunction & inflammatory diseases
Diabetes
Stroke
Restricted cardiac blood flow
Asthma relief
Dental plaque prevention
Cough medication
Summary

Methylxanthine similar to caffeine
Most usually found in chocolate
Oral administration, 96% bioavailability, excreted in urine
Very water soluble
Competitive Antagonist of G-coupled Adenosine receptors
Not lethal in humans, but very toxic to dogs and other animals

Methylxanthine known as theophylline
Targets the same adenosine receptors
Increases the toxicological potential of Theobromine when taken together
Additive metabolite effect
Monoamine oxidase inhibitor
High blood pressure drug
Lowers the LD50 of Theobromine by 50%
Increasing the toxicity
Reversed the typical effects of Theobromine, resulting in agitation, disorientation, and hyperthermia
Full transcript