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INTRODUCTION Presenter:
MAHEYA MIDHAT KHANDepartment Of PharmacyJinnah University For women, Karachi.
DEFINITION
the term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that
are physiologically active.
Deviation from Definition:
Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids.
Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline.
Plant Origin: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals
New Definition:
Alkaloids are cyclic organic compounds containing nitrogen in a negative state of oxidation with limited distribution among living
organisms.
ORIGIN AND HISTORY The term alkaloid was coined by Meissner, A German
Pharmacist, in 1819. The mankind has been using alkaloid for various
purposes like poisons, medicines, poultices, teas and etc. The French chemist, Derosne in 1803, isolated Narcotine. A significant contribution to the chemistry of alkaloids in
the early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine (1820) and strychnine (1818).
Several other alkaloids were discovered around that time, including xanthine (1817), atropine (1819), caffeine (1820),coniine (1827), nicotine (1828), and cocaine (1860).
Nomenclature:
Trivial names should end by "ine". These names may refer to: From plant generic name (Atropine)
From specific plant species (Cocaine)
From the common name of Drug (Ergotamine)
From physiological activity (emetine)
From the name of discoverer (Pelletierine)
From the prominent Physical character (Hygrine)
Distribution and occurrence:
Rare in lower plants. Dicots are more rich in
alkaloids than Monocots. Families rich in Alkaloids:
Apocynaceae, Rubiaceae, Solanaceae and Papaveracea.
Families free from Alkaloids: Rosaceae, Labiatae
Distribution in Plant:
All Parts e.g. Datura. Barks e.g. Cinchona Seeds e.g. Nux vomica Fruits e.g. Black
pepper Latex e.g. Opium Leaves e.g. Tobacco
Forms of Alkaloids:
• Free bases• Salts with Organic acids e.g. Oxalic, acetic
acids• Salts with inorganic acids e.g. HCl, H2SO4.• Salts with special acids: e.g. Meconic acid in Opium
Quinic acid in Cinchona • Glycosidal form e.g. Solanine in Solanum.
Function in Plants
• They may act as protective against insects and herbivores due to their bitterness and toxicity.
• They are, in certain cases, the final products of detoxification (waste products).
• Source of nitrogen in case of nitrogen deficiency.
• They, sometimes, act as growth regulators in certain metabolic systems.
• They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation.
EFFECTS OF ALKALOIDS ON HUMANS:
High Biological Activity Produce Vary Degrees Of Physiological
and Psychological Responses – Largely by interfering with Neurotransmitter
In large doses- highly toxic – fatal In small doses – many have therapeutic
value
Muscle relaxant, Pain killers, tranquilizers, Mind altering drugs, Chemotherapy
Physical Properties:
I- Condition:• Most alkaloids are crystalline solids. • Few alkaloids are amorphous solids e.g. emetine.
• Some are liquids that are either: Volatile e.g. nicotine and coniine, or Non-volatile e.g. pilocarpine and hyoscine.
II- Color:The majority of alkaloids are colorless but some are
colored e.g.:• Colchicine and berberine are yellow. • Canadine is orange.
• The salts of sanguinarine are copper-red.
Physical Properties:
III- Solubility: Both alkaloidal bases and their salts are soluble in
alcohol. Generally, the bases are soluble in organic solvents and
insoluble in water Exceptions: Bases soluble in water: caffeine, ephedrine, codeine,
colchicine, pilocarpine and quaternary ammonium bases. Bases insoluble or sparingly soluble in certain organic
solvents: morphine in ether, theobromine and theophylline in benzene.
Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents.
Chemical Properties:I- Nitrogen: Primary amines R-NH2 e.g.
Norephedrine
Secondary amines R2-NH e.g. Ephedrine
Tertiary amines R3-N e.g. Atropine
II- Basicity: R2-NH > R-NH2 > R3-N
According to basicity Alkaloids are classified into:
Weak bases e.g. Caffeine
Strong bases e.g. Atropine
Neutral alkaloids e.g. Colchicine
III- Oxygen: Most alkaloids contain Oxygen and are solid in nature e.g.
Atropine.
Some alkaloids are free from Oxygen and are mostly liquids e.g. Nicotine, Coniine.
Effect of heat:
Alkaloids are decomposed by heat, except Strychnine and caffeine.
Reaction with acids:
1- Salt formation.
2- Dilute acids hydrolyze Ester Alkaloids e.g. Atropine
IV- Stability:
COOH
R-CHNH2 R-CH2NH2 RN=CH RNH-CH-R’ CH2R’’ Schiff Base Alkaloid
COOH Transamination R’-CHO
R’-CHNH2 -CO2
Alkaloid Biosynthesis
Mannich Condensation
H-C-H R”carbonion
Amino Acids Schiff Base Alkaloid
-H2OCO2
Isolation of Alkaloids
• Process remained unchanged >1,000 years
Plant Material
Acid solutionEtOAc: neutral/weakly basic alkaloids
1) Methanol2) Concentrate3) Partition EtOAc/2% acid
Petroleum ether extracts non-polar fats and waxes
Residue: polar material
Wash with petroleum ether
Basic aqueous solution of quaternary alkaloids
1) Ammonia2) Partition with EtOAcEtOAc: basic alkaloids
Purification of Alkaloids
• Gradient pH as alkaloids are basic• Volatile alkaloids: distillation• Crystallisation
• Fractional or acid/base pair
• Chromatography• HPLC, GC, TLC and CC
Precursors of Alkaloids:Alkaloids
OrnithineTropane
Pyrrolidine
Pyrrolizidine
Tyrosine
Benzyl-iso-Quiniline
Tryptophan
Indole Quinoline
Lysine
Quinolizidine Piperidine
N
N
CH3
nicotine
from ornithine
N
O
N
O
strychnine
from tryptophan
O
HO
NCH3
HO
morphine
fromtyrosine
N OH
H3C
Lycopodine
from lysine
TRUE ALKOLOIDS
True alkoloids derived from amino acids Heterocyclic ring with nitrogen Highly reactive substances in low doses
also Bitter taste with white appeareance Form water soluble salts
examples: cocaine,morphine,nicotine,dopamine etc.
NICOTINE
Nicotine is a potent
parasympathomimetic
alkaloid found in the
nightshade family of plants (Solanaceae) and a stimulant drug .
It is made in the roots of and accumulates in the leaves of the nightshade family of plants.
Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form.
nicotine forms salts with acids that are usually solid and water soluble.
Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory (−)-nicotine. The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.
CHEMISTRY
Initially causes nausea and vomiting by stimulating vomiting center in brain stem and sensory endings in stomach. This becomes tolerant.
Stimulates hypothalamus to produce antidiuretic hormone, causing fluid retention.
Reduces activity coming in from muscles, producing relaxation.
Increases heart rate, blood pressure and contractility; but carbon monoxide in smoke combines with oxygen better than hemoglobin, so it decreases oxygen carrying capacity (suffocates cells).
PHARMACOLOGICAL EFFECTS
Nicotine is quickly and thoroughly distributed in the body, to brain, placenta, all body fluids (including breast milk).
Liver metabolizes 80–90 percent before excretion by kidneys. Elimination half-life is ~2 hours. The major metabolite of nicotine is cotinine, which is
basis for tests.
Uses: The primary therapeutic use of nicotine is in
treating nicotine dependence in order to eliminate smoking with the damage it does to health.
Nicotine medicines release a sufficient amount of nicotine into the body to help stop your craving to smoke
Believe it!
smoking (almost certainly due to nicotine) reduces risk of Parkinson’s disease reduces risk of Alzheimers
schizophrenics on neuroleptics smoke in very large numbers – why?
nicotine also can be neuroprotective (against ETOH WD neurotoxicity for example) suppress certain autoimmune diseases
Doses: In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), it stimulant
the nicotinic receptor(cholinergic), while high amounts (50–100 mg) can be harmful and blocks the receptors.
Side effects: Feeling sick (nausea)
Being sick (vomiting)
Indigestion (dyspepsia)
Headache
Dizziness
Dry mouth
Increase in saliva in the mouth
Throat irritation
Cough
Rash
Swelling (oedema)
Nasal irritation
Nose bleeds (epistaxis)
Nasal irritation
Watery eyes
Feeling thirsty
Stomach discomfort
Ear sensations
Inflammation of the blood vessels (vasculitis)
Nightmares
Chest pain
Shortness of breath (dyspnoea)
Sweating
MORPHINE Morphine is the most abundant opiate
found in opium, the dried latex extracted by shallowly scoring the unripe seedpods of the Papaver somniferum poppy. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium.
Morphine is an opioid analgesic drug. Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physiologicaldependence may take several months to develop.
Morphine was first isolated in 1804 by Friedrich Sertürner, which is generally believed to be the first ever isolation of a natural plant alkaloid in history.
Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus (Greek: Μορφεύς), for its tendency to cause sleep
CHEMISTRY Morphine is a benzylisoquinoline alkaloid with two
additional ring closures. It has:
A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturatedcyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility.
Two hydroxyl functional groups: a C3-phenolic OH (pKa 9.9) and a C6-allylic OH
An ether linkage between C4 and C5,
Unsaturation between C7 and C8,
A basic, 3o-amine function at position 17,
5 centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action.
USES
Relief of pain caused by heart attack or myocardial infarction.
Relief of the severe bone and joint pain associated with sickle cell crisis.
Pain relief before, during and after surgery.
General anesthsia to sedate a patient. A cough suppressant in cases where
cough is severe enough.
MECHANISM OF ACTION
Opioid receptors
As morphine binds to opioid receptors, molecular signalling activates the receptors to mediate certain actions.
There are three important classes of opioid receptors and these are:
μ receptor or Mu receptors - There are three subtypes of this receptor, the μ1, μ2 and μ3 receptors. Present in the brainstem and the thalamus, activation of these receptors can result in pain relief, sedation and euphoria as well as respiratory depression, constipation and physical dependence.
κ receptor or kappa receptor - This receptor is present in the limbic system, part of the forebrain called the diencephalon, the brain stem and spinal cord. Activation of this receptor causes pain relief, sedation, loss of breath and dependence.
δ receptor or delta - This receptor is widely distributed in the brain and also present in the spinal cord and digestive tract. Stimulation of this receptor leads to analgesic as well as antidepressant effects but may also cause respiratory depression.
ADR
dizziness drowsiness nausea vomiting stomach pain and
cramps diarrhea loss of appetite weight loss
dry mouth sweating weakness headache agitation nervousness mood changes confusion
1. ADRENALINEGeneral Characteristics Features:
• Have no nitrogen as part of heterocyclic ring
• Derived from amino acids like Phenylalanine, Tyrosine
• Physiologically active compounds
• Examples: Adrenaline, Ephedrine, Colchicines, Mescaline
SHIKIMATE PATHWAY
Shikimic Acid
Chorismic Acid
Prephenic Acid
Phenylalanine
TyrosineProto-AlkaloidsE.g. Ephedrine, Epinephrine etc.
ADRENALINE (Epinephrine)
Adrenaline is a hormone and a neurotransmitter• As a hormone it is synthesized by adrenal medulla of kidney
• As a neurotransmitter it is released by some sympathetic nerve endings.
CHEMICAL STRUCTURE
Adrenaline is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine
(R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-
1,2-diol
“Fight” OR “Flight”
Response of ADRENALIN
E
Blood flow to skeletal muscles
increases
Intestinal muscle relax
Breathing rate
increases
Heart rate
increases
Pupil dilate
Blood pressure
in arteries
increases
Blood sugar level
increases
EphedrineA phenethylamine found in EPHEDRA SINICA. PSEUDOEPHEDRINE is an isomer. It is an alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used for asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression.
Chemical properties of EphedrineChemical Names Ephedrine,
2-(methylamino)-1-phenylpropan-1-ol; Benzyl alcohol, alpha (1-methylaminoethyl)
Formula: C10H15NO
Molecular Weight 165.2322 g/mol
Boiling Point 260 deg C at 745 mm Hg
Melting Point 38.1 deg C
Solubility In water, 56,900 mg/L at 25 deg C ; 63,600 mg/L at 30 deg Celcius
Density 1.0085 g/cu cm at 22 deg C
Chemistry of EphedrineEphedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomer. By convention, the pair of enantiomers with the stereochemistry (1R, 2S and 1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R and 1S,2S) is called pseudoephedrine. Ephedrine is a substitute amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH).
SAR Ephedrine and pseudo ephedrine are the diastereomers Among the optical isomers of ephedrine and pseudo ephedrine only D(-) ephedrine can significantly block the adrenergic receptors there by lowering blood pressure.
04/15/2023Stucture-activity relationship
On R1 -substitution on Amino Nitrogen= CH3 (the activity of both alpha and beta receptor is maximal when R1 is Methyl.)
On R2- Substitution alpha to basic Nitrogen to Carbon 2 = CH3 (such substitution slows metabolism by MAO but has little over all effect on duration
of action)
On R3- Substitution on Aromatic Ring = H, (provides excellent receptor activity on both alpha and beta receptor)
Receptor Activity= on alpha and beta adrenergic receptors
ephedrine is less polar than the other compounds, and crosses the
blood brain barrier far better than the catecholamine do.
Because of its ability to penetrate the CNS, ephedrine has been used as a stimulant, and exhibits side effects
related to its actions in the brain.
Mechanism of Action
Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its direct and indirect actions on the adrenergic receptor
system, which is part of the sympathetic nervous system. Ephedrine increases post-synaptic
noradrenergic receptor activity by (weakly) directly activating post-synaptic α-receptors and β-
receptors, but the bulk of its effect comes from the pre-synaptic neuron being unable to distinguish between real adrenaline or nor adrenaline from
ephedrine.
Uses
Diseases of the respiratory tract with mild bronchospasms in adults and children over the age of six.
Spinal anesthetics during delivery
Used for breathing problems, asthma and nasal swelling/congestion caused by a cold or allergies.
Ephedrine is the active ingredient in ephedra or huang. It belongs to a class
of medications called sympathomimetics. It works like a naturally occurring
substance (adrenaline) that your body makes when it thinks it is in danger. It is a central nervous system stimulant that
increases your heart rate/blood pressure, narrows your blood vessels
(vasoconstriction), and opens up the lungs (bronchodilation).
Side effects
Nervousness Headache
ConfusionDeliriumhallucination, Pallorhypertension tachycardia, Palpitation Sweating, vomiting Anorexia
Restlessness Anxiety Tension Tremor Weakness Dizziness Vertigo
Nervous system
Nervous system side effects associated with large doses of ephedrine have included nervousness, insomnia, vertigo, and headache.
Cardiovascular
Cardiovascular side effects associated with large doses of ephedrine have included tachycardia and palpitation. Hypertension, stroke, and myocardial infarction.
Gastrointestinal
Gastrointestinal side effects have included nausea, vomiting, and anorexia.
Genitourinary
Urinary retention has mainly been reported in male patients with prostatism.
Genitourinary side effects have included dysuria and urinary retention.
Psychiatric
Psychiatric side effects associated with prolonged abuse of ephedrine have included symptoms of paranoid schizophrenia. Suicide and psychotic episodes have also been reported.
Caffeine:
“Anger - a better alternative to caffeine.” ― Ilona Andrews, Magic Rises
INTRODUCTION
Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid that occurs naturally in coffee beans .Caffeine is an alkaloid from methylxanthines called 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6,-dione or 1,3,7-trimethylxanthine.Some physiological effects associated with caffeine administration include central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, and diuresis.Caffeine is rapidly and almost completely absorbed in the stomach and small intestine and distributed to all tissues, including the brain.It is found in varying quantities in the seeds, leaves fruits of some plants, where it act as a natural pesticide.Beverage containing coffee such as coffee, tea soft drinks, & energy drinks.
HISTORY 1st use of caffeine as early as 600,000 BCE .
1820 - Caffeine was first isolated from coffee by German chemist Friedlieb Ferdinand Runge,.
1821 - . Pelletier coined the term "caffeine" from the French word for coffee (café), and this term became the English word "caffeine".
1821 - Pure caffeine extracted from coffee.
1880 - Caffeinated soft drinks appear.
1903 - Researchers remove caffeine from beans ‘without destroying the flavor’.
1923 - Decaffeinated coffee is introduced to the United States.
1940 - The US imports 70 percent of the world coffee crop.
1962 - American per-capita coffee consumption peaks at more than three cups a day.
1995 - Coffee becomes the worlds most popular beverage (overtaking tea ) .
Coffee contain caffeine and theophylline
Theophylline is a dimethylxanthines that have two rather than three methyl groups 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine,
Is considerably weaker than caffeine and having about one tenth the stimulating effect of either. It has a stronger effect on the heart and breathing than caffeine. For this reason it is often the drug of choice in home remedies for treating asthma bronchitis and emphysema. The theophylline found in medicine is made from extracts from coffee or tea.
Why do people become addicted to caffeine?
A person who drinks 1 cup of coffee a day over seven days will build a tolerance to this amount of caffeine. This person will have to consume 2 cups of coffee to feel the same effects as before but again will build a tolerance to that amount of caffeine. Over time this cycle will lead to an addiction to caffeine and will have negative side effects on the body.
Caffeine as a Drug
The behavioral effects of caffeine can be characterized principally as a reduction in fatigue and boredom, as well as a delay in the onset of sleep.
Recent evidence suggests that caffeine might lower the risk of developing Parkinson’s disease in men.
A comparable protective role in women is currently uncertain.
© Copyright 2011, Pearson Education, Inc. All rights reserved.
Caffeine as a Drug
Health risks from moderate consumption of caffeine are not clinically significant, except for the adverse effects on fetal development during pregnancy, the development of bone loss among the elderly, a possible adverse effect on the cardiac condition of patients already suffering from cardiovascular disease, and the aggravation of panic attacks among patients with this disorder. © Copyright
2011, Pearson Education, Inc. All rights reserved.
Mechanism of Action
Caffeine's primary mechanism of action is as an
antagonist of adenosine receptors in the brain.
Adenosine in the Brain
In the brain neurons are transmitting electrical energy.
When activity is too high adenosine molecules stop the neuron cells from firing.
Caffeine blocks adenosine receptors with its own molecule preventing the adenosine molecule from binding.Brain activity remains at its excited state and can even increase in activity because adenosine is unable to slow it down.
The binding of Adenosine to an adenosine receptor causes the receptor to undergo a shape change which triggers a biochemical cascade. The end result is the opening of ion channels and the slowing of activity.
The binding of caffeine to a adenosine receptor causes a shape change that does not initiate a biochemical cascade. Instead, neuronal activity remains the same or increase.
Adenosine Caffeine
Adenosine Receptor
Adenosine Receptor
Caffeine Extraction Processes
Super critical Fluid Extraction Microwave-assisted extraction ultrasonic extraction heat reflux extraction
Health Benefits of Caffeine
Caffeine helps ward off Alzheimer’s. In Japan researchers have shown that caffeine
increases memory. Caffeine detoxes the liver and cleanses the
colon when taken as a caffeine enema. Caffeine can stimulate hair growth on balding
men and women. Caffeine relieves post work-out muscle pain
by up to 48%. Caffeine can ease depression by increasing
dopamine in the brain.
Caffeine increases stamina during exercise. Caffeine protects against eyelid spasm. Caffeine may protect against Cataracts. Caffeine may prevent skin cancer. A new
study out of Rutgers University found that caffeine prevented skin cancer in hairless mice.
People who consume caffeine have a lower risk of suicide.
Caffeine may reduce fatty liver in those with non-alcohol related fatty liver disease. This study comes out of Duke University.
Negative Side Effects of Caffeine
Effects on Heart Rate and Blood Pressure
Osteoporosis Diabetes Loss of sleep Fertility and miscarriage Hormonal Effects
Caffeine products
Scitec Caffeine capsuleAlpecin Caffeine Shampoo
Plantur 39 Caffeine Tonic
Alert energy caffeine gum
Nestle Nescafe gold coffee
Cocacola Beverage
Awake caffeinated chocolate
Decaffeinated products
Nescafe decaf coffeeTassimo nabob decaf coffee
Zevia caffeine free cola
Twinings pure green tea
Conclusion
The good and bad of caffeine
Caffeine is part of modern life. Regular coffee drinkers include the majority of adults and a growing number of children. The recommendation for most people is to enjoy one or two cups of coffee a day, which will allow you to capitalize on its health benefits without incurring health drawbacks. Extensive recent research has put forth that coffee is far more healthful than it is harmful. Very little bad and a lot of good come from drinking it.
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Gary W. Arendasha,b,∗ and Chuanhai Caob,c. 2010. “Caffeine and Coffee as Therapeutics Against Alzheimer’s Disease” Journal of Alzheimer’s Disease 20 S117–S126
Greenland, S. 1993. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology., 4:366–374.
Hammar, N., Andersson, T., Alfredsson, L. et al. 2003. Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study. J. Intern. Med., 253:653–659.
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Higdon, Jane V., And Frei, Balz., 2006. ” Coffee and Health: A Reviewof Recent Human Research”. Critical Reviews in Food Science and Nutrition, 46:101–123
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James, J.E. 2004. Critical review of dietary caffeine and blood pressure:A relationship that should be taken more seriously. Psychosom. Med.,66:63–71.
Kawachi, I., Colditz, G. A., and Stone, C. B. 1994. Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br. Heart J., 72:269–275.
Kuffler SW, Edwards C (November 1958). "Mechanism of gamma aminobutyric acid (GABA) action and its relation to synaptic inhibition". J. Neurophysiol. 21 (6): 589–610. PMID 13599049.
Mukamal, K.J., Maclure, M., and Muller, J.E., 2004. Caffeinated coffee consumption and mortality after acute myocardial infarction. Am. Heart J., 147:999–1004.
Spiller, M.A. 1998. The Chemical Components of Coffee. In: Caffeine.pp. 97–161. Spiller, G. A., Ed., CRC Press, Boca Raton.
Tavani, A., Bertuzzi, M., Negri, E. et al. 2001. Alcohol, smoking, coffee and risk of non-fatal acute myocardial infarction in Italy. Eur. J. Epidemiol., 17:1131–1137
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