Tranquilizer Rescinnamine

Lysergic acid

Three main groups of ergot alkaloids exist:

1. The clavine type, a group of over 20 alkaloids, which is water insoluble and does not give lysergic acid on hydrolysis. This group includes elymoclavine, agroclavine (a potent uterine stimulant), and chanoclavine-I.

2. The aqueous lysergic acid derivatives such as ergo-novine, which in its maleate salt (or as methyl ergonovine maleate) is the drug of choice to treat postpartum hemorrhage.

3. The peptide ergot alkaloids, a group of water insoluble lysergic acid derivatives. This group includes ergot-amine, ergocornine, and ergocryptine. Ergotoxine, a mixture of three peptide ergot alkaloids, possesses strong sympatholytic action and is used as a peripheral vasodilator and antihypertensive. Dihydroergotoxine is used for vascular disorders in the aged.

Some ergot alkaloids (eg, 2-bromo-a-ergocryptine) stimulate prolactin release and are being evaluated for treatment of breast cancer.

Catharanthus and Vinca Alkaloids

Catharanthus and Vinca alkaloids, usually discussed together, are quite distinct. The most important alkaloids of the Catharanthus genus are vincaleukoblastine, leurocris-tine, and leurosine, all antileukemic agents. Vincaleukoblastine and leurocristine are used clinically. The most important alkaloid of Vinca is vincamine, used to treat hypertension, angina, and migraine headaches. Alkaloids of this type produce marked hypotensive effects and curare-like action. The ethers of vincaminol are potent muscle relaxants.

Rauwolfia

Rauwolfia alkaloids include reserpine, the first tranquilizer, rescinnamine, and deserpidine. Reserpine is a sedative and tranquilizer useful in treating hypertension. It is also used as a rodenticide.

Strychnine

Strychnine, from the seeds of many Strychnos species, is a widely known poison (although, in fact, it is only moderately toxic). Pharmacologically, strychnine excites all portions of the CNS; it is a powerful convulsant and death results from asphyxia. It has no therapeutic uses in Western medicine, although its nitrate is used in treating chronic aplastic anemia.

Cinchona Alkaloids

Cinchona alkaloids, derived from the dried stem or root bark of various Cinchona species, include quinine and quinidine. These alkaloids are bitter tasting white crystalline solids, sparingly soluble in water. Quinine is toxic to many bacteria and other unicellular organisms and was the only specific antimalarial remedy until the Second World War. It is a local anesthetic of considerable duration. Quinine is commonly used as the sulfate and dihydro-chloride. Quinidine, produced by the isomerization of quinine or found in Cuprea bark, is more effective on cardiac muscle than quinine and is used to prevent or abolish certain cardiac arrhythmias.

Camptothecine

Camptothecine, isolated from the Chinese tree Campto-theca acuminata Decsne, is used to treat cancer in the People's Republic of China.

Histidine-Derived Alkaloids

Histidine-derived alkaloids include pilocarpine and saxi-toxin. Pilocarpine stimulates parasympathetic nerve endings and is used to treat glaucoma. The main commercial source of pilocarpine is Pilocarpus microphyllus Stapf., known as Marnham jaborandi. Saxitoxin is an extremely toxic neuromuscular blocking agent found in the so-called coastal red tides of North America.

Monoterpenoid Alkaloids

Monoterpenoid alkaloids include chaksine, a guanidine alkaloid from Cassia lispikula Vahl, which induces respiratory paralysis in mice; /i-sky tan thine, which is tremori-genic; cantleyine, derived from a monoterpene before loganin; and those derived from secologanin, such as gen-tianine, which exhibits hypotensive, anti-inflammatory, and muscle-relaxant actions, gentioflavine, gentiatibetine, pedicularine, and actinidine, a potent feline attractant.

Diterpene Alkaloids

Diterpene alkaloids are not of commercial or therapeutic significance, but some have potent pharmacological activity, eg, aconitine and Erythrophleum alkaloids.

Steroidal and Triterpene Alkaloids

Steroidal and triterpene alkaloids are found in the plant families Solanaceae, Liliaceae, Apocynaceae, and Buxa-ceae. There are four main groups based on the botanical source: the Veratrum, Solanum, Holarrhena and Funtu-mia, and Buxus alkaloids.

The Veratrum alkaloids include jervine, protoveratrine A, and protoveratrine B; the latter two produce pronounced bradycardia and a fall of blood pressure by stimulation of vagal afferents. The Solanum alkaloids are of interest as potential sources of steroids. Examples of these alkaloids are tomatidine and solanidine. Some Solanum alkaloids exhibit fungistatic activity. Biosynthetically, the alkaloids are derived from acetate and mevalonate.

Alkaloid(s); identified or potential food sources Clinical effects

Toxic symptoms

Amatoxins (a-, /?-, -/-amanitins, amanin, amanullin); toxic mushrooms [Death Cup CAmanita phalloides, A. verna, A, virosa)] Liver and kidney damage (man)

Delayed vomiting, abdominal pain and diarrhea, coma, death; LDa (man, oral) = 0.11 mg/kg Arecoline; Areca nut or Betal nut (Areca catechu)

Parasympathomimetic agent, cathartic (horses); cholinergic (man)

Flushing, perspiration, bronchial spasms, contraction of pupils, diarrhea, dyspnea, and collapse; LD° (mouse, subcutaneous) = 102 mg/kg Caffeine; coffee, tea, cola nuts, guarana

Cardiac, respiratory, and psychic stimulation, diuresis; vascular cephalalgesia (man)

Nausea, restlessness, vomiting, insomnia, tremors, tachycardia, cardiac arrhythmia (man); LD50A (rat, oral) = 19.6 mg/kg Capsaicine; red peppers Skin irritant

Sweating, salivation (mammals) Carapine; papaya (Carica papaya) CNS depression (mammals) Bradycardia (mammals) Caulerpicin; marine algae (Caulerpa sertulariodes C. racemosa var. clavifera) Anesthesia (mammals)

Numbness of lips and tongue (man) Chavicine; black and white pepper (Piper nigrum) Sharp peppery taste (man) No information

Choline; brain, egg yolk, bivalve mollusks (Callista brevisiphonata), areca nut Lipotrophic agent, antihypercholesterolemic agent

Nausea, vomiting, diarrhea (man); LDa (rabbit, subcutaneous) = 450 mg/kg Convicine; fava bean (Vicia sativa or V. fava)

Inhibition of glucose-6-phosphate dehydrogenase, decreased or reduced glutathione levels in red blood cells Hemolysis, growth retardation (rat), hemoglobinemia (dog) Curry alkaloids (murrayanine, mukoeic acid, girinimbine murrayacine, koenimbine, koenine, koeniginine, koenigine, mahanimbine, Cyclomahanimbine, curryanine); curry plant (Murraya koenigii Spreng) For skin eruptions No information

Cystisine; milk [contaminated from Cystisus laburnum, Sophora secundiflora (mountain laurel) No information

Excitement, sweating, incoordination, convulsion, death (man, pig, cattle, horse); LDa (as nitrate, dog, subcutaneous) = 4.3 mg/kg

3,4-Dihydroxy-L-phenylalanine (DOPA); fava bean (Vicia fava) Decrease in reduced glutathione in red blood cells (man) No information Dopamine; banana, avocado, cephalopods

Hypertensive agent, increased cardiac output No information Dioscorine; wild yam (Dioscorea hirsutus, D. hispida) CNS stimulation: analeptic, diuretic, expectorant

Sialorrhea, nausea, vomiting, diarrhea, confusion, cold sweat, pallor, clonic convulsion, paralysis, asphyxia (man), emetic hemolytic agent; LDa (mouse, intraperitoneal) = 130 mg/kg Eptatretin; Pacific hagfish (Polistotrena stouti) Cardiac stimulant (frog, dog)

None, due to rapid detoxication

Ergot alkaloids (Eorgonovine, ergotamine, ergosine, ergocristine, ergocyptine, ergocornine, ergosinine, ergocristinine, etc); Barley, rye (contaminated from ergot produced by the fungi Claviceps paspali and C. pupurea) Uterine stimulation, analgesic for migraine headache

Tachycardia, hypertension, vomiting, diarrhea, mental confusion, hallucinations, convulsions, gangrene, gastrointestinal (GI) disturbance; LD" ergotamine, rat, intravenous) = 60 mg/kg Gelsemine; Honey [contaminated from yellow jasmine] (Gelsemium sempervirens) nectar] Uterine stimulation, CNS stimulant

Dizziness, dimness of vision, mydriasis, nausea, muscular debility, unusual prostration, weak pulse, dyspnea (man); minimum LD (rabbit, subcutaneous) = 0.15 mg/kg Glucobrassicin; broccoli, brussels sprouts, cabbage, cauliflower, kohlrabi, radish, rutabaga Goitrogenesis (rabbit, rat)

Hyperplasia of the thyroid; kidney and liver enlargement (rabbit, rat)

Alkaloid(s); identified or potential food sources Clinical effects

Toxic symptoms

Goitrin; cabbage, rape, rutabaga Goitrogenesis (rat)

Hyperplasia of thyroid, liver and kidney enlargement (rat) Gramine; barley (Hordeum vulgare)

Vasoactivity, stimulation of intestines and uterus (rabbit)

Hypertension, clonic convulsion, and excitation of respiratory center Histamine; derived from beer, chocolate, fish, sauerkraut, wine, and yeasts Vasoactivity (mammals)

Headache (man), hypotension (man, mammals); LD506 (mouse, intraperitoneal) = 12.7 g/kg, LDa (monkey, intravenous) = 52 mg/kg

Hordenine; germinated barley (Hordeum vulgare), sorghum (Sorghum vulgare), millet (Panicum miliaceum) Sympathomimetic intestinal stimulation, respiratory stimulation (cat, dog); uterine stimulation (guinea pig)

Hypertension (man, dog), psychostimulation, convulsion, respiratory inhibition (man), LD° (as sulfate, dog, oral) = 1.9 g/kg Islanditoxin; rice (contaminated from Pénicillium islandicum) Carcinogenic hepatotoxin (mouse)

Liver damage, liver cancer (mouse, rat); LD506 (mouse, oral) = 5.0 mg/10 g Laminine; marine algae (Laminaria spp) and others

Hypotension (rabbit); depression of contraction of smooth muscles (mouse, guinea pig) Hypotension (rabbit) Methyl pyrazine (various derivatives); green peas (Pisum sativum) No information No information Methyl pyrroline; black pepper (Piper nigrum) No information No information Mimosine; Leucaena glauca No information

Alopecia (mammals) Murexine (urocanyl choline); shellfish (Muricidae spp.)

Excitation of respiratory center, neuromuscular blocking, muscle relaxation (vertebrates and invertebrates)

Muscular and respiratory paralysis (vertebrates and invertebrates); LD100 (as oxalate, mouse, subcutaneous) = 310 mg/kg Muscaridine; mushroom fly agaric (Amanita muscaria) Uterine stimulation (rabbit, guinea pig)

Hashish or alcohol-like intoxication (man) Muscarine; mushroom fly agaric (Amanita muscaria and other mushrooms) Uterine stimulation (rabbit, guinea pig)

Sialorrhea, lacrimation, diaphoresis, nausea, vomiting, bradycardia, convulsions, coma, death; LD10o (mouse) = 16 //g/day Nicotine; tomato

Respiratory stimulation (man); uterine stimulation (cat, rabbit, pig); cerebral and visceral ganglial stimulation (man)

Hypotension (dog); respiratory depression and paralysis (cat); hyperglycemia, convulsion, dizziness, nausea (man), etc; LD (man, oral) = 40 mg/70 kg; LD506 (rat, oral) = 60 mg/kg Norepinephrine; banana (particularly the pulp), orange (trace), potato Vasoactivity sympathomimetic, adrenergic Hypertension

Pahutoxin; fishes [Hawaiian boxfish (Pahu), Ostraciontidae family] Neuromuscular effects (mammals)

Hemolysis (mammals); ataxia, respiratory distress, coma (mouse); minimum LD" (mouse, intraperitoneal) = 0.25 mg/g Phallotoxins (phalloidin, phalloin, phallisin, phallicidin); toxic mushrooms [Death Cup, (Amanita phalloides, A verna, A virosa)] Liver and kidney damage (man)

Vomiting, abdominal pain, diarrhea, coma, and death (man); LD (man, oral) = 3 mg/kg /Î-Phenylethylamine; Mushrooms, bitter almonds

Respiratory stimulation, intestinal relaxation, symphatomimetic (man)

Hyperventilation, hypertension, hypotension (cat); LD50 (mouse, intraperitoneal) = 350 mg/kg Piperine; black pepper (Piper nigrum) No information No information

Pyrrolizidine alkaloids; wheat and other cereals, legume (contaminated from Crotalaria laburnifolia, C. striata) No information

Liver damage, carcinogenesis, venoocclusive disease (mammals); glaucoma (rat, mouse); LD^' (mouse) = 20 mg/kg Sanguinarine; mustard oil and cereal grains (contaminated from Argemone mexicana) Expectorant; for chronic eczema and skin cancers

LD° (as sulfate, intraperitoneal, rat) = 450 mg/kg

Alkaloid(s); identified or potential food sources Clinical effects

Toxic symptoms

Saxitoxin; shellfish, bivalve mollusks, and other pelecypods (contaminated from the dinoflagellates Gonyaulax catenella and G. tamarensis)

Neural stimulation (mammals); hypotension (cat and rabbit); myocardial and respiratory depression (mammals)

Peripheral paralysis, tingling and numbness of hps, respiratory failure (man and other mammals); LD506 (man, oral) = 10-20 /<g/kg

Serotonine; avocado, banana, pineapple, octopus, papaya, plantain, passion fruit, red plum tomato Respiratory stimulation (dog); respiratory inhibition (cat)

Hypertension (man); CNS depression (most animals); inhibition of ovulation (rabbit); teratogenesis (mouse) Solanine (solanidine); Irish potato (Solanum tuberosum), tomato (Lycopersicon esculentum) Acetylcholine esterase inhibition (mammals)

Drowsiness, hyperesthesia, dyspnea, vomiting, diarrhea (man); LD° (rabbit, intravenous) = 25 mg/kg Tetrodotoxin; Pufferfish (Tetradontidae and Diodontidae families)

Neuromuscular blocking (mammals); hypotension (cat); respiratory inhibition, hypothermia (dog)

Weakness, dizziness, pallor and paresthesia, nausea, vomiting, sweating, salivation, muscular paralysis, cyanosis, respiratory paralysis, death (man); minimum LD (cat, subcutaneous) =11 mg/kg; LD506 (mouse, oral) = 325 mg/kg Tetramine; shellfish (Buccinidae and Cymatidae families)

Curare-like effects, hypotension, bradycardia (mammals, frog)

Salivation, lacrimation, miosis, peristalsis (mouse); motor paralysis (mammals) Threobromine; cacao bean; cola nuts; tea

Diuresis, myocardial stimulation, vasodilation, respiratory stimulation (cat) GI distress; LD506 (cat, oral) = 220 mg/kg Theophylline; tea

Diuresis, hypertensive cephaloanalgesia (man)

Nausea and vomiting, vertigo, insomnia, flushing, convulsions, death; LD50'' (mouse, oral) = 550 mg/kg Tomatine; tomato juice No information

Toxoflavin; Indonesian bongkrek (contaminated from Pseudomonas cocovenenans) No information

LD506 (mouse, oral) = 800 mg/kg LD506 (mouse, intravenous) = 2.0 mg/kg Trigonelline; green peas (Pisum sativum), coffee, soybeans, potatoes No information

LD6 (rat, subcutaneous) = 4.9 g/kg Tryptamine; plum (red and blue), orange, tomato

Vasoactivity, musculotropic (rabbit); intestinal and uterine contraction (rabbit, guinea pig) Hypertension, headache (man) Tyramine; avocado, banana, octopus, orange, spinach, potato, tomato Respiratory stimulation (rat, cat); vasoconstriction (mammals)

Paroxysmal hypertension, intracerebral hemorrhage (man); mydriasis, bradycardia (dog); hypothermia (cat); LD (rabbit, intravenous) = 250 mg/kg Vicine; fava bean (Vicia sativa or V. fava)

Inhibition of glucose-6-phosphate of dehydrogenase; decrease in reduced glutathione Hemolysis, growth retardation (rat); hemoglobinemia (dog)

Source: Ref. 1; see also reference under S. W. Pettetier.

6LD50 = median lethal dose.

Purine Alkaloids

Purine alkaloids are derivatives of the xanthine nucleus and include caffeine, theophylline, and theobromine, the principal constituents of plants used throughout the world as stimulating beverages.

Caffeine has the structure 1,3,7-trimethylxanthine. It is derived from cola, coffee (qv), tea (qv), guaraña, and maté. Theophylline, 1,3-dimethylxanthine, is found in tea. Theobromine, 3,7-dimethylxanthine, is found in cocoa and tea. The xanthine derivatives have pharmacological properties in common: central nervous system (CNS) and respiratory stimulation; skeletal-muscle stimulation; diuresis; cardiac stimulation; and smooth-muscle relaxation. Caffeine is used to increase CNS activity; it acts on the cortex to produce clear thought and to reduce drowsiness and fatigue. Theophylline is used in smooth-muscle relaxants. Theophylline, as the ethylenediamine salt, is used in preference to caffeine in cardiac edema and in angina pectoris.

Miscellaneous Alkaloids

Coniine is an extremely toxic alkaloid that induces paralysis of the motor nerve endings and is the primary toxic constituent of poison hemlock. It was the first alkaloid to be synthesized. Carpaine, a crystalline macrocyclic alkaloid that induces bradycardia, depresses the CNS and is a potent amoebicide. Alkaloids are found in the poisonous Amanita species of mushrooms, such as a- and /i-amanita toxins, ibotenic acid, muscimol, and muscazone. Maytan-sine and related ansamacrolides are potent antileukemic agents. Surugatoxin, found in the carnivorous gastropod Babylonia japonica, produces a pronounced mydriatic effect, sometimes resulting in death.

Ingestion and Human Health

The effects of natural alkaloids on humans and animals vary. This article is concerned mainly with food alkaloids and their clinical effects when ingested intentionally or accidentally. Table 1 summarizes the information.

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