(1999; 295 pages)
Bulbus Allii Sativi
Bulbus Allii Sativi consists of the fresh or dried bulbs of Allium sativum L. (Liliaceae) (1, 2).
Porvium sativum Rehb. (1, 3).
Selected vernacular names
It is most commonly known as "garlic". Ail, ail commun, ajo, akashneem, allium, alubosa elewe, ayo-ishi, ayu, banlasun, camphor of the poor, dai tóan, dasuan, dawang, dra thiam, foom, Gartenlauch, hom khaao, hom kía, hom thiam, hua thiam, kesumphin, kitunguu-sumu, Knoblauch, kra thiam, krathiam, krathiam cheen, krathiam khaao, l'ail, lahsun, lai, lashun, lasan, lasun, lasuna, Lauch, lay, layi, lehsun, lesun, lobha, majo, naharu, nectar of the gods, ninniku, pa-se-waa, poor man's treacle, rason, rasonam, rasun, rustic treacles, seer, skordo, sluôn, stinking rose, sudulunu, ta-suam, ta-suan, tafanuwa, tellagada, tellagaddalu, thiam, toi thum, tum, umbi bawang putih, vallaippundu, velluli, vellulli (1–13).
A perennial, erect bulbous herb, 30–60 cm tall, strong smelling when crushed. The underground portion consists of a compound bulb with numerous fibrous rootlets; the bulb gives rise above ground to a number of narrow, keeled, grasslike leaves. The leaf blade is linear, flat, solid, 1.0–2.5cm wide, 30–60 cm long, and has an acute apex. Leaf sheaths form a pseudostem. Inflorescences are umbellate; scape smooth, round, solid, and coiled at first, subtended by membraneous, long-beaked spathe, splitting on one side and remaining attached to umbel. Small bulbils are produced in inflorescences; flowers are variable in number and sometimes absent, seldom open and may wither in bud. Flowers are on slender pedicels; consisting of perianth of 6 segments, about 4–6mm long, pinkish; stamens 6, anthers exserted; ovary superior, 3-locular. Fruit is a small loculicidal capsule. Seeds are seldom if ever produced (8, 9).
Plant material of interest: fresh or dried bulbs
Bulbus Allii Sativi consists of several outer layers of thin sheathing protective leaves which surround an inner sheath. The latter enclose the swollen storage leaves called "cloves". Typically, the bulb possesses a dozen sterile sheathing leaves within which are 6–8 cloves bearing buds making a total of 10–20 cloves and 20–40 well-developed but short and embedded roots. The cloves are asymmetric in shape, except for those near the centre (1).
Odour strong, characteristic alliaceous (1, 6, 8); taste very persistently pungent and acrid (1, 6, 8).
The bulbs show a number of concentric bulblets; each is 5–10mm in diameter and consists of an outer scale, an epidermis enclosing a mesophyll free from chlorophyll, a ground tissue and a layer of lower epidermal cells. Dry scales consist of 2 or 3 layers of rectangular cells having end walls with a broadly angular slant. These cells contain many rhomboid crystals of calcium oxalate. The upper epidermal cells next to the dry scale layer consist of a single layer of rectangular to cubical cells next to which are several layers of large parenchymatous cells. Among these cells are interspaced many vascular bundles, each of which consists of xylem and phloem arranged alternately. Lower epidermis consists of cubical cells which are much smaller than the upper epidermal cells. The same arrangement of tissues is met within different bulblets, 2 or 3 of which are arranged concentrically (1, 6).
Powdered plant material
Pale buff to greyish or purplish white, with characteristic aromatic alliaceous odour and taste. It is characterized by the presence of sclereids of the epidermis of protective leaves, thin epidermis of storage cells, latex tubes, swollen parenchyma cells with granular contents, and lignified narrow spiral and annular vessels (1).
Bulbus Allii Sativi is probably indigenous to Asia (1, 7), but it is commercially cultivated in most countries.
General identity tests
Macroscopic and microscopic examinations and microchemical analysis are used to identify organic sulfur compounds (1), thin-layer chromatographic analysis to determine the presence of alliin (14).
The test for Salmonella spp. in Bulbus Allii Sativi products should be negative. The maximum acceptable limits of other microorganisms are as follows (2, 15, 16). Preparations for internal use: aerobic bacteria-not more than 105/g or ml; fungi-not more than 104/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 103/g or ml; Escherichia coli-0/g or ml.
Not more than 5.0% (2).
Not more than 1.0% (4).
Not less than 5.0% (4).
Not less than 4.0% (4).
Not more than 7% (2).
To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin for Bulbus Allii Sativi is not more than 0.05 mg/kg (2). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (15) and guidelines for predicting dietary intake of pesticide residues (17).
Recommended lead and cadmium levels are no more than 10 and 0.3mg/kg, respectively, in the final dosage form of the plant material (15).
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (15).
Other purity tests
Chemical tests and tests for foreign organic matter to be established in accordance with national requirements.
Qualitative and quantitative assay for sulfur constituents (alliin, allicin etc.) content by means of high-performance liquid chromatography (18–22) or gas chromatography–mass spectroscopy (23) methods.
Major chemical constituents
The most important chemical constituents reported from Bulbus Allii Sativi are the sulfur compounds (7, 9, 24, 25). It has been estimated that cysteine sulfoxides (e.g. alliin ) and the non-volatile γ-glutamylcysteine peptides make up more than 82% of the total sulfur content of garlic (25).
The thiosulfinates (e.g. allicin ), ajoenes (e.g. E-ajoene , Z-ajoene ), vinyldithiins (e.g. 2-vinyl-(4H)-1,3-dithiin , 3-vinyl-(4H)-1,2-dithiin ), and sulfides (e.g. diallyl disulfide , diallyl trisulfide ), however, are not naturally occurring compounds. Rather, they are degradation products from the naturally occurring cysteine sulfoxide, alliin . When the garlic bulb is crushed, minced, or otherwise processed, alliin is released from compartments and interacts with the enzyme alliinase in adjacent vacuoles. Hydrolysis and immediate condensation of the reactive intermediate (allylsulfenic acid) forms allicin . One milligram of alliin is considered to be equivalent to 0.45 mg of allicin (26). Allicin itself is an unstable product and will undergo additional reactions to form other derivatives (e.g. products –), depending on environmental and processing conditions (24–26). Extraction of garlic cloves with ethanol at <0°C gave alliin ; extraction with ethanol and water at 25 °C led to allicin  and no alliin; and steam distillation (100 °C) converted the alliin totally to diallyl sulfides ,  (24, 25). Sulfur chemical profiles of Bulbus Allii Sativi products reflected the processing procedure: bulb, mainly alliin, allicin; dry powder, mainly alliin, allicin; volatile oil, almost entirely diallyl sulfide, diallyl disulfide, diallyl trisul- fide, and diallyl tetrasulfide; oil macerate, mainly 2-vinyl-[4H]-1,3-dithiin, 3- vinyl-[4H]-1,3-dithiin, E-ajoene, and Z-ajoene (18–22, 24). The content of alliin was also affected by processing treatment: whole garlic cloves (fresh) contained 0.25–1.15% alliin, while material carefully dried under mild conditions contained 0.7–1.7% alliin (18–21).
Gamma-glutamylcysteine peptides are not acted on by alliinase. On prolonged storage or during germination, these peptides are acted on by γ-glutamyl transpeptidase to form thiosulfinates (25).
Fresh bulbs, dried powder, volatile oil, oil macerates, juice, aqueous or alcoholic extracts, aged garlic extracts (minced garlic that is incubated in aqueous alcohol (15–20%) for 20 months, then concentrated), and odourless garlic products (garlic products in which the alliinase has been inactivated by cooking; or in which chlorophyll has been added as a deodorant; or aged garlic preparations that have low concentrations of water-soluble sulfur compounds) (18, 24).
The juice is the most unstable dosage form. Alliin and allicin decompose rapidly, and those products must be used promptly (18).
Dried Bulbus Allii Sativi products should be stored in well-closed containers, protected from light, moisture, and elevated temperature.
Uses supported by clinical data
As an adjuvant to dietetic management in the treatment of hyperlipidaemia, and in the prevention of atherosclerotic (age-dependent) vascular changes (5, 27–31). The drug may be useful in the treatment of mild hypertension (11, 28).
Uses described in pharmacopoeias and in traditional systems of medicine
The treatment of respiratory and urinary tract infections, ringworm and rheumatic conditions (1, 4, 7, 9, 11). The herb has been used as a carminative in the treatment of dyspepsia (32).
Uses described in folk medicine, not supported by experimental or clinical data
As an aphrodisiac, antipyretic, diuretic, emmenagogue, expectorant, and sedative, to treat asthma and bronchitis, and to promote hair growth (6, 9, 13).
Bulbus Allii Sativi has a broad range of antibacterial and antifungal activity (13). The essential oil, water, and ethanol extracts, and the juice inhibit the in vitro growth of Bacillus species, Staphylococcus aureus, Shigella sonnei, Erwinia carotovora, Mycobacterium tuberculosis, Escherichia coli, Pasteurella multocida, Proteus species, Streptococcus faecalis, Pseudomonas aeruginosa, Candida species, Cryptococcus species, Rhodotorula rubra, Toruloposis species, Trichosporon pullulans, and Aspergillus niger (33–40). Its antimicrobial activity has been attributed to allicin, one of the active constituents of the drug (41). However, allicin is a relatively unstable and highly reactive compound (37, 42) and may not have antibacterial activity in vivo. Ajoene and diallyl trisulfide also have antibacterial and antifungal activities (43). Garlic has been used in the treatment of roundworm (Ascaris strongyloides) and hookworm (Ancylostoma caninum and Necator americanus) (44, 45). Allicin appears to be the active anthelminthic constituent, and diallyl disulfide was not effective (46).
Fresh garlic, garlic juice, aged garlic extracts, or the volatile oil all lowered cholesterol and plasma lipids, lipid metabolism, and atherogenesis both in vitro and in vivo (18, 43, 47–64). In vitro studies with isolated primary rat hepatocytes and human HepG2 cells have shown that water-soluble garlic extracts inhibited cholesterol biosynthesis in a dose-dependent manner (48–50). Antihypercholesterolaemic and antihyperlipidaemic effects were observed in various animal models (rat, rabbit, chicken, pig) after oral (in feed) or intragastric administration of minced garlic bulbs; water, ethanol, petroleum ether, or methanol extracts; the essential oil; aged garlic extracts and the fixed oil (51–64). Oral administration of allicin to rats during a 2-month period lowered serum and liver levels of total lipids, phospholipids, triglycerides, and total cholesterol (65). Total plasma lipids and cholesterol in rats were reduced after intraperitoneal injection of a mixture of diallyl disulfide and diallyl trisulfide (66). The mechanism of garlic's antihypercholesterolaemic and antihyperlipidaemic activity appears to involve the inhibition of hepatic hydroxymethylglutaryl-CoA (HMG-CoA) reductase and remodelling of plasma lipoproteins and cell membranes (67). At low concentrations (<0.5 mg/ml), garlic extracts inhibited the activity of hepatic HMG-CoA reductase, but at higher concentrations (>0.5 mg/ml) cholesterol biosynthesis was inhibited in the later stages of the biosynthetic pathway (68). Alliin was not effective, but allicin and ajoene both inhibited HMG-CoA reductase in vitro (IC50 = 7 and 9mmol/l respectively) (49). Because both allicin and ajoene are converted to allyl mercaptan in the blood and never reach the liver to affect cholesterol biosynthesis, this mechanism may not be applicable in vivo. In addition to allicin and ajoene, allyl mercaptan (50 mmol/l) and diallyl disulfide (5mmol/l) enhanced palmitate-induced inhibition of cholesterol biosynthesis in vitro (50). It should be noted that water extracts of garlic probably do not contain any of these compounds; therefore other constituents of garlic, such as nicotinic acid and adenosine, which also inhibit HMG-CoA reductase activity and cholesterol biosynthesis, may be involved (69, 70).
The antihypertensive activity of garlic has been demonstrated in vivo. Oral or intragastric administration of minced garlic bulbs, or alcohol or water extracts of the drug, lowered blood pressure in dogs, guinea-pigs, rabbits, and rats (52, 71–73). The drug appeared to decrease vascular resistance by directly relaxing smooth muscle (74). The drug appears to change the physical state functions of the membrane potentials of vascular smooth muscle cells. Both aqueous garlic and ajoene induced membrane hyperpolarization in the cells of isolated vessel strips. The potassium channels opened frequently causing hyperpolarization, which resulted in vasodilation because the calcium channels were closed (75, 76). The compounds that produce the hypotensive activity of the drug are uncertain. Allicin does not appear to be involved (43), and adenosine has been postulated as being associated with the activity of the drug. Adenosine enlarges the peripheral blood vessels, allowing the blood pressure to decrease, and is also involved in the regulation of blood flow in the coronary arteries; however, adenosine is not active when administered orally. Bulbus Allii Sativi may increase production of nitric oxide, which is associated with a decrease in blood pressure. In vitro studies using water or alcohol extracts of garlic or garlic powder activated nitric-oxide synthase (77), and these results have been confirmed by in vivo studies (78).
Aqueous garlic extracts and garlic oil have been shown in vivo to alter the plasma fibrinogen level, coagulation time, and fibrinolytic activity (43). Serum fibrinolytic activity increased after administration of dry garlic or garlic extracts to animals that were artificially rendered arteriosclerotic (79, 80). Although adenosine was thought to be the active constituent, it did not affect whole blood (43).
Garlic inhibited platelet aggregation in both in vitro and in vivo studies. A water, chloroform, or methanol extract of the drug inhibited collagen-, ADP-, arachidonic acid-, epinephrine-, and thrombin-induced platelet aggregation in vitro (81–87). Prolonged administration (intragastric, 3 months) of the essential oil or a chloroform extract of Bulbus Allii Sativi inhibited platelet aggregation in rabbits (88–90). Adenosine, alliin, allicin, and the transformation products of allicin, the ajoenes; the vinyldithiins; and the dialkyloligosulfides are responsible for inhibition of platelet adhesion and aggregation (4, 42, 91–93). In addition methyl allyl trisulfide, a minor constituent of garlic oil, inhibited platelet aggregation at least 10 times as effectively than allicin (94). Inhibition of the arachidonic acid cascade appears to be one of the mechanisms by which the various constituents and their metabolites affect platelet aggregation. Inhibition of platelet cyclic AMP phosphodiesterase may also be involved (91).
Ajoene, one of the transformation products of allicin, inhibited in vitro platelet aggregation induced by the platelet stimulators-ADP, arachidonic acid, calcium ionophore A23187, collagen, epinephrine, platelet activating factor, and thrombin (95, 96). Ajoene inhibited platelet aggregation in cows, dogs, guineapigs, horses, monkeys, pigs, rabbits, and rats (95, 96). The antiplatelet activity of ajoene is potentiated by prostacyclin, forskolin, indometacin, and dipyridamole (95). The mechanism of action involves the inhibition of the metabolism of arachidonic acid by both cyclooxygenase and lipoxygenase, thereby inhibiting the formation of thromboxane A2 and 12- hydroxyeicosatetraenoic acid (95). Two mechanisms have been suggested for ajoene's antiplatelet activity. First, ajoene may interact with the primary agonist–receptor complex with the exposure of fibrinogen receptors through specific G-proteins involved in the signal transduction system on the platelet membrane (92). Or it may interact with a haemoprotein involved in platelet activation that modifies the binding of the protein to its ligands (96).
Hypoglycaemic effects of Bulbus Allii Sativi have been demonstrated in vivo. Oral administration of an aqueous, ethanol, petroleum ether, or chloroform extract, or the essential oil of garlic, lowered blood glucose levels in rabbits and rats (24, 97–104). However, three similar studies reported negative results (105– 107). In one study, garlic bulbs administered orally (in feed) to normal or streptozotocin-diabetic mice reduced hyperphagia and polydipsia but had no effect on hyperglycaemia or hypoinsulinaemia (107). Allicin administered orally to alloxan-diabetic rats lowered blood glucose levels and increased insulin activity in a dose-dependent manner (24). Garlic extract's hypoglycaemic action appears to enhance insulin production, and allicin has been shown to protect insulin against inactivation (108).
Intragastric administration of an ethanol extract of Bulbus Allii Sativi decreased carrageenin-induced rat paw oedema at a dose of 100 mg/kg. The antiinflammatory activity of the drug appears to be due to its antiprostaglandin activity (109, 110).
A water or ethanol extract of the drug showed antispasmodic activity against acetylcholine, prostaglandin E2 and barium-induced contractions in guinea-pig small intestine and rat stomach (111). The juice of the drug relaxed smooth muscle of guinea-pig ileum, rabbit heart and jejunum, and rat colon and fundus (112, 113). The juice also inhibited norepinephrine-, acetylcholine- and histamine-induced contractions in guinea-pig and rat aorta, and in rabbit trachea (112, 113).
The efficacy of Bulbus Allii Sativi as a carminative has been demonstrated in human studies. A clinical study of 29 patients taking two tablets daily (~1000 mg/day) of a dried garlic preparation demonstrated that garlic relieved epigastric and abdominal distress, belching, flatulence, colic, and nausea, as compared with placebo (32). It was concluded that garlic sedated the stomach and intestines, and relaxed spasms, retarded hyperperistalsis, and dispersed gas (32).
A meta-analysis of the effect of Bulbus Allii Sativi on blood pressure reviewed a total of 11 randomized, controlled trials (published and unpublished) (113, 114). Each of the trials used dried garlic powder (tablets) at a dose of 600– 900mg daily (equivalent to 1.8–2.7 g/day fresh garlic). The median duration of the trials was 12 weeks. Eight of the trials with data from 415 subjects were included in the analysis; three trials were excluded owing to a lack of data. Only three of the trials specifically used hypertensive subjects, and many of the studies suffered from methodological flaws. Of the seven studies that compared garlic with placebo, three reported a decrease in systolic blood pressure, and four studies reported a decrease in diastolic blood pressure (115). The results of the meta-analysis led to the conclusion that garlic may have some clinical usefulness in mild hypertension, but there is still insufficient evidence to recommend the drug as a routine clinical therapy for the treatment of hypertension (115).
A meta-analysis of the effects of Bulbus Allii Sativi on serum lipids and lipoproteins reviewed 25 randomized, controlled trials (published and unpublished) (116) and selected 16 with data from 952 subjects to include in the analysis. Fourteen of the trials used a parallel group design, and the remaining two were cross-over studies. Two of the studies were conducted in an openlabel fashion, two others were single-blind, and the remainder were doubleblind. The total daily dose of garlic was 600–900mg of dried garlic powder, or 10g of raw garlic, or 18 mg of garlic oil, or aged garlic extracts (dosage not stated). The median duration of the therapy was 12 weeks. Overall, the subjects receiving garlic supplementation (powder or non-powder) showed a 12% reduction (average) in total cholesterol, and a 13% reduction (powder only) in serum triglycerides. Meta-analysis of the clinical studies confirmed the lipidlowering action of garlic. However, the authors concluded that the overall quality of the clinical trials was poor and that favourable results of betterdesigned clinical studies should be available before garlic can be routinely recommended as a lipid-lowering agent. However, current available data support the hypothesis that garlic therapy is at least beneficial (116). Another metaanalysis of the controlled trials of garlic effects on total serum cholesterol reached similar conclusions (117). A systematic review of the lipid-lowering potential of a dried garlic powder preparation in eight studies with 500 subjects had similar findings (118). In seven of the eight studies reviewed, a daily dose of 600–900mg of garlic powder reduced serum cholesterol and triglyceride levels by 5–20%. The review concluded that garlic powder preparations do have lipid-lowering potential (118).
An increase in fibrinolytic activity in the serum of patients suffering from atherosclerosis was observed after administration of aqueous garlic extracts, the essential oil, and garlic powder (119, 120). Clinical studies have demonstrated that garlic activates endogenous fibrinolysis, that the effect is detectable for several hours after administration of the drug, and that the effect increases as the drug is taken regularly for several months (43, 121). Investigations of the acute haemorheological (blood flow) effect of 600–1200mg of dry garlic powder demonstrated that the drug decreased plasma viscosity, tissue plasminogen activator activity and the haematocrit level (118).
The effects of the drug on haemorheology in conjunctival vessels was determined in a randomized, placebo-controlled, double-blind, cross-over trial. Garlic powder (900 mg) significantly increased the mean diameter of the arterioles (by 4.2%) and venules (by 5.9%) as compared with controls (122). In another double-blind, placebo-controlled study, patients with stage II peripheral arterial occlusive disease were given a daily dose of 800 mg of garlic powder for 4 weeks (123, 124). Increased capillary erythrocyte flow rate and decreased plasma viscosity and plasma fibrinogen levels were observed in the group treated with the drug (123, 124). Determinations of platelet aggregation ex vivo, after ingestion of garlic and garlic preparations by humans, suffers from methodological difficulties that may account for the negative results in some studies (24). In one study in patients with hypercholesterolinaemia treated with a garlic–oil macerate for 3 months, platelet adhesion and aggregation decreased significantly (125). In a 3-year intervention study, 432 patients with myocardial infarction were treated with either an ether-extracted garlic oil (0.1mg/kg/day, corresponding to 2 g fresh garlic daily) or a placebo (126). In the group treated with garlic, there were 35% fewer new heart attacks and 45% fewer deaths than in the control group. The serum lipid concentrations of the treated patients were also reduced (126).
The acute and chronic effects of garlic on fibrinolysis and platelet aggregation in 12 healthy patients in a randomized, double-blind, placebo-controlled cross-over study were investigated (30). A daily dose of 900 mg of garlic powder for 14 days significantly increased tissue plasminogen activator activity as compared with placebo (30). Furthermore, platelet aggregation induced by adenosine diphosphate and collagen was significantly inhibited 2 and 4 hours after garlic ingestion and remained lower for 7 to 14 days after treatment (30). Another randomized, double-blind, placebo-controlled study investigated the effects of garlic on platelet aggregation in 60 subjects with increased risk of juvenile ischaemic attack (29). Daily ingestion of 800 mg of powdered garlic for 4 weeks significantly decreased the percentage of circulating platelet aggregates and spontaneous platelet aggregation as compared with the placebo group (29).
Oral administration of garlic powder (800mg/day) to 120 patients for 4 weeks in a double-blind, placebo-controlled study decreased the average blood glucose by 11.6% (30). Another study found no such activity after dosing noninsulin- dependent patients with 700 mg/day of a spray-dried garlic preparation for 1 month (127).
Bulbus Allii Sativi is contraindicated in patients with a known allergy to the drug. The level of safety for Bulbus Allii Sativi is reflected by its worldwide use as a seasoning in food.
Consumption of large amounts of garlic may increase the risk of postoperative bleeding (128, 129).
Patients on warfarin therapy should be warned that garlic supplements may increase bleeding times. Blood clotting times have been reported to double in patients taking warfarin and garlic supplements (130).
Carcinogenesis, mutagenesis, impairment of fertility
Bulbus Allii Sativi is not mutagenic in vitro (Salmonella microsome reversion assay and Escherichia coli) (131, 132).
Pregnancy: non-teratogenic effects
There are no objections to the use of Bulbus Allii Sativi during pregnancy and lactation.
Excretion of the components of Bulbus Allii Sativi into breast milk and its effect on the newborn has not been established.
No general precautions have been reported, and no precautions have been reported concerning drug and laboratory test interactions, paediatric use, or teratogenic or non-teratogenic effects on pregnancy.
Bulbus Allii Sativi has been reported to evoke occasional allergic reactions such as contact dermatitis and asthmatic attacks after inhalation of the powdered drug (133). Those sensitive to garlic may also have a reaction to onion or tulip (133). Ingestion of fresh garlic bulbs, extracts, or oil on an empty stomach may occasionally cause heartburn, nausea, vomiting, and diarrhoea. Garlic odour from breath and skin may be perceptible (7). One case of spontaneous spinal epidural haematoma, which was associated with excessive ingestion of fresh garlic cloves, has been reported (134).
Unless otherwise prescribed, average daily dose is as follows (7): fresh garlic, 2–5g; dried powder, 0.4–1.2 g; oil, 2–5mg; extract, 300–1000mg (as solid material). Other preparations should correspond to 4–12mg of alliin or about 2–5mg of allicin).
Bulbus Allii Sativi should be taken with food to prevent gastrointestinal upset.
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