History

Antimicrobial action

Antioxidant effects

Cardiovascular effects

Physiological activity of Ajoene

Acid Reflux effect



History

The use of garlic as a medicine and condiment predates written history. The oldest recorded literature from the Sumerians is dated at 2600–2100 B.C. In these writings garlic was already widely cultivated, therefore its use must precede this. It is thought to be of Central Asian origin and features highly in the legends of both India and China. No-one knows exactly where the name garlic comes from, but it is assumed that the Anglo-Saxon ‘gar’ refers to the spear-like foliage and the ‘lic’ is referring to leek. Throughout written history there are always references to garlic. It was part of the staple diet of the Egyptian pyramid builders. Several cloves of garlic were also found in the tomb of Tutankhamen. The pharaohnes believed that by taking garlic to the afterlife, the food would always be well seasoned. Garlic was also associated with the Israelites and is mentioned in the bible during the time of the exodus.

“We remember the fish, which we did eat in Egypt
freely; the cucumbers, and the melons, and the leeks, and
the onions, and the garlick” (Numbers 11:5).

Garlic must have been of high value as is it not a nativeplant of Egypt and would have to have been imported. The Codex Ebers, an Egyptian medical papyrus translated in 1937, contained over 800 medical formulations, 22 of which contained garlic. The Romans also extolled the virtues of garlic. Pliny the elder, a roman naturalist, described in his Historia Naturalis how garlic could be used for gastrointestinal disorders, dog and snake bites, scorpion stings, asthma, madness, convulsions, tumours and consumption. Dioscorides, physician to the Roman army in 1 A.D., also recommended garlic to be used as a vermifuge. Use of garlic has been recorded by Hippocrates, ‘the father of modern medicine’, as a laxative and a diuretic, and also by Aristophanes and Galenal for the treatment of uterine tumours. More recently, the first evidence of its antimicrobial properties was established in France. During the plague in Marseilles, in 1721, four men were employed to remove the dead bodies. During the plague, none of them became infected. The secret was a macerated garlic and wine tincture, ‘viniagre des quatre voleurs’. This preparation is still available today. 1

Tutankhamen

Howard Carter and the mummy of Tutankhamen (1925)

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Antimicrobial action

Principals from garlic have been shown to have antiprotozoal, antibacterial, antifungal, and antiviral activities. They also modulate the cardiovascular and immune system as well as having antioxidant and anticancer properties.

Antiprotozoal properties Very little work has been done to establish the mechanisms of effects of garlic on protozoa. Several studies have shown the extract to be effective against a host of protozoa including Opalina ranarum (see the picture beside), O. dimidicita, Balantidium entozoon, Entamoeba histolytica , Trypanosomes, Leishmania, Leptomonas and Crithidia. Due to the occurrence of unpleasant side effects and increasing resistance to the synthetic pharmaceuticals recommended for the treatment of giardiasis, there has been increasing interest in the quest for natural alternatives. Researchers are looking at plants that have been used for gastrointestinal disturbance by users of alternative therapies for generations. Early work establishing garlic as a possible treatment for giardiasis was carried out in the former Soviet Union. It has been noted that garlic was often used for gastrointestinal complaints whilst investigating the historical use of garlic. By this time it had already been established that it had antibacterial, antifungal and antiviral properties.

This prompted an investigation into its possible use as an antiprotozoal against Entamoeba histolytica. Inhibitory activity was noted with crude extract at 25 μg ml–1 and the lethal dosage was established as approximately 50 μg ml–1. Encouraged by these results, a clinical trial was carried out on patients that had giardiasis. Garlic was established as an antigiardial, removing the symptoms from all patients within 24 h and completely removing any indication of giardiasis from the stool within 72 h at a dosage of 1 mg ml–1 twice daily aqueous extract or 0.6 mg ml–1 commercially prepared garlic capsules. No in vitro calculations were possible, as the workers could not culture the protozoa in vitro. Under certain conditions allicin, a major component of garlic shown to be antibacterial, degrades to diallyl trisulfide. This chemical is more stable than the extremely volatile allicin and is easily synthesised. In China it is commercially available as a preparation called Dasuansu and as been prescribed for Entamoeba histolytica and Trichomonas vaginalis infections. The antigiardial activity of this garlic component was assessed. It gave an IC50 of 14 μg ml–1 and was shown to affect cell morphology. Allicin, ajoene and organosulfides from garlic are also effective antiprotozoals. It has been suggested that microbial cells are more affected than human cells because they do not have an intracellular thiol content adequate to counterbalance the thiol oxidation by allicin and allicin-derived products. Ajoene has been shown to inhibit phosphatidyl choline synthesis in trypanosomes. 1



Antibacterial properties Garlic has been used for centuries in various societies to combat infectious disease. In India, garlic has been used to prevent wound infection and food spoilage. In Ireland, at the turn of the twentieth century garlic was used to combat pulmonary infection. During World War I garlic was used to alleviate intestinal infections in soldiers stationed in the Balkans. Historically it is believed that Louis Pasteur first described the antibacterial effect of garlic ‘juices’ in 1858, although no reference is available. More recently garlic has been proven to be effective against a plethora of gram-positive, gram-negative and acid-fast bacteria. These include Pseudomonas (see the picture beside), Proteus, Staphylococcus aureus , Escherichia coli, Salmonella , Klebsiella , Micrococcus, Bacillus subtulis , Clostridium , Mycobacterium and Helicobacter . It has been documented that garlic exerts a differential inhibition between beneficial intestinal microflora and potentially harmful enterobacteria. Inhibition observed in E. coli was more than 10 times greater than that seen in Lactobacillus casei for the same garlic dose. Exactly why this differential inhibition should occur is not clear, but may be due to differing compositions of bacterial membranes and their permeability to allicin.

The antibacterial activity of garlic is widely attributed to allicin. This is supported by the observation that if stored at room temperature the antibacterial effectiveness of garlic extract is greatly reduced. This reduction occurs to a much lesser extent if the extract is stored at 0–4°C, suggesting thermal instability of the active components. The intracellular effects of allicin are not well understood. It is known that allicin has sulfydryl modifying activity, and as such is capable of inhibiting sulfydryl enzymes. Cysteine and glutathione counteract the thiolation activity of allicin, and on addition to the reaction mixture the antibacterial activity is reduced. Garlic extract and allicin have been shown to exert bacteriostatic effects on some vancomycin- resistant enterococci. An inhibitory synergism was observed when used in combination with vancomycin. It is thought that allicin modifies the sulfydryl groups on the enzymes of the TN1546 transposon, which encodes vancomycin resistance, enhancing susceptibility to vancomycin 1.

More recently garlic extract has been shown to be an effective agent for controlling methicillin-resistant Staphylococcus aureus. Aqueous extract of garlic was tested for ability to inhibit the growth of a range of oral species and to inhibit the trypsin-like and total protease activity Porphyromonas gingivalis (see picture beside), which is considered to be one of the major aetiological agents of progressive periodontitis. Many data show that garlic extract inhibits the growth of oral pathogens and certain proteases and so may have therapeutic value, particularly for periodontitis. 2



Antifungal properties Antifungal activity was first established in 1936 during some working on epidermophyte cultures. Many fungi have proven susceptible, including Candida Torulopsis, Trichophyton (see the picture beside), Cryptococcus, Aspergillus, Trichosporon and Rhodotorula. Garlic extracts were shown to decrease the oxygen uptake, reduce the growth of the organism, inhibit the synthesis of lipids, proteins and nucleic acids and damage membranes. A sample of pure allicin was shown to be antifungal. Removal of the allicin from the reaction by solvent extraction decreased the antifungal activity. Activity has also been observed with the garlic constituents, diallyl trisulfide, against cryptococcal meningitis, and ajoene, against Aspergillus. Again thiol addition to the test reduced the activity, suggesting the blocking of thiol oxidation by allicin. Inhibition of respiratory activity is thought to be due to inhibition of succinate dehydrogenase. The adhesion of Candida Torulopsis is also greatly reduced in the presence of garlic extract. Again this effect is diminished by the addition of thiol compounds. The addition of ajoene to some fungal growth mixtures, including Aspergillus niger, C. albicans and Paracoccidiodes, has resulted in inhibition at concentrations lower than that experienced with allicin. Studies with aged garlic extract (with no allicin or allicin-derived constituents) showed no in vitro activity. However, when given to infected mice the number of organisms that were seen was reduced by up to 80%. 1



Antiviral properties In comparison with the antibacterial action of garlic very little work has been done to investigate antiviral properties. The few studies have reported that garlic extract shows in vitro activity against influenza A and B, cytomegalovirus , rhinovirus, HIV, herpes simplex virus 1 and 2 (see the picture beside), viral pneumonia and rotavirus. Allicin,diallyl trisulfide and ajoene have all been shown to be active. In the case of HIV, it is thought that ajoene acts by inhibiting the integrin- dependent processes. Allyl alcohol and diallyl disulfide have also proven effective against HIV-infected cells. No activity has been observed with alliin or S-allyl cysteine it appears that only allicin and allicin-derived substances are active. 1

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Antioxidant effects

Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water soluble organosulfur compounds, such as S-allyl cysteineand S-allylmercaptocysteine.

AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kB, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical–mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescenceaccelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic.

Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer’s disease. 3

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Cardiovascular effects

Dietary garlic has a lipid- and cholesterol-lowering effects. g-Glutamyl-S-alkylcysteines inhibit the blood-pressure regulation hormone. A detailed mortality study on patients who had prior heart attacks showed that of those given gelatine capsule containing garlic oil (ca. 6 mg/person/day) high in ajoene and dithiins for three years, there was significant reduction in serum lipids, a 33% reduction in new heart attack and a 45% reduction in total death compared to those consuming placebo capsules. Allicin is a specific inhibitor of acetyl-CoA synthetase from plants while diallyl disulfide inhibits 3-hydroxy-3-methylglutaryl CoA; in this manner lipid, cholesterol and fatty acid biosynthesis may be inhibted.

The inhibitory effect of garlic and onions o human platelet aggregationhas been known for two decades and has been variously attributed to adenosine, allicin, alliin, ajoene, polysulfides, and vinyl dithiins. The identity of the organosulfur compounds found in the blood or tissues after consumption of the plants remains unknown (apart from the compounds found in breath or sweat after ingestion of garlic). In view of the in vivo findings and observations of some researchers, it has been pointed out that allicin reacts immediately with the SH-group of free or enzyme-bound cysteine forming S-(allylthio)cysteine and it is unlikely that allicin itself is found in blood after consumption of garlic. Indeed S-(allylthio)-cysteine may well be responsible for much of the biological effects of garlic within the body. Several studies indicate that the components of freshly cut garlic and onion inhibit platelet aggregation and smooth muscles contraction through inhibition of cyclooxygenase and related enzymes.

The antiasthmatic effects of onion extracts has been demonstrated; some of the most active components are thiosulfinates and cepaenes. The compounds exert a wide range of pharmacological effects such as inhibition of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism, inhibition of histamine release and leukotriene biosynthesis, prevention of bronchal asthma in guinea pigs after inhalation of allergens and platelet-activating factor, and inhibition of inflammatory cell influx. Allicin is reported to inhibit human platelet aggregation in vitro without affecting cyclooxygenase or thromboxane synthase activity or cyclic AMP levels, possibly by influencing calcium movement. 4

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Physiological activity of Ajoene

Structure of Ajoene

Ajoene is cytotoxic toward a tumorgenic lymphoid cell line with an EC50 of 12 mM; it shows an IC50 of 1.6 mM and 5.1 mM towards the 5-lipoxygenase and cyclooxygenase enzymes, respectively; it synergistically potentiates the antiaggregatory action of prostacycline, forskolin, indomethacin and dypiridamole on human blood platelets. Administration of ajoene to dogs under conditions use in opeheart surgery prevents the thrombocytopenia induced by contact of blood with artificial surfaces; it shows excellent activity in preventing the loss of platelets and increasing the rate of restoration of platelet clotting activity. Other anticlotting agents (aspirin, heparine) had longer lasting effects and did not protect platelets. Ajoene is thought to inhibit platelet activation by impairingthe interaction of fibrinogenreceptors on the platelet surface with the rest of the membrane signal transduction microviscosity. Alternatively, it is suggested that ajoene alters the conformation of a hemoprotein implicated in platelet activation. Ajoene can also inhibit adhesive interactions of human neutrophiles and consequently effect in vivo superoxide anion formation. Ajoene possesses significant antifungal activity (see above). Ajoene inactivates human gastric lipase (HGL) , a sulfhydryl enzyme involved in the digestion and adsorption of dietary fats. This observation cossoborates previous reports on the ability of garlic to lower triacylglycerol blood levels (“blood thinning” effect of folk medicine). A garlic preparation prepared by dissolving fresh garlic extract in coconut oil (forming ajoene and dithiins) significantly decreases ADP-induced platelet aggregation in volunteers consumintg 0.25 mg Kg-1 daily for 4 weeks. 4

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Acid reflux effect

Anyone who has overindulged in onions is aware of the consequence. Gastroenterologists refer to the effect as “acid reflux and reflux symptoms”, e.g. regurgitation of the stomach contents into the esophagus with resultant “heartburn”. A more precise physiological description is inappropriate transient lower esophageal sphincter (LES) relaxation, e.g. erratic opening of the valve separating the esophagus from the stomach. Since, as we have already mentioned above, several of theorganosulfur compounds formed when onions are cut are potent inhibitors of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism, raw onions may cause heartburn by blocking these pathways. This inhibition might result, either singly or in combination, in the transient relaxation of LES as well as injury to the esophageal mucosa. 4

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Bad breath an further negative effects

Eating alliaceus plants causes bad breath and perspiration odors. Components of garlic breath and perspiration include: allyl methyl sulfide and disulfide, diallyl sulfide, 2-propenethiol, and p-cymene and (+)-limonene present in garlic distilled oils). Garlic Breath odor comes frome the lungs presumably by way of the blooa and not solely from particles of garlic retained in the structures about the mouth. After ingestion of 2 g of raw garlic, garlic odor in human urine was said to persist up to 96 hours while exhaled air no longer had an odor after 24 hours. When garlic is rubben on the foot, a garlic taste is soon detected. Presumably fat-soluble allicin is absorbed through the skin (as in the case of dimetyl sulfoxide) into the lymphatic system which carries it intact to the upper part of the body in a medium where no protein or cystein is present. Studies on nursing mothers have shown that their milk has more intense odor 2 hours after having ingested garlic. Furthermore it was found that nursing babies sucked more and ingested more milk when the milk smelled like garlic. 4

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