Gastric Ulcers – An Effective Alternative Treatment The Problem It is estimated that between 60 and 90% of horses are affected by gastric lesions including the colon (hind gut ulcers) and it is thought that the majority of ulcers are due to modern management methods of travelling, training, feeding and stabling. Any horse that is without food for more than four hours will have a low ph. in the stomach (greater acidity) which is damaging to the walls of the top (non- glandular) portion of the stomach, whilst horses with a constant supply of feed have a much higher (better) ph. and less chance of suffering from EGUS. Feedstuffs vary in pH balance, coarser materials form a mat in the upper portion of the stomach and mix with saliva to keep the pH in that region around 6 to 7 more alkaline. Medium-density feedstuffs are located in the middle zone of the stomach, and this area has a pH of 4 to 5. High density fluids are in the lower portion of the stomach and the pH is more acid at 1 to 2. The lower portion of the stomach is protected from acid production by a mucous coating. The upper non-glandular portion of the stomach is not intended to be exposed to stomach acid. Hydrochloric acid is secreted continually by the gastric glands which are located in the lower portion of the stomach. The discovery of this layering effect helps explain why exercise tends to increase the frequency of gastric ulcer formation in horses. Monitors implanted in working horses revealed the contractions of abdominal muscles forced the lower pH liquids from the lower portions of the stomach up through the coarser feedstuff layers, exposing the non-glandular portion to the corrosive acids. Even abdominal muscle contraction secondary to anxiety caused the same reaction. Acid secretion is up or down and is regulated by food intake. The stomach acts as its own pH meter and is stimulated by histamine which releases HCL by the parietal cells. Blocking the H2 (histamine 2) receptors suppresses gastric acid production. Within the pyloric gland mucosa, unique cell types which are located very close to each other constantly "test" the pH of the stomach and react in such a way as to keep the pH in the correct range. The type of food fed also has an effect, for instance feeding alfalfa and oat straw significantly raises the ph. level, whilst feeding high grain diets produces volatile fatty acids and lactic acid, both easily damage the upper portion of the stomach causing pain and inflammation. Many veterinarians quote stress as being a significant factor to the cause of ulcers, which would include travelling, confinement in a box for long periods and illness (laminitis, lameness, infections) all these events cause the body to release stress hormones and chemicals which ultimately lower the ph. of the stomach and damage the lining of the stomach. Another major cause of ulcers in horses is the use of NSAID’s given as pain relievers and anti-arthritics, the most commonly prescribed one being bute. NSAID’s prevent the production of prostaglandin, which is a key ingredient in the protection of the stomach. Long term use of any NSAID’s in the horse is considered to be detrimental to gut and liver health but balance is the key and if a horse is so lame it is unable to walk around the box then most owners would agree that the primary concern is to make it comfortable as quickly as possible and consider ulcer medication alongside. Nsaids are also thought to be responsible for ulcers in the hind gut Bacterial Infections More recent research has been directed at the relationship between the presence of ulcers and bacterial infections. Until the mid-1980s, it was felt that stress, NSAID’s poor eating habits or all of these factors working together led to the development of gastritis and ulcers. Since that time, evidence has been mounting that Helicobacter pylori (H. pylori) has a major role in causing these diseases The most recent research has indicated that the most common cause of ulcers and cancer in humans is infection with helicobacter pylori.
The first signs of ulcers can be nothing more than subtle changes in attitude or behaviour of the horse, i.e. sluggish movement, lacking in energy or becoming more nervous and spooky and resentment at having the girth tightened. Other signs include a change in the amount of food usually eaten, chewing wood in the stable or fencing (not trees) and the onset of windsucking, a sudden change in temperament especially of the grouchy or bad tempered type. Mild colic like symptoms turning round to look at his flanks, lying down and urinating excessively, sudden loss of coat condition maybe not as sleek and shiny as usual, coat looks slightly raised and flat coloured. The Solution-Treat the Ulcers
Gastrogard-the recommended veterinary route is treatment with Gastrogard, the down side to Gastrogard is that it is expensive, and irreversibly binds to the acid pump preventing the production of gastric acid and altering the overall pH of the stomach meaning the stomach ulcers are worse after the end of the treatment. Generic Omeprazole- is cheaper but it has the same action as Gastrogard and so will have the same consequences. Ranitidine-is a histamineH-2 receptor antagonist that inhibits the production of gastric acid production. Ranitidine is also known to give false positives for methamphetamine on drug tests and its use is not recommended for racing. Cimetidine-also an H2-receptor antagonist but must be withdrawn at least 2 weeks before racing.
Gastro-G the Natural Alternative There has been a huge increase in the interest and use of plant compounds from vets for the treatment of ulcers. Brazil and Japan lead the way in human research and have developed a primary health care product as a natural alternative to gastrogard, generic omeprazole, ranitidine and cimetidine which has now been adapted for use in horses. The study concluded that the lyophilized extract represented a more powerful gastroprotective effect than cimetidine. This study also observed an increase in gastric juice volume and effect on pH identical to that of cimetidine (Souza-Formigoni et al. 1991). Maytenus is grown as a medicinal crop to provide an efficacious dose and it provides a multi targeted approach for the + + relief of ulcers. ’Our studies in vitro showed that inhibition of gastric acid secretion occurs by inhibition of H , K ,-ATPase which is the final step of acid secretion and therefore one of the most important steps in the gastric acid secretion process’ (Baggio et al 2007) In controlled studies researchers and vets have found that maytenus illicifolia grown as a medicinal crop produces similar and better results in the prevention and treatment of gastric ulcers than Omeprazole, Cimetidine and Ranitidine. It also has a positive effect on hind gut ulcers. It has low toxicity, and has does not alter gut microbial flora even in long term use and as it has a reversible action it does not permanently damage binding sites ensuring a healthier stomach pH. The advantages of using anti ulcerogenic plants instead of a synthetic drug are that plants have many synergistic chemicals and are generally able to provide analgesic, anti bacterial and anti-inflammatory actions plus many flavonoid rich anti-oxidants to aid healing. ‘It was shown also that both epigallocatechin (tannin) as fridenelol (essential oil in maytenus) account for much of the protective effect of the gastric mucosa (Pereira et al., 1993, Ming et al., 1998). It is a fraction of the cost of Gastrogard at £4.50 per day (full dose for 1 month) with a ¼ daily dose recommended for prevention during stressful times and competition. It is a palatable and easily digested compound that can be included in the normal feed ration Its use in medicine has been well documented with no less than 11 patents lodged in South America, America and Japan for a variety of medical uses including the treatment of gastric ulcers. And also as a gastro protective medicine, a gastric anti- inflammatory and an anti-bacterial agent Manage the Cause Give half a pint of corn oil twice daily instead of grain for the added anti-inflammatory protection of omega 3 and 6 and make sure the horse has access to some sort of forage throughout the day. The other most important action to take during times of stress, travel and restrictions to grazing is to provide protection and buffering to the vulnerable top part of the
stomach by feeding an antacid product containing bicarbonate of soda or calcium carbonate. These can be effective but short lived with the effects said to last for maybe only an hour, therefore it may be better to buy the antacid in syringe form and give it whilst travelling rather than make it a permanent addition to the feed. More long lasting antacids are dihydroxy-aluminium sodium carbonate, aluminium phosphate and magnesium carbonate, these both neutralize gastric acid and protect and coat the mucosal lining of the stomach. Some products may also contain threonine and glutamine which are compounds known to increase the integrity and quality of the stomach wall and help produce mucus which is the bodyâ€™s natural buffer against the effects of hydrochloric acid. Many products that are antacids also contain probiotics such as yeas sac and prebiotics which are food for the friendly microbial populations that live in the hind gut rather than the stomach. Seaweed extracts are becoming an increasingly popular addition to gut soothing products reportedly able to lower gastric acid production but are more likely to be beneficial to the health of the hindgut and for its nutritional benefits especially the b vitamins.
Scientific Studies of Maytenus According to some studies (Carlini & Frochtengerten, 1988, Ming et al. 1998; Coulaud-Cunha et al. 2004; Carvalho et al. 2008) for M. ilicifolia presents a potent action against peptic ulcer and gastritis. Coulaud-Cunha et al. (2004) report that the action of M. ilicifolia in peptic ulcer and gastritis involves more than one mechanism of action, albeit not conclusively elucidated, not only due to a specific active ingredient but different phytocompounds. It was shown by Pereira et al. (1993) and Ming et al. (1998),that both the tannins, especially epigallocatechin, as essential oils, especially fridenelol, are responsible for part of the gastroprotective effect. Carlini & Frochtengarten (1988) Over long periods of treatment with a maintenance dose 3g daily of M. ilicifolia a potent gastroprotective action is observed with no changes in pH. This observation can be confirmed by Ferreira et al. (2004), in studies with lyophilized aqueous extract of leaves of M. ilicifolia in frogs, has proved that this inhibitory effect on mediators H 2 histamine in the parietal cells, and these second Gilman (1989), when stimulated, cause the activation of adenililciclase, initiating a series of complex biochemical and morphological changes, which leads to increased gastric secretion, which acts as an antagonist H 2 , and inhibiting the effect of gastrin. It was shown also that both epigallocatechin (tannin) as fridenelol (essential oil) account for much of the protective effect of the gastric mucosa (Pereira et al., 1993, Ming et al., 1998). Comparison with Cimetidine: The antiulcer activity was initially studied in using necrotizing agents such as aspirin, indomethacin (NSAID), Reserpine and immobilization at low temperatures. Carlini & Frochtengarten (1988) demonstrated, by studying these models and the lyophilized maytenus extract there was a marked gastroprotective effect. The study concluded that the lyophilized extract represented a more powerful gastroprotective effect than cimetidine. This study also observed an increase in gastric juice volume and effect on pH identical to that of cimetidine (Souza-Formigoni et al. 1991). A study using the crude hexane extract of M. ilicfolia , fraction rich in hydrocarbons and terpenoids, showed similar results to those obtained in previous studies using a dose of 4 mg / kg. (Faleiros et al., 1992). Ming et al (1998) and Pereira et al. (1993) state that the antiulcer activity is due primarily to tannins and catechin derivatives. Later studies showed that the antiulcer actions of tannin and catechin derivatives are enhanced by the presence of components of essential oils, and friedelin fridelol, suggesting that more than one component has a gastroprotective effect. Evidence of synergistic effect between the components of M. ilicifolia was corroborated by studies by Queiroga (2000), who demonstrated that the tannins when used separately and in models of ulcer induced by indomethacin, did not show activity. Studies by Ferreira et al. (1996) demonstrated that the ethanol extract shows activity similar to blocking H 2 as cimetidine, inhibits the increased production of HCl by the oxyntic cells of gastric fundus induced by histamine. Corroborating previous studies, Iwa et al (2001), demonstrated that epigallocatechin-3-gallate inhibits stress ulcers induced in rats by immersion in cold water for prolonged periods. This effect was blocked by the addition of pro-oxidants, suggesting that the antioxidant activity of epigallocatechin-3-gallate is part of its anti-ulcer activity
Comparison with Ranitidine: Souza-Formigoni et al. (1991) found that in studies with the infusion of leaves, both orally and intraperitoneally, using positive controls as ranitidine and cimetidine, have demonstrated that M. ilicifolia has comparable activity, higher in some cases than the activities of drug-control Comparison with Omeprazole: In a study done by Baggio C. et al 2007 gastric ulcers were induced using indomethacin rather than by the usual necrotizing agent ethanol. Indomethacin is a cox inhibitor and its application induces the appearance of severe lesions (Bulbena et al 1993) the use of this non-steroidal anti- inflammatory inhibits the formation of prostaglandin and produces severe bleeding lesions. Prostaglandins are responsible for the stimulation of mucosal mucus and bicarbonate and to increase mucosal blood flow and to limit back diffusion of acid into the epithelium. The researchers found that the flavonoid rich fraction of maytenus ilicifolia was 6.2 times more potent against the use of indomethacin than ethanol. Suggesting that the action of the maytenus is strongly involved in the cycloxygenase-prostaglandin system to promote gastro protection. The study concludes that as well as having gastro protective abilities maytenus ilicifolia has a proton + + pump inhibitory effect. ’Our studies in vitro showed that inhibition of gastric acid secretion occurs by inhibition of H , K ,ATPase which is the final step of acid secretion and therefore one of the most important steps in the gastric acid secretion process’ (Baggio et al 2007) ‘Omeprazole is a gastric acid pump inhibitor that regulates the final step in hydrogen ion production and blocks gastric acid + + secretion regardless of the stimulus. Omeprazole irreversibly binds to the gastric parietal cell’s H , K ATPase enzyme which pumps hydrogen ions into the lumen of the stomach in exchange for potassium ions.’ (Gastogard Patent) The evidence for Bacterial Infections as a cause of EGUS in horses More recent research has been directed at the relationship between the presence of ulcers and bacterial infections. Until the mid-1980s, it was felt that stress, NSAID’s poor eating habits or all of these factors working together led to the development of gastritis and ulcers. Since that time, evidence has been mounting that Helicobacter pylori (H. pylori) has a major role in causing these diseases The most recent research has indicated that the most common cause of ulcers and cancer in humans is infection with helicobacter pylor., Bezdecova B., and Futas J., (2009) examined ulcers in the glandular part of the equine stomach to determine whether there was a link between the presence of helicobacter pylori and helicobacter equorum and EGUS. The study concluded that there was sporadic infection with helicobacter pylori in horses with gastric ulcers and helicobacter equorum was found in a faucal sample of one horse without ulcerations. A further study by Husted et al. (2010) also examined lesions in the glandular part of the stomach. Lesions located in this region were found in 58% of 162 hospitalised horses and 47% of 345 racehorses, acid exposure would not be the primary causative factor. In humans and many animals including dogs, sheep and cattle, infection with the helicobacter pylori bacteria is a major risk to the development of glandular stomach ulcers and cancer. However the conclusion of this study was that helicobacter pylori could not be verified as being involved in the formation of lesions of the glandular stomach of the horse. An emerging pathogen E Fergusonii was found in one case of gastric erosion. The bacteria was found intercellular what was not known was whether this was a primary or secondary infection. As very limited amounts of bacteria were found in the glandular region, detection of a moderate to high amount of any bacteria at a glandular mucosa level is significant and further studies should be undertaken to clarify whether gastric infection by E. Fergusonii is an important part of the EGUS syndrome. In a study, led by Mabe et al. (1999), several tannins contained in maytenus ilicifolia were tested against H. pylori . The most active is epigallocatechin-3-gallate, whose MIC (minimum inhibitory concentration) was 8 μ g / ml. This study has also induced an experimental infection with H. pylori in rodents Gerbillus . Both a fraction of tannins and gallic catechists as epigallocatechin-3-gallate were effective in eradicating infection in all treated animals, while it persisted in controls,
suggesting greater efficiency of the tannins in vivo . There was also a significant reduction of inflammatory changes, foci of haemorrhage and ulceration in the treated animals .
Historical Use and General information The use of plants with pharmaceutical properties has received increased interest because of the discovery of many potent plant chemicals (discovered mainly through cancer research) and because it is believed that these medicinal plants have many attributes (anti inflammatory, analgesic, organ protective) with less of the side effects of synthetic drugs. Maytenus ilicifolia is popularly known as holy thorn cancerous, cancorosa of seven thorns and Maltena among other names (lorenzi and Mato, 2002, Brandao at al., 2006) it belongs to the Celestraceae family of 55 genera and 850 species in the atlantic sub-tropical and tropical South American forests. In Brazilian medicine Maytenus ilicifolia, Maytenus robusta and maytenus aquifolia are the native species and are collectively known as Espinheira Santa. It is widely available from pharmacists for the treatment of ulcers (capsules) and as a topical application for skin cancer. (Mossi et al., 2004) According to popular usage it is believed that M. ilicifolia can fight various diseases including gastritis, dyspepsia and gastric ulcers. It has analgesic, antiseptic, healing, diuretic, antibacterial and laxative effects (Colismbra, 1958). Cipriani et al. (2004) corroborates these claims. According to Carlini & Frochtengarten (1988), early studies of therapeutic efficacy of M. ilicifolia were performed by Aluizio France, Professor at the Faculty of Medicine of Parana, in 1922 he used the M. ilicifolia in patients with gastric ulcer and reported treatment success. Currently there are studies that say that M. ilicifolia also presents anticancer and antimicrobial activities (Ming et al., 1998, Pereira et al., 1992). Cipriani et al. (2004) report the discovery and characterization of arabinogalactans, essential polymers found in the cell walls of higher plants, which have immunological and gastro protective activity. This may help explain its use in the development of the anti-cancer drug Toxol as it has a highly immunosuppressive effect, especially when associated with surgical procedures and antiinflammatory steroids such as betamethasone and dexamethasone. Espinheira santa has a long and well documented history of use in urban areas and South American herbal medicine practices than in tribal areas, probably because of the types of illnesses that it treats. In Brazil, the leaves of the plant are brewed into a tea for the treatment of ulcers, indigestion, chronic gastritis, and dyspepsia (with a recorded history of use for these purposes dating back to the 1930s). The leaf tea is also applied topically to wounds, rashes, and skin cancer. In Brazilian pharmacies today, a topical ointment is made with espinheira santa and sold for skin cancer. In other herbal medicine systems in South America, espinheira santa for is used for anemia, stomach and gastric ulcers, cancer, constipation, gastritis, dyspepsia, liver disorders, and as a contraceptive. In Argentinean herbal medicine, the entire plant or leaves are infused or decocted for its antiseptic and wound healing properties and it is commonly used internally for asthma, respiratory and urinary tract infections, diarrhea, and to induce menstruation. Espinheira santa is used for skin cancer, however its most popular use has been for the treatment of ulcers, indigestion, chronic gastritis, and dyspepsia. ECOLOGY According to Magalh達es (2004), M. ilicifolia is found predominantly in the temperate and subtropical climate of southern Brazil, it has a preference for clay soils but well drained and high in organic matter. It requires frequent irrigation and annual mean rainfall and temperature will affect the tannin content but not the medicinal biochemical content (triterpenes and flavonoids). (Yariwake J.,et al 2004) The bush must also be planted in the shade with sufficient space between each plant, plants propagated in the full sun will result in severe phyto-chemical changes causing the plant to contain high amounts of tannins and although the tannins are very effective and desirable compounds (epicatechins) in the treatment of gastric ulcers an imbalance may cause undesirable side effects. (Radomski & Wisniewski 1998), Therefore, planting techniques should be standardised, especially when it comes to species with therapeutic use, since changes in its cycle of planting can result in abnormal concentrations, or even the disappearance of vital therapeutic constituents, or even the appearance of undesirable substances
CHEMICAL COMPOSITION AND MEDICINAL USES According to Lee et al. (1969), who were the first researchers to devote themselves to studies of phytochemicals contained in M ilicifolia. They demonstrated the presence of several phytochemical groups, especially terpenoids, tannins, alkaloids, macrolides and flavonoids, among others (Da Silva & Coimbra, 1958; Sim천es, 1986; Frochtengarten & Carlini, 1988, Pereira et al. 1992; Alonso 1998; Coulaud-Cunha et al., 2004, Esteban et al., 2009). The presence of these groups was further confirmed and their therapeutic potentials are now well known and well documented. There are several groups of compounds studied and classified in Maytenus ilicifolia including terpenes (maitenin, tringenona, isotenginona II congorosinas A and B, maiten처ico acid), triterpenes (friedelanol and friedelin), essential oils (friedenelol ), tannins, especially gallic (epicatechin, epigallocatechin and epigallocatechin gallate), glycolipids (monogalactosildiacilglicerol, digalactosildiacilglicerol, trigalactosildiacilglicerol, and tetragalactosildiacilglicerol sulfoquinovosildiacilglicerol) and, finally, the alkaloids (maiteina, and maitanprina maitensina) (Alonso, 1998; Carlini & Frochtengarten, 1988, Mendes et al., 2006). Ohsaki et al. (2004), described four new triterpenoids, designated by them maytefolinas A, B and C-3-caffeate uvaol.
ABSTRACTS An arabinogalactan was obtained from the leaves of Maytenus ilicifolia by hot aqueous 2% KOH extraction, followed by a freezing-thawing process and anion-exchange chromatography. It consisted of arabinose, galactose, galacturonic acid, and rhamnose in a 69:20:6:5 molar ratio. Methylation analysis, partial acid hydrolysis, and (13)C NMR spectroscopy indicated that it was an arabinogalactan containing a (1->4)-linked beta-Galp main chain, substituted at O-6 with Ara units, which were in turn substituted at O-5 (Araf) and/or O-4 (Arap), O-3, O-3,5, and O-2,5. This arabinogalactan is probably linked to O-4 of some Rhap units of a type I rhamnogalacturonan, formed by repeating (1->4)-alpha-D-GalpA-(1->2)-alpha-L-Rhap groups Thales R Cipriani, Caroline G Mellinger, Philip A J Gorin, Marcello Iacomini (2007) M. ilicifolia is one of frequently used medicinal plants in Brazil. Its leaves are used in homemade and industrial medicines for effective treatment of stomach ulcers. A polygalacturonic acid (PGA) was obtained from its leaves by aqueous extraction, followed by fractionation via a freezingthawing process and Fehling precipitation. Methylation analysis and 13C NMR spectroscopy showed PGA to consist of (1?4)-linked a-D-GalpA repeating units. It significantly inhibited ethanolinduced gastric lesions in rats, with an ED50 of 103 mg/kg, suggesting that it has a protective anti-ulcer effect. This polysaccharide may thus play an important role in the anti-ulcer effect of M. ilicifolia Thales R Cipriani, Caroline G Mellinger, Lauro M De Souza, Cristiane H Baggio, Cristina S Freitas 2009 Thirteen endophytic fungal strains of the genus Pestalotiopsis were isolated from the medicinal plant M ilicifolia Mart. ex. Reiss (commonly known as "espinheira santa") and their antimicrobial properties were investigated. Two isolates were successful in inhibiting the growth of the tested microorganisms (Escherichia coli, Klebsiella pneumoniae, Micrococcus luteus, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA)) using the technique of bioautographic thin-layer chromatography (TLC) agar overlay assay. An analysis based on a polyphasic approach integrating taxonomic information, morphological traits, RAPD markers, and the sequencing of the ITS1-5.8S-ITS2 of the rDNA led to the assignment of the isolates as belonging to the species Pestalotiopsis microspora, Pestalotiopsis vismiae, and Pestalotiopsis leucothoes. Therefore, the present study presents a new approach to the study of endophytic fungi of the genus Pestalotiopsis. Josiane Gomes-Figueiredo, Ida C Pimentel, V창nia A Vicente, Marcio R Pie, Vanessa Kava-Cordeiro 2010 Pristimerin has been shown to be cytotoxic to several cancer cell lines. In the present work, the cytotoxicity of pristimerin was evaluated in human tumour cell lines and in human peripheral blood mononuclear cells (PBMC). This work also examined the effects of pristimerin (0.4; 0.8 and 1.7 microM) in HL-60 cells, after 6, 12 and 24h of exposure. Pristimerin reduced the number of viable cells and increased number of non-viable cells in a concentration-dependent manner by tripan blue test showing morphological changes consistent with apoptosis. Nevertheless, pristimerin was not selective to
cancer cells, since it inhibited PBMC proliferation with an IC50 of 0.88 microM. DNA synthesis inhibition assessed by 5bromo-2'-deoxyuridine (BrdU) incorporation in HL-60 cells was 70% and 83% for the concentrations of 0.4 and 0.8 microM, respectively. Pristimerin (10 and 20 microM) was not able to inhibit topoisomerase I. In AO/EB (acridine orange/ethidium bromide) staining, all tested concentrations reduced the number of HL-60 viable cells, with the occurrence of necrosis and apoptosis in a concentration-dependent manner, results in agreement with trypan blue exclusion findings. The analysis of membrane integrity and internucleosomal DNA fragmentation by flow cytometry in the presence of pristimerin indicated that treated cells underwent apoptosis. The present data point to the importance of pristimerin as representative of an emerging class of potential anticancer chemicals, exhibiting an antiproliferative effect by inhibiting DNA synthesis and triggering apoptosis Patricia Marรงal Da Costa, Paulo Michel Pinheiro Ferreira, Vanderlan Da Silva Bolzani, Maysa FurlanToxicology in vitro an international journal published in association with BIBRA (2008) Volume: 22, Issue: 4, Pages: 854-863 Its use in medicine has been well documented with no less than 11 patents lodged in South America, America and Japan for a variety of medical uses including the treatment of gastric ulcers. And also as a gastro protective medicine, a gastric anti- inflammatory and an anti-bacterial agent. Patents: L08628 anti ulcerative drug L11341 Labelling of red blood cells and plasma protein L11832 flavonoid rich extract as anti- ulcerative drug L17000 analgesic and anti- inflammatory drug L15618 characterisation of adulteration M30433 anti fertility drug japan T16416 pharmacological effects T16484 anti ulcerative drug Safety In general, the administration of M. ilicifolia to humans and animals is very well tolerated (Geocze et al., 1988; Carlini et al., 1988). In a recent clinical study with 24 healthy volunteers, who received up to 2.000 mg of M. ilicifolia, did not show signs of toxicity (Tabach et al., 2001). According to the investigations carried out in the Paulista School of Medicine (Brazil), doses of M. ilicifolia did not exert toxic effects,nor were there any teratogenic effects in animals with acute nor chronic administrations (Carlini et al.,1988; Oliveira Souza et al., 1991). Only in intraperitoneal administration, combined in equal parts of Maytenus aquifolium, some effects on the SNC such as narcolepsy and general depressive state were observed (Oliveira Souza et al., 1991). A recent study demonstrated that the administration to pregnant rats of 1.000 mg/kg/day of a freeze-dried hydroalcoholic extract of the leaves, did not produce abortive effects nor was the dose embryotoxic. However an estrogenic activity due to uterotrophic effect in animals was observed using a maytenus ilicifolia root extract which is a common ethnopharmaceutical abortificant, which suggests a probable interference with estrogenic receptors. The extract also produced loss of the embryo in the phase of pre-implantation (Montanari and Bevilacqua, 2002 In a toxicity assessment a benzene extract of the aerial parts of espinheira santa given IP to rats had an LD50 of 0.10mg/kg. Given orally the LD50 was 1 gm/kg. A hot water extract given orally to rats was inactive, with an LD50>1 gm/kg. A methanol extract given IP to rats had an LD50 of 0.86 gm/kg. It was inactive when given orally, with an LD50>1 gm/kg.37
In another study a water extract was given IG to mice at 1.09 gm/kg and 272 mg/kg; no toxicity was seen. The chemical maytansine has shown embryotoxic and teratogenic activity in mice when given 0.36 Âľm/kgintraperitoneally on day 6, 7 or 8 of gestation.38 No mutagenic activity was seen for a water extract at 100 mg/plate.6 The plant is considered to be antimutagenic