O’brien P, Carrasco-Pozo C, Speisky H.

Graduate Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ont., Canada.

Chem Biol Interact. 2005 Oct 8; [Epub ahead of print]

PMID: 16221469 [PubMed - as supplied by publisher]

Piscaglia F, Leoni S, Venturi A, Graziella F, Donati G, Bolondi L.

Division of Internal Medicine, Department of Internal Medicine and Gastroenterology, University of Bologna, IT-40138 Bologna, Italy. Piscagl@med.unibo.it

Scand J Gastroenterol. 2005 Feb;40(2):236-9.

PMID: 15764158 [PubMed - indexed for MEDLINE]

Santanam N, Penumetcha M, Speisky H, Parthasarathy S.

Department of Pathology, LSU Health Science Center, 533 Bolivar St, New Oreleans, LA 70112, USA.

Atherosclerosis. 2004 Apr;173(2):203-10.

PMID: 15064093 [PubMed - indexed for MEDLINE]

Schmeda-Hirschmann G, Rodriguez JA, Theoduloz C, Astudillo SL, Feresin GE, Tapia A.

Laboratorio de Quimica de Productos Naturales, Instituto de Quimica de Recursos Naturales, Universidad de Taka, Casilla 747, Talca, Chile. schmeda@pehuenche.utalca.cl

PMID: 12747739 [PubMed - indexed for MEDLINE]

Kubinova R, Machala M, Minksova K, Neca J, Suchy V.

Department of Natural Drugs, Academy of Sciences, Czech Republic.

Pharmazie. 2001 Mar;56(3):242-3.

PMID: 11265593 [PubMed - indexed for MEDLINE]

Jang YY, Song JH, Shin YK, Han ES, Lee CS.

Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Korea.

Pharmacol Res. 2000 Oct;42(4):361-71.

PMID: 10987997 [PubMed - indexed for MEDLINE]

Almeida ER, Melo AM, Xavier H.

Laboratorio de Farmacologia do Departamento de Antibioticos, Universidade Federal de Pernambuco, Recife, Pernambuco, CEP 50670-901, Brazil.

Phytother Res. 2000 Mar;14(2):99-102.

PMID: 10685105 [PubMed - indexed for MEDLINE]

Vila R, Valenzuela L, Bello H, Canigueral S, Montes M, Adzet T.

Planta Med. 1999 Mar;65(2):178-9.

PMID: 10193210 [PubMed - indexed for MEDLINE]

Kang JJ, Cheng YW, Fu WM.

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.

Jpn J Pharmacol. 1998 Feb;76(2):207-12.

PMID: 9541284 [PubMed - indexed for MEDLINE]

Kang JJ, Cheng YW.

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, R.O.C.

Planta Med. 1998 Feb;64(1):18-21.

PMID: 9491763 [PubMed - indexed for MEDLINE]

Speisky H, Cassels BK.

Unidad de Bioquimica Farmacologica y Lipidos, Universidad de Chile, Santiago.

Pharmacol Res. 1994 Jan-Feb;29(1):1-12.

PMID: 8202440 [PubMed - indexed for MEDLINE]

Backhouse N, Delporte C, Givernau M, Cassels BK, Valenzuela A, Speisky H.

Departamento de Quimica Farmacologica y Toxicologica, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago.

Agents Actions. 1994 Oct;42(3-4):114-7.

PMID: 7879695 [PubMed - indexed for MEDLINE]

O’brien P, Carrasco-Pozo C, Speisky H.

Graduate Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ont., Canada.

Chem Biol Interact. 2005 Oct 8; [Epub ahead of print]

The increasing recognition of the participation of free radical-mediated oxidative events in the initiation and/or progression of cardiovascular, tumoural, inflammatory and neurodegenerative disorders, has given rise to the search for new antioxidant molecules. An important source of such molecules has been plants for which there is an ethno-cultural base for health promotion. An important example of this is boldo (Peumus boldus Mol.), a chilean tree whose leaves have been traditionally employed in folk medicine and is now widely recognized as a herbal remedy by a number of pharmacopoeias. Boldo leaves are rich in several aporphine-like alkaloids, of which boldine is the most abundant one. Research conducted during the early 1990s led to the discovery that boldine is one of the most potent natural antioxidants. Prompted by the latter, a large and increasing number of studies emerged, which have focused on characterizing some of the pharmacological properties that may arise from the free radical-scavenging properties of boldine. The present review attempts to exhaustively cover and discuss such studies, placing particular attention on research conducted during the last decade. Mechanistic aspects and structure-activity data are discussed. The review encompasses pharmacological actions, which arise from its antioxidant properties (e.g., cyto-protective, anti-tumour promoting, anti-inflammatory, anti-diabetic and anti-atherogenic actions), as well as those that do not seem to be associated with such activity (e.g., vasorelaxing, anti-trypanocidal, immuno- and neuro-modulator, cholagogic and/or choleretic actions). Based on the pharmacological and toxicological data now available, further research needs and recommendations are suggested to define the actual potential of boldine for its use in humans.

PMID: 16221469 [PubMed - as supplied by publisher]

Piscaglia F, Leoni S, Venturi A, Graziella F, Donati G, Bolondi L.

Division of Internal Medicine, Department of Internal Medicine and Gastroenterology, University of Bologna, IT-40138 Bologna, Italy. Piscagl@med.unibo.it

Scand J Gastroenterol. 2005 Feb;40(2):236-9.

A case is reported in which a several-fold increase in transaminases and gamma-GT was detected in an elderly male patient with fatty liver. The patient was regularly taking a mixture of herbal products, used as a laxative, for a number of years, with no alteration of blood chemistry until 6 months before the present observation. However, the composition of the mixture had been modified by the manufacturer in the past 5 months, with addition of boldo leaf extracts. Transaminases promptly returned to normal after withdrawal of the laxative. It is concluded that boldo leaf extracts might be hepatotoxic, at least in elderly patients with fatty liver.

Publication Types: Case Reports

PMID: 15764158 [PubMed - indexed for MEDLINE]

Santanam N, Penumetcha M, Speisky H, Parthasarathy S.

Department of Pathology, LSU Health Science Center, 533 Bolivar St, New Oreleans, LA 70112, USA.

Atherosclerosis. 2004 Apr;173(2):203-10.

A corollary to the oxidation hypothesis of atherosclerosis is that the consumption of antioxidants is beneficial. However, the literature is divided in support of this conclusion. In this study, Boldine, an alkaloid of Peumus boldus and reduced form of RU486, was tested for their antioxidant potency both in, in vitro oxidation system and in mouse models. Boldine decreased the ex-vivo oxidation of low-density lipoprotein (LDL). Two different in vivo studies were performed to study the effect of these compounds on the atherosclerotic lesion formation in LDLR(-/-) mice. In study I, three groups of LDLR(-/-) mice (N = 12 each) were fed an atherogenic diet. Group 1 was given vehicle and group 2 and 3 were given 1mg of Boldine or Red RU per day for 12 weeks. In study II, two groups of LDLR(-/-) mice N = 10 each) were fed an atherogenic diet. Group 1 was given vehicle and group 2 was given 5mg of Boldine per day. The results indicated that there was a decrease in lesion formation reaching a 40% reduction due to Boldine and 45% reduction by Red RU compared to controls. The in vivo tolerance of Boldine in humans (has been used as an herbal medicine in other diseases) should make it an attractive alternative to Vitamin E.

PMID: 15064093 [PubMed - indexed for MEDLINE]

Schmeda-Hirschmann G, Rodriguez JA, Theoduloz C, Astudillo SL, Feresin GE, Tapia A.

Laboratorio de Quimica de Productos Naturales, Instituto de Quimica de Recursos Naturales, Universidad de Taka, Casilla 747, Talca, Chile. schmeda@pehuenche.utalca.cl

Free Radic Res. 2003 Apr;37(4):447-52.

The dry leaves of Peumus boldus (Monimiaceae) are used in infusion or decoction as a digestive and to improve hepatic complains. Preliminary assays showed free-radical scavenging activity in hot water extracts of boldo leaves, measured by the decoloration of a methanolic solution of the 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH). Assay-guided isolation led to the active compounds. Catechin proved to be the main free-radical scavenger of the extracts. Lipid peroxidation in erythrocytes was inhibited by boldo extracts and fractions at 500 microg/ml with higher effect for the ethyl acetate soluble and alkaloid fractions. The IC50 for catechin and boldine in the lipid peroxidation test were 75.6 and 12.5 microg/ml, respectively. On the basis of dry starting material the catechin content in the crude drug was 2.25% while the total alkaloid calculated as boldine was 0.06%. The activity of boldine was six times higher than catechin in the lipid peroxidation assay. However, the mean catechin:total alkaloid content ratio was 37:1. The relative concentration of alkaloids and phenolics in boldo leaves and their activity suggest that free-radical scavenging effect is mainly due to catechin and flavonoids and that antioxidant effect is mainly related with the catechin content The high catechin content of boldo leaves and its bioactivity suggest that quality control of Boldo folium has to combine the analysis of catechin as well as their characteristic aporphine alkaloids.

PMID: 12747739 [PubMed - indexed for MEDLINE]

Kubinova R, Machala M, Minksova K, Neca J, Suchy V.

Department of Natural Drugs, Academy of Sciences, Czech Republic.

Pharmazie. 2001 Mar;56(3):242-3.

Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens.

PMID: 11265593 [PubMed - indexed for MEDLINE]

Jang YY, Song JH, Shin YK, Han ES, Lee CS.

Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Korea.

Pharmacol Res. 2000 Oct;42(4):361-71.

Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. Several antioxidants have been described as beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1, 10-dimethoxyaporphine) is a major alkaloid found in the leaves and bark of boldo (Peumus boldus Molina), and has been shown to possess antioxidant activity and anti-inflammatory effects. From this point of view, the possible anti-diabetic effect of boldine and its mechanism were evaluated. The experiments were performed on male rats divided into four groups: control, boldine (100 mg kg(-1), daily in drinking water), diabetic [single dose of 80 mg kg(-1)of streptozotocin (STZ), i.p.] and diabetic simultaneously fed with boldine for 8 weeks. Diabetic status was evaluated periodically with changes of plasma glucose levels and body weight in rats. The effect of boldine on the STZ-induced diabetic rats was examined with the formation of malondialdehydes and carbonyls and the activities of endogenous antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in mitochondria of the pancreas, kidney and liver. The scavenging action of boldine on oxygen free radicals and the effect on mitochondrial free-radical production were also investigated. The treatment of boldine attenuated the development of hyperglycemia and weight loss induced by STZ injection in rats. The levels of malondialdehyde (MDA) and carbonyls in liver, kidney and pancreas mitochondria were significantly increased in STZ-treated rats and decreased after boldine administration. The activities of mitochondrial manganese superoxide dismutase (MnSOD) in the liver, pancreas and kidney were significantly elevated in STZ-treated rats. Boldine administration decreased STZ-induced elevation of MnSOD activity in kidney and pancreas mitochondria, but not in liver mitochondria. In the STZ-treated group, glutathione peroxidase activities decreased in liver mitochondria, and were elevated in pancreas and kidney mitochondria. The boldine treatment restored the altered enzyme activities in the liver and pancreas, but not the kidney. Boldine attenuated both STZ- and iron plus ascorbate-induced MDA and carbonyl formation and thiol oxidation in the pancreas homogenates. Boldine decomposed superoxide anions, hydrogen peroxides and hydroxyl radicals in a dose-dependent manner. The alkaloid significantly attenuated the production of superoxide anions, hydrogen peroxide and nitric oxide caused by liver mitochondria. The results indicate that boldine may exert an inhibitory effect on STZ-induced oxidative tissue damage and altered antioxidant enzyme activity by the decomposition of reactive oxygen species and inhibition of nitric oxide production and by the reduction of the peroxidation-induced product formation. Boldine may attenuate the development of STZ-induced diabetes in rats and interfere with the role of oxidative stress, one of the pathogeneses of diabetes mellitus. Copyright 2000 Academic Press.

PMID: 10987997 [PubMed - indexed for MEDLINE]

Almeida ER, Melo AM, Xavier H.

Laboratorio de Farmacologia do Departamento de Antibioticos, Universidade Federal de Pernambuco, Recife, Pernambuco, CEP 50670-901, Brazil.

Phytother Res. 2000 Mar;14(2):99-102.

The hydro-alcohol extract of the dry leaves of Peumus boldus and boldine, showed abortive and teratogenic action and changes in the blood levels of bilirubin, cholesterol, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and urea in rats. The long term administration of the extract and boldine did not cause histological modification during a period of 90 days. Copyright 2000 John Wiley & Sons, Ltd.

PMID: 10685105 [PubMed - indexed for MEDLINE]

Vila R, Valenzuela L, Bello H, Canigueral S, Montes M, Adzet T.

Planta Med. 1999 Mar;65(2):178-9.

The composition and the antimicrobial activity of the essential oil from the leaves of Peumus boldus is investigated. Analyses of the oil obtained by hydrodistillation were carried out by GC and GC-MS using columns of two different stationary phases. Fractionation of the essential oil by column chromatography on silica gel was performed to improve identification of some constituents. More than 90% of the total oil (46 components) was identified, major constituents being monoterpenes (90.5%), among which limonene (17.0%), p-cymene (13.6%), 1.8-cineole (11.8%), and beta-phellandrene (8.4%) reached the highest percentages. Determination of the minimal bactericidal or fungicidal concentration against several microorganisms showed interesting activities towards Streptococcus pyogenes, Micrococcus sp., and Candida sp.

Publication Types: Letter

PMID: 10193210 [PubMed - indexed for MEDLINE]

Kang JJ, Cheng YW, Fu WM.

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.

Jpn J Pharmacol. 1998 Feb;76(2):207-12.

The effects of boldine [(S)-2,9-dihydroxyl-1,10-dimethoxy-aporphine], a major alkaloid in the leaves and bark of Boldo (Peumus boldus Mol.), on neuromuscular transmission were studied using a muscle phrenic-nerve diaphragm preparation. Boldine at concentrations lower than 200 microM preferentially inhibited, after an initial period of twitch augmentation, the nerve-evoked twitches of the mouse diaphragm and left the muscle-evoked twitches unaffected. The twitch inhibition could be restored by neostigmine or washout with Krebs solution. The twitches evoked indirectly and directly were both augmented initially, suggesting that the twitch augmentation induced by boldine was myogenic. Boldine inhibited the acetylcholine-induced contraction of denervated diaphragm dose-dependently with an IC50 value of 13.5 microM. At 50 microM, boldine specifically inhibited the amplitude of the miniature end plate potential. In addition, boldine was similar to d-tubocurarine in its action to reverse the neuromuscular blocking action of alpha-bungarotoxin. These results showed that the neuromuscular blockade by boldine on isolated mouse phrenic-nerve diaphragm might be due to its direct interaction with the postsynaptic nicotinic acetylcholine receptor.

PMID: 9541284 [PubMed - indexed for MEDLINE]

Kang JJ, Cheng YW.

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, R.O.C.

Planta Med. 1998 Feb;64(1):18-21.

The effects of boldine [(S)-2,9-dihydroxy-1,10-dimethoxyaporphine], a major alkaloid in the leaves and bark of boldo (Peumus boldus Mol.), on skeletal muscle were studied using mouse diaphragm and isolated sarcoplasmic reticulum membrane vesicles. Boldine, at 10-200 microM, has little effect on the muscle-evoked twitches; however, the ryanodine-induced contracture was potentiated dose-dependently. At higher concentrations of 300 microM, boldine by itself induced muscle contracture of two phases, which were caused by the influx of extracellular Ca2+ and induction of Ca2+ release from the internal Ca2+ storage site, the sarcoplasmic reticulum, respectively. When tested with isolated sarcoplasmic reticulum membrane vesicles, boldine dose-dependently induced Ca2+ release from actively loaded sarcoplasmic reticulum vesicles isolated from skeletal muscle of rabbit or rat which was inhibited by ruthenium red, suggesting that the release was through the Ca2+ release channel, also known as the ryanodine receptor. Boldine also dose-dependently increased apparent [3H]-ryanodine binding with the EC50 value of 50 microM. In conclusion, we have shown that boldine could sensitize the ryanodine receptor and induce Ca2+ release from the internal Ca2+ storage site of skeletal muscle.

PMID: 9491763 [PubMed - indexed for MEDLINE]

Speisky H, Cassels BK.

Unidad de Bioquimica Farmacologica y Lipidos, Universidad de Chile, Santiago.

Pharmacol Res. 1994 Jan-Feb;29(1):1-12.

Boldo (Peumus boldus Mol.), a Chilean tree traditionally employed in folk medicine and recognized as a herbal remedy in a number of pharmacopoeias, mainly for the treatment of liver ailments, has recently been the subject of increasing attention. Boldine, in particular, the major and most characteristic alkaloidal constituent of this plant species, now emerges as its most interesting active principle from the pharmacological viewpoint. The recent demonstration that boldine is an effective antioxidant in both biological and non-biological systems has opened up the perspective of a broad range of uses in medicine and industry. Given the toxicological data on this alkaloid, its antioxidative properties situate it as a potentially useful substance in many disease states featuring free-radical related oxidative injury. This review attempts to cover and discuss the studies conducted over the last four decades on the chemical and pharmacological properties of boldo and its main constituent.

Publication Types: Review, Review, Tutorial

PMID: 8202440 [PubMed - indexed for MEDLINE]

Backhouse N, Delporte C, Givernau M, Cassels BK, Valenzuela A, Speisky H.

Departamento de Quimica Farmacologica y Toxicologica, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago.

Agents Actions. 1994 Oct;42(3-4):114-7.

Boldine, an antioxidant alkaloid isolated from Peumus boldus, exhibits a dose-dependent anti-inflammatory activity in the carrageenan-induced guinea pig paw edema test with an oral ED50 of 34 mg/kg. Boldine also reduces bacterial pyrogen-induced hyperthermia in rabbits to an extent which varied between 51% and 98% at a dose of 60 mg/kg p.o. In vitro studies carried out in rat aortal rings revealed that boldine is an effective inhibitor of prostaglandin biosynthesis, promoting 53% inhibition at 75 microM. The latter in vitro effect may be mechanistically linked to the anti-inflammatory and antipyretic effects of boldine exerted in vivo.

PMID: 7879695 [PubMed - indexed for MEDLINE]