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OBJECTIVE: To evaluate the clinical efficacy of a standardized special root extract from the plant Petasites hybridus as a preventive therapy for migraine. METHODS: This is a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine. Eligible patients met International Headache Society criteria for migraine, were ages 18 to 65, and had at least two to six attacks per month over the preceding 3 months. The main outcome measure was the decrease in migraine attack frequency per month calculated as percentage change from baseline over a 4-month treatment period. RESULTS: Over 4 months of treatment, in the per-protocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg bid (p = 0.0012 vs placebo), 36% for Petasites extract 50 mg bid (p = 0.127 vs placebo), and 26% for the placebo group. The proportion of patients with a > or =50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of Petasites 75 mg at 1, 2, and 3 months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. CONCLUSIONS: Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine. Petasites 50 mg PO bid was not significantly more effective than placebo on the primary study endpoints.
BACKGROUND: Reactive oxygen radicals have been implicated in the pathophysiology of many neurologic disorders and brain dysfunctions. Kainic acid has been used as a model agent for the study of neurotoxicity of various excitatory amino acids, since it induces neuronal damage through excessive production of reactive oxygen species. Petasites japonicus MAX (butterbur), cultivated as culinary vegetables in Eastern Asia, contains various kinds of phenolic compounds as well as sesquiterpenes, such as petasin. In European countries, the extracts from roots of Petasites species have been used in the therapy of headache or asthma. AIM OF THE STUDY: The objective of our study is to examine the neuroprotective action of the Petasites japonicus MAX (butterbur) extract against oxidative damage in the brain of mice treated with kainic acid. METHODS: Male ICR mice, 6-8 weeks of age, were administered orally the butanol fraction from methanol extract of Petasites japonicus (BMP) or its subfraction (BMP-I or BMP-II) for 5 consecutive days. Thirty min after the final administration, the animals were challenged s. c. with kainic acid (45 mg/kg), and neurobehavioral activities were monitored. In addition, biomarkers of oxidative stress and neuronal loss in the hippocampus for the biochemical, neurobehavioral,morphological evaluations were analyzed 2 days after the kainic acid challenge. RESULTS: During 5-day treatment with BMP or BMP-1, the body weight gain was not significantly different from that of vehicle- treated control animals. Administration of kainic acid alone induced severe epileptiform seizures, causing a lethality of approximately 50%, and injuries of pyramidal cells in the hippocampus of mice which survived the challenge. Kainic acid exposure also resulted in a remarkable decrease in total glutathione level and glutathione peroxidase activity, and an increase in the thiobarbituric acid-reactive substance (TBARS) value in brain tissues. In comparison, coadministration with BMP (400 mg/kg) reduced the 54% lethality of mice, administered with kainic acid alone, to 25 % (P <0.05). Moreover, BMP at the same dose restored the levels of reduced glutathione and TBARS to control values (P <0.05). In further studies, BMP-I (200 mg/kg) ameliorated significantly (P <0.05) the kainic acid-induced behavioral signs, such as seizure activity, and all mice administered with BMP-I (200 mg/kg) survived the kainic acid toxicity. Consistent with the above, the administration with BMP-1 remarkably attenuated the neurobehavioral signs and neuronal loss in hippocampal CA1 and CA3 regions. CONCLUSION: On the basis of these results, the butanol fraction, especially BMP-I, of Petasites japonicus MAX extract is possibly suggested to be a functional agent to prevent oxidative damage in the brain of mice.
OBJECTIVE: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hydridus in the prophylaxis of migraine. METHODS: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a 4-week run-in phase, 60 patients received either the special Petasites hybridus extract petadolex or placebo at a dosage of 2 capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. RESULTS: The frequency of migraine attacks decreased by a maximum of 60% compared to the baseline. This reduction in migraine attacks with petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. CONCLUSIONS: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hydridus has for the prophylactic treatment of migraine.
OBJECTIVE: Migraine is still an unsolved problem. This clinical trial investigates the efficacy and tolerance of Petasites hybridus in the prophylaxis of migraine. METHODS: A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO2 extract from the rhizome of Petasites hybridus. Following a four-week run-in phase, 60 patients received either the special Petasites hybridus extract Petadolex or placebo at a dosage of two capsules (each capsule contains 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity and duration of migraine attacks as well as any accompanying symptoms. RESULTS: The frequency of migraine attacks decreased by a maximum of 60 percent compared to the baseline. This reduction in migraine attacks with Petadolex was significant (p < 0.05) compared to placebo. No adverse events were reported. Petasites was exceptionally well tolerated. CONCLUSIONS: The results suggest that migraine patients can benefit from prophylactic treatment with this special extract. The combination of high efficacy and excellent tolerance emphasizes the particular value that Petasites hybridus has for the prophylactic treatment of migraine.
The objective of this review was to evaluate the strength of evidence of effectiveness for Petasites hybridus in the prophylaxis of migraine. Several databases and other sources were searched to identify randomised-controlled trials investigating P. hybridus preparations. Two trials totalling 293 patients (60 and 233 patients) were included in this review. Both trials investigated the proprietary Petasites root extract Petadolex. The trials were described in narrative way, taking into consideration methodological quality scores. Pooling of data was not carried out due to the heterogeneity of the results. The extract at higher dose (150 mg) showed a greater decreased frequency of migraine attacks and a greater number of responders (improvement>50%) after treatment over 3-4 months than the extract at lower dose (100 mg) and placebo. Moderate evidence of effectiveness is, thus, available for a higher than the recommended dose of the proprietary Petasites root extract Petadolex in the prophylaxis of migraine. Further rigorous studies are required to confirm effectiveness and safety in long-term use before treatment with Petasites root extract can be recommended as an alternative option in the treatment schedule for the prophylaxis of migraine.
Rhizomes of butterbur, Petasites hybridus L. (Asteraceae), have been used since ancient times for the treatment of inflammatory diseases. In the present study, the effects of lipophilic extracts from rhizomes of Petasites hybridus on the formation and release of prostaglandin E2 were investigated. The extracts had different contents of petasin and isopetasin: A: 2.1 % and 0.4 %, B: 0.2 % and 0.1 %, C: 12.1 % and 6.1 % and D: 21.9 % and 9.4 %, respectively. Direct inhibition of cyclooxygenase (COX) -1 and -2 isoenzymes and inhibition of the expression of COX-2 and p42/44 MAP kinase in rat primary microglial cells were tested. All extracts were found to be only weak direct inhibitors of COX-1 (IC50> 400 microg/mL). However, most extracts revealed a strong inhibitory activity against the inducible isoform COX-2 ( A: IC50=30.4 microg/mL; B: IC50=60.6 microg/mL; C: IC50=22.6 microg/mL; D: IC50=20.0 microg/mL). This activity was not correlated to the content of petasin and isopetasin. Pure petasin and isopetasin neither inhibited COX-1 nor COX-2 (IC50 > 400 microM for both compounds and enzymes). Petasites extracts dose-dependently inhibited LPS-induced and thus COX-2-mediated PGE2 release in primary rat microglial cells (A: IC50= 2.4 microg/mL; C: IC50=5.8 microg/mL and D: IC50=4.6 microg/mL). Also this effect was independent from the petasin and isopetasin content. COX-2 synthesis in microglia was totally blocked with 5 microg/mL of C whereas COX-1 synthesis was not influenced. C and D did not affect the LPS-induced activation of p38 MAPK and IkappaBalpha, but they prevented the LPS-induced activation of p42/44 MAPK. Therefore, these Petasites hybridus extracts can be regarded as natural selective inhibitors of COX-2 and its expression, an effect which is independent from the petasin content.
Extracts from Petasites hybridus are in therapeutic use for more than 2000 years. They have been claimed to improve gastrointestinal pain, lung-diseases such as asthma and cough, as well as spasms of the urogenital-tract. We have investigated these claims in animal models of gastro-intestinal ulcers and confirmed that alcoholic extracts of Petasites hybridus block the ethanol-induced gastric damage and reduce small intestinal ulcerations induced in rats by indomethacin. Searching for a possible mode of action, we found that ethanolic extracts of Petasites hybridus inhibit the peptido-leukotriene biosynthesis in mouse peritoneal macrophages but leave prostaglandin biosynthesis unimpaired. We conclude that the active principle could be useful in the treatment of gastro-intestinal human diseases and that Petasites hybridus may contribute to the inhibition of calcium-dependent processes such as leukotriene biosynthesis.
Effect of carbon tetrachloride on the carcinogenicity of the flower stalk of Petasites japonicus was examined in 3 experimental groups of inbred strain ACI rats. Group 1 received 4% petasites diet until termination of the experiment and intragastric administration of CC14, once every 2 weeks, for a total of 15 times. Group 2 received only 4% petasites diet, and Group 3 CC14 and a basal diet. Another group of rats which were fed a basal diet served as a control groups. Both Group 1 and 2 showed the same incidence of hemangioendothelial sarcoma of the liver (6/22). However, the incidence of hyperplastic liver nodules (19/22) and liver cell adenomas (8/22) in Group 1 was significantly higher than in Group 2 (2/22, 0/22). No hyperplastic liver nodules or liver cell adenomas were noted in Group 3. These results indicate that the administration of CC14 probably enhanced the carcinogenic activity of Petasites japonicus in hepatocellular tumorigenesis. Three hemangioendothelial sarcomas of the liver induced in rats in Groups 1 and 2 were subcutaneously transplanted and established as transplantable tumor lines.
We tested the hypothesis that higher respiratory losses caused by higher temperatures in the lowlands, compared to montane sites, prevent growth of the montane hemicryptophyte Petasites albus (Asteraceae). In addition, we tested whether increased levels of herbivory enhanced carbon losses at lower elevations. Rhizomes of Petasites albus were transplanted to a montane and a lowland site. In the subsequent three growing seasons the plants were artificially defoliated to simulate mollusc herbivory. Whereas there were no altitudinal differences in the leaf number per plant, the leaf area was higher at the montane site. At the montane site, the leaf number and leaf area decreased with increasing damage, and the rhizome dry weight in the third year was much higher in the undamaged plants. In contrast, fructan concentrations in the rhizomes that were harvested at the end and at the beginning of the growing seasons were generally higher at the lowland site. No clear defoliation effects were observed on most harvest dates. The results indicate that the lower altitudinal limit of Petasites albus cannot be explained by the negative effects of higher temperatures or more leaf damage by herbivores in the lowlands, either alone or in combination. An explanation will require consideration of other site factors such as competition and possibly interactions with herbivory and carbohydrate storage.
Extracts from Petasites hybridus were found to inhibit peptido-leukotriene biosynthesis in isolated peritoneal macrophages. Chemical analysis by gas chromatography coupled with mass and infrared spectroscopy facilitated the identification of three isomeric oxopetasan esters, petasin, and isopetasin as the main compounds of these extracts. Fractionations obtained by column chromatography of the most effective extract indicated a correlation between peptido-leukotriene biosynthesis inhibition and the content of isopetasin, a sesquiterpene ester of isopetasol and angelic acid, as well as the isomeric oxopetasan esters. Petasin, a structural isomer of isopetasin, however, was found to be inactive. It may even reduce the peptido-leukotrine inhibitory effect of isopetasin. It is concluded that isopetasin and the oxopetasan esters in Petasites hybridus inhibit the biosynthesis of the vasoconstrictive peptido-leukotrienes. This effect may contribute to some of the medicinal properties of Petasites hybridus extracts such as, e.g., gastroprotection and spasmolytic activity.
Petasites formosanus, an indigenous species of Petasites, has been used to treat cardiovascular diseases such as hypertension for years. We have suggested recently that S-petasin, a major sesquiterpene from P. formosanus, inhibits vascular smooth muscle contraction through inhibition of voltage-dependent Ca(2+) channels, a phenomenon possibly responsible for the hypotensive effect of P. formosanus. This study was designed to examine the chronotropic and inotropic actions of S-petasin in the heart in vivo and in vitro. Administration of S-petasin (0.1-1.5 mg/kg i.v.) in anesthetized rats reduced heart rate dose-dependently. This response was consistent with significant suppression of both contractile amplitude and spontaneous firing rate of isolated atria, responses that were not antagonized by atropine (1 microM). Mechanical evaluation in isolated ventricular myocytes showed that S-petasin (0.1 to 100 microM) depressed peak myocyte contraction and intracellular Ca(2+) transients concentration-dependently. The duration of myocyte contraction was not affected. Whole-cell voltage clamp analysis revealed that S-petasin inhibited the L-type Ca(2+) current ( I(Ca,L)) concentration-dependently and shifted the steady-state inactivation curve of I(Ca,L) to more negative potentials. However, a receptor-binding assay failed to identify any significant interaction between S-petasin (0.1-300 microM) and the dihydropyridine binding sites of L-type voltage-dependent Ca(2+) channels. Taken together, these data show that the negative chronotropic and inotropic properties of S-petasin that can be ascribed mainly to I(Ca,L) inhibition, but not to blockade of dihydropyridine binding sites of L-type Ca(2+) channel or to muscarinic receptor activation.
Petasites formosanus is an indigenous species of the medicinal plant Petasites which has been used to treat hypertension. Both S-petasin and its isoform iso-S-petasin have been shown to be the effective ingredients in P. formosanus. However, their effect on heart function has not been revealed. This study was to examine the effect of iso-S-petasin on cardiac contractile function at the myocyte level. Ventricular myocytes were isolated from adult rat hearts and were stimulated to contract at 0.5 Hz under 1.0 mM extracellular Ca(2+). Contractile properties were evaluated using an IonOptix MyoCam system including peak shortening (PS), time to PS (TPS), time to 90% re-lengthening (TR(90)) and maximal velocity of shortening/re-lengthening (+/-dL/dt). Intracellular Ca(2+) properties were assessed by fura-2 and presented as Ca(2+)-induced Ca(2+) release (CICR) and intracellular Ca(2+) decay. Acute application of iso-S-petasin (10(-7) to 10(-4) M) elicited a concentration-dependent inhibition in PS and CICR, with maximal inhibitions of 51.0% and 31.0%, respectively. Iso-S-petasin also induced a concentration-dependent inhibition of+/-dL/dt without affecting TPS, TR(90), baseline intracellular Ca(2+) level or intracellular Ca(2+) decay. Elevation of extracellular Ca(2+) from 1.0 mM to 2.7 mM significantly antagonized the iso-S-petasin-induced depression in PS and CICR. These results demonstrated a direct depressant action of iso-S-petasin on ventricular contraction, which may work in concert with its antihypertensive action to reduce the cardiac load. The iso-S-petasin-induced decrease in CICR may play a role in its cardiac depressant effect.
A large production of leukotrienes (LTs) can be induced in human eosinophils or neutrophils by priming with granulocyte-macrophage colony-stimulating factor and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a. Here, we investigated the effects of a plant extract of petasites hybridus (Ze339) and its isolated active sesquiterpene ester petasin in these two in vitro cell models. Zileuton, a 5-lipoxygenase inhibitor, was used as a positive control. All compounds inhibited both cysteinyl-LT synthesis in eosinophils and LTB(4) synthesis in neutrophils. In contrast, only Ze339 and petasin, but not zileuton, abrogated PAF- and C5a-induced increases in intracellular calcium concentrations. These data suggest that Ze339 and petasin may block, compared to zileuton, earlier signalling events initiated by G protein-coupled receptors in granulocytes, perhaps at the level of or proximal to phospholipase C(beta). Taken together, petasin appears to be one major active compound of petasites hybridus extract, since it demonstrates the same inhibitory activities on calcium fluxes and subsequent LT generation in both eosinophils and neutrophils as Ze339 does.
The 3rd Petasites gathering took place in Romanshorn, Switzerland on March 29, 1996 and gave 16 European scientists the opportunity to transmit their latest considerable discoveries to interested researchers working in different scientific disciplines such as pharmacognosy, botany, chemistry, pharmacology, medicine or clinical pharmacy. The newest findings on Petasites hybridus as a significant plant drug showed very promising aspects of therapeutic utility. Great progress has been made in chemical analytical methods and the determination of pharmacological activities. Substantial advances have also occurred in the production of bioassay procedures and plant materials, particularly utilizing cell- and tissue-culture techniques.
The essential oil of the rhizomes of Petasites hybridus (Asteraceae) was investigated by gas chromatography, mass spectrometry, 1- and 2-dimensional NMR techniques and chemical correlations. Two new sesquiterpene hydrocarbons, petasitene and pethybrene, could be identified. Petasitene is the parent sesquiterpene hydrocarbon to the known norsesquiterpene albene. The absolute configuration of petasitene could be assigned by conversion of natural albene to petasitene by partial synthesis. Pethybrene is a tricyclic sesquiterpene hydrocarbon, which rearranges to the structurally related alpha-isocomene under acidic conditions. Several sesquiterpenes were isolated from the hydrodistillation products of Petasites hybridus and investigated by spectroscopic methods and chemical correlations
The methanol extract from Clerodendrum petasites S. Moore (CP extract) was assessed for anti-inflammatory and antipyretic activities on the experimental animal models. It was found that CP extract possessed moderate inhibitory activity on acute phase of inflammation in a dose-related manner as seen in ethyl phenylpropiolate-induced ear edema (ED(50)=2.34 mg/ear) as well as carrageenin-induced hind paw edema (ED(30)=420.41 mg/kg) in rats. However, CP extract did not elicit any inhibitory effect on arachidonic acid-induced hind paw edema in rats. In subchronic inflammatory model, CP extract provoked a significant reduction of transudation but had no effect on proliferative phase when tested in cotton pellet-induced granuloma model. CP extract also reduced the alkaline phosphatase activity in serum of rats in this animal model. Moreover, CP extract possessed an excellent antipyretic effect when tested in yeast-induced hyperthermic rats. It is postulated that the anti-inflammatory and antipyretic effects of CP extract are caused by the inhibition of the prostaglandin synthesis. Anyhow, CP extract did not possess any analgesic activity in acetic acid-induced writhing response in mice. The results obtained show that C. petasites has beneficial properties since it possesses potent antipyretic and moderate anti-inflammatory activities without ulcerogenic effect.
The Swiss company Zeller is developing an extract of the plant Petasites hybridus (butterbur) as an antiallergic agent. Petasites hybridus extracts have been known for some time to have therapeutic properties. Zeller's extract is codenamed ZE 339. In in vitro studies, ZE 339 inhibited cysteinyl-leukotriene synthesis in eosinophils and leukotriene B4 synthesis in neutrophils. In mid-2003, ZE 339 was approved, and launched, in Switzerland as Tesalin for the treatment of seasonal allergic rhinitis as a prescription-only product. Tesalin is available as film-coated tablets. Zeller has stated that hepatotoxicity cannot be totally excluded as a possible adverse reaction to Tesalin.