A.Vogel - Helhetsdoktorn

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B i o f o r c e M o n o g r a p h C o m m o n B u t t e r b u r ceae (Compositae) and almost ubiquitous in the Boraginaceae (e.g. Symphytum officinale, comfrey). The PAs are present as hydrophilic nontoxic N-oxides in the rhizome of the butterbur. It is only after “reductive toxification” by bacteria of the bowel flora that the now lipophilic PAs are absorbed and oxidised in the liver by cytochrome P-450, and then metabolised to toxic or carcinogenic (alkylating) pyrrole derivatives. In the worst case, PA intoxication can manifest itself as Budd-C h i a r i syndrome (hepatic vein occlusion). The carcinogenicity leads to benign and malignant epithelial hepatic tumours (hepatomas, hepatocellular carcinomas, cholangiomas, haemangioendotheliomas etc.) 14. Due to special extraction methods (see below), the concentrations of PAs in finished medicines are below the detection limit of 0.1 ppm 13 and are therefore safe toxicologically. 4 5-lipoxygenase (5-LO) (Ca-dependent) 5-hydroperoxieicosatetraenic acid (5-HPETE) LT B 4 (leukotactic) LT A 4 Petasines and synthetic 5-LO inhibitors LT C 4 LT D 4 LT E 4 Phospholipids Arachidonic acid (AA) Phospholipase A 2 Extraction methods Cyclo-oxygenases (COX1, COX2) Prostaglandins = Cysteinyl leukotriene = SRSA Actions of the SRSA (slow reacting substances of anaphylaxis): ● Contraction of smooth muscle in bronchi and blood vessels. ● Increase in vascular permeability with consequent perivascular oedema. Leukotriene receptor antagonists block the effect of cysteinyl leukotrienes LT C 4 ,LT D 4 and LT E 4 . Petasines and synthetic 5-lipoxygenase inhibitors block the synthesis of all leukotrienes. The leukotactic effect of the LT B 4 is thus also prevented. Inhibitory effect of the petasines (petasine, isopetasine, neopetasine) LT = Leukotriene Fig. 5: Arachidonic acid cascade and site of action of the petasines Rhizomes, which currently are still obtained from collection in the wild, are used for the preparation of Fig. 6: Sesquiterpenes of the furanopetasine chemovariety finished medicines. La r g e - s c a l e culture of the petasine chemovariety will be available soon in order to ensure sustained use of the plant. A licence application for an extract of the leaves is in process while going to press. The constituents are today extracted with liquid CO 2 (lipophilic) under increased pressure. This process results in extracts that are practically pyrrolizidine-free (detection limit of 0.1 ppm), as the hydrophilic PA N-oxides are not extracted alongside. The PA had to be removed from ethanolic extracts Fig. 7: Pyrrolizidine alkaloids are synthesised in the root as N-oxide derivatives. Reductive toxification to the tertiary alkaloids takes place only in the human digestive tract. Alkaloid N-oxide, polar, salt-like, nontoxic Integerrimin Furanoeremophilane Eremophilanlactone reductive toxification 2 examples of pyrrolizidine alkaloids Senkirkin subsequently by means of cation exchangers. Tea (equivalent to an aqueous extract) made from leaves or rhizomes should no longer be used, as the PA content exceeds the permitted 0.1 µg daily 13. tertiary alkaloid (senecionin), lipophilic, toxic
Indications Only the indications confirmed by studies are discussed in this chapter. However, for the sake of completeness, Table 1 lists the traditional uses of butterbur alongside the modern uses. Migraine prophylaxis Butterbur rhizome extract is effective in the prophylaxis of migraine; in a randomised, double-blind, placebocontrolled study of parallel groups of 60 patients (50 mg Petasites rhizome extract twice daily) for 12 weeks, the number of attacks per month (Fig. 8) fell from 3.3±1.5 at the start to 1.3±0 . 9 after 8 weeks (Tab. 2), which is equivalent to a maximum reduction of 60% (placebo 17.2%) compared to the baseline 1 5. The number of migraine days per month also fell significantly (p < 0.05) from 3.4±1.6 days at the start to 1.7±0.9 days after 12 weeks. The intensity and duration of the attacks did not decrease significantly. A.<strong>Vogel</strong> B i o f o r c e M o n o g r a p h C o m m o n B u t t e r b u r Table 1: Butterbur indications The tolerability was assessed by the patients as excellent. No adverse effects occurred. The extract employed is therefore comparable to the commonly used synthetic migraine prophylactic drugs propranolol (- 38.2%), timolol (- 43.9%) 16 and flunarizine (- 39%) 17 with regard to the percentage reduction in the number of attacks per month. The intensity and duration of the attacks were not influenced by these drugs either. The leukotriene antagonism of the butterbur rhizome extract might be involved in this prophylactic effect on migraine: in an open study in 17 patients, the leukotriene receptor antagonist montelukast, which is employed in the treatment of asthma, was significantly effective in reducing the frequency of migraine attacks 18. In addition, petasine inhibits a rise in the intracellular calcium concentration, just like the calcium antagonists (e.g. flunarizine) that have long been used in migraine prophylaxis. Indication traditional modern Migraine - + Tension headache ✔ (+) Cramp-like pains in the urinary tract ✔ + Cramp-like pains in the gastrointestinal and biliary area ✔ (+) Dysmenorrhoea ✔ (+) Emmenagogue ✔ - Back pain ✔ - Cough ✔ - Asthma ✔ (+) Allergic rhinitis - + [L] Wound healing, external ✔ [L] - Unless specially stated, rhizomes (extract or powder) were used. ✔ traditional use + indication confirmed by studies. – not used (+) indication inadequately confirmed by studies [L] leaf extract or pounded leaves used externally As with all drugs used for migraine prophylaxis, the mechanism of action has still not been elucidated in detail. Tension headaches The efficacy in tension headaches (vasomotor headaches) was demonstrated in a multicentre prospective clinical study of 33 patients in general practices in Switzerland 19. A general practice study by Gruia in 1986 of 22 patients for 4 weeks obtained similar results. H o w e v e r, the efficacy in migraine prophylaxis exceeded that in vasomotor headache 20. The available studies indicate efficacy in tension headaches. Spasm of the urogenital tract The spasmolytic activity of butterbur extracts, similar to papaverine, was demonstrated in 1951 by Bucher in the isolated guinea pig intestine 4. In 1955, Aebi et al. were the first to isolate and characterise two substances with a spasmolytic action from rhizomes of Petasites hybridus and named them petasine and isopetasine respectively 21. In a controlled study with 20 patients in each of the 2 treatment groups, a butterbur extract in the subacute stage of ureteric colic (i.e. after treating the acute symptoms with papaverine i.v.) demonstrated a similar effect to N-butylscopolamine (Buscopan ® ): the 2 groups received either 1 Buscopan ® tablet 5 times daily or 2 capsules of butterbur rhizome extract up to 2-hourly (max. 14 caps daily). Despite this high dosage, no adverse side effects occurred 22. A general practice clinical study in 40 patients showed a good effect in cystitis, renal/ureteric stones and pain in prostatitis 23. 5
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A.Vogel - Helhetsdoktorn

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