Characteristics, clinical effect profile and tolerability of a nasal spray preparation of Artemisia abrotanum L. for allergic rhinitis.

A nasal spray formulation containing an extract of Artemisia abrotanum L. was developed for therapeutic use in patients with allergic rhinitis and other upper airway disorders. The nasal spray preparation used contains a mixture of essential oils (4 mg/ml) and flavonols (2.5 microg/ml), of which some components have been shown to possess antiinflammatory, expectorant, spasmolytic as well as antiseptic and antimicrobial activities. The most important constituents in the essential oil fraction of the preparation are 1,8-cineole, linalool and davanone, while the flavonol fraction contains centauredin, casticin and quercetin dimethyl-ethers. No trace of thujon was observed in the essential oil of the Artemisia abrotanum L. genotype "Tycho" used for the manufacture of the nasal spray preparation. In 12 patients with diagnoses of allergic rhinitis, allergic conjunctivitis and/or bronchial obstructive disease, the nasal spray was given immediately after the appearance of characteristic allergic nasal symptoms. In 10 of the 12 patients, allergic rhinitis with nasal congestion, sneezing and rhinorrhea was dominant. After administration of the nasal spray, all patients experienced a rapid and significant symptom relief of nasal symptoms, comparable to the effect of antihistamine and chromoglicate preparations which several of the patients had used previously. The effect was present within 5 minutes after the administration and lasted for several hours. In 7 of the 10 rhinitis patients with concomitant symptoms of allergic conjunctivitis, a significant subjective relief of eye symptoms was also experienced. In 3 of the 6 patients who had a history of characteristic symptoms of endogenous, exogenous or exercise induced bronchial obstructive disease, there was a bronchial symptom relief by the nasal spray preparation which was experienced as rapid and clinically significant. It is concluded from the present proof of concept study, that a nasal spray formulation containing an extract characterised by a mixture of essential oils and flavonols from the Artemisia abrotanum L. genotype "Tycho", appears to be clinically useful and suitable for the prophylactic and therapeutic management of patients with allergic rhinitis and adjuvant symptoms.

Oxygenated sesquiterpenoids from a nonpoisonous sardinian chemotype of giant fennel (Ferula communis).

The roots of the nonpoisonous chemotype of giant fennel (Ferula communis) from Sardinia afforded a novel cadinanetriol (1), whose structure was established by spectroscopic data and confirmed by synthesis from the E,E-Delta (1(10),5) germacradiene allohedycariol. A number of known compounds were also identified. Despite the lack of morphological differences, a broad chemical diversity exists within giant fennel, underlying the contrasting data on its poisonous properties.

Honokiol and magnolol increase the number of [3H] muscimol binding sites three-fold in rat forebrain membranes in vitro using a filtration assay, by allosterically increasing the affinities of low-affinity sites.

1. The bark of the root and stem of various Magnolia species has been used in Traditional Chinese Medicine to treat a variety of disorders including anxiety and nervous disturbances. The biphenolic compounds honokiol (H) and magnolol (M), the main components of the Chinese medicinal plant Magnolia officinalis, interact with GABA(A) receptors in rat brain in vitro. We compared the effects of H and M on [3H]muscimol (MUS) and [3H]flunitrazepam (FNM) binding using EDTA/water dialyzed rat brain membranes in a buffer containing 150 mM NaCl plus 5 mM Tris-HCl, pH 7.5 as well as [35S]t-butylbicyclophosphorothionate (TBPS) in 200 mM KBr plus 5 mM Tris-HCl, pH 7.5. H and M had similar enhancing effects on [3H]MUS as well as on [3H]FNM binding to rat brain membrane preparations, but H was 2.5 to 5.2 times more potent than M. 2. [3H]FNM binding. GABA alone almost doubled [3H]FNM binding with EC50 = 450 nM and 200 nM using forebrain and cerebellar membranes, respectively. In the presence of 5 microM H or M the EC50 values for GABA were decreased to 79 and 89 nM, respectively, using forebrain, and 39 and 78 nM, using cerebellar membranes. H and M potently enhanced the potentiating effect of 200 nM GABA on [3H]FNM binding with EC50 values of 0.61 microM and 1.6 microM using forebrain membranes, with maximal enhancements of 33 and 47%, respectively. Using cerebellar membranes, the corresponding values were 0.25 and 1.1 microM, and 22 and 34%. 3. [3H]MUS binding. H and M increased [3H]MUS binding to whole forebrain membranes about 3-fold with EC50 values of 6.0 and 15 microM. Using cerebellar membranes, H and M increased [3H]MUS binding approximately 68% with EC50 values of 2.3 and 12 microM, respectively. Scatchard analysis revealed that the enhancements of [3H]MUS binding were due primarily to increases in the number of binding sites (Bmax values) with no effect on the high affinity binding constants (Kd values). The enhancing effect of H and M were not additive. 4. [35S]TBPS binding. H and M displaced [35S]TBPS binding from sites on whole rat forebrain membranes with IC50 values of 7.8 and 6.0 microM, respectively. Using cerebellar membranes, the corresponding IC50 values were 5.3 and 4.8 microM. These inhibitory effects were reversed by the potent GABA(A) receptor blocker R5135 (10 nM), suggesting that H and M allosterically increase the affinity of GABA(A) receptors for GABA and MUS by binding to sites in GABA(A) receptor complexes. 5. Two monophenols, the anesthetic propofol (2,6-diisopropylphenol, P) and the anti-inflammatory diflunisal (2',4'-difluoro-4-hydroxy-3-biphenyl carboxylic acid, D) also enhanced [3H]MUS binding, decreased the EC50 values for GABA in enhancing [3H]FNM binding and potentiated the enhancing effect of 200 nM GABA on [3H]FNM binding, although enhancements of [3H]MUS binding for these monophenols were smaller than those for H and M, using forebrain and cerebellar membranes. The enhancing effect of P and D on [3H]MUS binding were almost completely additive. 2,2'-biphenol was inactive on [3H]MUS and [3H]FNM binding. These, and other preliminary experiments, suggest that appropriate ortho (C2) and para (C4) substitution increases the GABA-potentiating activity of phenols. 6. The potentiation of GABAergic neurotransmission by H and M is probably involved in their previously reported anxiolytic and central depressant effects.

Novel natural vanilloid receptor agonists: new therapeutic targets for drug development.

The discovery that compounds lacking a recognizable vanillyl-like motif might act as vanilloids has given new impetus to a search for novel vanilloid receptor agonists and antagonists in compound libraries. The availability of cell lines transfected with a cloned human vanilloid receptor will further expedite this search. In this article, the pharmacological properties of unsaturated dialdehydes and triprenyl phenols that represent two newly discovered chemical classes of vanilloids will be discussed. The existence of vanilloid receptors in several brain nuclei as well as in non-neuronal tissues predicts novel, innovative therapeutic indications for vanilloids. However, these findings also suggest that vanilloids might cause side-effects. An exploration of the uses of unsaturated dialdehydes in indigenous medicine might help identify new therapeutic targets for vanilloids and avoid unwanted actions.

A new diels-alder-type adduct flavonoid from Dorstenia barteri.

A new Diels-Alder-type adduct, dorstenone (1), was isolated from Dorstenia barteri together with three known flavonoids, 4,2', 4'-trihydoxy-3'-prenylchalcone; 4,2',4'-trihydoxy-3, 3'-diprenylchalcone; and 5,7,4'-trihydoxy-8-prenylflavone. The structure of 1 was elucidated using a combination of highfield NMR techniques, particularly, gradient-enhanced HMQC and HMBC.

Urea derivatives from Pentadiplandra brazzeana.

Four urea derivatives were isolated from the roots of Pentadiplandra brazzeana, and their structures were elucidated by spectroscopic techniques. N-Benzyl-N'-(4-methoxybenzyl)urea (1) is a new compound, although N,N'-di-(4-methoxybenzyl)urea (2), N,N'-dibenzylurea (3), and p-methoxythiobenzaldehyde (4) are reported from a natural source for the first time.

Anti-plasmodial sesquiterpenoids from the African Reneilmia cincinnata.

A new isodaucane sesquiterpenoid, 6,7,10-trihydoxyisodaucane, was isolated from the fruits of Reneilmia cincinnata, together with the known sesquiterpenoids oplodiol, oplopanone, 5E,10(14)-germacradien-1 beta, 4 beta-diol, 1(10)E,5E-germacradien-4 alpha-ol and eudesman-1,4,7-triol. A large amount of 5-hydroxy-3,7,4'-trimethoxyflavone was also isolated. Their structures were established by NMR techniques using 1D and 2D experiments. Three of the known sesquirernenoids exhibited noteworthy anti-plasmodial activity against Plasmodium falciparum strains.

Strobilurin M, tetrachloropyrocatechol and tetrachloropyrocatechol methyl ether: new antibiotics from a Mycena species.

The antifungal and cytostatic compound strobilurin M (1) is a new variant of the strobilurins produced by Mycena sp. 96097, a tropical basidiomycete. The same fungus was found to produce tetrachloropyrocatechol (3a) and tetrachloropyrocatechol methyl ether (3b), new natural products, which exhibit antifungal, antibacterial and cytotoxic activities.

Minor components with smooth muscle relaxing properties from scented myrrh (Commiphora guidotti).

All sesquiterpenes present in a sample of scented myrrh were isolated and characterised. Seven compounds, with cadinane, guaiane, oplopane, and eudesmane skeletons, were obtained, of which two are new and two are reported from a natural source for the first time. The major component, T-cadinol, has previously been shown to possess smooth muscle-relaxing properties, and the major purpose of the investigation was to compare the effects of the minor and more polar sesquiterpenes with that of T-cadinol in the rat aorta. Like T-cadinol, the minor sesquiterpenes are more efficient in reducing K(+)-induced contractions than those induced by the alpha-adrenoceptor agonist phenylephrine, however, they were all less potent than T-cadinol.

Furanocoumarins with affinity to brain benzodiazepine receptors in vitro.

Eight furanocoumarins were isolated from a methanol extract of dried roots of Angelica dahurica. One of these, phellopterin, strongly (IC50 = 0.36 microM) inhibits the binding of [3H]diazepam to central nervous system benzodiazepine receptors in vitro, while the others, despite their structural similarities with phellopterin, are considerably less active.

Nidulal, a novel inducer of differentiation of human promyelocytic leukemia cells from Nidula candida.

Nidulal (1), a novel inducer of differentiation of human HL-60 promyelocytic leukemia cells, was isolated from fermentations of the basidiomycete Nidula candida together with low amounts of niduloic acid (2). Both compounds are bisabolane sesquiterpenes. Their structures were elucidated by spectroscopic methods. In reporter gene assays nidulal (1) preferentially activated the transcription factor complex AP-1-mediated expression of secreted alkaline phosphatase in COS-7 cells. In addition nidulal (1) and niduloic acid (2) exhibited weak cytotoxic and antibiotic activities.

Assays of the biological activities of two fatty acid derivatives formed in the edible mushrooms cantharellus cibarius and C. tubaeformis as a response to injury.

Cibaric acid (1) and 10-hydroxy-8-decenoic acid (2) are two fatty acid derivatives that are formed in the fruit bodies of Cantharellus cibarius (chanterelle) and C. tubaeformis as a response to injury. Unlike the potent defensive sesquiterpenes formed in injured fruit bodies of the pungent Lactarius species, compounds 1 and 2 only possess very weak antimicrobial and cytotoxic activity. Compound 2 was found to be a very weak direct-acting mutagen in the Ames test (<1 revertant/microgram and plate), while cibaric acid (1) was inactive in this assay. As 1 is destroyed during cooking, there are currently no reasons for suspecting that the consumption of C. cibarius poses a risk to consumers.

Inhibition of [3H] flunitrazepam binding to rat brain membranes in vitro by puerarin and daidzein.

Compounds acting on the central nervous system (CNS) have been isolated and identified from plants used for medicinal purposes. Radix Puerariae is used in Chinese traditional medicine for the treatment of drunkenness and alcoholic addiction. Benzodiazepine tranquilizers exert their pharmacological effects by modulating the efficacy of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at the GABA/benzodiazepine-chloride channel complex in the brain. Since some of the pharmacological effects of ethanol are thought to be mediated via the GABA/benzodiazepine-chloride channel complex, we investigated if extracts from Radix Puerariae contain active substances at the benzodiazepine receptor which could explain its reported usefulness for medical purposes. Therefore, a bioassay-guided purification of active substances from Radix Puerariae was initiated.

Spasmolytic flavonols from Artemisia abrotanum.

Four flavonols with spasmolytic activity have been isolated from a methanol extract of Artemisia abrotanum L. (Asteraceae), as the principles primarily responsible for the smooth muscle relaxing activity of this plant. The flavonols show a dose-dependent relaxing effect on the carbacholine-induced contraction of guinea-pig trachea, the EC50 values for compounds 1-3 are 20-30 mumol/l while compound 4 is less active.

Inhibition of kainic acid binding to glutamate receptors by extracts of Gastrodia.

S-(4-hydroxybenzyl)glutathione was isolated as the major principle responsible for the inhibition of the in vitro binding of kainic acid to brain glutamate receptors by water extracts of the plant Gastrodia elata. The affinity (IC50 value) of the compound is slightly lower compared to glutamate and glutathione.

Inhibition of [methyl-3H]diazepam binding to rat brain membranes in vitro by dinatin and skrofulein.

Two flavones, 4',5,7-trihydroxy-6-methoxy flavone (dinatin) and 4',5-dihydroxy-6, 7-dimethoxy flavone (skrofulein), were extracted from Artemisia herba alba L. Dinatin and skrofulein inhibited the binding of [methyl-3H]diazepam to rat brain membranes in vitro with IC50 of 1.3 and 23 mumol.L-1, respectively. The GABA-ratios (the ratio of IC50 values in the absence/presence of GABA in the binding assay) were 1.1 and 1.2 for dinatin and skrofulein, respectively. Both flavones induced a slight increase in [35S] TBPS binding. The data suggest that the flavones are antagonists or partial agonists of benzodiazepine receptors.

Sigmoidins J and K, two new prenylated isoflavonoids from Erythrina sigmoidea.

In addition to the two known compounds neotautenol [2] and erythrinassinate B [4], two new compounds, an isoflavanone named sigmoidin J [1] and a coumestan derivative named sigmoidin K [3], have been isolated and characterized from the root bark of the Cameroonian medicinal plant Erythrina sigmoidea. Their structures have been established as 7, 4'-dihydroxy-2',5'-dimethoxy-6'(gamma, gamma-dimethylally)isoflavanone [1] and 3,9-dihydroxy-2,10-(gamma, gamma dimethylallyl) coumestan [3], respectively, by spectroscopic techniques and from chemical evidence.

Prenylated isoflavanone from the roots of Erythrina sigmoidea.

A novel prenylated isoflavanone, sigmoidin I, has been isolated from the roots of Erythrina sigmoidea, in addition to the known isoflavones, corylin and neobavaisoflavone and the known pterocarpan, phaseollidin. Its structure was established as 7,4'-dihydroxy-3'-methoxy-5'-(3-methylbut-2-enyl) isoflavanone by means of spectroscopic analyses and chemical transformations. Neobavaisoflavone displayed antifungal potency in vitro with minimum inhibitory concentrations against Aspergillus fumigatus and Cryptococcus neoformans, of 50 mg ml-1.

Fatty acids and other compounds with nematicidal activity from cultures of Basidiomycetes.

In a screening for nematicidal activities in cultures of Basidiomycetes, cultures of Pleurotus pulmonarius and Hericium coralloides exhibited toxic effects towards the saprophytic nematode Caenorhabditis elegans. Subsequently S-coriolic acid (1), linoleic acid (2), p-anisaldehyde (3), p-anisyl alcohol (4), 1-(4-methoxyphenyl)-1,2-propanediol (5), and 2-hydroxy-(4'-methoxy)-propiophenone (6) were isolated from submerged cultures of P. pulmonarius. All compounds showed nematicidal activities towards C. elegans. The most active compounds were 1 and 2 with LD50 values between 5 and 10 ppm. Compounds 1, 4, and 5 have not been previously isolated from higher fungi, 6 is a new natural product. From cultures of H. coralloides, which exhibited both repellant and nematicidal effects, a nematicidal fatty acid mixture was obtained, containing linoleic acid, oleic acid, and palmitic acid as its main components.

Isolation and identification from Salvia officinalis of two diterpenes which inhibit t-butylbicyclophosphoro[35S]thionate binding to chloride channel of rat cerebrocortical membranes in vitro.

Ethanolic extracts from dried leaves of sage (Salvia officinalis) showed inhibition of [35S]tertiary-butylbicyclophosphorothionate ([35S]TBPS) binding to rat brain membranes in vitro. This ligand is considered to bind to the chloride channel of the GABA/benzodiazepine receptor complex in brain tissue. Substances having inhibitory activity were purified and their chemical structure identified as the diterpenes carnosic acid and carnosol (IC50 values of 33 +/- 3 microM and 57 +/- 4 microM, respectively). The two compounds did not affect binding of the ligands [3H]muscimol and [3H]diazepam to the GABA/benzodiazepine complex in vitro. Saturation experiments of [35S]TBPS binding indicated that carnosic acid decreases the binding affinity.