Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis.

OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

Pelargoniins, new ellagitannins from Pelargonium reniforme.

The range of natural ellagitannins is extended by identification of five new metabolites with 1C4 glucose core, designated as pelargoniins A-D and isocorilagin, and the new phyllanthusiin E methyl ester. They are accompanied in the aerial parts of Pelargonium reniforme by two known structurally related metabolites, corilagin and phyllanthusiin C, two phenolcarboxylic acids, brevifolincarboxylic acid and phyllanthusiin E, the gallotannin 1-O-galloyl-beta-D-glucopyranose, and the ellagitannins strictinin and isostrictinin having a 4C1-glucose core. The structures of these compounds were established from spectroscopic studies. This is the first example of the co-occurrence of ellagitannins with 4C1 and 1C4 glucopyranose core demonstrated for a member of the Geraniaceae.

Antifungal effects of hydrolysable tannins and related compounds on dermatophytes, mould fungi and yeasts.

A series of hydrolysable tannins and related compounds was evaluated for antifungal activities against filamentous fungi (Epidermophyton floccosum; Microsporum canis; Microsporum gypseum; Trichophyton mentagrophytes; Trichophyton rubrum; Trichophyton tonsurans; Trichophyton terrestre; Penicillium italicum; Aspergillus fumigatus; Mucor racemosus; Rhizopus nigricans) and opportunistic yeasts (Candida albicans; Candida glabrata; Candidata krusei; Cryptococcus neoformans), using the agar dilution method. While all samples had no activity against the filamentous fungi in concentrations of 1.1-5.9 microM (1000 microg/ml), the phenolic compounds displayed significant potencies against all the opportunistic yeasts tested but C. albicans, with minimum inhibitory concentrations ranging from 0.02 to 0.1 microM (16-125 microg/ml). Although the presence of galloyl groups in flavonoids did not necessarily produce activity, this structural element, an HHDP moiety or its oxidatively modified entity proved to be an important structural feature of hydrolysable tannins. Comparison of dilution methods provided strong evidence of dependence of MIC values on the test method. Employing the microdilution broth method, the ellagitannin corilagin (MIC 0.8 nM) was found to be similarly potentially active as amphotericin B (MIC 0.5 nM) and sertaconazole (MIC 0.9 nM) against Candida glabrata strains. The order of effectiveness observed being 64- and 4-8-fold increased for corilagin and the reference compounds respectively, when compared with that of the agar dilution test.

Evaluation of the antimicrobial potency of tannins and related compounds using the microdilution broth method.

The antimicrobial activity of a total of 27 tannins and related compounds was evaluated against 8 microorganisms, including 2 Gram-positive (Bacillus subtilis, Staphylococcus aureus), 4 Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis), and 2 yeasts (Candida albicans, Cryptococcus neoformans). The compounds tested were generally found to possess only weak to moderate antibacterial, but fairly high anticryptococcal activities. Attention is given to structure-activity relationships with emphasis on simple galloyl esters, hydrolyzable tannins and proanthcyanidins among this class of secondary products.