Samvisterin, a new natural antiplasmodial betulin derivative from Uapaca paludosa (Euphorbiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Uapaca paludosa is used in African traditional medicine for the treatment of malaria. MATERIALS AND METHODS: A bioguided fractionation of U. paludosa trunk bark extracts was performed on the basis of their antiplasmodial activity against Plasmodium falciparum. RESULTS: A new natural betulin derivative named samvisterin (2) was isolated. In addition, 12 already known compounds were isolated from U. paludosa and tested against P. falciparum: squalene (1); lupeol (3), betulonic acid methyl ester (4), ß-sitosterol (5), stigmasterol (6), betulin (7), betulinic acid (8), pentadecanoic acid (9), palmitic acid (10), margaric acid (11), stearic acid (12), methyl palmitate (13). With the exception of betulinic acid, all were isolated for the first time from U. paludosa. Their chemical structures were established on the basis of spectroscopic analysis. The antiplasmodial activity of compounds 1-8 was confirmed on the chloroquine-resistant strain of P. falciparum, FcM29-Cameroon, with IC50 values ranging from 0.7µg/ml (for 1) to 30µg/mL (for 3). The cytotoxicity of the fractions and isolated compounds was also determined on KB and Vero cell lines in order to determine the cytotoxicity/activity ratio of each one. CONCLUSIONS: The results obtained with samvisterin (2) show that this new compound is the most promising of the series, with a weak cytotoxicity leading to the best selectivity index values.

Skin reactions due to anti-epileptic drugs: several case-reports with long-term follow-up.

In this study, the clinical findings and management of allergic skin reactions induced by the most used antiepileptic drugs, Lamotrigine (LMT) and Carbamazepine (CBZ), were evaluated. Lamotrigine is an antiepileptic drug recently released in several countries; it is effective for a variety of seizure types in adults and children, both as an add-on agent and in monotherapy, and it is generally well tolerated. Clinical and epidemiologic evidence suggest serious cutaneous reactions to antiepileptic drugs are more likely to occur during the first 8 weeks and they appear to increase when drugs are administered with other anticonvulsants, such as Valproate (VPA). We selected 10 patients who presented an idiosyncratic skin rash when treated with carbamazepine (8 patients) and lamotrigine (2 patients) administered as monotherapy, and we followed up on these patients for several years. Seven reactions were mild/severe cutaneous eruptions; one Toxic Epidermal Necrolysis, a case of Stevens-Johnson and a case of Hypersensitivity Syndrome. All severe skin drug reactions were induced by Carbamazepine. In five patients the AEDs were ceased abruptly (sometimes with the administration of a different molecule), tapered in four and continued unchanged in one. We conclude that the discontinuation of the drug with substitution with another is the most effective treatment and that corticosteroids are helpful in mild cutaneous reactions, while in severe skin reactions, such as Toxic Epidermal Necrolysis, corticosteroids are only a complementary therapy since intravenous immunoglobulins are the first choice treatment.

Imiquimod, a topical immune response modifier, induces migration of Langerhans cells.

Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.