Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice.

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P = 0.0083) or zanamivir monotherapy (88% versus 26%, P = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1ß, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.

Natural microemulsions: formulation design and skin interaction.

Microemulsions are thermodynamically stable, colloidal drug delivery systems. This study presents the first substantiated comparison of natural, skin-compatible and biodegradable surfactants in terms of their suitability to form isotropic microemulsions and their skin interaction. Pseudoternery phase diagrams were constructed for lecithin, sucrose laurate and alkylpolyglycoside as single surfactants. Moreover, also mixed surfactant films of lecithin and alkylpolyglycoside as well as lecithin and sucrose laurate were tested. Large isotropic areas could be identified for lecithin, sucrose laurate and lecithin-sucrose laurate. One defined composition was chosen from the pseudoternery phase diagram, prepared with all investigated surfactants and 1:1 surfactant mixtures, respectively, and analysed for their effect on the stratum corneum on a molecular level by ATR-FTIR. Significantly higher frequency values of the symmetric and asymmetric CH(2)-stretching bands compared to the control were recorded for all microemulsions, indicating a hexagonal arrangement of the lipid chains. A similar trend was observed for the lateral packing of the alkyl chains as suggested by the shift of the CH(2)-scissoring bands. Moreover, diffusion cell experiments using porcine skin were performed with the two model drugs flufenamic acid and fluconazole. In both cases, the lecithin-based microemulsions showed the highest permeation rates followed by the alkylpolyglycoside-lecithin microemulsions.

Evaluation of dextran-flufenamic acid ester as a polymeric colon-specific prodrug of flufenamic acid, an anti-inflammatory drug, for chronotherapy.

Dextran-flufenamic acid ester (Dex-FFA) with varied degree of substitution (DS) was prepared by imidazolide method. Dex-FFA was stable in pH 1.2 or pH 6.8 buffer. The depolymerization degree of Dex-FFA by dextranase decreased as DS increased. Dex-FFA with DS of 13 or 20 released FFA up to 70% or 21% of the dose, respectively, on 24 h-incubation with the 10% cecal contents. FFA was liberated up to 29% of the dose on 24 h-incubation of dextranase pre-treated Dex-FFA with the homogenates of the upper intestine, whereas no FFA was detected devoid of dextranse-pretreatment. Upon oral administration of Dex-FFA (DS 13, 20 mg equivalent of FFA/kg) or FFA (10 mg/kg) to rats, t(max) for FFA with Dex-FFA administration delayed approximately 6 h compared with that of free FFA administration, while C(max) for FFA was similar. The plasma level for FFA became greater around 6 h after administration of Dex-FFA than free FFA and it was maintained throughout the period of 24 h-experiment. Dex-FFA markedly attenuated gastric ulcerogenicity of FFA. Taken together, Dex-FFA could be useful as a colon-specific prodrug which possesses anti-inflammatory properties and offers opportunities as a chronotherapeutic approach for the treatment of arthritis.

Discovering transthyretin amyloid fibril inhibitors by limited screening.

Insoluble protein fibrils, resulting from the self-assembly of a conformational intermediate are implicated to be the causative agent in several human amyloid diseases including familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). These diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of a lysosome or endosome. Here we identify several structural classes of small molecules that are capable of inhibiting the TTR conformational changes facilitating amyloid fibril formation. A small molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a promising approach to treat amyloid diseases and to rigorously test the amyloid hypothesis, the apparent causative role of amyloid fibrils in amyloid disease.

[Non-steroidal antirheumatic ointments in the treatment of primary periarticular and intramuscular fibrositis]. / Nesteroidní antirevmatika v mast'ové forme v lécbe prvotní kolemkloubní a nitrosvalové fibrozitidy.

The author presents his experience assembled in a short-term (two-week) therapeutic trial with Mobilisin ointment, which contains flufenamic acid, in 50 patients with primary localized periarticular and muscular fibrositis. The preparation was used locally three times per day-2-3 cm of ointment pressed from a tube. The patients were given a form in which they recorded every night the effect classified in four grades from the best to zero effect. In 49 the tolerance of the ointment was very good. In 45 patients a therapeutic effect was achieved (90%), comprising 21 (42%) where the effect was excellent, in 24 it was good or satisfactory (48%) and only in 5 patients no effect was recorded or the patents' statement was vague. In the first group of 21 patients 16 were able to abandon analgetic and anti-inflammatory treatment with non-steroid antirheumatics. Patients with the muscular form of fibrositis practically agreed in favour of the ointment. Gels according to these patients tissues. The authors remind that according to their experience gels, incl. Mobilisin, are suited for periarticular forms of fibrositis. It is also useful to rub the ointment in micro-massage to achieve a greater initial hyperaemia and better resorption. Mobilisin ointment may prove useful also in other disciplines, in particular orthopaedics, surgery, traumatology, neurology, rehabilitation and sports medicine.

[Plasma- and tissue concentrations following intramuscular administration of etofenamat. Pharmacokinetics of etofenamat and flufenamic acid in plasma, synovium, and tissues of patients with chronic polyarthritis after administration of an oily solution of etofenamat]. / Plasma- und Gewebespiegel-Studien nach intramuskulärer Applikation von Etofenamat. Pharmakokinetik von Etofenamat und Flufenaminsäure in Plasma, Synovia und Geweben von Patienten mit chronischer Polyarthritis nach Applikation öliger Lösung von Etofenamat.

Studies on Plasma and Tissue Concentrations of Etofenamate following Intramuscular Application/Pharmacokinetics of etofenamate and flutenamic acid in plasma, synovia and tissues of patients with chronic polyarthritis after application of oily etofenamat solution Pharmacokinetics of etofenamate (ETO, CAS 30544-47-9; Rheumon i.m.) and flufenamic acid (FLU, CAS 530-78-9) were investigated in plasma, synovial fluid, and tissues after single intramuscular application of etofenamate to patients with rheumatoid arthritis. 62 patients with indicated operative procedure in the knee-joint received a single dose of etofenamate dissolved in oil before operation. At definite times between 1.5 and 48 h post injectionem samples from 6 patients of each time group were collected. Samples of plasma, synovial fluid, synovial membrane, muscle, bone, hyaline cartilage, and fat tissue and in some cases meniscus cartilage were taken. Concentrations of ETO and its active metabolite, FLU, were determined by HPTLC. In all tissues investigated, concentration/time courses of ETO and FLU were observed. ETO and FLU were measured first in all matrices 1.5 h at the latest 3 h post injectionem. Pharmacokinetics in tissues follows that in plasma. Rate-limiting step is the liberation of drug from the oil depot. For a long period pharmacokinetics of ETO and FLU is mainly determined by the constant liberation from the oil depot (zero order kinetics of liberation). Zero order kinetics is deduced from the linear ascent of the cumulated AUC (in percent) vs. time plot. It is directly related to the liberation of drug from the galenical formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Allergic contact eczema to etofenamate and dwarf pine oil]. / Allergisches Kontaktekzem auf Etofenamat und Latschenkiefernöl.

A typical case of contact dermatitis following topical applications of etofenamat is reported and a short review of literature is given. Considering the frequent administration of etofenamat, contact sensitization is relatively rare.

[Pharmacology and toxicology of etofenamate. 1st Communication (author's transl)]. / Pharmakologie und Toxikologie von Etofenamat. I. Mitteilung.

1. The reliable antiphlogistic action of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate active principle of Rheumon Gel) in various experimental inflammatory models in animals is demonstrated following oral and cutaneous administration. 2. The proven inhibition of inflammatory edema by chronic administration of Rheumon gel evidences the percutaneous absorption of the active principle through the intact skin. 3. The effect of Rheumon gel sets in independently of whether the gel is applied to normal or to pathologically inflamed tissue areas. 4. Gastrointestinal mucous tolerance is better for etofenamate than for flufenamic acid, phenylbutazone and other anti-inflammatory drugs.