Drug combinations in the therapy of low response to phosphodiesterase 5 inhibitors in patients with erectile dysfunction.

Combinatorial drugs utilising a clinically-proven single agent approach in erectile dysfunction (ED) have led to the search for additional compounds to improve therapy and the safety profile. Selective inhibitors of Phosphodiesterase type 5, such as Sildenafil, demonstrate a defined failure rate in ED. The therapeutic concept to increase blood influx and or to decrease blood efflux in patients with ED under therapy encountered severe drawbacks. It appeared impossible to decrease the NO-content in the corpora cavernosa and associated organs followed by synchronized increase of NO by a second drug. One has to metabolically activate cAMP by the first acting compound followed by cGMP stimulation. The pharmacology of the counteractive drugs was investigated clinically and a combination of 50 mg sildenafil with 5 mg dihydro-ergotamine (DHE) was identified as of practical use in patients with low response to Sildenafil. The safety profile appeared to be improved by this combination therapy. The present study is a clinical follow-up of patients treated with different therapeutical regimens to document the effectiveness of Sildenafil in combination with DHE.

Fucosyltransferase IV and VII-directed selectin ligand function determines long-term survival in experimental tuberculosis.

In order to determine the relative importance of fucosyltransferase (Fuc-T)-directed functionalization of selectin ligands for chronic inflammatory and antibacterially protective responses in vivo, mice selectively deficient for Fuc-TIV, Fuc-TVII or both were infected by aerosol with Mycobacterium tuberculosis H37Rv. Fuc-TIV/Fuc-TVII-deficient, and to a lesser extent, Fuc-TVII-deficient mice succumbed significantly faster to infection than Fuc-TIV-deficient and wildtype (WT) mice, although no differentially increased bacterial load or qualitatively different histopathology was apparent in moribund mice. To determine if the cause of accelerated death was associated with defective induction of immune responses in the lung due to the diminished T cell content in the mediastinal lymph nodes of Fuc-T-deficient mice, intravenous infection in WT or double-deficient mice was performed. Again, Fuc-TIV/Fuc-TVII mice succumbed significantly faster than WT mice. To determine whether the early demise of Fuc-TIV/Fuc-TVII-deficient mice was due to accelerated tissue pathology, a mouse model of mycobacteria-induced granuloma necrosis was used. There was no difference in the kinetics and quality of caseation induced by Mycobacterium avium TMC724 in all mouse strains investigated. Together, our data show that a deficiency in Fuc-TVII, and in a more pronounced fashion, a combined deficiency in both Fuc-TIV and Fuc-TVII, leads to accelerated death following M. tuberculosis infection that is neither caused by increased bacterial proliferation nor by discernibly gross differences in tissue pathology. These results suggest that targeting selectin ligand function during treatment of chronic inflammatory disorders may run the risk of accelerating TB disease progression.