4,552 publications from this institution
My search for a selective antiviral chemotherapy started more than 40 years ago with interferon inducers, then shifted to nucleoside analogs with the discovery of BVDU (brivudin), a highly selective anti-HSV-1 and anti-VZV agent, and to dideoxynucleoside analogs such as d4T (stavudine), anti-HIV agents. The search culminated in the discovery of acyclic nucleoside phosphonates (ANPs) (in collaboration with Antonin Hol ´ y), a key class of compounds active against HIV, hepatitis B virus, and DNA viruses at large; the best known of these compounds is tenofovir. Along the way, the principle of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was established. This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an “ideal” NNRTI.
Purpose – This paper seeks to investigate the possibility of producing medical or dental parts by selective laser melting (SLM). Rapid Manufacturing could be very suitable for these applications due to their complex geometry, low volume and strong individualization.Design/methodology/approach – The SLM‐process has been optimized and fully characterized for two biocompatible metal alloys: Ti‐6Al‐4V and Co‐Cr‐Mo. Mechanical and chemical properties were tested and geometrical feasibility, including process accuracy and surface roughness, was discussed by benchmark studies. By developing a procedure to fabricate frameworks for complex dental prostheses, the potential of SLM as a medical manufacturing technique has been proved.Findings – Optimized SLM parameters lead to part densities up to 99.98 percent for titanium. Strength and stiffness, corrosion behavior, and process accuracy fulfil requirements for medical or dental parts. Surface roughness analyses show some limitations of the SLM process. Dental frame...
Inhibitors interfering with human immunodeficiency virus (HIV) gene regulation may have great potential in anti-HIV drug (combination) therapy. They act against different targets to currently used anti-HIV drugs, reduce virus production from acute and chronically infected cells and are anticipated to elicit less virus drug resistance. Several agents have already proven to inhibit HIV gene regulation in vitro. A first class of compounds interacts with cellular factors that bind to the long terminal repeat (LTR) promoter and that are needed for basal level transcription, such as NF-kappa B and Sp1 inhibitors. A second class of compounds specifically inhibits the transactivation of the HIV LTR promoter by the viral Tat protein, such as the peptoid CGP64222. A third class of compounds prevents the accumulation of single and unspliced mRNAs through inhibition of the viral regulator protein Rev, such as the aminoglycosidic antibiotics. Most of these compounds have been tested in specific transactivation assays. Whether they are active at the postulated target in virus replication assays has, for many of them, not been ascertained. Toxicity data are often lacking or insufficient. Yet these data are crucial in view of the toxicity that may be expected for compounds that primarily interact with cellular factors. Although a promising lead, considerable research is still required before gene regulation inhibitors may come of age as clinically useful agents.
Although the presence of free 2′‐hydroxyl groups in both strands of a double‐stranded RNA complex has been recognized as one of the major requisites for the interferon‐inducing activity of double‐stranded RNAs, we have found a particular analogue of (I) n · (C) n in which the 2′‐hydroxyls of the purine nucleotide strand were replaced by azido groups, (dIn 3 ) n · (C) n , to be highly effective in inducing interferon. Various other 2′‐azido analogues of (I) n · (C) n and (A) n · (U) n , i.e. (dIn 3 ) n · (br 5 C) n , (I) n · (dCn 3 ) n , (dAn 3 ) n · (U) n , (A) n · (dUn 3 ) n , (dAn 3 ) n · (rT) n and (dAn 3 ) n · (dUn 3 ) n , were inactive as inducers of interferon. In human fibroblast cultures, the interferon‐inducing activity of (dIn 3 ) n · (C) n equalled that of (I) n · (C) n . In other interferon‐induction systems (primary rabbit kidney cells, mouse L‐929 cells, intact rabbits), (dIn 3 ) n · (C) n was less active than (I) n · (C) n . As assessed by both radio‐chemical and biological means, (dIn 3 ) n · (C) n was more susceptible to degradation by pancreatic ribonuclease and human serum nucleases than was (I) n · (C) n . The t m of (dIn 3 ) n · (C) n was 52.5 °C, as compared to 62.5 °C for (I) n · (C) n , both determined in 0.15 M Na + , pH 7.0. Under the same conditions, (dIn 3 ) n · (br 5 C) n had a t m of 77 °C and (I) n · (br 5 C) n had a t m of 87 °C. The reactivity of (dIn 3 ) n · (C) n and (dIn 3 ) n · (br 5 C) n towards antibodies to double‐stranded RNA was evaluated by quantitative complement fixation, counterimmunoelectrophoresis and competitive radioimmunoassay. In these tests, (dIn 3 ) n · (C) n and (dIn 3 ) n · (br 5 C) n showed an immunoreactivity pattern comparable to that of (I) n · (C) n and (I) n · (br 5 C) n .
The penetration of 5-ethyl-2'-deoxyuridine (edoxudine, Aedurid) from gel base with and without the addition of urea and other adjuvant has been studied in an in vitro model using guinea pig skin. The formulation of 3% edoxudine gel with 5% urea showed the best results. In vivo experiments on hairless mice infected intracutaneously with herpes simplex virus type 1 also showed this formulation's good efficacy as compared to other formulations.
