Application of the EIIP/ISM bioinformatics concept in development of new drugs.

The development of a new therapeutic drug is a complex, lengthy and expensive process. On average, only one out of 10,000 - 30,000 originally synthesized compounds will clear all the hurdles on the way to becoming a commercially available drug. The process of early and full preclinical discovery and clinical development for a new drug can take twelve to fifteen years to complete, and cost approximately 800 million dollars. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role in improvement and acceleration of this time and money consuming process. Here we reviewed the application of the EIIP/ISM bioinformatics concept for the development of new drugs. This approach, connecting the electron-ion interaction potential of organic molecules and their biological properties, can significantly reduce development time through (i) identification of promising lead compounds that have some activity against a disease by fast virtual screening of the large molecular libraries, (ii) refinement of selected lead compounds in order to increase their biological activity, and (iii) identification of domains of proteins and nucleotide sequences representing potential targets for therapy. Special attention is paid in this review to the application of the EIIP/ISM bioinformatics platform along with other experimental techniques (screening of a phage displayed peptide libraries, testing selected peptides and small molecules for antiviral activity in vitro) in development of HIV entry inhibitors, representing a new generation of the AIDS drugs.

Antiatherosclerotic and antihyperlipidemic effects of octimibate sodium in rabbits.

Octimibate sodium (8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, sodium salt; NAT 04-152) was investigated for its antihyperlipidemic and antiatherosclerotic activities in New Zealand White rabbits. Hypercholesterolemia and atherosclerosis were induced by feeding a diet containing 0.3% cholesterol for 8 weeks. In addition, repeated injections of bovine serum albumin (BSA) were used to enhance the experimental atherosclerosis. Octimibate sodium, 10.0 and 30.0 mg/kg p.o., reduced both the increase in serum cholesterol levels and the aortic plaque-formation (by about 50% in the higher dose group) as compared to control animals. Serum triglyceride levels were not influenced. Biochemical and histological examinations of the aortas showed reduced cholesterol contents in the higher dose group and a dose-dependent inhibition of pathological changes in the aortas.

[Ultrastructural investigations on the effect of cyclophosphamide on experimental Trypanosoma cruzi infections (author's transl)]. / Ultrastrukturelle Untersuchungen zum Einfluss von Cyclophosphamid auf experimentelle Trypanosoma cruzi-Infektionen.

Strains of low virulent Trypanosoma cruzi are difficult to maintain in experimental hosts, but they can be activated by the immunosuppressive effects of cyclophosphamide (CY), a cancer chemotherapeutic agent. An attempt, using electron microscopy, to find out whether CY had any effect on the morphology of the bloodstream forms of the parasite failed to detect any differences when those from CY-treated hosts were compared with those from controls.

[Diagnosis of very early arteriosclerosis vascular changes using Duplex sonography]. / Die Diagnose sehr früher arteriosklerotischer Gefässwandveränderungen mit Hilfe der Duplexsonographie.

The technical evolution of ultrasonic equipment provides a high resolution imaging analysis of the vessel wall and thereby offers new possibilities in diagnosing very early atherosclerotic changes. The typical B-mode image in human and animal arteries shows parallel wall contures enclosing a hypoechoic space. In this study in Vitro- and in Vivo-experiments in rabbit aortas document the distance between these contures correlating histologically with a high cholesterol diet caused a broadening of the hypoechoic space in the rabbit aortic vessel wall. The data demonstrate that high resolution Duplex Sonography is a usefull noninvasive approach for the detection of very early atherosclerotic changes in arterial vessel walls in a stage before plaques can be identified.

Antimalarial properties of ebselen.

The seleno-organic compound ebselen showed anti-malarial activity in vitro against the murine Plasmodium berghei and the human P. falciparum. In P. berghei, the uptake and incorporation of [3H]-methionine and [3H]-adenosine was inhibited and the infectivity of plasmodia was reduced. Ebselen affects the development of asexual stages of chloroquine-resistant and -sensitive P. falciparum strains. Its IC50 for P. falciparum was about 14 mumol/l and that for P. berghei, about 10 mumol/l. The growth of P. falciparum was blocked by ebselen at all stages, including the invasion of erythrocytes by merozoites. In a human hepatoma cell line and in mouse peritoneal macrophages, no cytostatic or cytotoxic effects were found, indicating selective inhibition of plasmodia by ebselen. Its in vitro inhibitory effect is discussed in relation to its possible reactivity with thiol groups and its lack of an anti-malarial effect in infected mice.