We have previously measured the distribution and pharmacokinetics of biosynthetically labeled endotoxin of Salmonella Typhimurium with 3H (fatty acid residues) and 14C (glucosamine residues) in rats by administering saline containing 14C, 3H-LPS (200 μg/kg) intraperitoneally (IP) ( Kim et al., Toxicology and Industrial Health, 2014). We then developed a physiologically-based pharmacokinetic model (PBPK) using our measured distribution results in rats (Hutter and Kim, Toxicology and Industrial Health, 2014). To predict the dynamics of endotoxin exposure in human blood and its relationship with the production of cytokine levels as critical biomarkers for infection, a human 2-compartment model was developed to estimate levels of cytokine (TNF-alpha) in human blood during infection. The model was calibrated with published data for E5564 (a lipid A antagonist) at a dose of 3500 μg in humans (Wong, et al. J Clin Pharmacol, 2003 43:735-742). The model was validated using published results for E5564 at lower doses. The model was also validated using published results for ONO-4007, a lipid A synthetic agonist (deBono et al. Clin Cancer Res 2000 6:397-405). TNF-α was then fitted to the published results. This model can be useful for the risk assessment of antibacterial or immunotoxic effects of chemicals in the human body.
Alexander P. Malyshkin, male, microbiologist, graduated from Orenburg State Medical Academy in 1979 and worked for this academy as a researcher. After defending his Candidate of Science (Med.) dissertation (PhD thesis), he headed the Division of Laboratory Diagnosis of Orenburg Regional Tuberculosis Dispensary for some time. Dr. Malyshkin's field of research includes microbiology, immunology, and issues of infectious diseases and their prevention. He is the author of the active susceptibility hypothesis and a fundamentally new approach to the prevention of infectious diseases of plants, animals, and humans (including the HIV infection) based on it. The main recent work (now in press) is the chapter on the prevention of infectious diseases in the book Aquatic Plants and Plant Diseases (to be published by Nova Science). Dr. Malyshkin is exploring the possibility of collaboration in further developing and implementing his novel approach to disease prevention, which could be used, in particular, for breeding infection-resistant animal and plant varieties.
The active susceptibility concept regards infectivity as the host's capacity for attracting the microflora that serves useful functions in the body of a healthy carrier, rather than the property of the infective microorganisms. Roughly, it is not germs that infect us; it is we who infect ourselves with them. Infectivity stems from the necessity of the products of certain microbial genes for the host. This concept views asymptomatic healthy carriage of potentially dangerous microorganisms, which is found increasingly often, as a normal phenomenon. Accordingly, an epidemic results not so much from the emergence of a particularly pathogenic microorganism as from enhanced need in this organism (in the form of healthy carriage) and hence, active susceptibility to it across the population. Under certain conditions, this healthy carriage is transformed into an infectious disease, as is often the case with normal microflora. Therefore, decreasing the active susceptibility to the pathogen at the population level is the main prerequisite for preventing, or stopping the spread of, any bacterial or viral infection, as well as for treating it. To do this, the products of the microbial genes that are necessary for the host should be identified, obtained in commercial quantities, and used as therapeutic or prophylactic drugs.