Peritonitis in the baboon: a primate model which stimulates human sepsis

The physiological, hemostatic, and immunological responses of 12 chronically instrumented conscious baboons with sepsis due to Escherichia coli peritonitis were compared with that of similarly instrumented controls. Chronic indwelling cannulae were placed in the aorta and pulmonary artery to monitor pressure, cardiac output, and obtain blood samples. At t = 0 a sterile or E. coli-laden fibrin clot containing 1.9-6.7 x 10(11) CFU/kg was introduced into the peritoneal cavity. The control animals were group 1 (n = 3). The animals with peritonitis were divided into three groups depending on their clinical response. Group 2 animals (n = 3) were clinically well at the time of sacrifice (day 14), group 3 (n = 4) survived but were obviously sick on day 14, and group 4 (n = 5) died of sepsis. Implantation of a sterile fibrin clot was well tolerated with little hemodynamic change and a transient minimal inflammatory response in group 1. Implantation of an E. coli-containing clot elicited a hyperdynamic cardiovascular response and evoked a marked inflammatory reaction and a disseminated intravascular coagulopathy. Five of 12 (42%) E. coli animals died from sepsis. In general, the physiological, hemostatic, and immunological disturbances tended to be greatest in these animals. Autopsy revealed residual peritoneal inflammation and varying degrees of inflammation in the lungs, adrenal, spleen, liver, and kidneys in all the animals that received E. coli with the inflammatory infiltrate increasing in severity from group 2 through group 4. Tissue necrosis was observed only in the latter group. We conclude that the cardiovascular, hemostatic, and immunological responses of baboons with sepsis due to E. coli peritonitis exhibit a variable course that resembles the clinical manifestations of gram-negative sepsis in humans.     

Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody.

A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.     

Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery

Purpose

The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

Methods

Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (K_p,uu,brain) and cell (K_p,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.

Results

Assessment of K_p,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. K_p,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.

Conclusions

With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.     

Characterisation of exposure to total and hexavalent chromium of welders using biological monitoring

Inhalation exposure to total and hexavalent chromium (TCr and HCr) was assessed by personal air sampling and biological monitoring in 53 welders and 20 references. Median inhalation exposure levels of TCr were 1.3, 6.0, and 5.4 μg/m³ for welders of mild steel (MS, <5% alloys), high alloy steel (HAS, >5% alloys), and stainless steel (SS, >26% alloys), respectively. The median exposures to HCr compounds were 0.23, 0.20, and 0.08 μg/m³, respectively. Median concentrations of TCr in urine, blood plasma and erythrocytes were elevated in all welders, compared with the corresponding median concentrations in the reference group (p < 0.005). The TCr levels observed in plasma were two-fold higher in welders of SS and HAS than in welders of MS (p < 0.01). Exposure to HCr as indicated by median total content of Cr in erythrocytes was 10 μg/L in welders of SS, MS and HAS. Uptake of TCr during the shift was confirmed for welders of SS by a median increase of urinary TCr from pre- to post-shift of 0.30 μg/g creatinine. For welders of MS and HAS as a group TCr was not increased.     

Pseudo cluster randomization: a treatment allocation method to minimize contamination and selection bias

In some clinical trials, treatment allocation on a patient level is not feasible, and whole groups or clusters of patients are allocated to the same treatment. If, for example, a clinical trial is investigating the efficacy of various patient coaching methods and randomization is done on a patient level, then patients who are receiving different methods may come into contact with each other and influence each other. This would create contamination of the treatment effects. Such bias might be prevented by randomization on the coaches level. The patients of a coach constitute a cluster and all the subjects in that cluster receive the same treatment. Disadvantages of this approach may be reduced statistical efficiency and recruitment bias, as the treatment that a subject will receive is known in advance. Pseudo cluster randomization avoids this, because in pseudo cluster randomization, not everybody in a certain cluster receives the same treatment, just the majority. There are two groups of clusters: in one group the majority of subjects receive treatment A, while a limited number receive treatment B. In the other group of clusters the proportions are reversed. The statistical properties of this method are described. When contamination is present, the method appears to be more efficient than randomization on a patient level or on a cluster level.