Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant-methionyl human interleukin-2[alanine-125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats

Comparative pharmacotoxicity studies in rats were performed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or subcutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala-125] showed high bioavailability and nonlinear concentration profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 micrograms kg-1 day-1) indicated that r-metHuIL-2[ala-125], whether given intravenously or subcutaneously, was associated with increased circulating and infiltrating levels of lymphocytes and eosinophils. Bone marrow lymphoid hyperplasia and splenic extramedullary hematopoiesis were similarly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopathologic finding described as hepatocyte single cell necrosis which was observed following both intravenous and subcutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL-2[ala-125] via intravenous administration was 6 micrograms kg-1 day-1, while that for subcutaneous administration was 30 micrograms kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that subcutaneous administration may be a preferred clinical route of administration.     

Leucocyte interleukin-1-like activity in the common seal (Phoca vitulina) and grey seal (Halichoerus grypus)

Interleukin-1 (IL-1) is an important cytokine with predominantly proinflammatory activities, which have been characterized in many mammals. This study showed the production of IL-1-like bioactivity by cultured seal leucocytes. Increasing concentrations of lipopolysaccharide (LPS) (0-1 micrograms/ml) stimulated an increase in measurable IL-1-like activity in cell culture supernates. This activity increased for the first 24 h after LPS stimulation and the substance responsible had an apparent molecular weight of 17 kDa on gel filtration, similar to that described for other species. Specificity of the bioassay used was confirmed by blocking the bioactivity with an IL-1 receptor antagonist (IL-1 ra).     

Beta activity in aging and dementia

Considerable variation remains in the reported effects of disease, age and gender on high frequency electroencephalographic activity. We examined the topographic differences in relative and absolute beta power in the 14-54 Hz range in 49 subjects with dementia of the Alzheimer's type (DAT), 25 subjects with multi-infarct dementia (MID), and 62 normal control subjects (CON). Associations of these spectral parameters with age, gender and cognitive status were assessed. Normal control subjects showed modest positive correlations in frontal, central and parietal regions across the age range of 24-90 years but not across a narrower 60-90 year range. Women, particularly women over 60 years of age, showed increased relative and absolute beta power compared to men. Subjects with dementia showed global decreases particularly in relative power. Decreases were most prominent in central and parietal regions for DAT subjects, with MID subjects additionally showing prominent frontal decreases. DAT and MID subjects differed in their correlations of power with age, Folstein Mini Mental State Exam (MMSE) and gender across frontal, central, parietal and temporal regions. Differences in the regional attenuation of absolute and relative beta power within specific high frequency bands may reflect the disparate neuropathologic processes of DAT and MID, as well as the extent of brain dysfunction and the effects of gender.     

Imputation for exposure histories with gaps, under an excess relative risk model

An Onchocerca volvulus expression library was differentially screened to identify a molecular marker distinguishing sowda (lichenified onchodermatitis) from other onchocerciasis forms. One clone, PG3, was recognized by pooled sera from patients with sowda, but not by pooled sera from patients with generalized onchocerciasis; it was not recognized by sera from patients with lymphatic filariasis or other helminth infections. The DNA of PG3 hybridized strongly with O. volvulus Eco RI-digested DNA, but not with DNA from Brugia spp., Trichinella spp., and humans. A weak reaction was observed with DNA from O. gibsoni and Acanthocheilonema viteae. The PG3 DNA sequence showed a high homology with both human and nematode collagens. Confirmation of the collagen-like nature of the sowda-specific PG3 product was obtained by amino terminal sequencing of the PG3 expression product, as well as by demonstrating its susceptibility to collagenase digestion. The characteristic recognition of the O. volvulus collagen specified by clone PG3 was confirmed by measuring antibody levels to the expressed product in individual sowda and generalized onchocerciasis sera, respectively. Identification of a nematode collagen antigen mainly recognized in sowda patients raises the possibility that this extreme form of dermatitis might arise through cross-reactivity between anti-O. volvulus collagen antibodies and human collagen. However, a relationship between the PG3 recognition by antibodies and the sowda pathogenesis could not be demonstrated.     

Computer-based diagnosis support for the interpretation of Hess charts

RATIONALE AND OBJECTIVES: The use of gadolinium (Gd)-BOPTA as a magnetic resonance contrast agent for central nervous system disease was studied in a canine brain abscess model. METHODS: A Streptococcus faecalis brain abscess was evaluated in five dogs at 1.5T. Imaging was performed during the late cerebritis stage, at 5 to 7 days after surgery. Magnetic resonance scans were acquired before and at 1, 5, 15, 30, 45, and 60 minutes after contrast administration, using a dose of 0.1 mmol/kg. Scans also were acquired both before and after contrast injection with the implementation of magnetization transfer. RESULTS: Lesion enhancement, quantified by region-of-interest measurement, peaked at 5 minutes after contrast injection. Both the increase in lesion enhancement from 1 to 5 minutes after injection and the decrease from 5 to 15 minutes after injection, although small, were statistically significant (P < 0.004 and P < 0.03, respectively). The application of magnetization transfer improved lesion enhancement, as measured by signal difference/noise, by 39%. This result also was statistically significant (P < 0.001). CONCLUSIONS: In intraparenchymal brain infection, Gd-BOPTA provides effective lesion enhancement when used at a dose of 0.1 mmol/kg. Further research is needed to compare the magnitude of enhancement achieved with Gd-BOPTA, which has weak protein binding and both hepatobiliary and renal excretion, with that with Gd chelates, which have pure renal excretion.