Pharmacokinetic Profile of the Immunomodulating Compound Adamantylamide Dipeptide (AdDP), A Muramyl Dipeptide Derivative in Mice

A pharmacokinetic profile of ¹⁴C-AdDP with uniformly labelled alanine was investigated. It was shown that the distribution phase after an i.v. administration is very short with a half-life of 2.1 min. the half-life of elimination phase after the i.v. administration is about 2.85 hours, that is longer than those of MDP and its derivatives. the total body clearance (30 ml/min/kg) is caused predominantly by metabolism of the compound. All the radioactivity found in urine in a 48 hours interval after a s.c. administration represents only 3.1% of the administered dose. Only a smaller part of the excreted radioactivity is formed by unmetabolised AdDP. the concentration curve after a S.C. administration is characterized by a very fast absorption with a half-life shorter than 1 minute. the distribution and elimination phases are prolonged (20 min, 11 hours respectively) in comparison with an i.v. injection. the decreased absolute bioavailability after a s.c. administration (65%) is probably not biologically significant because of a slower release of the compound from the site of the S.C. administration. A relatively very high radioactivity was found in liver, kidney, thymus, spleen and brain very soon which suggest a very good penetration into tissues. It is an agreement with the high apparent distribution volume of peripheral compartment and higher lipophilicity of AdDP as compared to MDP.     

Age effects in serial hypothalamic-pituitary-adrenal monitoring

To evaluate age effects on hypothalamic-pituitary-adrenal (HPA) regulation in depressives, we studied 65 patients with major depressive disorder, endogenous subtype. With each patient serving as his or her own control, we compared weekly dexamethasone suppression test (DST) results among three age subgroups (less than 40 years, n = 18; 40-70 years, n = 40; greater than 70 years, n = 7). The oldest patient group had higher mean post-dexamethasone plasma cortisol concentrations both before and after treatment, and more were DST nonsuppressors. Life table analyses revealed that elderly patients who were DST nonsuppressors had significantly slower patterns of normalization during treatment and that fewer elderly patients ever achieved normal suppression. The results indicate that age effects on HPA function may be confounded with other aspects of depression, such as severity, chronicity and number of previous episodes.     

Molecular genetics of RH and its clinical application.

BACKGROUND: The RH genes RHD and RHCE encode two proteins that represent the clinically most important blood group system defined by the sequences of red cell membrane proteins. In the last five years the field has been moving from defining the underlying molecular genetics to applying the molecular genetics in clinical practice. MATERIALS AND METHODS: The state of the current knowledge is briefly summarized using recent reviews and original work since 2000. RESULTS: The RHD and RHCE genes are strongly homologous and located closely adjacent at the human chromosomal position 1p36.11. Part of the genetic complexity is explained by the clustered orientation of both genes with their tail ends facing each other. The SMP1 gene is located interspersed between both RH genes. Using additional genetic features of the RH gene locus, RHCE was shown to represent the ancestral RH position, while RHD is the duplicated gene. More than 150 alleles have been defined for RHD alone. They were classified based on antigenic and clinical properties into phenotypes like partial D, weak D and DEL. Among the D negative phenotype a large variety of non-functional alleles were found. The frequencies of these distinct alleles vary widely among human populations, which has consequences for clinical practice. CONCLUSION: Rhesus is a model system for the correlation of genotype and phenotype, facilitating the understanding of underlying genetic mechanisms in clustered genes. With regard to clinical practice, the genetic diagnostics of blood group antigens will advance the cost-effective development of transfusion medicine.     

Rh phenotype prediction by DNA typing and its application to practice

The complexity of the RHD and RHCE genes, which is the greatest of all blood group systems, confounds analysis at the molecular level. RH DNA typing was introduced in 1993 and has been applied to prenatal testing. PCR-SSP analysis covering multiple polymorphisms was recently introduced for the screening and initial characterization of partial D. Our objective is to summarize the accrued knowledge relevant to the approaches to Rh phenotype prediction by DNA typing, their possible applications beyond research laboratories and their limitations. The procedures, results and problems encountered are highly detailed. It is recommended that DNA typing comprises an analysis of more than one polymorphism. We discuss future directions and propose a piecemeal approach to improve reliability and cost-efficiency of blood group genotyping that may eventually replace the prevalent serology-based techniques even for many routine tasks. Transfusion medicine is in the unique position of being able to utilize the most extensive phenotype databases available to check and develop genotyping strategies.     

Inhibition of endotoxin-induced activation of human monocytes by human lipoproteins.

Toxicity of lipopolysaccharide (LPS) (endotoxin) is, to a large extent, mediated by the activation of monocytes/macrophages and subsequent release of monokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). It is known that LPS binds readily to serum lipoproteins and that LPS-lipoprotein complexes are less toxic than unbound LPS. Here we present data analyzing the impact of the LPS-serum interaction at the cellular level. By measuring IL-1 TNF-alpha, and IL-6, the interaction of different LPSs or lipid A with human serum could be shown to prevent the activation of human monocytes. The amounts of LPS inactivated by normal human serum did not exceed 10 ng/ml. The LPS-inactivating capacity of serum was shown to be a function of the lipoproteins. Other serum components, such as naturally occurring anti-LPS immunoglobulin G, complement, or nutritive lipids, had no significant influence in our system. Our experiments suggest that serum lipoproteins control endotoxin-induced monocyte activation and monokine release.     

CDw60 glycolipid antigens of human leukocytes: structural characterization and cellular distribution

Monoclonal CDw60 antibodies recognize glycolipid antigens with restricted surface expression on human leukocytes. They allow us to define new functional subpopulations of T lymphocytes and are able to induce costimulatory signals. In this report, we describe the molecular composition of CDw60 glycolipid antigens derived from different human leukocyte subpopulations. The glycolipids were isolated and their structures were identified by immunochemical methods. All molecules containing the CDw60 determinant were found in the disialoganglioside fraction. They were O-acetylated derivatives of the gangliosides II3 (Neu5Ac)2-LacCer (GD3), IV3 (Neu5Ac)2-nLc4Cer (DSPG), and VI3 (Neu5Ac)2- nLc6Cer (DSnHC), respectively. The most common CDw60 glycolipid antigen in human leukocytes was 9-O-acetyl GD3. In a comparison of various cell types, the highest concentration of 9-O-acetyl GD3 on a per cell basis was determined in granulocytes and in blood T lymphocytes, whereas B lymphocytes, thymus cells, and monocytes contained considerably smaller amounts of this molecule. Polar CDw60 antigens such as 9-O-acetyl DSPG and 9-O-acetyl DSnHC were only detected in granulocytes.