Enantioselective Pharmacokinetics of Homochlorcyclizine: Disposition of (+)- and (–)-Homochlorcyclizine after Intravenous and Oral Administration of Racemic Homochlorcyclizine to Rats

Abstract— Concentrations of homochlorcyclizine enantiomers in blood, urine, and tissues of the liver, lung, kidney, brain, heart, spleen, intestine and stomach of rats after drug administration were determined by high-performance liquid chromatography on a chiral stationary phase. After intravenous administration (10 mg kg^?1), homochlorcyclizine was rapidly distributed in many tissues, with the highest concentration in lung. No differences were found between enantiomers in blood concentrations. After oral administration (50 mg kg^?1), the concentrations of the (+)-isomer in nearly all tissues were higher than those of the (–)-isomer. The AUC_0-x values of the (+)- and (–)-isomers differed significantly. The absorption of racemic homochlorcyclizine from rat small intestine was not enantioselective. These results suggested that the different concentrations between enantiomers after oral administration were not caused by enantioselective absorption or distribution but rather by preferential first-pass metabolism of the (–)-isomer in the liver. The enantioselectivity of metabolism was also demonstrated by in-vitro experiments.     

A study of verbal and spatial information processing using event-related potentials and positron emission tomography

Abstract  The activated cerebral regions and the timing of information processing in the hemispheres was investigated using event-related potentials (ERP) and regional cerebral blood flow (rCBF) as the neurophysiological indicators. Seven men and one woman (age 19–27 years) were asked to categorize two-syllable Japanese nouns (verbal condition) and to judge the difference between pairs of rectangles (spatial condition), both tests presented on a monochrome display. In the electroencephalogram (EEG) session, EEG were recorded from 16 electrode sites, with linked earlobe electrodes as reference. In the positron emission tomography (PET) session, rCBF were measured by the ¹⁵O-labeled H₂O bolus injection method. Regions of interest were the frontal, temporal, parietal, occipital and central lobes, and the entire cerebral hemispheres. When the subtracted voltages of the ERP in homologous scalp sites were compared for the verbal and spatial conditions, the significant differences were at F7-F8 and T5-T6 (the 10–20 system). The latencies of the differences at T5–T6 were around 200, 250 and 320 ms. A significant difference in rCBF between the verbal and spatial conditions was found only in the temporal region. It was concluded that early processing of information, that is, registration and simple recognition, may be performed mainly in the left temporal lobe for verbal information and in the right for spatial information.     

Anticardiolipin Antibodies in Patients With Pregnancy Loss Induce Factor Xa Production in the Presence of (β2-Glycoprotein I

PROBLEM : Anticardiolipin antibodies (aCL) are commonly associated with recurrent pregnancy loss, though the mechanism is uncertain. Some investigators have indicated that aCL may be directed at a complex made up of cardiolipin and a blood anticoagulant, β2-glycoprotein I (β2GPI). We therefore investigated the effects of β2GPI-dependent aCL IgG enriched fractions, isolated from sera of patients with pregnancy losses, on blood coagulation. METHOD : β2GPI-dependent aCL were prepared from sera of three women with second trimester pregnancy losses, by cardiolipin affinity column chromography, following by anti-β2GPI affinity column chromatography. The effects of β2GPI and β2GPI-dependent aCL on the activation of factor X in vitro were examined. RESULTS : β2GPI inhibited the activation of factor X and β2GPI-dependent aCL blocked this inhibitory effect in a dose dependent manner. CONCLUSION : These results imply the possibility of β2GPI-dependent aCL induce hypercoagulation or thrombus by blocking the inhibitory effect of β2GPI on activation of factor X, which may result in pregnancy loss.     

Construction of a dimeric DNA-binding peptide model by peptide-anthraquinone conjugation

A peptide–anthraquinone conjugate was designed and synthesized containing linked peptide chains composed of Asp-Pro-Ala-Ala-Leu-Lys-Arg-Ala-Arg-Asn-Thr-Glu-Ala-Ala-Arg-Arg-Ser-Arg-Ala-Arg-Lys-Leu-Gln-Arg-Met, representing the basic region of GCN4. The two peptides were joined with anthraquinone at its 1- and 8-positions in a two-fold symmetric fashion, mimicking dimeric DNA-binding proteins. Experimental data indicated both an interaction of the anthraquinone moiety with the DNA double strand and an increase in the α-helicity of the peptide moieties of the ligand when it binds to DNA. © Munksgaard 1996.     

The effect of sodium cromoglycate on the antigen-induced nasal reaction in allergic rhinitis as measured by rhinomanometry and symptomatology

The protective effect of sodium cromoglycate (DSCG) on the allergic reaction in the nose was compared with placebo in a double blind crossover study of sixteen patients diagnosed as allergic rhinitis. The drug effect was assessed by both a rhinomanometric method and by symptom scores in all patients. DSCG protected the nasal mucosa against antigen challenge and was significantly better than placebo. There was a correlation between the objective and subjective assessments.     

A Preliminary Report on Autologous Bone Marrow Transplantation for the Treatment of Advanced Non-Hodgkin's Lymphoma

Four patients with advanced non-Hodgkin's lymphoma of unfavorablehistology were treated with marrow-lethal doses of cyclophosphamide(CY) and total body irradiation (TB1) followed by the infusionof cryopreserved autologous marrow. All four patients showedengraftment after autologous bone marrow transplantation andachieved complete remission (CR). Three of them, however, developedrelapse in 1.7, 12.9 and 14.5 mo respectively after the transplantation.The other patient has survived in drug-free CR for more than16.6 mo. There was no treatment-related death although therewere some tolerable complications. These data suggest that theCY-TBI regimen may be effective in inducing CR in patients withadvanced non-Hodgkin's disease but it does not contribute topreventing relapse.     

Diagnostic Significance of Two Fetal Proteins, {alpha}f and r{beta}s, in Hepatoma and Other Neoplastic Diseases

Incidences of f and rßs components were studied inserum samples from patients with various malignant and non-malignantdiseases. With the micro-Ouchterlony method, af was detectedexclusively in cases of hepatocellular carcinoma of which theincidence was 83.5%, whereas the incidence of rßswas 47.7%. However, rßs was also detected in somemalignant disease other than hepatocellular carcinoma, withan incidence of 16.5%, and was also detected in a small numberof cases of non-neoplastic liver diseases. Though not tumor-specific, rßs as one of the fetalserum proteins can be detected in cases of non-f-producing hepatomaand in cases of malignancies other than hepatoma. Thus, thedetection of this protein may be of diagnostic significance.Possible mechanism of the appearance of this protein in theblood was discussed.     

Umbilical cord blood as a rich source of immature hematopoietic stem cells

To investigate immaturity of hematopoietic progenitor cells in umbilical cord blood mononuclear cells (CB-MNC), the formation of macroscopic colonies and mixed-cell colonies was assayed by methylcellulose culture with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) and compared with bone marrow (BM)-MNC. Moreover, distribution of the subpopulations divided by CD34, CD38, HLA-DR and CD33 was compared by flow-cytometry. Colonies derived from CB-MNC were so large that they could be observed with the naked eye and consisted of a variety of types of hematopoietic cells. Mixed-cell colonies were formed to a much greater extent in CB-MNC than in BM-MNC. Addition of EPO, IL-3, and SCF had rapid effects on the growth of mixed-cell colonies. The subpopulations of immature hematopoietic progenitor cells (CD34⁺, CD38⁻, HLA-DR⁻), which are supposed to be able to differentiate into hematopoietic precursors and stromal cells, were significantly higher in CB-MNC (8.7±6.6%) than in BM-MNC (0.0±0.1%; P < 0.001). These results suggest that CB is a rich source of immature hematopoietic progenitor cells compared to BM.