The discovery of the double-helical structure of DNA, the elucidation of the genetic code, and the determination of the three-dimensional structure of several proteins are some of the outstanding achievements of biochemistry and life sciences in the latter half of the last century. Proteins play key roles in almost all the biological processes and the biological function of a protein depends on its conformation which is defined as the three-dimensional arrangement of the atoms of a molecule. The three-dimensional structure, however, is not rigid but fluctuated. Structural fluctuation plays an important role in bio-macromolecules. How about “functional fluctuation” in biological systems? The present review proposes that functional fluctuation is also very important for understanding the mechanism of supramolecules, biological processes in living cells, and the interaction between biological systems. This new theme is pretty well supported by our recent experiments for neuro-immune crosstalk, gene transfection with cationic liposomes, and cell signaling in embryonic stem cells.
Lansoprazole is extensively metabolized by CYP2C19 and CYP3A4 in the liver, whereas rabeprazole is primarily converted non-enzymatically to rabeprazole-thioether, with only some being oxidized by CYP2C19 and CYP3A4. Lansoprazole and rabeprazole possess asymmetric sulfur in their chemical structure and have typically been used clinically as a racemic mixture. This article reviews the pharmacokinetic differences between enantiomers of lansoprazole and rabeprazole in relation to the CYP2C19 genotypes. In our studies in healthy Japanese subjects, the magnitude of contribution of each lansoprazole enantiomer for CYP2C19 was greater than that for CYP3A4. CYP2C19 influenced the disposition of (S)-lansoprazole to a greater extent than the (R)-enantiomer. The R/S ratios for the AUC of lansoprazole in CYP2C19 homEMs, hetEMs and PMs was 12.7, 8.5 and 5.8, respectively. On the other hand, (R)-rabeprazole disposition was influenced to a greater degree by CYP2C19 genetic polymorphisms than (S)-rabeprazole. However, the R/S ratios for the AUC of rabeprazole in CYP2C19 homEMs, hetEMs and PMs was only 1.8, 2.2 and 2.4, respectively, suggesting a lesser effect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole compared to lansoprazole. Such a difference in the AUC between rabeprazole enantiomers is likely to be dependent on stereoselectivity in the CYP3A4-mediated metabolic conversion from rabeprazole-thioether to rabeprazole. Both enantiomers of these PPIs have been reported to possess equal potency. Therefore, particularly with lansoprazole, the use of (R)-lansoprazole alone would be highly desirable for use in clinical applications.
Itch, a skin sensation that provokes a desire to scratch, is a common complaint. Severe itch accompanying various skin diseases such as atopic dermatitis is an important issue related to the quality of life. Although histamine from mast cells has been thought to play an essential role in itch, many severe pruritic diseases respond poorly to the H1 histamine receptor antagonists. Therefore the precise mechanisms and mediators of itch in most pruritic diseases are unclear. To investigate the detailed mechanisms of the induction of itch, we have developed a mouse model. Studies using this model have demonstrated that keratinocytes play an important role in the induction of itch. The identification of keratinocyte stimulus factors and of products in keratinocytes could lead to developing new antipruritic medicines.
Medical staff, including physicians, nurses, pharmacists, nutritionists, laboratory medical technologists, social workers, and case managers, should act as a team to support patients with human immunodeficiency virus (HIV) infection. The therapeutic purpose of a potent cocktail of anti-HIV drugs is to maintain undetectable plasma levels of HIV over the long term. To achieve this, it is necessary to maintain treatment compliance. However, noncompliance frequently occurs because of a poor understanding of HIV therapy or difficulty in taking anti-HIV drugs. Thus pharmacists should contribute as HIV medical team members by providing medication counseling to ensure treatment compliance or delivering drug information to achieve successful HIV therapy. We describe the roles of pharmacists on HIV medical teams at Ehime University Hospital in examples of nutritional disorder or pregnant women with HIV.
Metastatic breast cancer (MBC) is almost always incurable, and the median survival is of the order on 18—24 months. Combination therapy with adriamycin (ADR) and docetaxel (DOC) is more effective against MBC than the previous therapy due to differences between their mechanisms. However, the combination of ADR and DOC induces severe adverse effects, limiting its clinical use in many patients with MBC. The biologic functions of most living organisms are organized along an approximate 24 h time cycle or circadian rhythm. Chronotherapy is defined as the administration of medications using biological rhythms to optimize the therapeutic outcomes and/or control adverse effects. To decrease adverse effects, many antitumor drugs have been particularly studied in humans and animals. The toxicities of ADR and DOC have also been found to depend on dosing-time in animals and humans. This study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve antitumor effects by considering a chronopharmacological approach, dosing-interval and dosing-sequence to the combination chemotherapy of ADR and DOC in mice. In the results, we demonstrate that the dosing schedule based on dosing-sequence, dosing-interval and dosing-time not only significantly reduced leukopenia and toxic death but also significantly increased the inhibition rate of tumor growth compared with the dosing schedule without an interval between each injection, commonly used in clinical practice. These findings suggest that the therapeutic index of combined chemotherapy can be improved by choosing an optimal dosing-schedule (dosing-interval, dosing-sequence and dosing-time).
An overview is presented on the reports available so far on pre-Columbian maize covering the regions of India, Mideast, Africa and Iberia. Frequent observations of maize recorded in the past on the East and the West Coast of Africa and at the ports in the Mideast show that maize was one of the staples of the natives well before 1492. It is also evident that maize in the West Africa was disseminated to Iberia and Lombardy in the pre-Columbian time. An earlier contact between the Old and the New World is strongly suggested.
In the present study, the effects of liquid crystal-related compounds on the megakaryocytopoiesis and thrombopoiesis were evaluated in vitro using CD34+ cells prepared from human placental and umbilical cord blood (CB). About 20 kinds of compounds were tested for their effects on the clonal growth of CB CD34+ megakaryocytic progenitor cells (CFU-Meg) in plasma clot culture. The compounds, dissolved in DMSO, were added to the cultures within a concentration range of 10—100 nM. When used alone, none of the compounds supported the clonal growth of CFU-Meg. However, when thrombopoietin (TPO) was used as a growth factor, three compounds increased CFU-Meg clonal growth significantly, producing approximately 1.3—1.4 fold increases in the total number of megakaryocyte colonies in comparison with the control. These compounds promoted mainly mature CFU-Meg-derived small colonies, suggesting that their target is relatively mature CFU-Meg. These effective compounds were examined in liquid culture supplemented with TPO alone for 14 days. Although there was no evident promotion of the total number of cells harvested from the culture, two compounds suppressed cell growth significantly. Only one compound enhanced the generation of CFU-Meg in the harvested cells. Although these results do not indicate a strong correlation between the chemical structure of each compound and biological effectiveness, the incorporation of phenylpyridine and phenylpyrimidine and binding of a hydroxyl residue into the structure may play an important role in the activity. Thus, liquid crystal-related compounds whose biological action was previously unknown have been shown to act as regulators of hematopoiesis.