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YAKUGAKU ZASSHI, 125(2),169-175, 2005
The Autocrine Motility Factor (AMF) identified as a tumor cell motile stimulation factor is a key molecule of invasion and metastasis. The AMF is also identified as neuroleukin (NLK) and maturation factor (MF) which are secreted phosphohexose isomerase (PHI, PGI) from anaplastic cells. Tumor AMF promotes cellular locomotion or invasion, and regulates tumor MMPs secretion or apoptotic resistance. The AMF was thought to be an autocrine factor as the name shows it, and it is peculiar to malignant cells. However we found paracrine effect of AMF against tumor surrounding host tissues. Especially, endothelial cells which are essential parts of tumor induced angiogenesis or ascites accumulation express the AMF-receptor and they responded to AMF stimulation. Metastasis is a most complicated biological phenomenon that a large number of molecules or factors induced by tumor and host are related, thus AMF is also unusual molecule reacting between tumor and host tissues, and therefore AMF should be a target of treatment or diagnosis of cancer.
Key words--Autocrine Motility Factor (AMF); phospho glucose isomerase (PGI); metastasis; cell motility; angiogenesis; apoptosis
YAKUGAKU ZASSHI, 125(2),177-185, 2005
To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0 ± 12.4 years, weight: 50.9 ± 10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (−) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2 ± 4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4 ± 3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7 ± 4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.
Key words--mycophenolate mofetil; diarrhea; cytomegalovirus infection; receiver-operating characteristic curve; side effect
YAKUGAKU ZASSHI, 125(2),187-196, 2005
Ketamine has been widely used in the operation as intravenous and intramuscular injections, since ketamine has dissociative anesthetic properties. When it is given in sub-anesthetic dose, ketamine is known to have an analgesic effect. The analgesic effect is observed for patients with neuropathic pain when administrated not only by injection but also orally. In Japan, since ketamine is not commercially available except injection forms, patients have to take it as solution of injections for the oral medication. Since the solution of injections has extremely bitter taste, patients intensely desire the development of preparations without the bitterness. In the present study, we prepared oral gel dosage forms of ketamine using agar. It is simple to prepare this dosage form, and most pharmacists can prepare it easily in many hospitals. This gel dosage form met content uniformity requirements and the shape of that was maintained intact during the dissolution test (for 10 hours). The release rate was reduced by additions of additives such as sugar and a flavor in the gel. The reason for the reduction in release could be the suppression of ketamine diffusion depended on the micro-viscosity of solution in the gel. The ketamine contents and the release profile of the gel preparations were unchanged at the room temperature for 12-week storage. The gel preparations in this study would be useful for the oral medication of ketamine, since it is easy for patients to carry them when they go out and the intensely bitter taste could be improved by the addition of a flavor.
Key words--ketamine; oral preparation; analgesic; agar; release rate
YAKUGAKU ZASSHI, 125(2),197-203, 2005
In the present study, we devised a simple method for detecting the drug interaction between oral iron preparations and phenolic hydroxyl group-containing drugs, using the coloring reaction as indicator, due to the formation of complexes or chelates. In the method, oral iron preparations and test drugs in amounts as much as single dose for adults were added to 10 ml of purified water to make sample suspensions for testing. Thirty minutes after mixing an oral iron suspension and a test drug suspension, the change of color in the mixture was observed macroscopically and graded as 0 to 3, with a marked color change judged as grade 3 and no color change as grade 0. Screening of 14 test drugs commonly used orally was carried out. When using sodium ferrous citrate preparations as oral iron, 5 were classified as grade 3, 2 as grade 2, 4 as grade 1, and 3 as grade 0, respectively. To verify usefulness of the method, the interactions suggested by screening were pharmacokinetically assessed by measuring serum concentrations of the drug in mice. When a levodopa or droxidopa preparation, judged as grade 3 in screening, was concomitantly administered with an iron preparation, a significant reduction in bioavailability of the test drug was observed, indicating possible drug interaction between the test drug and oral iron. Combined administration of an acetaminophen preparation, judged as grade 1, and oral iron preparation showed no influence on the bioavailability of the test drug, implying no detectable interactions between them. In conclusion, the simple method devised in the present study is useful for precognition of drug interactions between oral iron preparations and phenolic hydroxyl group-containing drugs, and the drugs with a higher grade in screening may induce drug interactions with oral iron.
Key words---drug interaction; oral iron; phenolic drug; levodopa; droxidopa
YAKUGAKU ZASSHI, 125(2),205-211, 2005
Advances in molecular biology are being made in the fields of science, medicine, and pharmacy. The majority of students graduating from pharmaceutical university departments will be required to have knowledge of molecular biology techniques. Although it is not difficult to perform DNA experiments in a laboratory, they involve a series of operations. Therefore it is difficult to include such experiments in the curriculum for students at our university because of safety concerns and the experimental equipment and time required. This paper introduces a convenient experiment on plant DNA polymorphism using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method that we developed. This experiment enables each student to handle DNA safely. Total DNA is extracted from a piece of leaf derived from Aconitum carmichaeli or Aquilegia flabellate, the nuclear 5.8S rRNA region is amplified by PCR, and the PCR product is digested by restriction enzymes. Different polymorphisms in the plants can be visualized on electrophoregrams. The total time required for the experiments is 2 days (about 4 h per day). In the field of pharmacognosy, authentication of herbal medicine using genetic analysis is increasingly important. Plant DNA polymorphisms required the same knowledge and techniques as genetic analysis and are part of the course content in medicinal plant science. The PCR-RFLP experiment proposed here is a suitable method to acquire molecular biological knowledge and techniques.
Key words--plant DNA polymorphism; convenient experiment; 5.8S rRNA gene; polymerase chain reaction-restriction fragment-length polymorphisms; Aconitum carmichaeli; Aquilegia flabellata
YAKUGAKU ZASSHI, 125(2),213-217, 2005
Zingiber officinale Roscoe has been used as a folk medicine in China. An aqueous extract of Z. officinale Roscoe inhibited the hydrolysis of triolein emulsified with phosphatidylcholine by pancreatic lipase in vitro and it reduced the elevation of rat plasma triacylglycerol levels 1 and 2 h after oral administration of a lipid emulsion containing corn oil. These results suggest that the aqueous extract of Z. officinale Roscoe might inhibit the intestinal absorption of dietary fat by inhibiting its hydrolysis. Therefore we investigated the antiobesity effects of the aqueous extract of Z. officinale Roscoe by feeding a high-fat diet to mice for 8 weeks. Body weights at 2-8 weeks and final parametrial adipose tissue weights were significantly lower in mice fed the high-fat diet containing 3% aqueous extract of Z. officinale Roscoe than in the controls fed the high-fat diet. Feeding a high-fat diet containing 1% aqueous extract of Z. officinale Roscoe also significantly reduced final parametrial adipose tissue weights that were elevated in mice fed the high-fat diet alone. Our data suggest that the antiobesity effect of aqueous extract of Z. officinale Roscoe in mice fed a high-fat diet may be due in part to the inhibition of intestinal absorption of dietary fat by the active compounds of Z. officinale Roscoe.
Key words--Zingiber officinale Roscoe; pancreatic lipase; high-fat diet; mice
YAKUGAKU ZASSHI, 125(2),219-224, 2005
The vasorelaxant effects of forsythiaside (compound 1) from the fruits of Forsythia suspensa on isolated rat aortic rings were studied. Compound 1 showed a slow relaxation activity against norepinephrine (NE)-induced contractions of rat aorta with/without endothelium. This compound did not affect contractions induced by a high concentration of potassium (K+ 60 mM), while it inhibited NE-induced vasocontraction in the presence of nicardipine. These results show that the inhibition by compound 1 of NE-induced vasocontraction is due to a decrease in calcium influx from the extracellular space caused by NE.
Key words--forsythiaside; Forsythia suspensa; vasorelaxant effects; receptor-operated Ca2+-channels
YAKUGAKU ZASSHI, 125(2),225-229, 2005
In this study, the elucidation of the toxicity mechanism was undertaken regarding the IC50 of the oxygen uptake rate (OUR) with relevance to the biosorption as a toxicity evaluation of chemical substances for activated sludge (AS). At the IC50 of<100 mg/l, malachite green (MG) and crystal violet (CV) were confirmed in the group showing relatively strong OUR inhibition. These dyes were markedly biosorbed by AS in a short time. The biosorption for AS showed a weak tendency in linear alkyl benzene sulfonate (LAS), alkyl ethoxy sulfonate (AES), alpha-olefine sulfonate (AOS), sodium dodecyl sulfate (SDS), formaldehyde (FA), benzalkonium chloride (BZaC), benzethonium chloride (BZeC), rhodamine 6G (R-6G) and fuchsine (Fuc) in which the IC50 belonged to the 100-1000 mg/l group, when it was compared with CV and MG. In ethanol (EtOH), isopropanol (PrOH), nile blue (NB), evans blue (EB), methylene blue (MB), methyl orange (MO), paraquat (PQ), chlorophyllin (Chl) and auramine (Aur), the IC50 was large, and the biosorption of AS was weak at 0-15%. The biosorption of MG for AS followed the adsorption isotherm equation Y=0.002X0.511 of Freundrich. The correlation coefficient was γ=0.998 (n=8), and a very high correlation was obtained. In the qualitative OUR curve by AS pretreated with MG or CV which belonged to the IC50 small group, the inhibition of remarkable OUR was observed. Therefore, the findings of the present investigation suggest that the inhibition of the OUR for AS by the tested chemical substances was markedly affected by the biosorption.
Key words--activated sludge; biosorption; oxygen uptake rate; adsorption isotherm; chemical substance