Aromatic secondary amides such as benzanilide (1) exist in a trans-amide form both in the crystal and in the solution, whereas N-methylbenzanilide (2) exists in cis form in the crystal, and predominantly in a cis form in the solution. Similar cis conformational preferences were observed in aromatic N,N'-dimethylated ureas and guanidines, in which two aromatic rings are located face to face. The cis preferences of N-methylated amides, ureas and guanidines could be utilized to construct interesting aromatic architecture. N,N',N''-Trimethyl-N,N',N''-triphenyl-1,3,5-benzenetricarboxamide (20) and a cyclic triamide (24) have crystal structures in which three N-phenyl groups direct to the same orientation (syn conformation). 1,2-Bis(N-benzoyl-N-methylamino)benzene (22), which have no fixed asymmetric center, afforded chiral crystals by simple recrystallization. Furthermore, aromatic multi-layered structures could be built and applied to obtain aromatic molecules which have potent DNA-binding ability.
Rheumatoid arthritis (RA) is a common, frequently severe, chronic inflammatory disease. Although the cause of RA remains unknown, recent advances in understanding its pathogenesis have been substantial. Despite the use of a variety of medications, the treatment of RA is not fully effective in most patients. A T-helper type 1 (Th1)/T-helper type 2 (Th2) cytokine imbalance has been suggested to be of pathogenic importance in several diseases. In this review, the information of cytokine balance in both the experimental model of arthritis and patients with arthritis were summarized. Furthermore, to characterize the cytokine balance at a single cell level, we analyzed the subtypes of cytokine-secreting cells in an experimental model of arthritis using a dual color enzyme-linked immunospot assay (Stardust assay) which we newly developed. These information including our findings might provide us the clue for diagnosis and therapy of arthritis.
An interaction between cyclosporine A(CyA) injection and infusion tubes were examined. We used polyvinyl chloride(PVC) and polybutadiene(PB) tubes. CyA injection (Sandimmun®) was diluted (0.495 mg CyA/ml) with saline and dripped through infusion tubes. The amounts of unsolved substances, loss of CyA dose and leached di (2-ethylhexyl) phthalate (DEHP) during the drip study were compared. CyA was not lost into the PB tube and no DEHP was leached. Therefore, using PVC tube, 11.9 mg of CyA were lost with in 24 h after the beginning of the administration, and the concentration of leached DEHP amounted to 93.6 μg/ml at 12 h. We also investigated the effects of the component of the einfusion solution on the loss of CyA into PVC tube using saline, electrolyte maintenance solution, 5% glucose and 10% maltose. Sugar-containing solutions were found to have less effects than other solutions on the loss of CyA dose and DEHP leaching. The leaching of DEHP may be a major factor for the generation of unsolved substances and the loss of CyA dose. In the clinical use of CyA injection, PB tube is the best selection and the sugar-containing solution is a second selection when PB infusion tubes are hard to obtain.
The drug eruptions are known to often become more severe by the readministration of causative drugs. It is an important theme to prevent the relapse of the drug eruptions. We have been monitoring drug adverse reactions at our hospital since October, 1980. We divided fifteen years from October, 1980 to September, 1995 into three periods; the first period (Oct., 1980-Sep. 1985), the second period (Oct., 1985-Sep., 1990), and the third period (Oct., 1990-Sep., 1995), and discussed the trend of the drug eruptions appeared among these three periods. The number of the drug eruptions increased. But the proportion to the total drug adverse reactions and to the number of patients slightly decreased. The eruptions in women much increased and in the patients of forties or older generations also increased. But in patients of thirties or younger generations decreased. While nonsteroidal anti-inflammatory drugs (NSAIDs) other than pyrines, antibiotics other than penicillins and cephalosporins and drugs affecting the cardiovascular system and the metabolism tend to increase, pyrines, penicillins, iodic and biliary contrast media tend to decrease. The incubation period before the eruption appeared is less than three days in most antibiotics and anti-inflammatory drugs. But it is more than four days in most drugs for chronic diseases. Other symptoms such as nausea, fever and liver dysfunction were shown in 9.2% of the drug eruptions. In 8.9% of the drug eruptions a relapse of allergic reactions included eruptions were also found. In some cases the drug eruptions exacerbate by re-administration of β-lactam antibiotics. In the case of administration of drugs, it is necessary to pay attention to dermatitis caused by the drugs. And we recognized the importance of the system for the prevention of the relapse of drug eruptions including injections.
This study was carried out to investigate the effects of Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine, on the gastric function including the gastric emptying rate (GER) and intragastric pH in rats. Additionally, the effects of the GER and intragastric pH on tolbutamide absorption after oral administration were examined. The GER measured at 40 min after dosing was reduced to about 70% by the pretreatment of Sho-saiko-to (500 mg/kg). The plasma tolbutamide concentration in the rats treated with a 250 mg/kg dose of Sho-saiko-to was significantly lower than that in the control group. Plasma tolbutamide concentrations increased along with the GER in the group co-administered Sho-saiko-to, and there were significant correlations between the GERs and plasma levels in both time points at 20 and 40 min after administration. In the study using pylorus-ligated rats, Sho-saiko-to significantly elevated the intragastric pH, but induced no change in the concentrations of tolbutamide dissolved in the gastric content. Additionally, Sho-saiko-to did not change the area under the plasma concentration-time curve (AUC) of tolbutamide up to 60 min after administration into the stomach loop, and gastric absorption has been considered to minimally contribute to whole absorption of tolbutamide in the gastrointestinal tract. These results indicate that Sho-saiko-to has an inhibitory effect on the function of gastric emptying in rats. The reduced gastric emptying could affect gastrointestinal absorption, resulting in the lower plasma concentration of tolbutamide after oral administration. Furthermore, it is suggested that Sho-saiko-to can raise the intragastric pH but affect neither the intragastric dissolution nor the gastric absorption of tolbutamide.
Glibenclamide(GLI) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). We investigated The enhancing effect of switching iontophoresis on the transdermal absorption and reduction of skin irritation to develop a transdermal dosage form of GLI. The 0.1% of Gli suspensions in 0.2 M tris-HCl buffer of pH 7.4, 8.0 and 8.5 were prepared as donor solutions. We examined drug permeation through the excised rat abdominal skin, drug absorption in rats and reduction of skin irritation after application of switching iontophoresis for 1 h using DC 10 V. The solubility of GLI in 0.2 M tris-HCl buffer increased with a rise in pH. In the permeation study, GLI was permeated continuously and the cumulative amount of permeated GLI increased using an alkaline donor solution. In the drug absorption study, the application group of pH 8.5 gave higher plasma concentration levels than those of pH 7.4 and 8.0 groups. The skin irritation evoked by the application of iontophoresis was pathologically studied. A total irritation score (TIS) was estimated as a judging standard for the skin damage. The TIS value increased dependently with a rise in pH. However, it was considered that the skin irritations were not serious and small matters. The results demonstrate the possibility of iontophoretic transdermal administration of GLI and the effect of drug solubility in the donor solution on the absorption of GLI.
We previously demonstrated that Amaryllidaceae alkaloids, lycorine and lycoricidinol, inhibit induction of apoptosis by calprotectin derived from neutrophils, and that the latter alkaloid showed suppression in rat adjuvant-induced arthritis model. These findings suggest that the alkaloids have a modulating activity against inflammatory reaction. To explore further the mechanism of the suppression for inflammation, we studied the effect of the alkaloids on macrophage tumor necrosis factor (TNF-α) production in vitro, since TNF-α is recognized as a pivotal cytokine to regulate inflammation. As a result of this study, lycorine and lycoricidinol inhibited TNF-α production of murine macrophages stimulated with lipopolysaccharide (ID50 were 0.2 μg/ml and 0.002 μg/ml, respectively). The inhibition was also observed in macrophages treated by Gram-positive bacteria, Enterococcus faecalis. Both lycorine and lycoricidinol reportedly have inhibitory activity for protein biosynthesis. Although the inhibition of TNF-α production by lycoricidinol was mainly due to the inhibition of protein biosynthesis, lycorine showed inhibition against TNF-α production at lower concentrations than the case that they inhibited 35S-Cysteine/35S-Methionine incorporation into macrophages. These facts sugges that the inhibition of TNF-α production is not due to the inhibitory activity against protein translation at least at lower concentrations. From these results, it was concluded that these alkaloids exert inhibitory effects not only on neutrophil apoptosis-inducing protein, calprotectin, but also on macrophage TNF-α production.
We studied the effects of 17 kinds of Kampo-formulations prescribed for the treatment of peptic ulcer on H,K-ATPase activity. The activity was strongly inhibited by San-o-shashin-to (三黄瀉心湯, IC50=82 μg/ml), Bukuryo-in (茯苓飲, IC50=110 μg/ml), Shakuyaku-kanzo-to (芍薬甘草湯, IC50=170 μg/ml), Hange-koboku-to (半夏厚朴湯, IC50=290 μg/ml), Dai-saiko-to (大柴胡湯, IC50=340 μg/ml), Irei-san (胃苓散, IC50=380 μg/ml) than other Kampo-formulations. Among the 17 kinds of crude drugs contained in these Kampo-formulation, Rhei Rhizoma, Coptidis Rhizoma, Glycyrrhiza Radix, Cinnamomi Cortex, and Poria have notable inhibitory effects (IC50=19∼57 μg/ml). H,K-ATPase activity was inhibited by sennoside A (Rhei Rhizoma), sennoside B (Rhei Rhizoma), ergosterol (Poria), coptisine (Coptidis Rhizoma), glycyrrhizin (Glycyrrhiza Radix), glycyrrhetic acid (Glycyrrhiza Radix), gallic acid (Cinnamomi Cortex) in the 21 components of these crude drugs (IC50=1.6∼7.9×10-4M). The inhibition of San-o-shashin-to and Bukuryo-in is considered to be mainly attributed to Rhei Rhizoma and Poria, respectively. The anti-gastric ulcer effects of San-o-shashin-to and Bukuryo-in may be ascribed to the inhibition of H,K-ATPase activity.
Postoperative nausea and vomiting (PONV) with morphine therapy develops in more than 60% of patients after surgery, markedly reducing patient QOL. The prophylactic effect of several antiemetics has already been studied, but evaluations, and even those using the same drug, are not uniform. The present research involved a meta-analysis of randomized controlled trials on prophylactic drug therapy for PONV in patients receiving morphine for the treatment of postoperative pain. The efficacy of the prophylactic administration of the drugs was examined. As a result, meta-analysis of five drugs was possible and the evidence of efficacy was shown for three drugs ranked in order of an increasing odds ratio (OR) and confidence interval (CI): dexamethasone (OR: 0.23, 95% CI: 0.15-0.35, p<0.00001), droperidol (OR: 0.27, 95% CI: 0.21-0.34, p<0.00001), and metoclopramide (OR: 0.48, 95% CI: 0.30-0.75, p<0.001). These results suggest that the three drugs are effective in prophylactic treatment for PONV. Of them, dexamethasone used as a prophylactic drug for PONV provided the best results. Dexamethasone was shown to reduce the incidence of PONV from 66-80% to 16-50% with a dose of 1.25 to 10 mg and to be suitable as a first drug of choice.
An extraction method based on the phase separation of aqueous micellar solutions of n-octyl-β-D-thioglucoside (OTG) was applied to the concentrating conjugated bilirubin in urine. The analyte in sample solutions could be efficiently concentrated into a small volume of surfactant-rich phase, while hydrophilic matrix components including urinary protein, ascorbic acid, and saccharide remained in the aqueous phase. The concentrated OTG negligibly affected the diazo reaction and the subsequent spectrophotometric detection. Conjugated bilirubin was successfully determined in the concentration range from 0.05 μg/ml to 5 μg/ml with a 96-well microplate reader absorption spectrophotometer.