应用小鼠在Y形迷宫中的自主选择能力测定急性及慢性东莨菪碱与吗啡对记忆的影响

应用Ｙ型迷宫研究了急性与慢性东莨菪碱和吗啡对小鼠记忆能力的影响。单剂量东莨菪碱（１ｍｇ／ｋｇｉｐ）和吗啡（１０ｍｇ／ｋｇｉｐ）均能显著损害小鼠的短时记忆（ｗｏｒｋｉｎｇｍｅｍｏｒｙ）。重复给药后东莨菪碱的这种作用很快消失。但吗啡每天一次，连续３次给药这种作用加强，连续５次给药这种作用反而减弱。东莨菪碱不能损害小鼠长时记忆（ｒｅｆｅｒｅｎｃｅｍｅｍｏｒｙ），而吗啡对长时记忆有损害作用。结果还提示小鼠短时记忆不受自发活动能力的影响。     

Enhanced rectal absorption and reduced local irritation of the anti-inflammatory drug ethyl 4-biphenylylacetate in rats by complexation with water-soluble beta-cyclodextrin derivatives and formulation as oleaginous suppository.

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes

Pancreatic -cell dysfunction and insulin resistance are observed in type 2 diabetes. Under diabetic conditions, oxidative stress and ER stress are induced in various tissues, leading to activation of the JNK pathway. This JNK activation suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the JNK pathway plays a central role in pathogenesis of type 2 diabetes and may be a potential target for diabetes therapy.     

Single dose tolerance to the analgesic effect of clonidine and cross-tolerance between morphine and clonidine

A single dose of clonidine developed tolerance to its analgesic effect. The tolerance reached its peak acutely on the 2nd day and lasted more than 5 days. Neither the analgesic effect nor the development of tolerance was modified by the pretreatment with naloxone. On the 2nd day, clonidine tolerant animals were also tolerant to morphine, but morphine tolerant animals, after a single dose of morphine on the 1st day, were not tolerant to clonidine. On the 5th day, however, clonidine tolerant animals were tolerant to morphine, and vice versa. Thus, the interaction between morphine and clonidine was "one-way" on the 2nd day, and cross-tolerance was only demonstrated on the 5th day. With a treatment with clonidine plus naloxone on the 1st day, the development of cross-tolerance to morphine was completely suppressed on the 2nd day but not on the 5th day. These results confirmed our previous finding that acute and delayed tolerance are different in nature, and the development of tolerance to morphine and clonidine are partially underlaid with a common mechanism which is not mediated by opioid receptors.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State

The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl--cyclodextrin (HP--CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an en-dothermic peak at 48°C representing the glass transition of NP, an exothermic peak at 105°C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125°C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171°C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP--CyD, the exothermic peak at 125°C for the Form B to A transition disappeared and a new en-dothermic peak appeared at 163°C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP--CyD matrix. Upon storage at 60°C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP--CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate. The present data suggest that HP--CyD is useful for the preparation of a fast dissolving form of metastable NP through glassy NP.     

Chronic unilateral ureteral obstruction represented as renin-dependent hypertension

A 50-year-old woman developed renin-dependent hypertension immediately after accidental unilateral ureteral ligation during hysterectomy, and the hypertension lasted for 5 months. Surgical release of the obstruction was carried out 157 days after the ligation. Then, her blood pressure was normalized. However, the obstructed kidney showed intensive tubulointerstitial fibrosis and functional recovery was not obtained. This case suggests that the renin-angiotensin system may be upregulated in human kidney during unilateral ureteral obstruction for a long duration.     

Short‐ and long‐term effect of sitagliptin after near normalization of glycemic control with insulin in poorly controlled Japanese type 2 diabetic patients

Aims/Introduction

The aim of the present study was to examine the short‐ and long‐term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients.

Materials and Methods

We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1‐week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long‐term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin.

Results

After 1‐week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1–2 weeks brought out the long‐term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs.

Conclusions

These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients.