薬理と治療

近年,主流となってきたバイオ医薬品は,その効果が高い一方で高価である。バイオシミラーの導入に数年前から取り組んできたEU においては,すでにいくつかのバイオシミラーがバイオ医薬品に代わりつつあり,医療費の削減という点から注目を集めている。バイオシミラーはオリジナルとなるバイオ医薬品と高い同等性を有するが,高分子化合物であり,化学構造式上,同一でない可能性があるため,「similar」の呼称が用いられている。日本においては,バイオシミラーの導入はまだ進んでおらず,認知度が低いのが現状であるが,今後は本格的に導入が進んでいくことが予測される。そこで,バイオシミラーの有用性・安全性がどのように担保されているのか,また導入審査の責任者としてバイオシミラー導入をどのように考えていけばよいのか議論していただいた。

Background Because the quantities of information are increasing in the informed consent of investigational drugs, an informed consent form of more than 30pages is not rare at the present. It seems to be difficult for depressive patients to understand such kind of document and do the decision making of the participation in clinical trials as a subject. This study was performed to know the desirable method that was better than the current information presentation method in the informed consent form of investigational drugs for depressive patients. Methods The explanation document consisting of 27 pages in size of A4 which was generally used and the explanation document consisting of three parts with a quantity same as the former one were made. Part 1 was“concise explanation document about the clinical trial in general”, part 2 was“explanation document about the clinical trial concerned”, and part 3 was “supplement explanation document for the patient who wanted to know more detailed information”. Using these two kinds of explanation document, the survey was performed to clarify about an impression called“easy to read”,“friendly”, and “easy to understand”in 20 depressive patients compared with 61 healthy Japanese citizens. Results The depressed patients felt that the document consisted of three parts was more “easy to read”,“friendly”, and“easy to understand”, than healthy Japanese citizens. Conclusions It is necessary for the current explanation document in informed consent form of investigational drugs to be devised depending on the pathological condition of depressive patients.

Background Once-a-Week-Avonex Syringe(30 μg Interferon beta-1a Intramuscular)was approved in Japan in November 2006 for the treatment of relapsing multiple sclerosis. To further improve convenience of the injection procedure, an autoinjector with a built-in prefilled syringe(Avonex Pen)was developed. Objective To evaluate the relative convenience of these two administration methods. Methods The 31 evaluators(10 pharmacists, 11 nurses, and 10 clerks)prepared the drug administration using Avonex Syringe and Avonex Pen and performed two mock injections of each product into an artificial muscle. The evaluation was made based on a 5-point scale[+2:Avonex Pen is better, +1:Avonex Pen is slightly better, 0:Both products are same, -1:Avonex Syringe is slightly better, -2:Avonex Syringe is better]in terms of various items such as convenience and ease of use during preparation of drug and administration, and comprehensive evaluation. Results Avonex Pen was rated significantly better than Avonex prefilled Syringe for most of the items surveyed(13/20 items)with the mean score +1.0 point or higher. In the comprehensive evaluation, Avonex Pen was significantly higher than Avonex prefilled Syringe (0.74±1.03, P=0.0002). Conclusions The results of this study suggest that Avonex Pen is a preferable product to Avonex Syringe. The advantage of Avonex Pen may potentially support self-injection in terms of convenience and ease of use during drug administration. Therefore, Avonex Pen may provide clinical benefits such as improvement of compliance and persistence of Interferon beta-1a treatment for MS patients. Supported by Biogen Idec Japan Ltd.

Objective We examined effect of placenta extract on the activities of hepatic sympathetic, adrenal sympathetic, pancreatic sympathetic and gastric vagal nerves in rats. Methods A polyethylene catheter was inserted into the duodenal cavity for intraduodenal injection. For recording efferent autonomic nerve activities, distal ends of the hepatic sympathetic nerve, adrenal sympathetic nerve, pancreatic sympathetic nerve, and the gastric branch of the ventral subdiaphragmatic vagal nerve were ligated and hooked to a pair of silver wire electrodes after laparotomy. Electrical changes in nerve activities were amplified, filtered and monitored on an oscilloscope. Results Intraduodenal injection of 10% placenta extract slightly but not significantly reduced the hepatic sympathetic nerve activity. Adrenal sympathetic nerve and pancreatic sympathetic nerve activities were significantly increased after intraduodenal injection of 10% placenta extract. On the other hand, 10% placenta extract significantly reduced the gastric vagal nerve activity. Conclusion The present results indicated that placenta extract has a modulatory effect on autonomic nerve activities, and this modulation some how be related to the physiological functions of placenta extract.

Objectives To evaluate the effect of carbonated beverage containing resistant maltodextrin on the postprandial serum triglyceride levels and the safety of long-term intake and excessive intake of the beverage. Methods For evaluation of the effect on postprandial serum triglyceride levels, a doubleblinded crossover study was performed. Ninety volunteers were randomly divided into two groups and ingested a fat-rich diet together with 1 bottle(350 mL)of the beverage that either did or did not contain resistant maltodextrin. Serum triglyceride levels were measured before and 2, 3, 4,and6 hours after ingestion. For the safety evaluations of long-term intake and excessive intake of the beverage, two double-blinded parallel group studies were performed respectively. Forty volunteers were randomly divided into two groups for each study, and took daily 1 bottle(350 mL)of the beverage that either did or did not contain resistant maltodextrin for 12 weeks(long-term intake)or 3 bottles of each beverage daily for 4 weeks (excessive intake). Results Intake of the beverage containing resistant maltodextrin significantly suppressed the elevation of postprandial serum triglyceride levels at 3 and 4 hours compared to levels with intake of placebo beverage(P<0.05). In the long-term and excessive intake trials, no abnormal changes attributed to ingestion of the test beverage in clinical findings such as laboratory blood test, urinalysis and physical examination were observed. Conclusion These results indicated that carbonated beverage containing resistant maltodextrin taken with a meal had an inhibitory effect on the postprandial serum triglyceride elevation and were safe for long-term and excessive intake.

Objectives According to an epidemiological survey by the Fatigue Study Group of Ministry of Health, Labour and Welfare in 1999, about 60%(47.2 million)of Japanese working population complained of fatigue, moreover according to a survey in Aichi Prefecture by Health Labour Sciences Research in 2012, 51% of the population was aware of fatigue. These results show that the social environment related to fatigue has not changed in the last 10 years. However, there have been no established recommendations for fatigue, and few antifatigue medicines or foods have been developed. Oxidative stress is known to cause fatigue, so antioxidants are potential candidates for anti-fatigue agents. Imidazole dipeptides, which are abundant in whale meat, are reported to have strong antioxidative effects. We investigated the effect of whale meat extract on fatigue induced by physical load and by daily activities in humans. Methods In this double-blind, placebo-controlled, crossover trial, 12 healthy volunteers were randomized to oral administration of whale meat extract(400mg of imidazole dipeptides)or placebo for 29 days. The subjects took 12 capsules of whale meat extract or placebo twice a day for 29 days. As a fatigue-inducing physical load, the subjects performed workload trials on a cycle ergometer at fixed workloads for 4 hours and then rested for 4hours. We evaluated subjective fatigue sensation using the visual analogue scale and autonomic nervous system by accelerated plethysmography. Moreover we evaluated fatigue induced by daily activities using the Chalder fatigue scale in the 4-week administration period. Results The administration of oral whale meat extract administration attenuated fatigue sensation and modulated sympathetic dominance induced by physical load, and decreased the total score of Chalder fatigue scale in the 4th week. Conclusions These results show that whale meat extract has an effect on attenuating fatigue induced by physical load and daily activities, so it is a promising candidate for antifatigue food.

Objective Lactobacillus gasseri(L. gasseri)SBT2055 inhibits dietary fat absorption in rats, and exerts preventive effects on abdominal adiposity in both rats and humans. We evaluated the effects of the L. gasseri SBT2055 on body fat accumulation in obese subjects. Methods Volunteers(n=101;54 male, 47 female;BMI of 25 to 30 kg/m2)were given 100 g of fermented milk containing L. gasseri SBT2055(107 cfu/g)or placebo daily for 12 weeks. Results After 12 weeks, abdominal visceral fat area in the test sample group was significantly reduced compared with the placebo group. Conclusions These results indicated that SBT2055-fermented milk reduces the abdominal adiposity including visceral fat.

In this study, soymilk fermented with Lactobacillus delbrueckii subsp. delbrueckii TUA4408L (TUA4408L)was used in an experimental diet to examine whether its intake affects i)stool frequency, ii)the number of days with bowel movement, iii)stool quantity, and iv)stool consistency. This single-blind study involving 21 female test subjects(mean age, 32.7±5.3 years)with a tendency for constipation was conducted in four 2-week-long phases, including i)an observational phase, ii)a control diet phase(intake of 90 g of a diet without soymilk and TUA4408L twice per day), iii)a resting phase, and iv)an experimental diet phase(intake of 90 g of the experimental diet containing soymilk and TUA4408L twice per day). According to the results, the number of days with bowel movement, stool frequency and stool quantity during the experimental diet phase increased significantly compared to those during the control diet phase(P<0.01or P<0.05). As for stool consistency, compared to the control diet phase, banana-like or toothpaste-like stool increased and hard, nut-like stool decreased during the experimental diet phase. In other words, there was an improvement in stool consistency. These results indicate that the intake of soymilk fermented with TUA4408L shows promise in improving bowel movement.

Objectives We developed a vinegar drink containing indigestible dextrin and mixed herbal extract. In this study, we investigated the effect of the vinegar drink on postprandial blood glucose level of volunteers.Methods We performed a double-blind cross-over trial. A total number of 32 volunteers(16men and 16 women:average age 48.6±8.5)whose postprandial blood glucose level increased more than 140 mg/dL, ingested a 140 mL of vinegar drink containing indigestible dextrin and mixed herbal extract or a placebo drink with white rice as a test meal. The blood glucose level was measured before and30, 60, 90 and 120minutes after the intake of test meal, and compared the changes between the vinegar drink group and placebo group. Results We observed no significant effect of the vinegar drink on postprandial blood glucose level of total 32 volunteers. However, with the exception of subjects with unstable blood glucose, we observed significant suppressive effect of the vinegar drink on the AUC value and the blood glucose level at 60 minutes after the intake of test meal. Conclusions These results suggest that the vinegar drink containing indigestible dextrin and mixed herbal extract may suppress the elevation of the postprandial blood glucose level in the subjects whose blood glucose level tends to rise.

Objective We examined the effect of catechins with a galloyl moiety to reduce dietary lipid absorption in humans. Methods A randomized double-blind placebo-controlled crossover study was conducted. The beverage(340 mL/bottle)contained 190.9 mg of tea catechins with a galloyl moiety. Fifteen healthy adult subjects were randomly divided into two groups. Group A was requested to consume the drinks, containing catechins with a galloyl moiety, everyday for 10 days and then the placebo for 10 days, after an 11 day interval between these intake periods. On the contrary, Group B consumed the placebo first for 10 days and then the catechin drinks for 10 days, after an 11 day interval between the periods. Each subject in the catechin group was given 3 bottles of the test beverage/day and each subject in the placebo group was given 3 bottles of the placebo beverage/day. During the treatment period, subjects were given the same menu(Male:2244±35.6 kcal, 84±0.6 g lipids, Female:1944±35.6 kcal, 66±0.6 g lipids)at each meal. On the last 3 days of each treatment period, feces were collected in order to measure the excretion of lipids. Results Lipid excretion into feces was found to be significantly higher in the test beverage consumption cases than in the placebo beverage ones on third day. Serum total cholesterol and LDL cholesterol were significantly lower in the test beverage consumption cases than in the placebo beverage ones. Conclusions Our present observations suggest that consumption of catechins with a galloyl moiety could increase lipid excretion into feces.