薬理と治療

It seems that the development of new drugs are perceived to be late in spite of the rapid advancement of the technology by many Japanese people. It may depend on the fact that the process for the development of new drugs are not widely known. Then, I tried to show the general process for the development of new drugs based on my experience. Starting development on some drugs is decided based on several factors such as expected positioning, expected sales, expected cost and portfolio. Modified chemical structures are selected based on the potency, selectivity and safety. Most pharmacological experiments, safety pharmacological studies, toxicological studies and ADME studies are conducted before the initiation of clinical studies. At Phase 1, basically, safety is ascertained using healthy volunteers（usual cases）or cancer patients （anticancer drugs）, and dose response and optimal dose in addition to safety is confirmed at Phase 2. Comparison with commercially available drugs is done at Phase 3. Bridging strategy utilizing abroad clinical data was adopted almost 20 years ago. Currently, Global studies incorporating multiple countries with one protocol are widely conducted. The number of patients required in one country can be reduced by sharing the patient number, and period for clinical studies has been shortened. Safety monitoring with quick reporting is needed throughout the clinical studies. Some different approach is needed in the case of bio︱technical drugs which have been widely developed these days. I also would like to shortly introduce the expected drugs which will be launched soon.

Objectives We aimed to investigate the characteristics and medical economics effects of prescription inquiries made by pharmacists concerning prescription for home healthcare patients and outpatients. Methods We classified inquiries made in 46 pharmacies and calculated drug cost savings. For cases where adverse events might have occurred if appropriate inquiries had not been made, medical costs savings were calculated using the Diagnosis Procedure Combination system. Results There were 675 inquiries out of 15,088 prescriptions（4.5％）, and 131 inquiries out of 994 prescriptions（13.2％）, for outpatients and home healthcare patients, respectively. The drug cost savings per inquiry was 491.8 yen for outpatients and 142.0 yen for home healthcare patients. The annual medical cost savings estimated in pharmacies nationwide for outpatients （home health care patients）are 16.6 billion yen（0.1 billion yen）of drug costs, 26.1 billion yen（2.4 billion yen）for medical costs from avoiding side effects, and 25.3 billion yen（1.6 billion yen）from avoiding lack of therapeutic effect, totaling 68 billion yen（4.2 billion yen）. Conclusions Although prescriptions for home healthcare patients have lower drug and annual medical cost savings per inquiry than prescriptions for outpatients, they are highly likely to lead to prescription inquiries. The research suggests that the proportion of medical cost savings effects other than drug costs may be high.

Objectives CAPECITABINE SAWAI（CAPECITABINE）is a generic oral anticancer drug of XELODA® in tablet formulation containing 300 mg capecitabine. The purpose of this study was to examine the pharmacological effect and pharmacokinetics in both formulations in human colon cancer cell line（COLO205）tumor-bearing nude mice model. Methods Bioequivalence of CAPECITABINE to XELODA® was evaluated in COLO205 tumor-bearing nude mice. Concentration of capecitabine and 5-fluorouracil（5-FU, the active metabolite of capecitabine）in plasma and tumor tissues were analyzed after a single dose of CAPECITABINE or XELODA®. Tumor size was measured during treatment with each formulation for 10 consecutive days. Antitumor effect was evaluated on the basis of tumor volume and weight after treatment for 10 consecutive days. Body weights before and after treatment were similarly evaluated. Results CAPECITABINE was bioequivalent to XELODA® in terms of capecitabine and 5-FU in mice. Both formulations showed remarkable rises of 5-FU in tumor tissue and also had equivalent antitumor activities in COLO205 tumor-bearing mice. Antitumor activities in CAPECITABINE and XELODA® were dose-dependently and significantly increased. Moreover, body weights were not influenced by treatments of both formulations. Conclusions Bioequivalence of CAPECITABINE and XELODA® was confirmed in terms of pharmacokinetics and antitumor effectiveness in tumor-bearing mice. These results indicate that both formulations have similar pharmacokinetic and pharmacodynamic effects in vivo and suggest that CAPECITABINE is clinically equivalent to XELODA®.

The impact of an α-linolenic acid（ALA）-rich emulsion on blood pressure in hypertensive rats was assessed. Male, eight-week-old spontaneously hypertensive rats（SHR）were divided into four groups of six rats each to be fed different diets:control oil, ALA-rich oil, control oil emulsion or ALA-rich emulsion. The rats were fed their respective diets for 56 days, and their systolic blood pressure measured weekly. Blood tests were also conducted. The results indicated that after eight weeks of ingesting their respective diets, the systolic blood pressures in rats fed ALA-rich emulsion were significantly lower than rats fed control oil, control oil emulsion and ALA-rich oil. Serum bradykinin concentrations were significantly higher in groups fed ALA-rich oil or emulsion compared to the control oil group. From these results, ALA-rich emulsion was shown to suppress the rise in blood pressure and the mechanism appears to be an increase in vasodilation caused by rising blood bradykinin concentrations. Further, it was thought that the blood pressure-lowering effect of ALA-rich oil was maintained even in an emulsified form.

Background Several human studies have demonstrated the beneficial effects of fish collagen hydrolysates（CHs）on facial skin parameters, including skin moisture, elasticity, and roughness. However, no clinical reports have assessed CHs derived from different parts of the same organism. Thus, the present clinical study assessed the effects of CHs derived from fish scales and those derived from fish skin on human facial skin. Methods The present randomized double-blind placebo-controlled clinical study evaluated 82 subjects. These subjects received CHs derived from Tilapia scales（CH︱A group; n＝28）, CHs derived from Tilapia skin （CH︱B group; n＝28）, or maltodextrin（placebo group; n＝26）. Skin parameters, such as skin moisture, elasticity, wrinkles, and roughness, were compared among the groups at the baseline, and 4 and 8 weeks after starting daily intake of CHs or placebo. Additionally, the safety of CH administration was evaluated. Results Significant improvements in facial skin moisture, elasticity, wrinkles, and roughness were noted in the CH︱A and CH︱B groups when compared with the findings in the placebo group. In addition, there were no adverse effects during the study. Conclusion CHs derived from fish scales and those derived from fish skin have similar effects on human facial skin with regard to moisture, elasticity, wrinkles, and roughness. Our findings suggest that the physiological functionality of CHs might be maintained even when they are derived from different parts of the same organism.

Objectives β-cryptoxanthin（CRX）, a carotenoid abundant in ripe kumquats, possesses functions important for human health. In this study, we aimed to investigate whether serum β-CRX concentrations are increased by continuous ingestion of ripe kumquats for 7 days in healthy adults. Methods In a randomized, open-label, simultaneous controlled comparison study, 9 healthy subjects（2 males and 7 females, 20 to 69 years old）were assigned to 3 groups：5 kumquats ingested group（per day for 7 days）；10 kumquats ingested group（per day for 7 days）；and control group（subjects who did not consume kumquats）. The primary endpoint was serum β-CRX concentration. The secondary endpoints were natural killer cell activity, interleukin-6 values, fatigue-related scales（Chalder fatigue scale and visual analog scale）, health-related quality of life, and adverse events. These tests were assessed at the 1st（baseline）, 3rd, 5th, and 8th days and 5 weeks after ingestion of ripe kumquats. Adverse events were assessed for all test periods. Results The change in serum β-CRX concentration from baseline significantly increased on the 8th day in the 10 kumquats ingested group compared with the control group（P＜0.05）. Moreover, the Chalder fatigue scale scoring significantly improved in the 10 kumquats ingested group compared with the control group（P＜0.05）. There was no significant difference in other endpoints between the kumquats ingested group and control group. Conclusions In summary, ingestion of 10 ripe kumquats per day for 7 days increased serum β-CRX concentration compared with the control group, suggesting that kumquats may have anti-fatigue effects.（ UMIN000024868）

Objective The present study aimed to verify that the ingestion of tea flower extract, mulberry leaf extract, and chitosan would reduce the postprandial blood glucose and triglyceride level of the healthy subjects. Methods In Trial 1, 40 subjects whose fasting blood glucose level were less than 125 mg╱dL, postprandial blood glucose level at 30 min or 60 min were more than 140 mg╱dL and postprandial blood glucose level at 120 min were less than 200 mg╱dL were enrolled in randomized, double-blind, placebo-controlled, cross over study. They ate 200 g of rice after ingesting of 150 mL water with tablets containing tea flower extract, mulberry leaf extract, and chitosan （test tablets）or placebo tablets. The blood glucose level was measured before and 30, 60, 90, 120 minutes after the intake of rice. In Trial 2, 50 subjects whose fasting blood triglyceride level were less than 200 mg╱dL were enrolled in randomized, double-blind, placebo-controlled, cross over study. They ate a bowl of soup containing 40.0 g of total fat （high fat diet） after ingesting of 150 mL water with the test tablets or placebo. The blood triglyceride level was measured before and 2, 3, 4, 6 hours after the intake of high fat diet. Results Ingestion of the test tablets suppressed the AUC（area under the curve）values of postprandial blood glucose level（Trial 1）and the AUC values of postprandial blood triglyceride level（Trial 2）. Conclusions These results suggest that ingestion of tea flower extract, mulberry leaf extract, and chitosan reduce the postprandial blood glucose and triglyceride level. （UMIN ID:UMIN000032752, UMIN000032754）

Objectives The aim of this study was to evaluate the effect of drink containing Lactobacillus paracasei subsp. paracasei NY1301 on defecation（fecal properties and fecal microflora）. Methods One hundred nineteen healthy volunteers with a tendency for constipation were enrolled in a placebo-controlled, randomized, double-blind, parallel-group study. The volunteers were given test drink ontaining forty billion of Lactobacillus paracasei subsp. paracasei NY1301 or a placebo daily for two weeks. Results Compared to before ingestion period, defecation frequency and fecal properties were significantly improved throughout ingestion period by test drink and placebo. The fecal analysis showed that Lactobacillus sp. and B. longum subsp. longum were significantly increased after ingestion of test drink. Conclusions In conclusion, the distinct effect of drink containing Lactobacillus paracasei subsp. paracasei NY1301 on defecation were observed, and fecal analysis indicate that Lactobacillus paracasei subsp. paracasei NY1301 improve the intestinal environment by increase of Lactobacillus sp. and B. longum subsp. longum. It was expected sufficiently about improving the intestinal environment, bowel movement and fecal property（. UMIN000031414）

Objective To investigate the effects of an oral nutritional supplement drink containing Lactobacillus paracasei MCC1849 on the immune system of elderly people. Methods A randomized open-label trial was conducted from March 2017 to October 2017 on 62 Japanese adult participants（aged≥65 years）who reported of daily fatigue. Participants were equally, but randomly, assigned to either the test or control beverage group（31 in each group） using a computerized random-number generator. They consumed one bottle of their assigned drink each day for 4 weeks. The effects on improving the immune system were assessed based on the immunological vigor scores, a questionnaire, salivary test, blood test, and physical examination at baseline and at 4 weeks. Results Sixty subjects were analyzed as per-protocol set（n＝30 each）. After consuming the drink, immune strength scores in the test beverage group were significantly higher than those in the control beverage group at 4 weeks（P＜0.05）. Furthermore, subjective symptoms such as“Ihave less laugh than before”（P＜0.05）and“There is no definite reason, but I am tired”（P＜0.05）were significantly alleviated. Conclusions Consumption of an oral nutritional supplement drink containing Lactobacillus paracasei MCC1849 for 4 weeks possibly improved the immune system of elderly people by preventing the decline of immune strength and improving quality of life-related subjective symptoms of fatigue. Trial registration UMIN-CTR: UMIN000026387 Foundation Clinico Co., Ltd.

Objectives The objective of this study was to evaluate the safety of excessive intake of heat-induced yeast extract（Cerepron®）in healthy adult subjects. Methods An open trial was conducted in 10 volunteers（5 males and 5 females）. Volunteers were given 500 mg╱day of heat︱induced yeast extract for 4 consecutive weeks. Body weight, body mass index（BMI）, body fat percentage, blood pressure, heart rate, blood parameters, urine parameters, and subjective symptoms were recorded throughout the study. Results No adverse effects and no clinically concerning changes in body weight, BMI, body fat percentage, blood pressure, heart rate, blood parameters, urine parameters were observed throughout the study. Conclusions These results indicate that the excessive intake of heat-induced yeast extract （500 mg╱day for 4 weeks）was found to be safe in healthy adults.

Objectives Vascular pain in patients receiving oxaliplatin（L-OHP）is associated with a low pH of L-OHP in a 5％ glucose solution（5％ Tz）. In the present study, we examined the pH of several generic versions of L-OHP in 5％ TZ to evaluate the risk of vascular pain. Methods One original and 5 generic versions of L-OHP were used. The pH value was determined using a pH meter. The pH value of 250 mL of 5％ Tz containing 200 mg of L-OHP and 6.6 mg of dexamethasone were measured at 0, 1, 3 and 6 h, and the appearance of the solutions was simultaneously checked. We also compared the estimated cost of 5 generic products based on the use results at Fukuoka University Hospital for fiscal year 2016. Results At 3 h, the pH values of generic A, generic C and the original product were 7.07, 7.20, and 7.07, respectively. The pH profile of generic A was equal to the profile of the original product. No change was seen in the appearance of any of the original or generic products. The estimated cost of generic A was the lowest of all generic products. In comparison to the original product, the use of generic A could reduce the cost associated with L-OHP by 35,928,914 yen. Conclusions We selected generic A in our hospital because it had the same pH profile as the original drug and because the cost was lower than that of any of the other generic drugs. When considering the development of hospital formulary, especially for generic drugs in which the pH profile is associated with side effects, the nature of the solution should be carefully checked.