薬理と治療

10月4 ～ 5日の2日間にかけて，第14回CRCと臨床試験のあり方を考える会議2014 in 浜松（メインテーマ「響け，未来の医療へ！～プロフェッショナリズムのハーモニー～」，アクトシティ浜松）が開催された。開会式では，会議代表の鈴木千惠子氏（浜松医科大学医学部附属病院臨床研究管理センター）があいさつし，「楽しく学び，実りの多い2日間にしてほしい」と参加者に呼びかけた。会議代表企画（臨床研究・治験をとりまく環境が変わる—とおとうみから今を伝える— ）の第一部教育講演［座長：渡邉裕司（浜松医科大学医学部臨床薬理学講座／附属病院臨床管理センター）］では，臨床研究・治験をとりまく環境の変化に対する政府の取り組みについて，河野典厚氏（厚生労働省医政局研究開発振興課治験推進室）と井上隆弘氏（文部科学省研究振興局ライフサイエンス課）がそれぞれの立場で講演を行った。さらに，第二部［座長：楠岡英雄（国立病院機構大阪医療センター），梅村和夫（浜松医科大学医学部薬理学講座／附属病院臨床研究管理センター）］では，浜松地域の医療機関が連携して臨床研究・治験の活性化を図る「とおとうみ臨床試験ネットワーク」の活動について鈴木千惠子氏が現状報告を行ったうえで，幹事病院の病院長（もしくは代理）および浜松市医師会長が登壇し，パネルディスカッションを行ったので報告する

Orexins are initially known to be a hypothalamic peptide critical for feeding and normal wakefulness. In addition, orexins are also involved in the regulation of nociceptive processing, suggesting a novel potential therapeutic approach for pain treatment. Morphological results show that orexin A is distributed in DRG neurons. SNL of neuropathic pain has been widely used for various investigative works on neuropathic pain mechanisms. We have investigated the effects of lidocaine and orexinA on high K＋︱induced［Ca2＋］i increase in sham and segmental spinal nerve ligation（SNL）model rat dorsal root ganglion （DRG）neurons. Ten male Wistar rats were randomly assigned for one independent experiments（n＝5⊠2）：sham group, experimental group（SNL group）. DRG neurons were depolarized by exposure to 50 mM K＋ and the rise of ［Ca2＋］i was measured using fura︱2 as an indicator. Nifedipine and lidocaine strongly inhibited on the high K＋︱induced depolarization［Ca2＋］i increase in sham and SNL groups. OrexineA inhibited on the high K＋︱induced depolarization ［Ca2＋］i increase in SNL rat DRG neurons, but was little or no effect in sham group. Thus, the effect of orexinA on high K＋︱induced［Ca2＋］i increase was considered to be due to blocking Ca2＋ influx through L︱type Ca2＋ channel, which may have important implications for nociceptive modulation and pain.

Objective We examined effect of placenta extract on the proliferation and TypeⅠcollagen mRNA expression of human skin fibroblast. Methods Normal human skin fibroblast were treated with 0.16, 0.32, 0.64％ placenta extract. After 48 hours, the proliferation of skin fibroblast was determined by Cell Counting Kit︱8. For the expression of COL1A1, which encodes the major component of type Ⅰ collagen, total RNA was isolated from skin fibroblast treated with placenta extract for 48 hours and analyzed using RT︱qPCR. Results Placenta extract stimulated the proliferation of human skin fibroblast in a dose︱dependent manner. Further, the expression of COL1A1 gene was also promoted by placenta extract. Conclusion These results indicated that placenta extract has effective components on the activation of skin fibroblast, and this activation of fibroblast may be contribute to recovery of wrinkle and wound healing.

Objectives Sitagliptin is an orally active, potent and selective dipeptidyl peptidase ︱4（DPP︱4）inhibitor for the treatment of type 2 diabetic patients. Sitagliptin acts through increasing incretin（GLP︱1 and GIP）hormone concentration, and reduces plasma glucose and HbA1c levels. Previously we reported that sitagliptin also reduces plasma triglyceride（TG）and remnant cholesterol（Jpn Pharmacol Ther 2011；39：217︱23）. Bezafibrate reduces mainly plasma TG and remnant cholesterol. Bezafibrate is reported to have a lowering effect of plasma glucose. However, there is little information about the effects of the combination therapy. In this study we investigated the effects of the combination therapy with sitagliptin and bezafibrate on glycemic control, lipids, hepatic function and renal function in type 2 diabetic patients. Methods Twenty︱two patients with type 2 diabetes were studied. All patients were treated with diet therapy only. Mean age was 64 years, mean BMI was 24.5 kg╱m2 and mean HbA1c （NGSP）was 7.2％ at the start of the study. Patients were treated with sitagliptin（50 mg╱day）for 3 months before the combination therapy. Bezafibrate（200 mg╱day）was added on. Patients were treated with the combination therapy with sitagliptin and bezafibrates over 7 months. HbA1c, plasma lipid levels, hepatic function and renal function were compared before and after the sitagliptin monotherapy or the combination therapy with sitagliptin and bezafibrate. Results Sitagliptin monotherapy significantly reduced HbA1c level （7.2±0.2％→6.3±0.2％,P＜0.001）. Add︱on therapy with bezafibrate significantly reduced HbA1c level（6.3±0.2％ →6.0±0.1％, P＜0.05）. Sitagliptin monotherapy significantly reduced TG level（275±16→143±8 mg╱dL, P＜0.001）. Add︱on therapy with bezafibrate significantly reduced TG level（143±8→108±5 mg╱dL, P＜0.001）. Sitagliptin monotherapy significantly reduced serum creatinin level（1.03±0.06→0.89±0.05 mg╱dL, P＜0.05）. Add︱on therapy with bezafibrate significantly reduced creatinin level（0.89±0.05→0.83 ±0.04 mg╱dL, P＜0.05）. Hepatic functions（AST, ALT, γ︱GTP）tended to decrease after the monotherapy and the combination therapy, but these changes were not statistically significant. Conclusion It is concluded that the combination therapy with sitagliptin and bezafibrate is more effective to reduce HbA1c as well as plasma TG than sitagliptin monotherapy in type 2 diabetic patients. Furthermore, the combination therapy showed the improvement of serum creatinin level. This finding suggests that the combination therapy protects and improves diabetic nephropathy.

Objectives The aim of this prospective observational post︱marketing surveillance of the specified drug︱use survey was to evaluate the clinical safety and efficacy of long︱term combination therapy of pioglitazone with biguanide︱based medicine in patients with type 2 diabetes mellitus. Methods This survey was conducted from February 2009 to January 2012 with the central registration system. Pioglitazone （15︱45 mg）was administered once daily for 12 months additionally to patients with type 2 diabetes mellitus who had inadequate glycemic control despite traetment with biguanide. Results The incidence of adverse drug reactions was 8.98％ （79╱880 subjects）. The frequent adverse drug reactions were edema（2.27％）, body weight increase（1.82％）and peripheral edema（0.68％）. Hypoglycemia was reported in 3 subjects（0.34％, 3 events）, but all those events were not serious and recovered. HbA1c was reduced from 8.34±1.217％ at baseline to 7.49±1.163％ at final evaluation. The reduction of HbA1c was observed at 3 months and maintained until 12 months in this survey. Similar finding was also observed for fasting blood glucose. These results of efficacy were consistent with the previous studies and revealed no significant safety issues. Conclusion Our findings suggest that the combination therapy with pioglitazone and bigua-nide︱based medicine in patients with type 2 diabetes mellitus is clinically safe, efficacious and useful.

Objective A post︱marketing surveillance was conducted to obtain information on the safety and efficacy of mitiglinide calcium hydrate, a short︱acting insulin secretagogue（Glufast® Tablet）, for a long︱term combination therapy with α︱glucosidase inhibitor in patient with TypeⅡdiabetes. Methods This surveillance was conducted using a prospective central registration method. An observation period was 18 months. The collected information included the patientʼs background, concomitant medication, laboratory test values and adverse events. Results Adverse drug reactions were reported in 45 of 972 patients（4.63％）. The most frequently reported adverse drug reaction was hypoglycaemia, which was observed in 27 cases （2.78％）, no cases of serious hypoglycaemia were reported. There were no reports of an increased incidence rate of adverse drug reactions and hypoglycaemia related to long︱term concomitant treatment. HbA1c levels（NGSP）were measured to be 7.88±1.29％ at the start of concomitant therapy, 7.13 ±1.09％ after 12 months and 7.10±0.99％ after 18 months. HbA1c levels measured at each of the assessment time︱points were significantly lower（both P＜0.01）than that measured at the baseline, and showed that improvement of the glycemic control was maintained during the 18 months of concomitant therapy. Conclusions In this surveillance, information of approximately 1000 patients was collected and safety and efficacy were investigated. The results showed no new safety issues during the 18 months of concomitant therapy, and a continuous improvement of glycemic control was observed.

Objectives A randomized double︱blind placebo︱controlled trial was performed to examine the effects of oral supplementation with fish︱derived collagen peptide on human skin damage induced by ultraviolet irradiation. Methods Before and after ingestion of 5 g of collagen peptide or placebo for 4 weeks, ultraviolet irradiation at 1.5 minimal erythema dose was applied to the back skin of Japanese adult males aged 20︱59 years with skin photo typeⅡ or Ⅲ. Erythema（a＊value）and melanin （Mexameter value）were measured on days 1（irradiation day）, 4, and 8. The water content of the stratum corneum and trans︱epidermal water loss were determined on days 1, 4, 8, 11, and 15. Results Erythema increased evidently on day 4 and decreased on day 8, while melanin increased slightly on day 4 and evidently on day 8. No significant differences were observed between the collagen peptide group and the placebo group for erythema and melanin before or after ingestion. However, when a stratified statistical analysis was performed for subjects older than 30 years of age, significant suppression of erythema was detected on day 4 in the collagen peptide group after ingestion for 4 weeks. No significant changes were detected for the water content and trans︱epidermal water loss. No adverse side effects attributable to collagen peptide ingestion were observed. Conclusions The present results suggest that supplemental ingestion of fish︱derived collagen peptide has beneficial effects on human skin for suppressing erythema induced by ultraviolet irradiation, particularly in older subjects above 30 years of age.

Objectives We carried out two double︱blind, placebo︱controlled, parallel group studies to evaluate the safety of long︱term intake and excessive intake of the biscuits containing highly cross︱linked starch（HXLS）from tapioca. Methods For long︱term intake study and excessive intake study, 24 healthy volunteer subjects were randomly divided into two groups, respectively. In the long︱term intake study, subjects ingested one package（28 g）of the test biscuits containing 7 g（as fiber）of HXLS or the same amount of the placebo biscuits without HXLS per day for 12 weeks. In the excessive intake study, subjects ingested one package（47g）of the test biscuits containing 21 g（as fiber）of HXLS, which is triple amount of long -term study, or the same amount of the placebo biscuits per day for 4 weeks. Results No unusual changes were observed in physical, blood, urinary examination and medical interview on HXLS containing biscuits in the long︱term intake study and the excessive intake study. Conclusion These results suggest that the biscuits containing HXLS was safe for both long-term and excessive intake.

Objective We examined the effect of the new sweetener involving multitol and polydextrose comparing blood glucose elevation by 50 g loading test with glucose. Methods A randomized double︱blind placebo︱controlled crossover trial was conducted in 30 subjects（male 11, female 19）with FBS（fasting blood sugar level） ＜126 mg╱dL. They were randomly divided into two groups（Group A and Group B）. Group A╱B ingested the drinks including 50 g of the new sweetener involving multitol and polydextrose╱50 g of glucose（the placebo）in the first period, and ingested the drinks including 50 g of glucose╱50 g of the new sweetener in the second period 1week after the first period. Blood samples were drawn before and 30, 60, 90 and 120 minutes after the ingestions and their serum Glucose and Insulin levels were measured. Results In comparison with the placebo, the new sweetener significantly lowered the postprandial glucose at 30, 60, 90 and 120min after ingestion, and lowered the area under the curve of blood glucose（AUC）（P＜0.05）. Conclusions These results suggest that the elevation of postprandial glucose is suppressed by the new sweetener.

Objective The aim of this study was to evaluate the intake of lactic bacteria （Lactobacillus brevis）on skin conditions in women who had mild dry skin conditions. Methods Ten female subjects（average of 35.1±8.6 years old）who had mild dry skin conditions received lactic bacteria（4 g；～4⊠1010cells）daily for 8 weeks, and skin conditions including skin hydration state, transepidermal water loss （TEWL）, and skin viscoelasticity were evaluated. Results The intake of lactic bacteria for 8 weeks significantly improved TEWL in the left forearm（from 7.35±1.61 to 6.83±1.27 g╱m2h；P＜0.05 by paired Studentʼs t︱test）. Regarding the skin viscoelasticity, the parameters R5（net elasticity）and R7（the ratio of elastic recovery to the total deformation）significantly increased after 8 weeks of the intake of lactic bacteria（from 0.403±0.055 to 0.433±0.034Ur╱Ue and from 0.268 ±0.045 to 0.289±0.032Ur╱Uf, respectively；P＜0.05 by paired Studentʼs t-test）. A questionnaire revealed that subjective skin conditions significantly improved after the intake of lactic bacteria for 8 weeks. Conclusions The intake of lactic bacteria is suggested to improve both objective and subjective quality of skin conditions.