Search

Decisions concerning approval of human papillomavirus (HPV) vaccines and their use are based on expert evaluation of the vaccines. However, the quantitative differences between vaccine benefits and risks are difficult for non-experts to understand. In this study, we developed a new method to calculate the benefits and risks of the HPV vaccines using disability-adjusted life year (DALY) as the mono-scaled weight for various benefits and risks relevant to the vaccines. We evaluated benefits as a gain of DALY values for cervical cancer and risks as the loss of DALY values for various adverse events by the vaccination. To calculate the loss of DALY values, we integrated all adverse events in the International Classification of Diseases chapters. The novel method reflected the men-women ratio of this epidemiological disease to a certain extent. Among the vaccinated women, 111372 and 477190 received a bivalent and quadrivalent vaccine, respectively. The DALY rate of cervical cancer was 148.7. The calculated benefit for the bivalent and quadrivalent vaccines was 149.1 and 638.8, respectively, and set as the theoretical maximum. The risk was calculated as 129.3 and 49.6 in the bivalent and quadrivalent vaccines, respectively. Since HPV vaccines prevent several other cancers, the benefit of the vaccination extends beyond the risk according to this new method.

Compassionate use is a system that provides patients with exceptional access to investigational new drugs to treat life-threatening diseases that have no effective conventional treatments. The purpose of this study was to characterize and assess the current status of the compassionate use program's application in Japan by evaluating expanded access clinical trials (EACTs) conducted between 2016 and 2021. In this study, a data set containing all EACTs, and pivotal clinical trials (PCTs) conducted in Japan between February 2016 and April 2021 was obtained from the Pharmaceutical and Medical Devices Agency, systemically reviewed, and analyzed. During the 5 years since EACTs began in Japan, out of 2,031 PCTs, 31 EACTs were conducted in Japan. Twenty-four trials (77.4%) of the 31 EACTs used anticancer drugs and 5 of those trials (16.1%) were conducted in children. Furthermore, we conducted an EACT survey for drugs with a high degree of social and patient demands as recommended in the EACT notification. Among the 2,031 PCTs, we found 152 trials with high degree of social and patient demands. Of these, EACT was implemented in 17 trials (11.2%). Days from the start of the EACT to the submission of new drug applications and the approval were 9.0 (67.0-56.5) and 208.0 (172.8-308.8) days, respectively. Of the 31 EACTs conducted, 24 (77.4%) drugs have been approved as of August 2021. This first comprehensive study on EACTs clarified the current status and issues of Japan's compassionate use system and the 5 years since the program initiated.

Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development.In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs.The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time.US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

WHAT IS KNOWN AND OBJECTIVE Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. METHODS Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. RESULTS AND DISCUSSION Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. WHAT IS NEW AND CONCLUSION The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

Drug time lags occur between the date that new drugs are first approved, often in the USA, and approval is granted in other countries. Multi-regional clinical trials (MRCTs) are a key strategy for simultaneous global development and regulatory submission of new drugs. However, no studies have evaluated the impact of MRCT versus local development on key time points in the drug development lifecycle between the USA and Japan. It is important for pharmaceutical companies planning drug development in Japan to understand when they can start development, when they can catch up in case of development initiation delay, length of time the development period might take, and amount of time that market exclusivity is lost, if Japan does not participate in the MRCT. The aim of this study was to investigate differences in drug lag in development initiation, New Drug Application (NDA) submission and drug approval, as well as differences in the development and review periods, by local trials and MRCTs between Japan and the USA. We also assessed the advantages and disadvantages of MRCTs for these lags in Japan. We analyzed drug approvals in Japan between 2016 and 2020 and divided them into local and MRCT groups. Lags in development initiation, NDA submission, and approval of new drugs were calculated by subtracting each date in Japan from the corresponding date in the USA. Our study period was divided into three periods based on the International Conference on Harmonization (ICH) E17 guideline, published in 2017, and the guideline for the Phase I trials in the Japanese population prior to MRCTs, published in 2014. In addition, subgroup analyses by therapeutic area, regulatory background, modality, capital style, and sales ranking (2020) were conducted. We analyzed 174 approvals in Japan and the USA. The differences in the drug lags for development initiation, NDA submission, and approval between the local and MRCT groups were 4.9, 3.5, and 3.2 years, respectively. All three lag times were shorter for the MRCT group than the local group. A development initiation lag in the local group has expanded since publication of the guidelines. For the people of Japan, important drug lags were identified in development initiation, NDA submission, and drug approval dates between local trials and MRCTs that include Japan. It is difficult to recover fully from the delay caused by local development, and it is important to understand the further expansion of drug lags, in cases where Japan is not involved in the MRCT.

The growing prevalence of Alzheimer's disease (AD) worldwide has sparked the implementation of national policies to support the growing burden among caregivers of AD/dementia patients. This study aims to quantify and compare the burden of AD/dementia caregivers and evaluate how different living arrangements might impact health outcomes among caregivers in Japan, five European countries (5EU), and the United States (US).This is a cross-sectional study based on existing data from the 2018 National Health and Wellness Survey. Health outcome measures included health-related quality of life (HRQoL), health state utilities, work productivity and activity impairment (WPAI), and measurement of depression and anxiety amongst AD/dementia caregivers and non-caregivers. Pairwise comparisons between AD/dementia caregivers in Japan, 5EU, and the US were conducted. Multivariate analysis was used to compare across groups within each region, with adjustment for potential confounding effects.A higher proportion of caregivers of AD/dementia patients in Japan were 65 years or older as compared to 5EU and US. On the contrary, female caregivers were significantly higher in the US than Japan and 5EU. The HRQoL and health state utilities index scores amongst AD/dementia caregivers were highest in Japan and lowest in the US. Caregivers in Japan incurred the lowest WPAI among the three regions. The proportion of AD/dementia patients reportedly living in an institution was highest in Japan as compared to the US and EU. Notably, US caregivers whose patients lived in an institution experienced significantly less caregiving burden as compared to caregivers whose patients lived in the community.The caregiving burden among AD/dementia caregivers was substantial across the three regions, with similarities and differences between the West and Japan. The lower caregiving burden in Japan was potentially associated with national policies supporting long-term healthcare and institutionalized nursing care facilities for AD/dementia patients.

Background: Stroke has been found to have a seasonally varying incidence; blood pressure, one of its risk factors, is influenced by humidity and temperature. The relationship between the incidence of stroke and meteorological parameters remains controversial. Objective: We investigated whether meteorological conditions are significant risk factors for stroke, focusing on the fluctuation of weather elements that triggers the onset of stroke. Methods: We collected ambulance transportation data recorded by emergency personnel from Gifu Prefecture. We included cases where the cause of the transportation was stroke and excluded cases of trauma. We combined these data with meteorological data as well as data on average temperature, average air pressure, and humidity provided publicly by the Japan Meteorological Agency. Our target period was from January 2012 to December 2016. Results: In the 5-year target period, there were 5,501 occurrences of ambulance transportation due to stroke. A seasonal tendency was confirmed, since ambulance transportation for stroke occurred more frequently at low temperatures (p < 0.001). Temperature (odds ratio: 0.91; p < 0.001) and humidity change (odds ratio: 1.50; p = 0.016) were identified as risk factors for ambulance transportation due to stroke. An increase in temperature incurs a lower risk than a decrease (odds ratio: 0.58; p = 0.09), although there is no statistically significant difference. Conclusions: Meteorological effects on the frequency of ambulance transportation due to stroke were studied. A lower temperature and radical humidity change were identified as risk factors for ambulance transportation due to stroke, and a decrease in temperature was also associated. We speculate on the possibilities of using meteorological data to optimize the assignment of limited medical resources in medical economics.

Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee's request. First-in-class drugs were developed at the Committee's request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

Background Although there are accelerated approval pathways based on the data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs in small and large clinical trials and verified whether small clinical trials could reflect the efficacy results of large clinical trials. Design: All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression-free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression and Spearman’s correlation analyses were performed. Results A total of 61 comparable small and large clinical trials were identified. For all endpoints, significant linear trend and correlation were detected (P < 0.001). In particular, the correlation coefficients of median OS and ORR were high (0.852 and 0.873, respectively). Conclusion The median OS, median PFS, and ORR data of small clinical trials precisely reflected the efficacy data of large clinical trials. Thus, the efficacy data of small clinical trials can be used to predict the efficacy data of a large population. These results support the accelerated approval pathway based on promising efficacy data of small populations in anticancer drug development.

Aims: Understanding the burden of cancer in Japan is becoming increasingly important to address the socio-economic consequences of the disease. This study broadly examined the cancer burden in term...

The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents No difference in the total number and types of approved drugs among the 3 regions was found (P =.173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions (P

Drug time lags occur between the date that new drugs are first approved, often in the USA, and approval is granted in other countries. Multi-regional clinical trials (MRCTs) are a key strategy for simultaneous global development and regulatory submission of new drugs. However, no studies have evaluated the impact of MRCT versus local development on key time points in the drug development lifecycle between the USA and Japan. It is important for pharmaceutical companies planning drug development in Japan to understand when they can start development, when they can catch up in case of development initiation delay, length of time the development period might take, and amount of time that market exclusivity is lost, if Japan does not participate in the MRCT.The aim of this study was to investigate differences in drug lag in development initiation, New Drug Application (NDA) submission and drug approval, as well as differences in the development and review periods, by local trials and MRCTs between Japan and the USA. We also assessed the advantages and disadvantages of MRCTs for these lags in Japan.We analyzed drug approvals in Japan between 2016 and 2020 and divided them into local and MRCT groups. Lags in development initiation, NDA submission, and approval of new drugs were calculated by subtracting each date in Japan from the corresponding date in the USA. Our study period was divided into three periods based on the International Conference on Harmonization (ICH) E17 guideline, published in 2017, and the guideline for the Phase I trials in the Japanese population prior to MRCTs, published in 2014. In addition, subgroup analyses by therapeutic area, regulatory background, modality, capital style, and sales ranking (2020) were conducted.We analyzed 174 approvals in Japan and the USA. The differences in the drug lags for development initiation, NDA submission, and approval between the local and MRCT groups were 4.9, 3.5, and 3.2 years, respectively. All three lag times were shorter for the MRCT group than the local group. A development initiation lag in the local group has expanded since publication of the guidelines.For the people of Japan, important drug lags were identified in development initiation, NDA submission, and drug approval dates between local trials and MRCTs that include Japan. It is difficult to recover fully from the delay caused by local development, and it is important to understand the further expansion of drug lags, in cases where Japan is not involved in the MRCT.

Patients with cancer experienced reduced health-related quality-of-life (HRQoL), increased work productivity and activity impairment (WPAI), and indirect costs. With the current emphasis on economic evaluation of health technology in Japan, it is important to understand how indirect costs correlate with HRQoL and patient characteristics. It is also crucial to assess the patient characteristics associated with the HRQoL, WPAI, and indirect costs among patients with any types of cancer.This cross-sectional study used data from the 2017 Japan National Health and Wellness Survey (NHWS). Respondents self-reported their HRQoL and WPAI by answering validated SF-12v2 and WPAI questionnaires, respectively. Indirect costs were derived using the human capital method. Correlation between HRQoL components and indirect costs were assessed using Spearman's rank-order correlation. Correlation between patient characteristics and HRQoL, WPAI, and indirect costs were analyzed using generalized linear models.A total of 1,540 patients with any types of cancer, 254 with breast cancer, and 144 with colorectal cancer were included in the analyses. There was significant negative correlation between the indirect costs and HRQoL components among patients with any types of cancer. Patients with lower comorbid burden, higher household income, employed, married, or living with partner, never smokers, and exercised tended to have higher HRQoL. Being never smokers, having lower comorbid burden, normal weight, and exercised were associated with lower WPAI measures. Additionally, patients who were older, not married, not obese, and not smoking tended to incur lower indirect costs.The negative correlation between HRQoL and indirect costs among patients with cancer emphasized the needs to improve health outcomes and reduce indirect costs of patients. The factors associated with cancer burden identified in this study provide insights to allow targeted intervention to improve HRQoL and lessen the WPAI and indirect cost among cancer patients in Japan.

The approval of anticancer drugs in Japan has increased to meet high medical demand. To maximize the benefits of anticancer drugs, adverse drug reactions (ADRs) must be properly managed. However, in some cases, clinically significant safety issues are detected after launch, and safety-related regulatory actions (SRRAs) are implemented. We aimed to determine the characteristics of SRRAs for anticancer drugs approved in Japan and to identify factors related to the drug development and regulatory approval process associated with the occurrence of an SRRA. We defined an SRRA as the issuance of a ‘Yellow Letter’, ‘Blue Letter’, or an official notification by the Ministry of Health, Labor and Welfare. Anticancer drugs approved in Japan as new active ingredients from April 2004 to July 2016 were analyzed using publicly available information. The Kaplan–Meier survival curve was plotted to estimate the probability of the occurrence of an SRRA, and the Cox proportional hazards model was used to identify risk factors associated with the occurrence of an SRRA. Independent variables were selected using backward/forward stepwise selection according to Akaike’s Information Criterion. An SRRA was implemented for 38 of 63 anticancer drugs. Approximately 70% of SRRAs occurred within 2 years after approval, and the median time between approval and the occurrence of an SRRA was 1.6 years (interquartile range 0.94–2.4). No Yellow Letter was issued during the follow-up period; however, one Blue Letter was issued for ‘acute lung injury and interstitial pneumonia’ for sorafenib. According to official notifications, ‘clinically significant adverse reactions’ was the most revised section of package inserts (62%). The probability of an SRRA at the 1-, 2- and 3-year follow-up was 15.9% (95% confidence interval [CI] 6.4–24.4%), 41.3% (95% CI 27.8–52.3%), and 56.8% (95% CI 41.8–68.0%), respectively. Monoclonal antibodies were associated with a low risk of occurrence of an SRRA (hazard ratio [HR] 0.29, p = 0.019), while the large number of patients in pivotal studies (per 100 patients) was associated with a high risk of occurrence (HR 1.07, p = 0.012). The high-risk period for the occurrence of an SRRA for anticancer drugs in Japan was within 2 years after approval. Among the factors related to the drug development and regulatory approval process, anticancer drugs in the form of non-monoclonal antibodies, and whose pivotal studies included a large number of patients, were more likely to be associated with an SRRA. Postmarketing follow-up should therefore be carefully performed, especially in the first 2 years after approval and for non-monoclonal antibody anticancer drugs. Moreover, postmarketing follow-up is crucial, even if large-scale pivotal studies for regulatory approval have already been performed.

The approval of orphan anticancer drugs is encouraged in Japan to meet high social demand. However, approval lag and its main component, submission lag, between the USA and Japan continues to be an issue for these drugs. We aimed to identify the main reasons for submission lags with orphan anticancer drugs, to compare these between orphan and non-orphan anticancer drugs, and to identify factors associated with the main reasons for submission lags for orphan anticancer drugs. We investigated anticancer drugs approved in Japan between April 2004 and December 2017 using publicly available information. We used Pearson’s product moment correlation coefficient to identify correlations between submission lag and initiation lag or development-time lag, and we used the Mann–Whitney U test to compare contributors to submission lags for both orphan and non-orphan anticancer drugs. We used multiple regression analysis to identify potential factors associated with the main reasons for submission lags for orphan anticancer drugs at the indication level. Independent variables were selected using backward/forward stepwise selection according to the Akaike information criterion. In Japan, the number of approved indications for orphan anticancer drugs consistently increased between 2004–2007 and 2016–2017. The median submission lag for orphan anticancer drugs in 2016–2017 was 515.0 days [interquartile range (IQR) 182.0–999.0], and this lag was significantly correlated with the initiation lag (correlation coefficient 0.77, P

The approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orphan anticancer drugs in 2016–2017 was 727.0 days (interquartile range, IQR, 310.0–1054.3). The approval lag was significantly correlated with the submission lag (correlation coefficient = 1.00, P

The Breakthrough Therapy Designation (BTD) program was established in the USA in 2012 to expedite the development of new potential “breakthrough” drugs with promising early clinical evidence over available therapies. The majority of BTDs are oncology drugs, and previous research has reviewed the impact of this designation on drug development in the USA. Recent trends in the globalization of oncology drug development suggest that expedited programs in the USA may influence drug development timing in other countries. We examined the influence of BTD in the USA on the development initiation date, development period, and approval of oncology drugs in Japan. We analyzed oncology drugs approved in Japan between 2013 and 2017 that were also approved in the USA. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information. We analyzed 72 approvals for oncology drugs. The development periods for BTD drugs, both in Japan and in the USA, were shorter than those for non-BTD drugs. Additionally, the difference both in the development start date and in the approved date between the USA and Japan was smaller for BTD drugs than that for non-BTD drugs. BTD designation itself and/or the characteristics and target diseases of drugs that are eligible for BTD in the USA may constitute factors that facilitate a shorter development period, earlier development initiation and earlier approval in Japan.

The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281.0 days [interquartile range, 263.3–336.0]; 222.5 patients [66.0–454.3]) were significantly lower than those on non-orphan drugs (353.0 days [277.0–535.5]; 521.0 patients [303.5–814.5], respectively) (P

Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective.Data on US pediatric clinical trials were obtained from ClinicalTrials.gov . Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries.A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries ( P.05).Our results suggest that (1) the pharmaceutical industry utilizes regulatory frameworks in making business decisions regarding pediatric clinical trials, (2) disease area affects the involvement of European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs.

Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer’s disease (AD), with no effective results. To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease. The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5 years (2014–2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer’s Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer’s Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E e4 genotype and years of education as covariates. Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031). Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.

Background: The human papillomavirus (HPV) vaccine coverage is very low in Japan since the government suspended the active encouragement of the vaccination. We aimed to conduct a benefit–risk assessment of HPV vaccination and explore different consequent scenarios to identify potential improvements to the current Japanese immunization program. Methods: To calculate social benefit–risk of HPV vaccine, we used the Markov model to represent the natural history of HPV and adverse events (AEs) using disability-adjusted life year (DALY) as the outcome. Benefits and risks were calculated as the sum of negative and positive outcomes corresponding to all preventable diseases and AEs associated with HPV vaccination, respectively. The benefit–risk balance in 2050 was estimated using published data. Results: Our model was confirmed by published cervical cancer incidence and mortality rates. The benefit–risk balance in 2050 showed that the most effective scenario was the introduction of 9-valent HPV vaccine targeting female individuals aged 10–29 years for routine vaccination starting in 2020, although there is possibility of increased risks of AEs for the vaccinated age group post resumption of recommendations. Conclusion: Our benefit–risk assessment of HPV vaccine helped estimate various scenarios pertaining to HPV vaccination and identify the best strategy regarding HPV vaccination. This benefit–risk assessment approach may be used for other vaccines and vaccination programs.

Although Japan has implemented a universal health care system that is universal in terms of free access to health care services, it is managed by fragmented and financially insecure insurance societies that have cumulative deficits even with government subsidies. In terms of insurance premiums, the system is regressive to low-income and unstable workers, and the social benefit scheme only captures 1.6% of this population. The Japanese government is continuously instituting new health care policies to reduce growing health care expenditures. Recent health care reforms may improve economic efficiency, but the changes remain limited to controlling access to health services and pricing measures.

Aims: As the number of cancer patients increases in Japan, and people are living longer with cancer, the need for caregivers of cancer patients is expected to increase substantially. This s...

Caspofungin (CPFG) is an echinocandin antifungal agent that inhibits the synthesis of β-1, 3-D-glucan, a critical component of the cell wall of target fungi. Several clinical studies have confirmed the efficacy and safety of CPFG in patients with febrile neutropenia (FN); however, there are no reports available in Japanese patients with FN. Therefore, we investigated the therapeutic efficacy and pharmacokinetics of CPFG as an empirical therapy in a Japanese hospital. Twenty-four Japanese patients, who were diagnosed with FN at Gifu University Hospital from February 2014 to August 2017, were enrolled. Blood samples were collected at the end of CPFG dosing (0.5 h after the infusion) on day 1 and immediately prior to the next infusion on days 2, 3, and 4. The concentration of CPFG in plasma was measured by high-performance liquid chromatography. The efficacy was assessed by five of the component endpoints, and safety was monitored according to the Common Terminology Criteria for Adverse Events. CPFG showed an excellent effect against FN (75%, 18/24), without any serious hepatic or renal toxicity. Regarding the pharmacokinetics, the plasma concentration of CPFG was significantly correlated with body weight; although, no correlation was observed between the plasma concentration of CPFG and the other factors investigated, such as gender or laboratory results. These results suggest the high efficacy, safety, and tolerability of CPFG as an empirical antifungal therapy for Japanese patients with FN.

Background: Stroke has seasonal incidence; blood pressure, one of its risk factors, is influenced by humidity and temperature. The relationship between stroke incidence and meteorological parameters remains controversial. We investigated whether meteorological conditions are stroke risk factors, focusing on fluctuations of weather elements that trigger stroke onset. Methods: We collected the ambulance transportation data of Gifu Prefecture between January 2012 and December 2014. We included cases where the cause of transportation was stroke and excluded trauma cases. We combined these with meteorological data provided publicly by the Japan Meteorological Agency and preformed logistic regression analysis. Findings: In the target period, there were 3314 events of stroke-related ambulance transportation. Seasonal tendency was confirmed, and frequent transportation for stroke occurred at low temperature (p

Japan has been preparing to implement a Health Technology Assessment (HTA) process in 2018. Through a 2-year pilot program implemented in 2016, the government examined the criteria for applicable products and the necessary infrastructure to review both the content and quality of the data and to conduct cost-effectiveness assessments to be incorporated into the current Japanese reimbursement and pricing scheme. A survey of the pharmaceutical industry was conducted to understand the current landscape and to identify issues and challenges of implementing HTA in Japan.A semi-structured 19-item questionnaire was designed, and a survey was conducted via face-to-face or phone interviews. Answers were transcribed in English after the interviews and confirmed by e-mail. The survey focuses on pharmaceutical companies that develop new innovative products to be associated with the planned HTA.Differences between Japanese and global pharmaceutical companies were observed in terms of dedicated HTA teams in place, the use of quality of life data, and relationships with external vendors. Addressing a shortage of HTA professionals in Japan is critical to implement HTA. The survey found that list prices compared to those proposed by companies was an issue.Although the government decided to implement HTA for the pricing scheme in 2018, a shortage of experts and researchers remains a challenge. Findings suggest HTA should not be used solely to reduce pharmaceutical spending, as the impact by the HTA implementation will be temporary and discourage innovation.

Recent trends in globalization and the complexity of drug development have resulted in the possibility that expedited programs in one country may now influence drug development in another. We examined the effects of expedited programs in the United States on the development of oncology drugs in Japan.Among oncology drugs approved in Japan between 2007 and 2016, we analyzed those that were approved in both the United States and Japan. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information.We analyzed a total of 108 approvals for oncology drugs. The difference in the development start date between the United States and Japan for drugs granted Breakthrough Therapy designation was smaller than that for drugs without this designation ( P.01). The development period in Japan for drugs granted Breakthrough Therapy, Accelerated Approval or Fast Track designations was significantly shorter than that for drugs without these designations ( P.05). In addition, the development period of oncology drugs in Japan tended to be significantly shorter as the number of expedited program designations increased ( P.006 for trend).The characteristics and the target disease of the drug that could be eligible for expedited program(s) in the United States, which was supported by the designation, were one of the factors influencing the development of oncology drugs in Japan.

Purpose Multiregional clinical trials (MRCT) are a standard strategy used to improve global drug approval efficiency and the feasibility of clinical trials. Japan is the world's third largest drug market with a unique health care system, making it a key inclusion as an operational region for MRCT (MRCT-JP) for global drug development. We aimed to identify the factors required for efficient drug development by comprehensively reviewing the clinical trials of drugs approved in Japan to identify the factors associated with whether or not MRCT-JP is implemented. Methods We surveyed the review reports and summaries of application data published by the Pharmaceuticals and Medical Devices Agency. We identified drugs for which the clinical trial data package included MRCT-JP and selected the same number of drugs for which the clinical trial data package did not include MRCT-JP from the most recent survey period for comparison. We also examined other publication information, in addition to the review reports, as necessary. The influence of each explanatory variable was analyzed by logistic regression analysis, with whether or not MRCT-JP was implemented as the explanatory variable. Statistical significance was set at 5%. Findings In the survey period up to September 2017, 165 drugs developed with MRCT-JP were approved for manufacture and sale in Japan. “Respiratory system,” “inhalation,” “biological drug,” and “under review” evaluation status for the United States, European Union, and other areas, “approved” evaluation status for the United States, “new ingredients,” “priority review,” “non-Japanese firm,” and “Top 1–10” and “Top 11–20” drug sales rankings for pharmaceutical companies were identified as potential factors leading to the implementation of MRCT-JP. In contrast, “general anti-infectives for systemic use,” “various,” “external,” “chemical compound,” “unsubmitted” evaluation status for both the United States and European Union, and “Top 51+” drug sales rankings were potential factors for not implementing MRCT-JP. Implications Therapeutic classification and agent type, in addition to capital type and United States and European Union evaluation status suggested by a previous study, were associated with implementing MRCT-JP. It is important to determine the best way to utilize MRCT-JP to maximize the value of products. Our findings were based on successful cases and may therefore be helpful for designing clinical development plans. Appropriate use of MRCT-JP will improve productivity in the pharmaceutical industry.

Objective The aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity. Methods The movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non-ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed. Results In the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patient’s doctors. Conclusion We have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders.

Background Information on health-related quality of life (HRQoL) and economic burden are becoming more important in order to select the optimal treatments while considering increasing medical costs. However, limited research focusing on them has been done. We aim to compare HRQoL, work productivity, and estimated economic losses between patients with any types of cancer and non-cancer patients in Japan. Methods Data were obtained from the 2017 Japan National Health and Wellness Survey database including 30,001 participants, a cross-sectional survey representative of the Japanese adult population. Respondents without cancer were identified as the non-cancer group. Mental component summary (MCS) and physical component summary (PCS) of the SF-12v2 were used. The economic losses estimated from annual indirect costs derived from work productivity and activity impairment (WPAI) score and average wage were calculated using the human capital method. Results Cancer patients with who undergo treatment (A: N = 330), not cancer treatment currently (B: N = 1,210) and non-cancer patients (C: N = 28,070) were included in the analysis. Undergo cancer treatment patients had significantly lower compare to other groups on MCS value (43.68 vs. 46.38 vs. 46.55, A vs. B p Conclusion Patients with any types of cancer had higher burden compared to those without in terms of lower HRQoL, higher WPAI, and higher indirect costs. These findings would be useful for the discussion of the value in cancer treatments by multiple perspectives and health technology assessment process.

Background Combination therapy is a hallmark of cancer treatment. Approved combination therapies of anti-cancer drugs are classified into the following groups; broader than (Broad), the same as (Same), or a part of (Narrow) the series of combination regimen in clinical data packages submitted to Pharmaceuticals and Medical Devices Agency. Some anti-cancer drugs have restrictions in approved combination therapies although they have sufficient clinical findings except for the clinical data packages. In this context, the main objective is to investigate the relationships between approved combination therapies and clinical data packages, clarifying the drug profiles and target indications for each label description. This study can provide important information about approved combination therapy, which lead to secure and consistent access to effective anti-cancer drug combination therapy for cancer patients in Japan. Methods All approved indications which have been approved as "Cancer" since April 2006 to March 2017 were in scope. Number of approval records for combination therapy, difference in the combination regimen in clinical data package and condition of approved indication in label description, and number of combination therapy regimens in clinical data package and condition of approved indication were investigated. Results Among the eligible 97 approvals, 26 were approval for combination therapy. Among the 26 combination approvals, 9 consisting of 4 drugs were approved as Broad and out of 9, 7 were line extensions. Broad had average 2 combination regimens in clinical data packages while Same average 1 and Narrow average 4. Conclusions If the drugs whose efficacy has been established in several clinical trials and the regimen used in combination therapy in each clinical trial is different, Broad will be applied. There was no relationship between the number of combination therapy regimens in clinical data package and condition of approved indication.

As diseases know no national boundaries, drug development must be designed at a global level. Drugs are highly regulated to maximize the benefits to public health, which is assessed on a regional basis. The complexity and diversity of stakeholders increase dramatically once multiple international regions are involved. Each stakeholder in drug development depends on customized criteria to make decisions for its own benefit. Thus, a huge gap exists among drug discovery researchers, developers, clinicians, patients, and regulatory bodies. With reasonable scientific evidence gathered and analyzed, mutual agreement can be reached. We believe that this important role of regulatory science and academic involvement will create harmony. By practicing diverse, innovative regulatory scientific research, academia has the potential to become the core of communication among various stakeholder groups. Furthermore, another important responsibility of academia, i.e., knowledge, provides additional aspects to the field of drug development. Those who understand regulatory science can contribute to the efficient achievement of innovative, effective, safe drugs. Thus, research and education are essential roles of academia to allow a better understanding of the balance between benefits and risks. Communication and knowledge will promote the prompt delivery of better medical products to patients in need.

SUMMARY Pancreatic b cell regeneration remains poorly understood, yet stimulation of adult b cell neogenesis could lead to therapies for type 1 and type 2 diabetes. We studied the effect of embryonic stem (ES) cell transplantation on pancreas regeneration following b cell injury. Female Balb/c nude mice were treated with streptozotocin to induce hyperglycemia and received an ES cell transplant 24 hr later beneath the renal capsule. Transplantation of ES cells prevented hyperglycemia in a subset of mice, maintaining euglycemia and mild glucose tolerance up to 5 weeks. Pancreata of euglycemic mice showed histological evidence of b cell regeneration and expression of pancreas and duodenum transcription factor-1 (PDX-1) and neurogenin 3 (Ngn3) in ductal epithelium. Cell tracing analysis indicated that significant b cell neogenesis from progenitor cells occurred between 2 to 3 weeks following injury in ES cell–transplanted mice but not in sham-transplanted animals. Significantly, whereas pancreas-localized ES cells or their derivatives were adjacent to sites of regeneration, neogenic pancreatic epithelia, including Ngn3 1 cells, were endogenous. In conclusion, transplanted ES cells can migrate to the injured pancreas. Transplantation is associated with enhanced endogenous regeneration characterized by expression of Ngn3 and increased b cell differentiation from endogenous progenitor cells. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 57:1149–1158, 2009)

The role of estrogens in the regulation of pubertal growth independently of GH and its receptor was studied in male mice with disrupted GHRKO. E2 rescued skeletal growth rates in GHRKO associated with an increase in hepatic and serum IGF-I. These data show that E2 rescues pubertal growth during GH resistance through a novel mechanism of GHR-independent stimulation of hepatic IGF-I production. Introduction: Growth hormone (GH) and estrogen play a pivotal role in pubertal growth and bone mineral acquisition. Estrogens can affect GH secretion and thereby provide a GH-dependent mechanism for their effects on skeletal growth. It is presently unclear if or to what extent estrogens are able to regulate pubertal growth and bone mineral accrual independently of GH and its receptor. Materials and Methods: Estradiol (E2; 0.03 μg/day by subcutaneous silastic implants) was administered to orchidectomized (ORX) male mice with disrupted GHR (GHRKO) and corresponding WTs during late puberty (6–10 weeks). Longitudinal and radial bone growth, IGF-I in serum and its expression in liver, muscle, and bone, and liver gene expression were studied by histomorphometry, RIA, RT-PCR, microarrays, and Western blotting, respectively. Results: E2 stimulated not only longitudinal (femur length and growth plate thickness) and radial growth (cortical thickness and periosteal perimeter), but also rescued longitudinal and periosteal growth rates in ORX GHRKO, whereas no significant changes occurred in WT. E2 thereby upregulated serum IGF-I and liver IGF-I synthesis (+21% and +52%, respectively) in ORX GHRKO, whereas IGF-I synthesis in femur or muscle was unaffected. Study of the underlying mechanism of the stimulation of hepatic IGF-I expression showed that E2 restored downregulated receptor signaling systems, such as the estrogen receptor α and the prolactin receptor. E2 thereby recovered the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway as evidenced by a significantly increased activation of the transcription factor STAT5 in ORX GHRKO. Conclusions: Our data show a stimulation of skeletal growth through upregulation of hepatic IGF-I by a hormone other than GH. E2 rescues pubertal skeletal growth during GH resistance through a novel mechanism of GHR-independent stimulation of IGF-I synthesis in the liver.

Cellular redox state is an important metabolic variable, influencing many aspects of cell function like growth, apoptosis, and reductive biosynthesis. In this report, we identify NADPH as a candidate signaling molecule for exocytosis in neuroendocrine cells. In pancreatic -cells, glucose acutely raised the NADPH-to-NADP ratio and stimulated insulin release in parallel. Furthermore, intracellular addition of NADPH directly stimulated exocytosis of insulin granules. Effects of NADPH on exocytosis are proposed to be mediated by the redox proteins glutaredoxin (GRX) and thioredoxin (TRX) on the basis of the following evidence: 1) Expression of GRX mRNA is very high in -cells compared with other studied tissues, and GRX protein expression is high in islets and in brain; 2) GRX and TRX are localized in distinct microdomains in the cytosol of -cells; and 3) microinjection of recombinant GRX potentiated effects of NADPH on exocytosis, whereas TRX antagonized the NADPH effect. We propose that the NADPH/GRX/ TRX redox regulation mediates a novel signaling pathway of nutrient-induced insulin secretion. Diabetes 54: 2132–2142, 2005

Type 2 diabetes is a disorder of hyperglycemia resulting from failure of beta cells to produce adequate insulin to accommodate an increased metabolic demand. Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet. Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation. To elucidate the role of this pathway in beta-cell function we studied glucose homeostasis in Eif2s1(tm1Rjk) mutant mice, which have an alanine substitution at Ser51. Heterozygous (Eif2s1(+/tm1Rjk)) mice became obese and diabetic on a high-fat diet. Profound glucose intolerance resulted from reduced insulin secretion accompanied by abnormal distension of the ER lumen, defective trafficking of proinsulin, and a reduced number of insulin granules in beta cells. We propose that translational control couples insulin synthesis with folding capacity to maintain ER integrity and that this signal is essential to prevent diet-induced type 2 diabetes. ispartof: Nature Medicine vol:11 issue:7 pages:757-764 ispartof: location:United States status: published

INTRODUCTION:Japan plans to introduce Health Technology Assessment (HTA) in 2018 after a two-year trial period. Japan currently requires HTA for certain innovative products which may have a large budget impact. Through this trial implementation, the government can examine the criteria of applicable products, the necessary infrastructure to conduct and evaluate HTA, the quality of data content, and localization to meet the current Japanese reimbursement and pricing scheme. However, the pharmaceutical industry in Japan is still puzzled by this introduction. The aim of this study is to visualize the issues and implementation challenges of HTA in Japan through a survey of the pharmaceutical industry.METHODS:A semi-structured nineteen-item questionnaire was designed and the survey was conducted through face-to face or phone interviews. Answers were summarized after the interview and confirmed with the respondents via e-mail. The survey focused on pharmaceutical companies which develop new innovative products.RESULTS:The differences between Japanese and non-Japanese pharmaceutical companies were observed in terms of HTA staff expertise and experience, the source of HTA data, and relationships with external vendors. Many respondents stated that a sufficient number of HTA professionals in Japan is critical to implement HTA, and raised a concern that the same public experts who are involved in HTA preparation may also review HTA submissions. Although companies are generally pessimistic about HTA for pharmaceutical pricing, they also have some positive views that HTA may be used as an indicator to enable stakeholders to understand product value. Many are unsure about the link between HTA and pharmaceutical prices.CONCLUSIONS:If HTA is implemented for an extended number of products, a shortage of experts may cause delays of HTA review and appraisal processes. Consequently, product launch and patient access will be delayed. Practical timing of HTA review and appraisal after product launch could affect the results of re-pricing.

Purpose The incidence of Alzheimer's disease (AD) has been steadily increasing worldwide. AD is a serious disease that has both societal and economic impacts. The greatest risk factor for AD is aging. Thus, because of the rapidly aging population in Japan, the development of new, effective drugs for AD is urgently needed. The goal of the present article was to analyze the status, clarify the problems, and discuss the scientific and political challenges of disease-modifying drug development for AD. Methods Public data, official documents, literature, and news releases were surveyed and discussed. Findings Compared with diabetes mellitus drugs, there is a lack of quantitative surrogate end points among AD drugs. Much AD drug development has focused on amyloid-β and its associated pathways; however, these drugs have not shown efficacy in Phase III clinical trials. Thus, the US Food and Drug Administration has appealed for a new draft industrial guidance for the development of AD drugs, including those for early-stage AD. In Japan, the Minister of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency have also taken action, including the publication of potential new guidelines for clinical evaluation and development of new AD therapeutics, including drugs. Moreover, scientific initiatives to develop novel AD drugs are ongoing. Implications The development of quantitative surrogate end points remains necessary to improve the development of AD drugs. Therefore, collaboration among industry, government, and academia should be encouraged. Following the principles of regulatory science, strategies to develop drugs for illnesses with unmet needs can be framed by investigating the effects of past, current, and future AD drug development initiatives.

We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.

SK-896 [(Leu13)motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI0–20) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI0–20 induced by SK-896 at a dose of 0.25 µg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI0–20 was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI0–20. The effects of these drugs on human motilin (0.25 µg/ kg/h for 20 min) induced MI0–20 were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.

We investigated the relationship between gastrointestinal (GI) transit and motility during postoperative ileus in dogs undergoing a single laparotomy. We combined X-ray radiography for a GI transit study with chronically implanted force transducers (FTs) for a GI motility study. Radio-opaque markers made of polyethylene and steel wires or barium sulfate were used to examine solid substance transit or liquid substance transit. For a while after the end of the operation, postoperative ileus was observed, with weak irregular contractions of the GI tract. Transmission of the contractions to the lower GI tract was then observed. The start point of interdigestive migrating contraction (IMC)-like motility was observed in the order of small intestine (I-IMC), duodenum (D-IMC), and stomach (G-IMC), and IMC proceeded gradually after the operation. The gastric emptying time of a solid marker was 73.6 +/- 2.3 h (n = 5), and depended on the time of first occurrence of G-IMC (r = 0.674, p = 0.006). The gastric emptying of the liquid marker was finished before the time of the first occurrence of G-IMC, and its small intestinal transit time correlated with the time of the first occurrence of G-IMC (r = 0.888, p = 0.018). Using combined X-ray radiography and FTs we found that recovery from postoperative ileus was aided by GI motility in which contractions were transmitted from the stomach to the lower GI tract, like IMC.

The enantiomers, (R)-(-)-1 and (S)-(+)-1, of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide [(+/-)-1] were prepared from optically active benzyl 4-acetylamino-2,3-dihydro-2-methylbenzo[b]furan-7-carboxylate [(R)-(+)-6, (S)-(-)-6], respectively. The requisite (R)-(+)-6 and (S)-(-)-6 were prepared by large-scale preparative HPLC on chiral stationary phases (CSPs). The absolute configuration of (S)-(+)-1 was determined by single crystal X-ray analysis. The serotonin 5-HT4 receptor agonistic activity of (S)-(-)-1 hemifumarate (SK-951) which was hemifumarate of (S)-(+)-1 was about twice that of the other enantiomer (R)-(+)-1 hemifumarate which was hemifumarate of (R)-(-)-1.

A 3D-quantitative structure-activity relationship (3D-QSAR) study was carried out using comparative molecular field analysis (CoMFA) of the 5-HT4 agonistic activity of benzamide type compounds, which had been already synthesized and reported to show 5-HT4 agonistic activity. The chosen alignment yielded a good cross-validated result (γ-2cv=0.628). This CoMFA model was able to predict the 5-HT4 agonistic activity of three structurally different compounds. Consequently, 5-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-6-chloro-3, 4-dihydo-2H-1-benzopyran-8-carboxamide (22) was obtained as the most potent 5-HT4 agonist.