Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.
Metabolic syndrome is a complex of disorders that includes visceral obesity, insulin resistance, hypertension, and dyslipidemia. It is characterized by an increased risk for serious cardiovascular events. Adipocytes are now recognized to contribute to the development of cardiovascular complications in metabolic syndrome via the release of several bioactive substances (adipocytokines). Obesity induces an increase in the volume of perivascular adipose tissue (PVAT), which is located outside the blood vessels. In recent years, PVAT has been reported to produce/release vasoactive adipocytokines. Thus, PVAT can modulate vasomotor function by releasing vasorelaxing/vasocontracting factors, resulting in the development of cardiovascular disease due to metabolic syndrome. By using animal models (SHR/NDmcr-cp rats, SHRSP.Z-Leprfa/IzmDmcr rats, and B6.BKS (D)-Leprfa/J mice), we have demonstrated that chronic oxidative-nitrative stress is closely linked to the development of vascular dysfunction in response to nitric oxide (NO) in resistant arteries with increasing age/exposure to metabolic abnormalities. Further, our recent findings have led us to believe that PVAT helps in the regulation of vasodilation to compensate for the impaired vasodilation observed in pathophysiological conditions in the mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats. However, a breakdown of the compensatory system occurs with long-term exposure to metabolic abnormalities. We propose the concept of the functional regulation of vascular tissue by PVAT in metabolic syndrome.
Gefitinib and erlotinib target the ATP cleft in the tyrosine kinase EGFR, which is overexpressed in 40-80 percent of non-small-cell lung cancer (NSCLC) and many other epithelial cancers. However, the application of gefitinib is ultimately limited by the emergence of mutations and other molecular mechanisms conferring drug resistance. Furthermore, it has been considered that acquired resistance to gefitinib is associated with a clinically significant risk of accelerated disease progression. We previously established a new gefitinib-resistant NSCLC cell line, HCC827GR, which harbors the T790M mutation. Using HCC827GR, we found that the inhibition of adenosine A2a receptors of NSCLC regulated cancer proliferation and exacerbation, indicating that adenosine A2a receptors may be new targets for a novel strategy in NSCLC therapy. These findings suggest that multilayered crosstalk between G-protein coupled receptors (GPCRs) and EGFR may play an important role in regulating downstream signaling molecules that are implicated in the development of gefitinib-resistant NSCLC.
Although protein replacement is an effective treatment for serum protein deficiencies such as diabetes and hemophilia, recombinant protein products are not available for all rare inherited diseases due to the instability of the recombinant proteins and/or to cost. Gene therapy is the most attractive option for treating patients with such rare diseases. To develop an effective ex vivo gene therapy-based protein replacement treatment requires recipient cells that differ from those used in standard gene therapy, which is performed to correct the function of the recipient cells. Adipose tissue is an expected source of proliferative cells for cell-based therapies, including regenerative medicine and gene transfer applications. Based on recent advances in cell biology and extensive clinical experience in transplantation therapy for adipose tissue, we focused on the mature adipocyte fraction, which is the floating fraction after collagenase digestion and centrifugation of adipose tissue. Proliferative adipocytes were propagated from the floating fraction by the ceiling culture technique. These cells are designated as ceiling culture-derived proliferative adipocytes (ccdPAs). We first focused on lecithin:cholesterol acyltransferase (LCAT) deficiency, an inherited metabolic disorder caused by lcat gene mutation, and ccdPAs as a therapeutic gene vehicle for LCAT replacement therapy. In our recent in vitro and animal model studies, we developed an adipose cell manipulation procedure using advanced gene transduction methods and transplantation scaffolds. We herein introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies and describe their future applications for other intractable diseases.
Childhood maltreatment, which markedly increases risks for psychopathology, is associated with structural and functional brain differences. Especially, exposure to parental verbal abuse (PVA) or interparental violence during childhood is associated with negative outcomes such as depression, posttraumatic stress disorder (PTSD), and reduced cognitive abilities. Other forms of childhood maltreatment have been associated with brain structure or developmental alteration. Our earlier studies elucidated potential discernible effects of PVA and witnessing domestic violence during childhood on brain morphology, including gray matter volume or cortical thickness. Brain regions that process and convey the adverse sensory input of the abuse might be modified specifically by such experiences, particularly in subjects exposed to a single type of maltreatment. Exposure to multiple types of maltreatment is more commonly associated with morphological alterations in the corticolimbic regions. These findings fit with preclinical studies showing that sensory cortices are highly plastic structures. Using tasks with high and low monetary rewards while subjects underwent functional MRI, we also examined whether neural activity during reward processing was altered, or not, in children and adolescents with reactive attachment disorder (RAD). Significantly reduced activity in the caudate and nucleus accumbens was observed during a high monetary reward condition in the RAD group compared to the typically developed group. The striatal neural reward activity in the RAD group was also markedly decreased. The present results suggest that dopaminergic dysfunction occurred in the striatum in children and adolescents with RAD, potentially leading to a future risk of psychiatric disorders such as dependence.
Keio University Faculty of Pharmacy opened an insurance pharmacy on its campus in 2001. This pharmacy was opened with the objectives of 1) educating pharmacists to serve the regional community; 2) heightening students' motivation; and 3) providing practical education geared to the needs of actual healthcare settings. Since my appointment as director in 2003, I have led various initiatives to determine an ideal business model for a university pharmacy. This paper reports these initiatives and discusses the mission and future prospects of university pharmacies. In terms of education, all 4th-year students provide medication guidance to simulated patients at our university pharmacy counters, and are briefed by pharmacists about pharmacy administration and dispensing activities. Over three periods each academic year, trainees from other universities have been accepted for long-term on-site training. Students also work at local facilities for elderly persons to learn how to effectively communicate with this demographic and to better understand their unique pharmacokinetic profiles, impaired QOL, etc. Students can also participate in health promotion and drug education courses for regional residents, and support their self-medication. Pharmacies are important points of contact with local communities where residents' lives can be medically monitored. It is important for pharmaceutical universities to operate their own pharmacies in order to determine and stay abreast of the evolving challenges society expects pharmaceutical science to address. University pharmacies need to become models for general community pharmacies.
By law, medical faculties are mandated to have a designated partner hospital for the purposes of student practical training. In contrast, pharmacy faculties do not have such a legal requirement for student training in a community pharmacy setting. Nevertheless, there are several public and private universities that do have community pharmacies. However, there is no national university that has established both an educational hospital and a community pharmacy. When Kanazawa University (KU) established a graduate school with a clinical pharmacy course, the faculty of KU deemed it necessary to set up an independent community pharmacy for the purpose of practical training. Thus, in 2003, the Acanthus Pharmacy was set up as the first educational community pharmacy in Japan, managed by a nonprofit organization, with the permission of the Ishikawa Pharmaceutical Association and local community pharmacists. Since that time, Acanthus has managed a clinical pharmacy practice for students from both the undergraduate and graduate schools of KU. From 2006, the undergraduate pharmacy program was changed to a 6-year program, and the Acanthus Pharmacy has continued its roles in educating undergraduate pharmaceutical students, medical students, and as a site of early exposure for KU freshmen. From our experience, it is important to have a real clinical environment available to university pharmacy faculty and students, especially in training for community pharmacy practices.
Hokkaido Pharmaceutical University (HPU), according to its educational mission, seeks to “develop medical professionals who contribute to community medicine”, and it has produced more than 6300 graduates since 1974. With recent medical advancements and a progressively aging society, the role of the pharmacist in community medicine has diversified and is increasing in importance. Therefore, in April 2012, the Hokkaido Pharmaceutical University Affiliated Pharmacy was established as a for-profit business of the Educational Foundation of the Hokkaido University of Science, the parent body of HPU. The pharmacy is located near the Sapporo station; it is operated by six pharmacists and four clerks, and supported by three faculty members who are engaged in providing HPU student education such as on-site clinical training, in addition to their pharmacy duties such as home care pharmaceutics. For the first two years it was open, the pharmacy focused on the establishment of pharmacy administration and fiscal consolidation. In April 2015, the Pharmacy Management Committee set the pharmacy's future vision, as well as its mid-term strategy, which consists of the four main components of pharmacy practices, education, research, and social contribution, in order for the pharmacy to serve as a model of community pharmacy.
Gifu Pharmaceutical University Pharmacy was established in front of Gifu University Hospital (GUH) as a pharmacy attached to the university, the first in Japan in 1998. When GUH moved in 2004, Gifu Pharmaceutical University Pharmacy was built in its current location. One of the priorities of the design of the new facility was easy access to those with disabilities. For example, ramps, wheelchair accessible restrooms, and handicap-friendly waiting-room chairs were installed. In cooperation with GUH, we introduced a two-dimensional bar code system for prescriptions. This promoted the efficiency of compounding medicines. In addition, starting in 2006, we introduced digital drug-history records at Gifu Pharmaceutical University Pharmacy. We also increased the staff of the affiliated pharmacy in 2006. We designed the system of the affiliated pharmacy for long-term pharmacy practice. Currently, we accept pharmacy students visiting pharmacy of early exposure and long-term pharmacy practice. Today, the pharmacy fills an average of 80 prescriptions a day, primarily from GUH. Our staff consists of six pharmacists, one full-time office manager, and three part-time office assistants. In keeping with our role as a community pharmacy, we hold regular lectures and an education forum for pharmacists. We also carry out clinical studies.
Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in psychopharmacological research topics. During this period, we identified a number of novel regulatory mechanisms that control the prefrontal dopamine system through functional interaction between serotonin1A and dopamine D2 receptors or between serotonin1A and σ1 receptors. Our findings suggest that strategies that enhance the prefrontal dopamine system may have therapeutic potential in the treatment of psychiatric disorders. We also found that environmental factors during development strongly impact the psychological state in adulthood. Furthermore, we clarified the pharmacological profiles of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine, providing novel insights into their mechanisms of action. Finally, we developed the female encounter test, a novel method for evaluating motivation in mice. This simple method should help advance future psychopharmacological research. In this review, we summarize the major findings obtained from our recent studies in mice.
The number of patients with metabolic disorders is dramatically increasing all over the world. The diseases often exhibit multiple metabolic disturbances including diabetes, hyperlipidemia, and obesity, and so on, recognized as a concept of metabolic syndrome. It is important to consider the common underlying pathophysiological bases of such metabolic diseases at the suggestion of the teachings of a parable, “The blind men and an elephant,” whereby each blind man investigates a different part of the elephant. The lesson could even be applicable to each aspect of the disorders. Physical exercise as well as dietetics harbor versatile preventive and therapeutic potency against diverse metabolic diseases. Thus further investigation into molecular and physiological mechanisms underlying beneficial effects of therapeutic exercise and diet will provide us with significant clues to the elephant behind the disorders. Moreover, it could be of great benefit if such non-drug treatments, which may be hard to achieve for most patients, were replaced with medication. Recently, we demonstrated evidence that activators of 5′AMP-activated protein kinase (AMPK) could be satisfactory exercise mimetics in terms of metabolome. In this review, metabolomic analysis on the significant roles of AMPK in contracting skeletal muscles is described. In addition, our novel prodrug strategy providing extremely hydrophobic agents with marked hydrophilicity by conjugation with branched glycerol oligomers, which can be widely applicable in general to drug design for good pharmacokinetic properties in drug discovery, is introduced.
An accurate continuous intravenous injection via a peristaltic finger infusion pump has been utilized at outpatient clinics recently. An infusion element designed for this pump is necessary for the accurate handling of the pump, and for proper use of this equipment, we need accurate information. Our experiments have shown that medication administration has occasionally been incomplete at the calculated input time when a peristaltic finger infusion pump has been used. In this paper, we have investigated the cause of the delay in the administration time and the effect of the attachment procedure using a combination of features from three kinds of such infusion pumps and five kinds of exclusive polyvinyl chloride (PVC) infusion sets, under various conditions. Our results suggest that the time required for complete administration was correlated to the input time when five kinds of PVC tubing without stretching were attached to three kinds of peristaltic finger infusion pumps (R2=0.9998-1.0000). However, when the PVC tubing was stretched 1-3 cm and was attached to the pump, the time required for complete administration of the solution was prolonged compared to the recommended listed input time (p<0.01-0.05, ANOVA, Tukey-Kramer multiple comparison). Therefore, we suggest that the procedure technique used by the medical staff and involving the infusion pump adversely prolonged the time required for completion of the administration of medication. In our opinion, pharmacists must provide information concerning not only the drugs, but also the medical devices used to the physicians and nurses.
Falls are common in elderly patients and are often serious. Several drugs have been associated with an increased risk of fall. Older adults often take multiple drugs for chronic diseases, and thus may be at increased risk from drugs associated with fall. We investigated the association between drug use and falling in hospitalized older people, with the goal of identifying medications that may increase the risk of a fall. A retrospective case control study was performed at the National Hospital Organization Kumamoto Saishunso Hospital in Japan. Medications taken by patients who fell (n=57) were compared with those taken by patients who did not fall (n=63). The median age (interquartile range; IQR) of the fall and non-fall groups were 75.0 (67.0-83.0) and 80.0 (70.3-84.5) years, respectively. The characteristics of the two groups were similar, with no significant differences in age, sex, or body weight. The probability of falling increased when the patients used zolpidem [odds ratio (OR)=2.47; 95%CI: 1.09-5.63; p<0.05] and calcium channel antagonists (OR=0.299; 95%CI: 0.13-0.68; p<0.01), and was also related to physical factors (OR=2.27; 95%CI: 1.01-5.09; p<0.05). Elderly patients taking zolpidem may fall due to sleepiness, and blood pressure control may be important to prevent orthostatic high blood pressure. In the treatment of elderly people, medical staff should try to choose drugs that prevent fall or are not associated with falling.