Cis-diamminedichloridoplatinum(II) (cisplatin), which was first introduced as a clinical anticancer agent in the 1970s, is still among the most-utilized agents in current cancer chemotherapy. The discovery of cisplatin antitumor activity has catalyzed drug discovery research on antitumor platinum coordination compounds with improved efficacy. Some of new compounds show fewer side effects or expanded clinical applications. Apart from some clinical inconveniences, such as side effects, the high therapeutic efficacy of platinum-based agents implies that further modifications may lead to more effective anticancer platinum drugs which are effective against cancers that are typically resistant to chemotherapy, such as pancreatic cancer, and platinum-refractory cancer. Most of the cisplatin analogs cause cross-resistance to cisplatin, probably because of the similar biological consequences. It is suggested that platinum complexes which interact with DNA; the most probable target molecule, through a mechanism different from that of cisplatin can provide unique anticancer spectra required for next-generation anticancer drugs. Therefore, we synthesized a series of azolato-bridged dinuclear Pt(II) complexes with a general formula, [{cis-Pt(NH₃)₂}₂(μ-OH)(μ-azolato)]²⁺, which can form 1,2-intrastrand crosslinks with a minimal DNA distortion, whereas clinical platinum-based drugs provide 1,2-intrastrand crosslink with severe DNA distortion. Indeed, they exhibit much higher in vitro cytotoxicity than cisplatin, and we have recently found one of the dinuclear Pt(II) complexes exhibits markedly high in vivo antitumor efficacy against pancreatic cancer. Here, I update our drug-discovery research on the series of azolato-bridged dinuclear Pt(II) complexes that may be more effective and safer than current anticancer chemotherapeutic agents.

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  Active studies of skin science have gradually clarified the underlying mechanisms of skin problems regarding skin beauty. The major skin problems are the alterations in appearance such as the hyperpigmentation and wrinkling caused by age. Those skin alterations are accelerated by solar light, particularly by ultraviolet rays, and it has been reported that reactive oxygen species (ROS) also involves in most of those processes. Thus, the reduction of oxidative stress induced by intracellular ROS is one approach to prevent and improve hyperpigmentation and wrinkling. Zn²⁺ is well-known as an inducer of MT (metallothionein) and γGCS (γ-glutamyl cysteinyl synthetase: a rate-limiting enzyme of glutathione synthesis) via the up-regulation of their mRNAs through a metal transcription factor. The inductions of both MT and glutathione are expected to reduce oxidative stress due to the more effective scavenging of intracellular ROS. Several complexes of Zn²⁺ and amino acids were synthesized and then evaluated for effects on MT synthesis in HaCaT keratinocytes. Among the complexes tested, we found a superior induction by a Zn²⁺ glycine complex, Zn(Gly)₂. The anti-pigmentation and anti-wrinkling effects of Zn(Gly)₂ are introduced in this paper.

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  Zinc, one of essential trace elements, functions as a structural component in more than 300 different enzymes in the human body, playing crucial roles in performing a number of functions, including protein and DNA synthesis. Also hereditary or dietary zinc deficiency leading to pathological changes such as growth retardation, skin symptoms and taste disorders in human has been well investigated. Polaprezinc (Promac^®, Zeria Pharmaceutical Co., Ltd.), a chelate compound consisting of zinc and L-carnosine, is a zinc-related medicine approved for the first time in Japan, which has been clinically used to treat gastric ulcers. Its mechanism of action is believed to oxygen radical scavenging, anti-oxidation, and acceleration of wound healing. Further, as zinc deficiency is known to be a primary cause of taste disorders, a clinical phase III study is in progress to determine taste disorders as a new indication of polaprezinc. The pharmacological action of polaprezinc, however, on taste disorders remains unclear. So we examined the effect of polaprezinc on taste disorders induced by feeding rats a zinc-deficient diet and clarified its mechanism of action in restoring the reduced zinc content in the lingual epithelium and improving delayed cell proliferation of taste bud cells due to zinc deficiency. In this review, we primarily make reference to our own data on the pharmacological action of polaprezinc on taste disorders and introduce recent research on the effects of polaprezinc in treating other diseases.

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  There is an increase in cardiovascular disease and cardiovascular risk after menopause. Development of animal models of cardiovascular disease in postmenopause is critical to define pathophysiological mechanism underlying cardiovascular injury and to advance in the therapy. We first developed a rat model of postmenopausal cardiac myocardial hypertrophy and dysfunction. Rats were surgically ovariectomized (OVX) and subjected to pressure overload (PO) by aortic banding. We found marked reduction of protein kinase B (Akt) activity and endothelial nitric oxide synthase (eNOS) phosphorylation. Since we found bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) (VO(OPT)), as strong stimulator of Akt in vivo, we treated it for OVX-PO hypertrophy model. Interestingly, VO(OPT) treatment significantly attenuated cardiac hypertrophy and prevented the progress from hypertrophy to heart failure. The cardioprotective effects of VO(OPT) were closely associated with increases in Akt activity and eNOS phosphorylation in the left ventricule. The cardiac hypertrophy and contractile dysfunction were significantly improved by VO(OPT) treatment. Taken together vanadium compound are possible therapeutics for cardiac hypertrophy and heart failure following hypertension in postmenopausal women.

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  Copper (Cu) is essential for our daily life and it is found at approximately 110 mg in human adults with the body weight of 70 kg, in which this metal occurs at 46 mg in the bone and 26 mg in the muscle. Although Cu exists in the brain (approximately 5 mg/kg), liver (6 mg/kg), kidney (13 mg/kg), erythrocytes (90 mg/L), bile (6 mg/L) and serum (120 mg/L), its organ-specific distribution is not yet known. In metalloenzymes such as oxidoreductases, Cu is abundantly found and greatly contributes in life functions. In addition, intracellular Cu transport system has been revealed in connection with iron (Fe) and zinc (Zn) intracellular transport systems. In spite of such great contribution of Cu in life, no Cu-containing pharmaceutics have yet been known. Under such background, the author and his research group have tried to examine a possibility of Cu compounds as potential pharmaceutics. In the review, the following topics are concerned; (1) improvement of cardiovascular dysfunction in animals by di-nuclear Cu-asprinate complex on the basis of the results on its reactive oxygen scavenging (ROS) effect, (2) blood glucose-lowering effect of mono-nuclear Cu-picolinate complex in streptozotocin (STZ)-induced type 1-like diabetic animals, based on the results on in vitro insulinomimetic activity, and (3) anti-diabetic effect of copper sulfate in animals with regard to the inhibition of α-glucosidase activity. These results suggest that copper ion and its complexes are possible seeds for developing Cu-containing pharmaceutics in the future.

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  With recent development of nanotechnology, nanomaterials (NMs) have been developed with innovative function and expected to cause a paradigm shift in various industry such as cosmetics, medicine and food. NMs begin to establish firm position in Japan as base of various industrials, in fact, a part of them have been already applied to various products. On the other hand, it is suggested that these innovative properties may induce unknown biological responses. It is concerned about the effect of these innovative properties to human health. Based on these situations, to evaluate risk of NMs, it is started to collect information about safety of NMs (Nano Safety Science). With this in mind, we analyzed the relationship between particle size and the in vitro effect of amorphous nanosilica (nSP) using human keratinocyte cells (HaCaT). Our results indicate that exposure to nSP of 70 nm diameter (nSP70) induced an elevated level of reactive oxygen species (ROS), leading to DNA damage. On the other hand, a markedly reduced response was observed using submicron-sized silica particles. Next, we investigate relationship between endocytosis, generation of ROS and DNA damage using endocytosis inhibitor, cytochalasin D (CytoD). As result, CytoD -treatment reduced nSP70-mediated ROS generation and DNA damage. This suggested that endocytosis is involved in nSP70-mediated cellular effects. Thus, particle size affects amorphous silica-induced ROS generation and DNA damage in HaCaT cells. We believe that clarification of the endocytosis pathway of nSP will provide useful information for hazard identification as well as the design of safer forms of nSP.

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  Living organisms eliminate foreign low-antigenic substances, such as drugs and environmental pollutants, by detoxification mediated by metabolizing cytochrome P450 (CYP). We have examined the possible regulation of CYP expression by enteric bacteria. Cyp mRNA expression levels, Cyp3a protein expression level, and the activity of Cyp3a in hepatic microsomal fractions were compared in germ-free (GF) and specific pathogen-free (SPF) mice. We evaluated hepatic Cyp3a11 mRNA expression levels and Cyp3a metabolic activity in GF and SPF mice after five days of antibiotic administration. The fecal levels of lithocholic acid (LCA)-producing bacteria and hepatic taurolithocholic acid (TLCA) were also measured. Cyp mRNA expression levels, Cyp3a protein expression level, and the activity of Cyp3a in SPF mice were higher than those in GF mice, indicating that enteric bacteria increases hepatic Cyp3a expression. The effects of enteric bacteria-reducing antibiotics on Cyp3a expression were examined. We observed that decreasing enteric bacteria with antibiotics in SPF mice caused a significant decrease in the hepatic Cyp3a11 mRNA expression, TLCA, and fecal LCA-producing bacteria compared to the group that did not receive antibiotics. No change in Cyp3a11 expression was observed in GF mice that were treated with antibiotics. Administration of LCA to GF mice showed an increase in Cyp3a11 expression similar to that of SPF mice. The enzymes of the enteric bacteria are believed to metabolize and detoxify drugs by either reduction or hydrolysis. The results of this study indicate that changes in enteric bacteria may alter the expression and activity of hepatic drug metabolizing enzymes and pharmacokinetics. Therefore, enteric bacteria should be closely monitored to ensure the safe use of drugs.

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  MicroRNAs (miRNAs) are small noncoding RNAs of about 20 nucleotides in length and participate in the post-transcriptional regulation of gene expression. Accumulating evidence indicates that miRNA binds to 3′-UTR of its target mRNAs and thereby destabilizes the transcripts or suppresses the translation. It is expected that miRNAs could have diverse functions and therefore play a role in the gene expression caused by the drug treatment, which have yet to be determined. Demonstration of the participation of specific miRNA in the drug-mediated gene expression would make it a biomarker for the toxicological assessment and help an understanding of molecular machinery of the drug-drug interaction. Under these backgrounds, we investigated the change of miRNAs in the liver of mice treated with phenobarbital, a typical inducer for drug-metabolizing enzymes, and demonstrate the participation of miRNAs in the phenobarbital-regulated gene expression. We investigated the relationship between phenobarbital-mediated changes in miRNA and mRNA by using Agilent miRNA microarray and DNA microarray, followed by real time RT-PCR. From these experiments, it was suggested that the phenobarbital-induced changes in cyp2c29 and mrp3 are regulated by miR-30a and miR-29b, respectively. In addition, we obtained evidence that indicates a phenobarbital-mediated decrease in miR-122, a highly abundant liver-specific miRNA, leads to the activation of the transcription factor CAR and thereby induces drug-metabolizing enzymes.

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  Human beings are exposed or otherwise a subjected to a various chemical compounds. Various nanomaterials are contained in the chemical compounds which are used in many fields. Nanomaterials are also used in cosmetics: titanium dioxide and zinc oxide are examples. Consumers who apply cosmetics to their skin as well as workers at industrial plants may thus be exposed to these nanoparticles. Therefore, it is of great importance to evaluate the safety of these nanoparticles. In this review, we describe the possibility of nanoparticle penetration to skin following exposure, which makes it urgent to evaluate the safety factors. In general, it is necessary to take account of the desquamation rate of the stratum corneum and the permeation pathway and size of nanoparticles when considering such penetration. One layer of the human stratum corneum is peeled off per day. Therefore, a chemical compound of which the skin penetration is lower than the desquamation rate does not permeate through the skin, when the compound infiltrates the stratum corneum. Hence, compounds with a molecular weight of more than 500 Daltons do not permeate through the stratum corneum. However, we must also pay attention to the appendage routes, although the aforementioned layer is the primary permeation route of nanoparticles. The contribution of appendage routes must be taken into consideration.

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  Polycyclic aromatic hydrocarbons (PAHs), some of which are carcinogenic/mutagenic, are generated by combustion of fossil fuels and also released through tanker or oilfield accident to cause a large scale environmental pollution. PAHs concentration in China is especially high in East Asia because of many kinds of generation sources such as coal heating systems, vehicles and factories without exhaust gas/particulate treatment systems. So, the atmospheric pollution caused by PAHs in China has been seriously concerned from the view point of health effects. Like yellow sand and sulfur oxide, PAHs exhausted in China are also transported to Japan. Additionally, strongly mutagenic nitrated PAHs (NPAHs), estrogenic/antiestrogenic PAH hydroxides (PAHOHs) and reactive oxygen species-producing PAH quinones (PAHQs) are formed from PAHs by the chemical reaction during the transport. Furthermore these PAHOHs and PAHQs are produced by the metabolism in animal body. In the biological activities caused by the above PAH derivatives, the structure-activity relationship was observed. In this review, our recent results on the generation of PAH derivatives by atmospheric transport and metabolism are reported. Also, the existing condition of PAHs as atmospheric pollutants is considered.

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  A diverse array of nanomaterials (NMs) such as amorphous nanosilica and carbon nanotubes have become widespread in use due to the development of nanotechnology. NMs are already being applied in universal fields because they have unique physicochemical properties. On the other hand, the increasing use of NMs has raised public concern about their potential risks to human health. In particular, recent reports indicated that carbon nanotubes induced mesothelioma-like lesions in mice, in a way similar to those induced by crocidolite asbestos. However, current knowledge of the potential risk of nanomaterials is considered insufficient. Because NMs have the potential to improve the quality of human life, it is essential to ensure the safety of NMs and provide information for designing NMs with safety. Especially, few studies have examined the effect of NMs on maintenance of pregnancy. Similar to the cases of thalidomide, a lot of evidence shows that fetuses are affected more than adults by a variety of environmental toxins because of physiological immaturity. Therefore it is essential to examine the effect of NMs on fetuses and pregnancies. Here we introduce the potential risk of amorphous nanosilica, most widely used NMs in food and the cosmetics field, to induce fetotoxicity and useful information for developing NMs with safety.

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  “Collaborative Development of Advanced Practical Education Program to Train Pharmacists with Leadership” applied jointly by the pharmaceutical departments of fourteen national universities was selected to receive the special expenditure support of Ministry of Education, Culture, Sports, Science and Technology for fiscal year 2010 under “the Training of Highly Skillful Professionals and Improvement of the Quality of the Function of Professional Education”. This project is to promote the collaborative development of the educational program which will make it possible to further advance and substantiate the education of pharmacists in the six year course of the pharmaceutical department for the ultimate purpose to introduce pharmacists with leadership who can play an active role and fill in a leadership position in a wide range of responsibilities into the society which, more and more, has come to expect pharmacy to take the initiative in acting against health hazards caused by infections, foods and environmental pollution as well as to meet the diversification of healthcare. To be more specific, this project is to try and evaluate the following programs repeatedly based on the plan-do-check-act (PDCA) cycle: 1) Practical medical and pharmaceutical education program; 2) Program concerning research on long term themes and advanced education; 3) Program concerning training and education of SPs (standardized patients or simulated patients) and PBL (problem-based learning) tutorial education; and 4) Program concerning the method of evaluation of education. Through this repeated trial and evaluation, this project ultimately seeks to construct a highly effective practical educational program which integrates each university's achievements and educational attempts rich in originality.

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  The six-year pharmacy program started in April 2006 in Japan. In the new program, students in the fifth year of the pharmacy course undergo a long-term practice experience (pharmacy clerkship) in community pharmacy and hospital pharmacy settings as compulsory 20 course credits. The new pharmacy practice experience started in May 2010. A start of the new system was a chance as for beginning movement, thus we conducted the questionnaire survey for the following steps. The finding obtained from our questionnaires indicated that many universities had already planned to execute new approaches, such as an advanced practice at outpatient units, an with medical students, and so on.

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  This article summarizes detailed facts obtained from the questionnaire conducted in 2010 at about 14 National Universities on the topic of “Research programs and advanced educational programs for undergraduate students”. The contents of the questionnaire included: (1) Research programs based on the coalition of university and hospital and/or community pharmacy, other Graduate Schools, such as School of Medicine etc., and the University Hospital, (2) Educational systems for the achievement of research programs and their research outcomes, (3) Research programs based on pharmacist practices, (4) Ongoing advanced educational programs for undergraduate students, taking advantage of the coalition with Graduate School, School of Medicine (and Dentistry), and University Hospital. Some of the advanced educational programs outlined in this questionnaire will be carried out by our group in the coming years and the educational benefits together with associated problems shall as well be clarified. This approach will be informative for the development of the leader-oriented pharmacist programs for the college of Pharmacy.

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  Simulated/standardized patient-based (SP) education and problem-based learning (PBL) tutorial education become a powerful tool to heighten the pharmacy students' will to learn in order to cultivate the responsibility to contribute to public health and welfare as a clinical professional and to facilitate students' competences to solve problems by themselves. What this program is trying to do is: 1) to establish the system to train, educate and supply SP who are effective in the training and education of pharmacy students in close cooperation with the medical schools and their affiliated hospitals; 2) to improve the quality of the current PBL tutorial education and thereby establish it as an advanced education program in the education of senior students. We carried out the questionnaire to National University Corporation which establishes a school of pharmacy, as to the training and education of SP. The analysis of the answers to the questionnaire revealed the present status of SP in the Pharmaceutical Objective Structured Clinical Examination (OSCE) in the Pharmaceutical Common Achievement Test, and the existence of the problems on how to standardize SP as well as how to cover such expenses. Furthermore, the activity of the first year consisted of the exchange and sharing of information regarding the existing method of training and education of SP and PBL tutorial education and the identification of the problems to be solved in order to improve the quality of the educational program.

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  Formative assessment which refers to frequent, interactive assessments of student progress and understanding is one of the most effective strategies for promoting high student performance and developing students' “learning to learn” skills. Portfolio (personal record of learning) is a useful tool for tracking individual student progress toward learning goals. We conducted the questionnaire survey in 14 National Universities on approach to the formative assessment methods and the use of portfolio in the long-term practice experience (pharmacy clerkship) at community pharmacy and hospital pharmacy which was undergone for the first time in 2010. The finding obtained from our questionnaires implicated that portfolio is useful for sharing information among student, tutorial pharmacist and faculty members. All universities have provided tools for visible assessment of student achievement. However, they are not used enough for feedback on student performance, and formative assessment is not practiced systematically. A reason seems to be differences in understanding of it. In addition to improvement of the tools to support formative assessment, promotion of effective assessment practice will need for systematic evaluation.

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  We established a practical training program to nurture pharmacists who can give smoking cessation instructions. The program was provided to 85 interns (45 males and 40 females) in Teikyo University Hospital. The one-day practical training was provided to groups comprised of five members each. The training consisted of studies on the adverse effects of smoking, general outlines of the outpatient smoking cessation service, experiencing Smokerlyzer, studies about smoking-cessation drugs, studies about a smoking cessation therapy using cognitive-behavioral therapy and motivational interviewing, and case studies applying role-playing. Before and after the practical training, we conducted a questionnaire survey consisting of The Kano Test for Social Nicotine Dependence (KTSND) and the assessment of the smoking status, changes in attitudes to smoking, and willingness and confidence to give smoking cessation instructions. The overall KTSND score significantly dropped from 14.1±4.8 before the training to 8.9±4.8 after the training. The confidence to give smoking cessation instructions significantly increased from 3.4±1.9 to 6.2±1.3. Regarding the correlation between the smoking status and willingness and confidence to give smoking cessation instructions, the willingness and confidence were lower among the group of interns who either smoked or had smoked previously, suggesting that smoking had an adverse effect. A total of 88.2% of the interns answered that their attitudes to smoking had “changed slightly” or “changed” as a result of the training, indicating changes in their attitudes to smoking. Given the above, we believe that our newly-established smoking cessation instruction training is a useful educational tool.

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  Since 2005, the Japanese pharmacy education program has changed to a six year-system from a four year-system with the aim to help students obtain a higher level of clinical knowledge and skill regarding humanity and morality. Under the new pharmacy education system, the correct assessment of vital signs is observed in pharmacy practice so that pharmacists can sell “over the counter drugs (OTC)” safely. From this point of view, we started a pharmacy practice that recognizes a series of vital signs, i.e., blood pulse, blood pressure, respiratory sound, and electrocardiogram, using a physical figure subjecting to 4th-year students (n=142) . After the practice, a questionnaire was conducted in order to assess the satisfaction of the practice. The results suggested that students could successfully learn physical assessment by using physical figures (ratios more than grade 4: 60%). Students could also evaluate the necessity of physical assessment (ratios more than grade 4: 70%), suggesting the practice of using physical figures was accepted by most students.

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  A survey was conducted among pharmacists providing “home-visit guidance on drug management” to patients taking medication for dementia. Factors related to medication adherence among patients and pharmacists' acquisition of patient information were then verified. The survey items were: (1) patient attributes (degree of care received, bed-ridden, family composition, and living environment); (2) the person controlling medications; (3) drug storage method and location; (4) dispensing method; (5) patient management of visiting nurses; (6) patient management of visiting physician; (7) details of pharmacist's home-visit guidance; (8) medication adherence; (9) five items related to cognitive function (short-term memory, autonomous judgment, fluctuations in level of consciousness, excitation and loss of orientation, understanding); and (10) ten items related of ADL (mobility in bed, transferring, mobility within the home or outdoors, dressing upper/lower body, eating, toilet use, individual hygiene, bathing). The t test was used to verify the number of items of patient information concerning cognitive function and physical function that pharmacists could acquire at a visit. It was suggested that pharmacists were able to acquire more patient information (①cognitive function and ②ADL) when they visited patients cared for at home, compared to facility residents (①p=0.008, ② p=0.006). Thus, it was suggested that there is a latent risk concerning the pharmacist's ability to discover problems with administration of medications among facility residents. These findings demonstrate that it is essential for pharmacists to be more proactive about providing home-visit guidance.

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