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Since the start of the 6-year program in pharmacy education, outcome-based education has progressed, and students' experience of onsite pharmacy practice has increased their awareness of their roles as pharmacists. This progress has been confirmed by student reports submitted at the end of onsite practice. In addition, the results of undergraduate students' graduation research as well as those of clinical research carried out in graduate schools are presented at the annual meetings of the Pharmaceutical Society of Japan (PSJ) and its local branches. Research activity is also promoted by the various divisions of the PSJ that represent a wide range of pharmacy-related fields, including the Division of Clinical Pharmaceutical Sciences. In this way, the PSJ effectively connects researchers in basic and clinical fields, promoting the development of both translational research and reverse-translational research based on needs and ideas brought from the clinic to the basic sciences. Following their presentation at academic meetings, clinical research outcomes are often published in academic journals, including in the three academic journals published by the PSJ: Yakugaku Zasshi, Biological and Pharmaceutical Bulletin, and Chemical and Pharmaceutical Bulletin. Yakugaku Zasshi accepts submissions of case studies, case reports, and survey reports related to clinical pharmacy, which can be submitted in either English or Japanese. As the foundational society for pharmacy and pharmaceutical sciences in Japan, the PSJ is committed to continuing advances in basic and clinical pharmacy research. In the last part of this review, I discuss graduate schools of pharmacy and pharmaceutical sciences.
An allegedly novel human trypsinogen cDNA clone termed trypsinogen hL was recently reported in the Biological & Pharmaceutical Bulletin (2003; 26: 361-364). This "new" trypsinogen sequence was isolated by PCR using human lung cDNAs as template and was presumed to be a new member of the human trypsinogen family. However, trypsinogen hL does not match any sequence in the human genome; whereas it is 100% identical to mouse trypsinogen 7. Thus, trypsinogen hL is not of human origin, and its cloning from a human cDNA library was clearly a result of contamination with mouse genetic material. Publication of this cloning artifact could have been avoided by a simple BLAST search of GenBank or other sequence databanks.
Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Biological and Pharmaceutical Bulletin, 31, 2008, 638) and patients with influenza. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine-administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-pre-administered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms.
Citrus aurantium L. is popularly used to treat anxiety, among other indications suggesting central nervous system action. Previous studies showed anxiolytic effect in the essential oil from peel in mice evaluated on the elevated plus maze [Carvalho-Freitas, M.I.R., Costa, M., 2002. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biological and Pharmaceutical Bulletin 25, 1629-1633.]. In order to better characterize the activity of the essential oil, it was evaluated in two other experimental models: the light-dark box and the marble-burying test, respectively related to generalized anxiety disorder and to obsessive compulsive disorder. Mice were treated acutely by oral route 30 min (single dose) or once a day for 15 days (repeated doses) before experimental procedures. In light-dark box test, single treatment with essential oil augmented the time spent by mice in the light chamber and the number of transitions between the two compartments. There were no observed alterations in the parameters evaluated in light-dark box after repeated treatment. Otherwise, single and repeated treatments with essential oil were able to suppress marble-burying behavior. At effective doses in the behavioral tests, mice showed no impairment on rotarod procedure after both single and repeated treatments with essential oil, denoting absence of motor deficit. Results observed in marble-burying test, related to obsessive compulsive disorder, appear more consistent than those observed in light-dark box.
In northern hemispheres, October heralds the onset of autumn and we are reminded that its cool breezes will soon blow wintry as 1996 draws to a close. Tempus fugit! The swift passage of time also reminds us that the first volume of The Oncologist will soon conclude with its sixth issue in December. However, before 1996 becomes history, let's pause and reflect on the pledges we made to our readership at the beginning of the year. The Founding Editors conceived the Journal to provide authoritative, topical, innovative articles in an attractive format for a very special reader: the busy, practicing physician who cares for cancer patients. Our commitment is to critically review and publish papers designed to interpret the vast amounts of data available to physicians. As the famed radiotherapist and Founding Editor, Eli Glatstein, summarized, "The Oncologist emphasizes the interpretation rather than the data." The Oncologist to date has published more than forty manuscripts from international authorities. The inaugural issue featured, among other highly acclaimed papers, "Locally Advanced Breast Cancer," by Valero, Buzdar and Hortobagyi, and David Kuter's "Thrombopoietin: Biology and Clinical Applications." Fidias, Chabner and Grossbard contributed "Purine Analogs for the Treatment of Low-Grade Lymphoproliferative Disorders" in the next issue, and Pavletic and Armitage proffered an update on "Bone Marrow Transplantation for Cancer." Issue 4 highlighted Jemi Olak and Arthur Ng's "Diagnosis and Management of Early-Stage Non-Small Cell Lung Cancer," as well as "Multimodality Therapy for Esophageal Cancer" by Siewert, Stein and Fink. In this current issue, "Dose Intensity of Chemotherapy for Childhood Cancers," by Smith, Abrams, Trimble and Ungerleider, and "Surgical Sphincter Preservation in Rectal Cancer" by Peter M. Schlag present contemporary and authoritative views of two important clinical topics which also document the Journal's intent to discuss both adult and pediatric cancer care. Our Meet The Professor section is fast becoming a popular feature which attracts comments from readers and responses from the author professor. We call your attention to Professor Barrie R. Cassileth's fascinating article, "Alternative and Complementary Cancer Treatments," and her commentary in this issue. The Physician Education section has presented hematopoiesis through informative and beautifully illustrated papers with texts by distinguished hematologists and molecular biologists. In this issue, we feature the first Patient Care section, From The Bethesda Post, wherein clinical trials and experimental treatments are announced. In cooperation with The Cancer Letter, The Oncologist News Bulletin presents late-breaking news pertinent to the world's cancer care community. With this issue, we have instituted an addition to this section, featuring information from Memorial Sloan-Kettering Cancer Center on a study involving Ashkenazi Jewish women. We urge cancer centers, pharmaceutical and biotechnology companies to avail themselves of this section by sending our editorial office your newsworthy reports. We hope that our readers are benefiting from the Journal and enjoying the art which has graced it. In order to assess how well we are fulfilling our pledges to our readership, we need to hear from you. Tell us how we can make The Oncologist more relevant to your medical practice. We promise to share your comments with our Editorial Board to further enhance the Journal. In so doing, we will draw closer to fulfilling our pledge to you, our readers.
Priority reviews of new drug applications are resource intensive and drugs approved through this process have a greater likelihood of acquiring a serious safety warning compared to drugs approved through the standard process. Therefore, when Health Canada uses priority reviews, it is important that it accurately identifies products that represent a significant therapeutic advance. The purpose of this study is to compare Health Canada's use of priority reviews to therapeutic ratings from two independent organisations, the Patented Medicine Prices Review Board (PMPRB) and the French drug bulletin Prescrire International, over the period 1 January 1997-31 December 2012. Cohort study. Annual reports of the Therapeutic Products Directorate, and the Biologics and Genetic Therapies Directorate; evaluations of therapeutic innovation from PMPRB and Prescrire International; WHO Collaborating Centre for Drug Statistics Methodology. Assessments by PMPRB and Prescrire International treated as a gold standard for postmarket therapeutic value. Drug-by-drug comparison between the review status from Health Canada and the therapeutic status from PMPRB/Prescrire using κ values, and positive and negative predictive values. Analysis of the per cent of all new drug applications put into the priority review category over the 16-year period. Health Canada approved 426 new drugs, and 345 were evaluated by PMPRB and/or Prescrire. 91 had a priority review and 52 were assessed as innovative (p=0.0003). Agreement between Health Canada and PMPRB/Prescrire was only fair (κ=0.330). The positive predictive value for Health Canada's review assignments was 36.3% and the negative predictive value was 92.5%. Health Canada's assignment of a priority approval to a new drug submission is only a fair predictor of the drug's therapeutic value once it is marketed. Health Canada should review its criteria for using priority reviews.
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To develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations. "Horizontal" systematic review incorporating different sources of evidence. Electronic search of Medline and hand search of guidelines. Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes. Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed. Meta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review. This horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.
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Phenotype-based screening has emerged as an alternative route for discovering new chemical entities toward first-in-class therapeutics. However, clarifying their mode of action has been a significant bottleneck for drug discovery. For target protein identification, conventionally bioactive small molecules are conjugated onto solid supports and then applied to isolate target proteins from whole proteome. This approach requires a high binding affinity between bioactive small molecules and their target proteins. Besides, the binding affinity can be significantly hampered after structural modifications of bioactive molecules with linkers. To overcome these limitations, two major strategies have recently been pursued: (1) the covalent conjugation between small molecules and target proteins using photoactivatable moieties or electrophiles, and (2) label-free target identification through monitoring target engagement by tracking the thermal, proteolytic, or chemical stability of target proteins. This review focuses on recent advancements in target identification from covalent capturing to label-free strategies.