Objective: For safe use of drugs, it is indispensable to carry out proper and continuous risk management throughout preclinical to post-marketing phases.  In Japan, denosumab, a novel anti-RANKL antibody for treatment of bone metastasis, was approved in April 2012.  Since beginning of clinical use, severe hypocalcemia has been reported as adverse drug reactions.  In this study, the role of pharmacists in minimization of risks of newly introduced drugs was examined using denosumab as an example.
Methods: Firstly, the description on prevention of hypocalcemia in approval review report and different versions of drug package inserts of denosumab were compared.  Secondly, the differences in ratio of hypocalcemia in patients using denosumab with or without concomitant use of Ca and vitamin D preparations in Kobe City Medical Center General Hospital between April 2012 and July 2013 were examined.
Results: During the few months after beginning of clinical use of denosumab, many cases on the onset of severe hypocalcemia induced by denosumab had been reported.  Therefore, drug package insert was revised to enhance and recommend Ca and vitamin D supplementation.  Before the in-house enforcement in our hospital, of 26 patients, 6 patients were administered with denosumab without Ca and vitamin D preparations and 2 of them developed hypocalcemia over Grade 3.  After the in-house enforcement, no significant changed in serum Ca level in the 20 patients with Ca and vitamin D preparations were observed.
Discussion: Severe side effects can be avoided if hospital pharmacists take appropriate measures based on rational evaluation of proper information.
Conclusions: For risk minimization, pharmacists must evaluate and manage the risks of newly introduced drugs.

BACKGROUND: The canonical Wnt/β-catenin signaling pathway is a fundamental regulatory system involved in various biological events. ICG-001 selectively blocks the interaction of β-catenin with its transcriptional co-activator cyclic AMP response element-binding protein (CBP). Recent studies have provided convincing evidence of the inhibitory effects of ICG-001 on Wnt-driven disease models, such as organ fibrosis, cancer, acute lymphoblastic leukemia, and asthma. However, the effects of ICG-001 in atopic dermatitis (AD) have not been investigated. OBJECTIVE: To investigate whether β-catenin/CBP-dependent signaling was contributed in the pathogenesis of AD and ICG-001 could be a therapeutic agent for AD. METHODS: We examined the effects of ICG-001 in an AD-like murine model generated by repeated topical application of the hapten, oxazolone (Ox). ICG-001 or vehicle alone was injected intraperitoneally every day during the development of AD-like dermatitis arising from once-daily Ox treatment. RESULTS: Ox-induced AD-like dermatitis characterized by increases in transepidermal water loss, epidermal thickness, dermal thickness accompanied by increased myofibroblast and mast cell counts, and serum levels of thymic stromal lymphopoietin and thymus and activation-regulated chemokine, and decreases in stratum corneum hydration, were virtually normalized by the treatment with ICG-001. Elevated serum levels of periostin tended to be downregulated, without statistical significance. CONCLUSION: These results suggest that β-catenin/CBP-dependent signaling might be involved in the pathogenesis of AD and could be a therapeutic target.
Animals ; Asthma ; Chemokine CCL17 ; Cyclic AMP Response Element-Binding Protein ; Cyclic AMP ; Dermatitis ; Dermatitis, Atopic ; Fibrosis ; Mast Cells ; Mice ; Myofibroblasts ; Oxazolone ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Water

Azoospermia/therapy* ; Female ; Humans ; Male ; Microdissection ; Pregnancy ; Pregnancy Rate ; Retrospective Studies ; Sperm Injections, Intracytoplasmic ; Sperm Motility ; Sperm Retrieval ; Spermatozoa ; Testis