Severe stomatitis caused by chemotherapy and radiotherapy is accompanied by severe pain and results in a poor quality of life. We used a spray preparation of indomethacin (IM; 0.25% IM dissolved in phosphate buffer, pH 7.4), a nonsteroidal anti-inflammatory drug (NSAID) to control the pain associated with stomatitis at the University of Tsukuba Hospital. This review specifically aimed to collect information on the use of the IM spray preparation, from our previous studies, to facilitate its proper use in a hospital setting. On studying the stability of the IM spray preparation, we concluded that the preparation should be kept in the refrigerator for daily use, and that it can be stored for at least 2 months at 4°C, and for 24 months at −20°C. To evaluate the efficacy of the IM spray preparation, we retrospectively surveyed its analgesic effects. Using the 10-grade Visual Analogue Scale in 23 patients, we found that pain associated with stomatitis was reduced from 10 to 4.7 after application of the spray. In conclusion, our study results on the stability and efficacy of the IM spray preparation have led to the proper use of the spray in cancer patients with stomatitis caused by chemotherapy and radiotherapy.
Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (p<0.01; paired t-test). The median duration to best response was 14 days (range: 1-49). CTCAE scores decreased in 132 patients (75.4%), including 62 (35.4%) who achieved grade 0. There were no unexpected safety events. Rebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM.
Translational research is important for applying the outcomes of basic research studies to practical medical treatments. In exploratory early-phase clinical trials for an innovative therapy, researchers should generally manufacture investigational agents by themselves. To provide investigational agents with safety and high quality in clinical studies, appropriate production management and quality control are essential. In the Department of Pharmacy of Kyoto University Hospital, a manufacturing facility for sterile drugs was established, independent of existing manufacturing facilities. Manuals on production management and quality control were developed according to Good Manufacturing Practices (GMP) for Investigational New Drugs (INDs). Advanced clinical research has been carried out using investigational agents manufactured in our facility. These achievements contribute to both the safety of patients and the reliability of clinical studies. In addition, we are able to do licensing-out of our technique for the manufacture of investigational drugs. In this symposium, we will introduce our GMP grade manufacturing facility for sterile drugs and discuss the role of GMP grade hospital preparation in translational research.
Apoptotic cells generated during development and immune responses in animals are rapidly engulfed by phagocytes, such as macrophages and dendritic cells. When the engulfment process malfunctions, the apoptotic cells undergo secondary necrosis, which results in the release of noxious cellular components into the extracellular space. Thus, the efficient clearance of apoptotic cells is indispensable for the maintenance of tissue homeostasis; however, the molecular mechanisms underlying the engulfment of apoptotic cells remain largely unknown. To identify the molecules that are involved in this process, we developed a functional screening strategy using a retrovirus cDNA library. Using this assay, we isolated cDNA clones encoding RhoG and Rab5 which enhanced the engulfment of apoptotic cells. In addition, we found that Rac1, which is very similar to RhoG, and Rab5 are necessary for engulfment; their activities were successfully visualized by a combination of fluorescence resonance energy transfer technology with time-lapse imaging techniques. We further determined that G protein-coupled receptor kinase 6 (GRK6), originally identified as a kinase responsible for the desensitization and downregulation of G-protein-coupled receptors, activates Rac1 independent of the two known intracellular engulfment pathways in phagocytes. GRK6-deficient macrophages exhibited impaired phagocytosis of apoptotic cells. Consequently, GRK6-deficient mice developed autoimmune phenotypes such as an increase in the amount of anti-dsDNA in serum and the deposition of immune complexes in the kidney. Thus, our findings contributed to the understanding of the molecular mechanisms that regulate apoptotic engulfment in phagocytes.
Measurement of biological compounds is important for the clarification of biological phenomena. For the quantification of trace amounts of biological compounds, efficient separation and sensitive analytical methods are necessary. The present author developed HPLC-fluorescence and chemiluminescence detection methods for biological compounds such as catecholamines, amino acids, and thiols. In this review article, two studies are summarized: one on the development of an on-chip liquid chromatography method using pillar array columns with low-dispersion turns; and another on the development of simultaneous analytical method of biothiols by HPLC with fluorescence detection under hydrophilic interaction chromatography conditions.
A decrease in nitric oxide (NO) production may induce pathological conditions associated with endothelial dysfunction and diabetes. Although a decrease in NO production caused by impaired Akt/endothelial nitric oxide synthesis (eNOS) signaling has been demonstrated at the aorta in the presence of diabetic vascular complications, little is known regarding the details of the mechanism. We identified G-protein-coupled receptor kinase 2 (GRK2) as a critical factor in diabetic endothelial dysfunction. GRK2 plays a role in many physiological functions including regulation of G-protein-coupled receptors (GPCRs). We found that the vasculature affected by type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction caused by impaired Akt/eNOS signaling. GRK2 activation also induces changes in the subcellular localization of GRK2 and β-arrestin 2, a downstream protein, from the cytosol to membrane. In mouse aorta GRK2 may be, on translocation, a key negative regulator and an important regulator of β-arrestin 2/Akt/eNOS signaling, which has been implicated in diabetic endothelial dysfunction. Furthermore, in the aortic membrane of type 2 diabetic model mice under insulin stimulation, the impaired Akt/eNOS signaling was improved by a selective GRK2 inhibitor. These results suggest that in diabetes the GRK2 inhibitor ameliorates vascular endothelial dysfunction via Akt/eNOS signaling by inhibiting GRK2 activity and enhancing β-arrestin 2 translocation to the membrane under GPCR or non-GPCR stimulation, thereby contributing to blood pressure- and blood glucose-lowering effects. We propose that the GRK2 inhibitor may be a promising therapeutic target for cardiovascular complications in type 2 diabetes.
This study investigated the required duties of pharmacists in a kaifukuki rehabilitation ward from the viewpoint of the ward physicians and nurses. A questionnaire survey was distributed to 27 facilities with kaifukuki rehabilitation wards. The questionnaire examined which duties the physicians and nurses expected from pharmacists while on the ward (4 areas, 10 items), as well as the time required for pharmacists to carry out those duties. Multivariate analysis was used to investigate which types of work took the most time for pharmacists on kaifukuki rehabilitation wards. Responses were received from 43 physicians and 184 nurses who worked on the kaifukuki rehabilitation wards of 19 facilities. The results revealed that the essential duties performed by pharmacists were the management of medical supplies, instruction on the use of self-medicating drugs at the time of introduction, and monitoring drug side effects. Furthermore, some duties, such as the distribution of medicines and changing or suggesting new drugs, required pharmacists to spend extended time on the ward. The responses indicated that physicians and nurses recognized the necessity for pharmacists to perform ward duties along with their routine work. This study shows that physicians and nurses working in kaifukuki rehabilitation wards demand proactive participation from pharmacists in appropriate medical therapy, such as instruction in the administration of medications and assessment at the time of prescription changes.
A generic drug is defined as a drug product that is comparable to a brand name drug in terms of dosage, form, strength, route of administration, quality, performance characteristics, and indicated use. Generic drugs for topical use, in the case of sheet-like products, are required to be the same as the original drug in terms of application area and dosage form. The composition of such generic drug formulations may differ from that of the original product. The adhesive of any pharmaceutically-active tape that directly contacts the skin plays a role in delivering the active ingredient into the skin, and affects the sensation and ease of handling. Therefore, adhesives are an important ingredient in these products. Thus, the aim of this study was to characterize original and generic lidocaine tape products, and to evaluate the adhesive properties of each. The tack force, peel strength and shear adhesion were measured as adhesive properties. In addition, in vitro drug releasing profiles and skin permeation profiles of the products were evaluated. In vivo transdermal absorption was also evaluated to predict the possibility of adverse effects. Adhesive properties differed among the three analyzed products. These differences may have been caused by differences in the adhesives. Drug-releasing profiles and skin permeation profiles also differed among the three products, even though the pharmacokinetics were not significantly different. By obtaining an adequate understanding of the characteristics of original and generic products, we will be able to provide better tailor-made medications for drug therapies for patients.
Intravenous azithromycin (AZM) was approved for use in December 2011 in Japan. In general, intravenous AZM injections are diluted to 1 mg/mL, with a total infusion volume of 500 mL to avoid phlebitis. Patients in intensive care units (ICUs) require small infusion volumes. We retrospectively evaluated the total AZM infusion volume in 65 ICU patients receiving AZM treatment from December 2011 to August 2014. Thirteen patients (20.0%) received a reduced volume [100 mL (5 mg/mL) or 250 mL (2 mg/mL)] using an infusion pump over 2 h. No peripheral phlebitis was observed in any patient. Based on this result, it is assumed that AZM can be safely administered to ICU patients even though the volume of solvent is reduced. AZM is widely recommended for the treatment of community-acquired respiratory infections and is used in patients with severe infections. Further investigation is required in additional patients to understand the effects of AZM volume reduction in greater detail.
Over-the-counter (OTC) drugs play an important role in self-medication. To ensure patient safety, pharmacists should ask patients to pay attention to possible adverse events (AE) associated with OTC drugs and educate patients about the symptoms related to those AEs. The aims of the present study were as follows: (1) to assess the tendency of AEs to occur with OTC drug use in Japan; (2) to detect a safety signal for OTC drugs using the reporting odds ratio (ROR); and (3) to evaluate clustery features, which include suspected drugs and therapeutic classifications, and safety signal indices (number of reports and the ROR), using cluster analysis. The number of reports of AEs following use of combination cold remedy, antipyretic and analgesic remedy, and herbal medicine was 1007, 566, and 221, respectively. We set the cluster number at five; clustery features obtained were as follows: (1) high reporting rate for skin and subcutaneous tissue disorder AEs was the largest group related to combination cold remedy; (2) high reporting rate for nervous system disorder AEs including dizziness was the second largest group. The same medicinal ingredient may demonstrate similar tendencies of the occurrence of AEs and similar clustery features in the Japanese Adverse Drug Event Report database. Our analysis of AEs associated with OTC drugs may be useful for pharmacists and patients alike. Further studies are required to draw better-informed conclusions.