Analysis of patients with hypomagnesemia using the Japanese Adverse Drug Event Report database (JADER).

PURPOSE: In order to clarify the occurrence of hypomagnesemia in Japan, we conducted a database search and analysis using the Japanese Adverse Drug Event Report database (JADER). METHODS: Among the cases recorded in JADER between April 2004 and December 2015, we targeted "hypomagnesemia" and analyzed the patients' backgrounds, drug involvement, other adverse events reported with hypomagnesemia, the time of hypomagnesemia onset, outcomes, and year when reported. For drugs with three or more reports, the signal index was calculated using the Reporting Odds Ratio (ROR) method. In addition, the association between hypomagnesemia onset and other adverse events was investigated using association analysis. RESULTS: The total number of reported hypomagnesemia cases was 201. Males accounted for 62.7%, and patients in their sixties formed a large peak. Three or more cases were reported for 23 causative drugs, among which anti-EGFR antibody, calcineurin inhibitor, platinum antitumor agent and proton pump inhibitor accounted for the majority. ROR analysis detected signals for 18 drugs, and an association was found between hypomagnesemia and other electrolyte abnormalities for those drugs. The median time until onset of hypomagnesemia was classified into three patterns: around 10 days, around 30 days, and longer. Analysis of the report year revealed an increasing tendency in recent years, although increases/decreases were evident depending on fiscal years. CONCLUSION: Our survey was able to reveal the factors associated with the occurrence of hypomagnesemia.

Development and Characterization of Oral Spray for Stomatitis Containing Irsogladine Maleate.

The stomatitis caused by anticancer agents and radiation therapy deteriorates patient QOL, potentially causing eating disorders as a result of pain. Although gargling and ointments can be used in the treatment of stomatitis, patients must spit out mouthwash after use, while ointment application requires a finger to be inserted into the oral cavity. In contrast, sprays eliminate these potential compliance problems. Therefore, we developed a stomatitis spray that remains on the oral mucosa. It has been reported that irsogladine maleate (IM) is effective against stomatitis via oral administration. IM is water insoluble; thus, it was dissolved with various cyclodextrins (CDs). Furthermore, we examined combination with gum ghatti (GG), a mucoadhesive polymer. The interaction between mucin and GG was examined by Quartz Crystal Microbalance with Dissipation monitoring. We found that GG exhibited mucoadhesion. Furthermore, we examined the healing effects of IM on stomatitis in a stomatitis model hamster. We found that stomatitis healed after direct application of IM. However, the model used in this experiment is not based on stomatitis caused by anticancer agents. Further study is therefore necessary.

Evaluation of the efficacy and safety of changes in antiretroviral regimens for HIV-infected patients.

PURPOSE: Antiretroviral therapy is now available for HIV-infected patients, and so-called highly active antiretroviral therapy (HAART) now makes it possible to strongly suppress viral proliferation and restore immunity. However, the development of new drugs and regimens for HAART is still in progress, with the aim of overcoming a number of associated problems. For this purpose, changes in the prescribed anti-HIV drugs are often made. In the present study, we attempted to clarify the actual effects of such treatment modifications in patients who had been started on HAART. METHODS: We retrospectively investigated HIV-infected patients who had been started on HAART at Kitasato University Hospital between April 1997 and March 2013. The patients' backgrounds, characteristics and laboratory data were established from the hospital medical records. RESULTS: The total follow-up time was 447.3 person-years. The patients remained on their initial regimen for a median period of 2040 days, and 39 patients took a second regimen for a median of 2714 days. There was no treatment failure due to regimen change. The reason for the regimen change was adverse effects in 49 cases, poor adherence/virological failure in 4, immunological failure in 3, patient request in 2, and proposals made by health care workers, or for simplification, in 11. The number of patients who required regimen change due to renal dysfunction showed a gradual increase. The number of times anti-HIV drugs were taken per day was not altered when the regimen changed, being mainly once or twice a day. CONCLUSION: In the present study, there were no instances of treatment failure due to regimen change. Through appropriate regimen change, it is possible to avoid serious adverse effects, and to improve patient adherence. Further adverse effects associated with long-term antiretroviral therapy, and reduction of adherence through medication fatigue should be considered. Drug selection and regimen change should be considered in relation to long-term prognosis.

Evaluation of renal adverse effects of combination anti-retroviral therapy including tenofovir in HIV-infected patients.

PURPOSE: In order to maintain plasma HIV-RNA concentration in HIV-infected patients, below the detection limit combination anti-retroviral therapy (cART) are used. Although the nucleoside/nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF) is a first-line drug commonly used, it is associated with renal dysfunction. Nevertheless, only few clinical studies have focused on TDF in combination with new anti-HIV drugs, including the protease inhibitor (PI) darunavir (DRV), or the integrase strand transfer inhibitor (INSTI) raltegravir (RAL). Here we report the influence of such cART involving TDF on renal function. METHODS: We retrospectively investigated 68 patients under cART that included TDF between November 2004 and May 2012. We used hospital records to establish each patient's background and characteristics, CD4 cell count, plasma HIV-RNA concentration, drug combinations, renal function, and anti-retrovial therapy history. RESULTS: In all patients who had received cART, the plasma HIV-RNA concentration had fallen to less than 40 copies/mL by week 24 after the start of the therapy, and an increase in the CD4 cell count was observed. For each drug used in combination with TDF, the plasma HIV-RNA concentration and CD4 cell count showed a similar trend. After week 12, the estimated glomerular filtration rate (eGFR) had significantly decreased in all patients. The eGFR was significantly lower in those received PI on week 24 and in those received INSTI on week 12. The eGFR was significantly reduced in PI group who received atazanavir + ritonavir (ATV/RTV) on week 60. The eGFR in the DRV/RTV group tended to decrease. The eGFR in the PI and ATV/RTV group was significantly lower than in the efavirenz (EFV) group on week 96. CONCLUSION: It selecting drugs to include in combination therapy of HIV-infected patients, consideration should be given to the risk of renal dysfunction. There is a need to monitor renal function when TDF is combined with ATV/RTV, DRV/RTV or RAL.

Characteristics of adverse event reports among people living with human immunodeficiency virus (HIV) in Japan: Data mining of the Japanese Adverse Drug Event Report database.

The development of new anti-HIV drugs and advances in antiretroviral therapy (ART) regimens have enabled longer and more effective treatments in people living with HIV (PLWH). However, the aging of PLWHs is another issue that needs to be addressed. In addition to ART, many PLWHs frequently receive medications for various comorbidities. However, real-world data on the occurrence of adverse events in PLWHs and their causative drugs are rare. Therefore, this study aimed to clarify the characteristics of adverse event reports among PLWHs in Japan. PLWH cases with adverse events were comprehensively searched and analyzed using the Japanese Adverse Drug Event Report database (JADER). Despite changes in guideline-recommended ART regimens, anti-HIV drugs were the main cause of adverse events in PLWHs throughout the study period. However, considerable variations have been observed in the reporting rate of anti-HIV drug classes registered as causative drugs in JADER, especially for anchor drugs. In other words, the reporting rate of integrase strand transfer inhibitors has increased in recent years, while that of protease inhibitors and non-nucleoside reverse transcriptase inhibitors has decreased. Immune reconstitution inflammatory syndrome was the most reported adverse event and was frequently noticed by healthcare providers managing patients with HIV infections. The trends in adverse event reports for female and older patients differed from those for the overall population. This study may provide insights that can help in the establishment of optimal management strategies for PLWHs.

Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.

Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.

AW551984: a novel regulator of cardiomyogenesis in pluripotent embryonic cells.

An understanding of the mechanism that regulates the cardiac differentiation of pluripotent stem cells is necessary for the effective generation and expansion of cardiomyocytes as cell therapy products. In the present study, we have identified genes that modulate the cardiac differentiation of pluripotent embryonic cells. We isolated P19CL6 cell sublines that possess distinct properties in cardiomyogenesis and extracted 24 CMR (cardiomyogenesis-related candidate) genes correlated with cardiomyogenesis using a transcriptome analysis. Knockdown of the CMR genes by RNAi (RNA interference) revealed that 18 genes influence spontaneous contraction or transcript levels of cardiac marker genes in EC (embryonal carcinoma) cells. We also performed knockdown of the CMR genes in mouse ES (embryonic stem) cells and induced in vitro cardiac differentiation. Three CMR genes, AW551984, 2810405K02Rik (RIKEN cDNA 2810405K02 gene) and Cd302 (CD302 antigen), modulated the cardiac differentiation of both EC cells and ES cells. Depletion of AW551984 attenuated the expression of the early cardiac transcription factor Nkx2.5 (NK2 transcription factor related locus 5) without affecting transcript levels of pluripotency and early mesoderm marker genes during ES cell differentiation. Activation of Wnt/ß-catenin signalling enhanced the expression of both AW551984 and Nkx2.5 in ES cells during embryoid body formation. Our findings indicate that AW551984 is a novel regulator of cardiomyogenesis from pluripotent embryonic cells, which links Wnt/ß-catenin signalling to Nkx2.5 expression.

Clinical assessment of bortezomib for multiple myeloma in comparison with thalidomide.

PURPOSE: We studied the efficacy and safety of bortezomib (BOR) for treatment of multiple myeloma in comparison with thalidomide (THAL) by reference to adverse events, and searched for laboratory markers that could be used for prognostication of patients. METHODS: Biochemical data of patients receiving BOR and THAL for treatment of multiple myeloma at the Japanese Red Cross Narita Hospital were investigated retrospectively, after obtaining Institutional Review Board approval. Judgment of curative effects complied with the effects criteria of the International Myeloma Working Group (IMWG). RESULTS: BOR showed a higher rate of effectiveness than THAL for refractory multiple myeloma, and its effects were rapid. BOR treatment prolonged the survival time of THAL-resistant patients. The efficacy of BOR was unrelated to patient age, the number of previous therapeutic regimens, or the disease period. After medication with BOR, patients in whom it had been effective tended to show an increase of the serum alkaline phosphatase (ALP) level. Thrombocytopenia (86.2%) and leucopenia (69.0%) were observed at high frequencies, but no previously unreported adverse events or fatalities were associated with BOR therapy. CONCLUSION: It is suggested that BOR has therapeutic efficacy for multiple myeloma as a first-line medical treatment and/or for patients with THAL resistance, and can improve prognosis and survival. Since serum ALP elevation was observed in many patients for whom BOR was effective, this may be a predictor of BOR efficacy.

Study of the compatibility of oral magnesium oxide preparations sold in Japan with the ICH-Q3D guideline for elemental impurities.

Magnesium oxide has been widely used as an antacid and constipation remedy. Currently in Japan, magnesium oxide preparations manufactured by five medical companies are marketed as prescribed generic drugs. In this study, we focused on metal elemental impurities present in 330 mg magnesium oxide tablets manufactured by each of these companies. The content of such impurities was determined by atomic absorption spectrometry and inductively coupled plasma mass spectrometry. We confirmed whether the content conformed to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guideline for Elemental Impurities (ICH-Q3D) based on the 30% control threshold. The content of these impurities varied among the five products (preparations A-E), but in all cases met the oral permitted daily exposure (PDE) criteria stipulated in ICH-Q3D. In 5 lots of preparation C and all lots of preparation D, the equivalent cadmium (Cd) intake for a daily maximum dosage of 2 g was higher than the 30% control threshold of 1.5 µg/day. By cluster analysis, preparations A-E were classified into preparations A + B and C + D + E and/or preparations A + B, C + D and E. The present study showed that all 5 preparations sold in Japan meet the PDE value standard of ICH-Q3D, and that preparations A and B meet the 30% control threshold. It is important that for preparations failing to meet the criteria, further improvements need to be sought, and impurities in magnesium oxide preparations need to be monitored to ensure their safety.

Relationship between LDL-C reduction after coronary revascularization and prevention of recurrence of cardiovascular events.

PURPOSE: The purpose of our study was to optimize lipid-lowering therapy in patients undergoing coronary revascularization and to determine whether the percentage change in low-density lipoprotein-cholesterol (LDL-C) level in the 3 months after coronary revascularization could be used as a predictor of the time to recurrence of coronary artery disease (CAD). METHODS: Biochemical values of patients undergoing lipid-lowering therapy after receiving coronary revascularization at the Nippon Medical School Chiba Hokusoh Hospital, Japan, were retrospectively investigated. Recurrence of a cardiovascular event (CVE) was defined by death, myocardial infarction, or angina caused by coronary revascularization more than 3 months after the first event. RESULTS: Of 171 patients under secondary preventive care who had at least one recurrence of a CVE, 75 showed evidence of objective stenotic lesions on coronary angiography. Among these 75 patients, exclusion of those in whom coronary revascularization had not been performed at disease onset, balloon dilatation had been used, serum lipid levels had not been measured, or coronary revascularization had been applied to restenosis left 44 patients suitable for inclusion in the study group. Although the mean value of high density lipoprotein-cholesterol did not change in the 3 months after coronary revascularization, that of (LDL-C) significantly decreased. A significant positive correlation was identified between % decrease in LDL-C and number of days to CVE recurrence. The average LDL-C value (102.8+/-21.7 mg/dL) in the group of patients with no recurrence within 5 years was significantly lower than that (135.3+/-46.1 mg/dL) in the recurrence group (P = 0.0088). The % of patients achieving the LDL-C target level (non-recurrence group vs. recurrence group: 50.0% vs. 16.7%; P = 0.032) and the % decrease in LDL-C (31.0%+/-12.6% vs. 9.6+/-21.0%, P = 0.0012) were significantly greater in the non-recurrence group than in the recurrence group. CONCLUSIONS: From our present study, a decrease in LDL-C 3 months after revascularization surgery reduces the rate of CVE relapse. The % LDL-C decrease could serve as a useful predictor of CVE recurrence, in addition to LDL-C values and achievement of the LDL-C target level.

3-Hydroxy-3-methylglutaryl (HMG)-COA reductase inhibitors and phosphodiesterase type V inhibitors attenuate right ventricular pressure and remodeling in a rat model of pulmonary hypertension.

PURPOSE: We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. METHODS: The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a femoral artery for measurement of mean arterial pressure, another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP), and another into a femoral vein for administration of test drugs. RESULTS: Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) and simvastatin (2 mg/kg/day, p.o. 0 - 28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 - 28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S)) induced by a combination of a prostacyclin analogue, beraprost (100 mg/kg/day, 0 - 28 days) and simvastatin (2 mg/kg/day, 0 - 28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 - 28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 - 28 days) + sildenafil (5 mg/kg/day, p.o. 0 - 28 days) significantly reduced Lung/BW. CONCLUSION: Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simbastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone.

Investigation of the clinical efficacy and dosage of intravenous ciprofloxacin in patients with respiratory infection.

PURPOSE: Infection control is particularly vital in hospitals, and proper use of antimicrobial drugs is one of the most important roles of hospital pharmacists. In this study, we surveyed patients who had been prescribed single-use ciprofloxacin (CPFX), and evaluated the blood concentration of CPFX from the predictive AUC (area under the concentration curve). METHODS: This study was performed retrospectively to 112 adult patients diagnosed as having respiratory infections who had been treated as inpatients with intravenous CPFX for more than 3 days at Toho University Omori Hospital in Tokyo. The predictive AUC of each patient was obtained from the modified formulae reported by Forrest et al. (1993) [1]. The relation between the antimicrobial activity of CPFX and pharmacokinetic/pharmacodynamic (Cmax, AUC and AUC/MIC (minimum inhibitory concentration)) was studied. RESULTS: Although CPFX is excreted from the kidney, standard treatment with this drug does not take renal function into consideration. Our results indicated that CPFX was effective in less than 50% of the patients who received it. Moreover, the AUC/MIC ratio in both the effective group and the failure group was less than 125 when the clinical target was gram-negative bacteria. CONCLUSION: These results suggest that the clinical use of CPFX for the treatment of infectious diseases does not reach the target AUC/MIC ratio, and that the concentration of CPFX is not within the range to which many pathogens are susceptible in a large proportion of patients. To ensure the effective treatment of patients with infectious diseases and to prevent the development of resistance in bacteria, we recommend therapeutic drug monitoring (TDM) of CPFX in hospitals.

[Development of "Patient Friendly Formulations" to Counter the Side Effects of Cancer Chemotherapy].

　Anticancer drug-induced stomatitis develops in 30% to 40% of cancer patients undergoing chemotherapy. However, medications for this condition are not commercially available in Japan. The "hospital formulation" is a customized medicine which hospital pharmacists prepare when doctors cannot carry out the medical therapy most suitable for a patient using commercial medicines. However, as the duties of pharmacists increase, use of the "hospital fomulation" decreases. Therefore, development of "hospital fomulations" based on individual evidence has a limit. Irsogladine maleate (IM) is a drug with gastric mucosal protective properties. IM increases intracellular cAMP levels in the gastric mucosa and activates communication between cells. It has been reported that the oral administration of IM reduces the incidence of 5-FU-based chemotherapy-induced stomatitis. However, there have been no reports on the effect of the direct use of IM in treating stomatitis. Therefore, we studied the development of an IM oral spray for stomatitis treatment, and obtained evidence of a direct effect in an animal experiment using a stomatitis model. Next, rebamipide mouthwash was administered to patients who had stomatitis caused by cancer chemotherapy. The total scores were classified into Grades 0 to 4 and evaluated as a stomatitis evaluation score (SES). When comparing SES and changes in the stomatitis area in patients, gradual reductions in the extent of stomatitis were observed, even during the period when SES did not change. Having patients fill in an observation chart was effective for grasping changes in symptoms in outpatients.

Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification.

Thyroid hormones have marked cardiovascular effects in vivo. However, their direct effects on vascular smooth muscle cells have been unclear. Because thyroid hormones play critical roles in bone remodeling, we hypothesized that they are also associated with vascular smooth muscle calcification, one of the pathological features of vascular sclerosis. To test this hypothesis, we examined the effects of 3',3,5-triiodo-L-thyronine (T3) on the expression of calcification-associated genes in rat aortic smooth muscle cells (RAOSMCs). Quantitative RT-PCRs revealed that a physiological concentration of T3 (15 pmol/L free T3) increased mRNA level of matrix Gla protein (MGP), which acts as a potent inhibitor of vascular calcification in vivo, by 3-fold in RAOSMCs, as well as in cultured human coronary artery smooth muscle cells. In RAOSMCs transiently transfected with a luciferase reporter gene driven by the MGP promoter, T3 significantly stimulated luciferase activity. In addition, RNA interference against thyroid hormone receptor-alpha gene diminished the effect of T3 on MGP expression. Aortic smooth muscle tissues from methimazole-induced hypothyroid rats (400 mg/L drinking water; 4 weeks) also showed a 68% decrease in the MGP mRNA level, as well as a 33% increase in calcium content compared with that from the control euthyroid animals, whereas hyperthyroidism (0.2 mg T3/kg IP; 10 days) upregulated MGP mRNA by 4.5-fold and reduced calcium content by 11%. Our findings suggest that a physiological concentration of thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to prevention of vascular calcification in vivo.

Pharmacological studies on fullerene (C60), a novel carbon allotrope, and its derivatives.

Fullerene (C(60)), a condensed ring aromatic compound with extended pi systems, is a novel carbon allotrope. Because of its poor solubility in polar solvents, investigation of the biological and pharmacological properties of fullerene has been difficult. Recently, water-soluble fullerene derivatives have been synthesized, and we and others have found that they have potent and selective pharmacological effects on organs, cells, enzymes, and nucleic acids. In the presence of fullerene C(60) derivative (10(-5) M), endothelium-dependent relaxations induced by agonists in the vascular system were eliminated and acetylcholine-induced contractile response of smooth muscle was observed. Some investigators have reported free radical-scavenging activity and direct nitric oxide-quenching activity of fullerene derivatives. Knowledge of the chemical modifications, biological significance, and materials applications of functionalized fullerenes is growing rapidly; and these compounds are emerging as new tools in the field. The focus of this review is to introduce several pharmacological effects of fullerenes and to discuss the possible mechanisms of the pharmacological actions caused by previously synthesized fullerenes.