Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

Antiplatelet Effect of Mirtazapine via Co-blocking of the 5-HT2A and α2-Adrenergic Receptors on Platelets.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant. MTZ is reportedly associated with an increased risk of bleeding. However, the underlying mechanism remains unclear. In this study, we investigated the antiplatelet effect of MTZ in mice via light transmission aggregometry to elucidate the mechanism of MTZ-induced bleeding. The results of the ex vivo study showed that the oral administration of MTZ (20 or 100 mg/kg) significantly suppressed platelet aggregation mediated by the synergic interaction of 5-hydroxytryptamine (5-HT) and adrenaline. Additionally, MTZ significantly suppressed platelet aggregation, mediated by the synergic interaction of ADP and 5-HT or adrenaline. Similar results were obtained in vitro, under the condition of 5-HT- and adrenaline-induced platelet aggregation. Overall, the results suggest that MTZ exerts antiplatelet effect by co-blocking 5-HT2A and α2-adrenergic receptors on platelets and suppresses platelet aggregation mediated by ADP, increased by either 5-HT or adrenaline. Thus, a detailed monitoring of bleeding is recommended for patients taking MTZ.

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine.

Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dose-dependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapine-induced acute hyperglycemia.

Relationship Between Leukotriene Receptor Antagonists on Cancer Development in Patients With Bronchial Asthma: A Retrospective Analysis.

BACKGROUND/AIM: An association between leukotriene receptor antagonists (LTRA) and cancer has been previously reported, but the relationship between LTRA use and cancer prevention remains controversial. This study aimed to clarify the cancer-preventive effect of LTRA in Japanese patients with bronchial asthma. PATIENTS AND METHODS: We obtained information from a large populationbased medical information database to analyze data on patients who were newly diagnosed with bronchial asthma between 2006 and 2015. Eligible participants were patients who were prescribed an LTRA for at least 30 days (LTRA users) and those who were not using LTRA (LTRA non-users) during the objective period. LTRA users and LTRA non-users were matched 1:1 using propensity scores. RESULTS: The 1:1 propensity score matching of LTRA users and LTRA nonusers facilitated the inclusion of 3,744 participants each, in these two subgroups. The results of the Cox proportional hazards model after adjustment for covariates showed no significant difference in the cancer risk between LTRA users and non-users [adjusted hazard ratio (HR)=0.83, 95% confidence interval (CI)=0.59-1.16]. The subgroup analysis showed no significant difference in the cancer risk between the LTRA low-cumulative dose group and LTRA non-users, or between the LTRA medium-cumulative dose group and LTRA non-users. In contrast, the LTRA high-cumulative dose group had a significantly lower risk of developing cancer compared with LTRA non-users (adjusted HR=0.57, 95% CI=0.33-0.98). CONCLUSION: LTRA use may prevent cancer in patients with bronchial asthma.

The antiplatelet effect of mirtazapine is mediated by co-blocking 5-HT2A and α2-adrenergic receptors on platelets: An in vitro human plasma-based study.

Mirtazapine (MTZ) is a noradrenergic and specific serotonergic antidepressant that has been associated with an increased risk of bleeding. However, there is insufficient evidence confirming this association. We hypothesised that 5-HT2A and α2 receptor-mediated inhibitory effects of MTZ on platelets suppress platelet aggregation and increase the risk of bleeding. In this study, we examined the antiplatelet effect of MTZ on human platelets to test our hypothesis. Blood samples for platelet aggregation tests were obtained from 14 healthy volunteers. The antiplatelet effect of MTZ was evaluated using light transmission aggregometry. MTZ significantly suppressed platelet aggregation mediated both by the synergistic interaction of serotonin (5-HT) and adrenaline and the synergistic interaction of ADP and 5-HT or adrenaline. In conclusion, MTZ exerts its antiplatelet effects by co-blocking the 5-HT2A and α2-adrenergic receptors on platelets and also suppresses platelet aggregation induced by ADP and 5-HT or adrenaline. Therefore, when MTZ is used, especially for patients with a high risk of bleeding, the significance of its use must be considered carefully. In addition, the platelet aggregation pattern by adrenaline + 5-HT, ADP + adrenaline, and ADP + 5-HT was similar between humans and mice; however, this study did not directly compare the effects of MTZ on human and murine platelets. Therefore, under the conditions for inducing platelet aggregation using adrenaline + 5-HT, ADP + adrenaline, and ADP + 5-HT, mouse platelets can be used in the evaluation of the efficacy of antiplatelet drugs in humans.

Effect of Sucrose on Cisplatin-induced Fatigue-like Behavior in Mice: Comparison With Fructose and Glucose.

Background/Aim: Fatigue is the most common symptom in patients with cancer undergoing radiation therapy or cancer chemotherapy. However, cancer-related fatigue remains undertreated and poorly understood. Materials and Methods: Mice were administered a single dose of cisplatin (10 mg/kg, intraperitoneally) or saline (as a control) and then treated with sucrose, fructose, glucose (each at 500 or 5,000 mg/kg, orally), or saline (control) daily for 4 days. cisplatin-induced fatigue-like behavior was investigated by assessment of running activity on a treadmill. The influence of glucose intake on tumor growth was also examined in Lewis lung carcinoma (LLC)-bearing mice. Results: Administration of sucrose and glucose improved cisplatin-induced fatigue-like behavior in mice, whereas administration of fructose showed only slight antifatigue effects. Although glucose-fed mice showed increased tumor growth, this was balanced out by the powerful cytotoxicity of cisplatin. Conclusion: Sucrose, and especially glucose, may improve patient quality of life during treatment with anticancer agents by preventing fatigue without interfering with the antitumor effects of cisplatin.

Risk Factors Associated With Unplanned Acute Care in Outpatient Chemotherapy With Oral Anticancer Drugs as Monotherapy or Combination Therapy With Injectable Anticancer Drugs.

BACKGROUND/AIM: Recently, the number of patients with cancer receiving outpatient chemotherapy using oral anticancer drugs has increased, but the currently available outpatient cancer chemotherapy is not safer than that available before. The present study aimed to identify risk factors associated with unplanned acute care (UAC) requiring outpatient chemotherapy-related consultation and hospitalisation. PATIENTS AND METHODS: We conducted a case- control study among 1,674 patients who received oral anticancer drug treatment either alone or in combination with injectable anticancer drugs at National Cancer Center Hospital East, Japan, between December 1, 2014, and November 30, 2015. RESULTS: Body mass index (BMI) was identified as a risk factor for UAC during chemotherapy. Patients with a BMI of <18.5 kg/m2, classified as underweight according to the World Health Organization classification of nutritional status, had a significantly higher risk of UAC. CONCLUSION: A low BMI immediately before the occurrence of chemotherapy-related UAC is a risk factor for adverse effects; therefore, underweight patients need more careful monitoring and supportive care.

Examining the association between the "My Pharmacist" model and the service quality of community pharmacies.

BACKGROUND: In Japan, patients can freely choose medical facilities. Many visit different medical facilities for different diseases, and for convenience, often utilize the pharmacies neighboring these facilities. Accordingly, a "My Pharmacy" model was recommended, in which patients select a single pharmacy using their own judgement to receive proper medication services. A "My Pharmacist" model, in which the pharmacist is constantly involved in the treatment of a patient, was also proposed. However, patients' evaluations of pharmacist/pharmacy services under these models have not been investigated. OBJECTIVE: To examine how a patient's constant involvement with the same pharmacist and pharmacy is associated with their evaluation of the quality of pharmacy services. METHODS: A cross-sectional survey using a self-administered questionnaire was conducted among patients who used pharmacies periodically. Patients evaluated the pharmacist/pharmacy services and were classified into 4 groups ("My Pharmacy/My Pharmacist," "My Pharmacy/Multiple Pharmacists," "Multiple Pharmacies/My Pharmacist," and "Multiple Pharmacies/Multiple Pharmacists") according to the form of their usage of pharmacies and pharmacists. An intergroup comparison was then performed and correlations within each group analyzed. RESULTS: Data from 3,492 individuals using 147 pharmacies were analyzed. "My Pharmacy" users had significantly higher scores than did "Multiple Pharmacies" users on patient experience of proper medication services (e.g., identifying duplicate medication) (p < 0.001). "My Pharmacy/My Pharmacist" users scored higher than the other three groups on four evaluation factors, including "pharmacy/pharmacist's interpersonal services" ("sharing and utilizing patient information," "enhanced health support function," and "consideration towards patients"), "patient satisfaction with the pharmacy," "placing more emphasis on quality of interaction with pharmacist than on waiting time," and "attitude when visiting healthcare facilities" (all p < 0.001). CONCLUSION: The findings indicate that highly tailored, in-person services provided by "My Pharmacists" are associated with not only with the degree of patients' overall satisfaction, but also their evaluation of "the quality of pharmacist services."

[Prevention of pressure ulcers].

Even though they have not been diagnosed with a recognized disease, many people have or are at risk of contracting debilitating conditions. They can be referred to as being in the "ill-health zone." For example, many bedridden elderly develop pressure ulcers. The prevention and treatment of pressure ulcers should focus on two main factors: the role of pressure in the development of circulatory disorders; and increased dermal pH. In preventing the development of circulatory disorders resulting in pressure ulcers, using an air or polyurethane mattress is helpful. However, changing the mattress has little effect if the position of the bedridden person is not also changed regularly. To avoid an increase in dermal pH, caregivers should apply moisture-repellent cream and/or oil to the sacral region after careful cleansing. It is important that such preventive measures and treatment be performed daily, and caregivers should be educated on this need and subsequently monitored. Pharmacists have a role in caring for those in the ill-health zone.

[Knowledge of guideline for asthma and a demand at the pharmacy--questionnaire based exploration].

BACKGROUND: To achieve a good control for asthma, cooperation of pharmacists is necessary. It is important to establish the system that the patients easily obtain advice about asthma from pharmacists and to spread the guideline. METHODS: For the first step, we explore the knowledge and usage of asthmatic guideline among pharmacists in the drug stores in this study. The questionnaires were distributed to 465 drug stores in the Seibu, minato-ku and bunnkyo-ku, Tokyo. RESULTS: The knowledge of guideline was 79% but the existence of guideline booklet at the pharmacy was 24%. The major demand at the pharmacy was to distribute pamphlet around 10 pages which contained treatment at the pregnancy and prevention of asthma. DISCUSSION: To spread usage of asthmatic guideline at the pharmacy, newly-devised plan is required.

[What Is Involved in the Training Program for a Japanese Academic Detailer?]

'Academic Detailing' is an approach to providing doctors with information about medicines based on the latest non-commercial evidence-based data for proper prescription. Overseas, pharmacists have been active as academic detailers. Academic Detailing in Japan, as a new approach to disseminating comparative drug information based on basic pharmaceutical sciences and clinical evidence, will influence clinical decision making by doctors, and contribute to better patient-centered medical care. Pharmacists have been participating in ensuring the proper use of drugs by their patients by entering their homes or wards. However, in the future, it is necessary to take steps to improving pharmaceutical decision making by doctors. Therefore, we are considering the following educational points in the Japanese version of training an academic detailer. "A: We shall compare medicines based on basic pharmaceutical sciences and the latest non-commercial evidence-based data. B: We shall understand the point of using medicines based on the patient's condition. C: We shall choose cost-effective drugs from the viewpoint of pharmacoeconomics. And D: We shall acquire communication skills for effective academic detailing." In the future, this first class of Academic Detailers who facilitate academic detailing in the health care field will be pioneers. They will also participate in research to track and quantify the effects of academic detailing.

Clinical application of the leukocyte migration test and new diagnostic criteria for identifying causative agents in patients with drug-induced liver injury.

BACKGROUND/AIMS: We examined the usefulness of the leukocyte migration test (LMT) in the identification of agents causing drug-induced liver injury (DILI). METHODOLOGY: In 14 patients who were tentatively diagnosed as having DILI in Kitasato Institute Hospital, pharmacists collected and evaluated drug information and patients' medication histories to identify causative agents. Simultaneously, LMT and drug lymphocyte stimulation test (DLST) were performed. Furthermore, scoring was performed according to the diagnostic criteria established by the International Consensus Meeting (ICM) and the Digestive Disease Week-Japan 2004 (DDW-J). RESULTS: LMT-positive agents showed a higher ICM score compared to DLST-positive agents. The rate of LMT-positive agents was examined with respect to ICM assessment, and 0%, 25%, 33%, and 100% of agents regarded as unrelated/unlikely, possible, probable, and highly probable showed positive reactions on LMT, respectively; the rate of LMT-positive agents increased with the degree of the agent's involvement. When the results of LMT were applied to the DDW-J criteria, there was a correlation with the ICM criteria in comparison to scoring based on the results of DLST. CONCLUSIONS: LMT may be useful for identifying agents causing DILI. Furthermore, the collection and evaluation of drug and patient information and in vitro testing in the identification of causative agents may support more reliable diagnosis.

Reduction of Medical Cost through Pharmaceutical Inquiries by Community Pharmacists and Relation with Iyaku Bungyo Rates: A Nationwide Survey on Prescription Inquiries.

This nationwide survey aimed to evaluate reduction of drug and medical costs due to prevention of serious adverse drug reactions through pharmaceutical inquires by community pharmacist, and investigate relation with iyaku bungyo (separation of dispensing from medical practice) rates. Using the national list of pharmacies, 10% of pharmacies were randomly selected by prefecture and asked to participate in an Internet-based survey. The survey period was 7 days, from July 21 to July 27, 2015. Of the 5575 pharmacies queried, 818 responded to the survey (response rate: 14.7%). The proportion of inquiries to total prescriptions was 2.6%. Among these, the proportion of prescriptions changed in response to inquiry was 74.9%. An estimated 103 million yen was saved by reducing drug costs, and 133 million yen was saved by reducing medical costs due to prevention of serious adverse drug reactions. Comparison of prescription change rates between pharmacies with high and low iyaku bungyo rates indicated that the proportion of prescriptions changed was significantly higher in pharmacies with high iyaku bungyo rates than in those with low iyaku bungyo rates (78.2% vs. 69.9%, p<0.01). The findings suggest that inquiries about prescriptions are useful in ensuring the safety of pharmacotherapy and reducing the cost of healthcare. They also suggest that iyaku bungyo promotes prescription changes through inquiries, leading to proper use of pharmaceutical products.

[A research of letter color visibility in package insert information using simulator].

Package insert of pharmaceutical drug is one of the most prioritized information for pharmacists to secure safety of patients. However, the color of character, size, font and so on are various company by company product to product from a viewpoint of visibility. It may be cause a serious accident in case visibility is unclear, although it is the most important information. Moreover, package insert with high visibility is required for color vision defectives from a viewpoint of a universal design. Then, the authors selected the package insert which has the boxed warning in the ethical pharmaceutical currently stored mostly in the present health insurance pharmacy and quantified the red color using the color meter. We advocate the state of a suitable package insert from a viewpoint of a universal design, whether the red color is high visible or not for color vision defectives using simulator.

[Medical economics research on awareness of community pharmacists about raising pharmaceutical questions regarding prescriptions issued by physicians].

This study examined the impact of pharmaceutical inquiries regarding prescriptions on drug costs by surveying the actual condition of inquiries at 13 pharmacies. The study also investigated the significance of inquiries from a medical economics perspective by calculating the medical cost savings realized by preventing adverse drug reactions (ADRs). As a result, the total change in drug costs for the 13 pharmacies after pharmaceutical inquiries represented an increase of ¥9,018/month. However, upon recalculating the cost of drugs by assuming that those with an "Incomplete entry in the prescription (compared with previous prescription, etc.)" should in fact have been prescribed, and excluding them, the total drug costs for the 13 pharmacies is decreased to ¥154,743/month, translating to a cost-savings of ¥7.2/prescription. The study then undertook a comprehensive assessment based on the Diagnosis Procedure Combination (DPC) system to determine the total medical cost-savings for 5 patients in whom ADRs could have occurred if the prescriptions had not been modified as a result of pharmaceutical inquiries. The obtained figure of ¥1,188,830 suggests that pharmaceutical inquiries contribute to reduced medical costs. The findings of this study indicate that pharmaceutical inquiries regarding prescriptions by staff pharmacists not only ensure the proper delivery of drug therapy to patients, but are also effective from a medical economics perspective.

Salacia reticulata inhibits differentiation of 3T3-L1 adipocytes.

UNLABELLED: ETHOPARMACOLOGICAL RELEVANCE: Salacia reticulata, a herbal medicine which has been used for the treatment of early diabetes in Ayurvedic medicine, is reported to have an anti-obesity effect and to be useful in the treatment of diabetes mellitus, insulin resistance and other metabolic diseases. AIM OF THE STUDY: The present study was performed to elucidate the mechanism of action of Salacia reticulata with special attention to the adipocytes as the tissue primarily involved in the pathology of metabolic diseases. MATERIALS AND METHODS: Mouse-derived adipocyte precursor 3T3-L1 cells were treated with differentiation inducers in the presence or absence of Salacia reticulata (SRCD). We determined triacylglycerol accumulations, differentiation makers, released glycerol and adiponectin. Mangiferin, the primary component of SRCD, was also treated to 3T3-L1 cells. RESULT: Concurrent administration of the extract of SRCD and differentiation inducers resulted in a significant inhibition of differentiation into mature adipocytes. SRCD also exhibited significant inhibitory action on the expression of genes and proteins of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT-enhancer binding protein (C/EBP)α, as well as on the activity of glycerol-3-phosphate dehydrogenase (GPDH), a differentiation marker, and caused a reduction in the concentration of released adiponectin. However, SRCD had no influence on lipolysis as indicated by the release of glycerol into the culture medium. The primary component of SRCD, mangiferin, was investigated for its effect on adipocytes; mangiferin caused no suppression of fat accumulation, suggesting that a component of SRCD other than mangiferin may be involved in the inhibition of adipocyte differentiation. CONCLUSIONS: The above results suggest that the inhibitory action of SRCD on adipocyte differentiation, and not the promotion of lipolysis, is involved in the suppression of fat accumulation.

[Survey on the awareness of community pharmacists about raising pharmaceutical questions regarding prescriptions issued by physicians].

Community pharmacists can provide effective pharmaceutical care by questioning the physicians about their prescriptions. The regulatory authority (Ministry of Health, Labour and Welfare or the like) has been issuing instructions/advice to health insurance-covered pharmacies about the nature of questions to be asked to physicians under the national health insurance system. However, this practice has been facing similar kind of problems almost every year. To identify the reasons for repetition of the problems and facilitate proper application of drug therapy at hospitals, we recently examined the nature of questions asked to physicians by conducting a survey of 165 health insurance-covered pharmacies belonging to 8 district branches of the Japan Pharmaceutical Association. When the pharmacists were asked to express their view whether each of the 18 sample questions included in the past surveys was actually necessary, the most frequent answer from the respondents (n=1980) was "neutral" (42.9%), followed by "unnecessary" (29.0%) and "necessary" (26.6%). Further, 55.5% respondents answered that it is necessary to refer to publications of the concerned fields (guidelines, etc.) when questioning the prescriptions. However, the responses about the possible reasons for judging the necessity of the questions suggested that sometimes the pharmacists failed to understand the details of such publications. The results from this study suggest that a high percentage of community pharmacists believed that there was little need to ask questions about prescriptions if the suggestions made by the regulatory authority about the relevant questions were taken into account. Further, our study findings suggested that pharmacists working at clinics cannot present a clear-cut rationale for their judgment about the necessity of asking questions about prescriptions under the current circumstances where sufficient information collection and the evaluation of need for asking questions about prescriptions are not possible.