Risk Evaluation of Proton Pump Inhibitors for Panitumumab-Related Hypomagnesemia in Patients with Metastatic Colorectal Cancer.

Hypomagnesemia commonly occurs as a side effect of panitumumab treatment. In severe cases, temporary discontinuation or dose reduction of panitumumab may be necessary. Proton pump inhibitors (PPIs) are reportedly potential risk factors for hypomagnesemia. We conducted a multicenter study to assess the impact of PPIs on the risk of grade 3-4 hypomagnesemia in patients with metastatic colorectal cancer (mCRC) receiving panitumumab. We adjusted for potential bias using a propensity score-matched analysis and retrospectively reviewed the medical records of patients. Hypomagnesemia severity was graded according to the Common Terminology Criteria for Adverse Events, version 5.0. A total of 165 patients were enrolled in this study. The incidence of grade 3-4 hypomagnesemia was significantly higher in the PPI group than in the non-PPI group, both before (20.0% [30/60] vs. 8.0% [8/105], p = 0.026) and after propensity score matching (16.2% [6/37] vs. 0% [0/37], p = 0.025). In the propensity score-matched cohort, the risk of grade 3-4 hypomagnesemia was significantly higher in the PPI group (odds ratio, 2.19; 95% confidence interval, 1.69-2.84; p = 0.025). These findings suggest that concomitant use of PPIs significantly increases the risk of grade 3-4 hypomagnesemia in patients with mCRC receiving panitumumab. Therefore, close monitoring of these patients is imperative.

Application Site of Transdermal Scopolamine Influences Efficacy and Drug Concentration in Salivary Glands in Rats.

Transdermal scopolamine applied to the postauricular area is used to treat drooling. We investigated the duration of action of scopolamine ointment and the effect of the application site on drug efficacy and concentration in the salivary glands of rats. Scopolamine ointment was applied to the skin over the salivary glands (SSG) and back (SB). Saliva volume was measured after intraperitoneal administration of pilocarpine. Blood and salivary glands were collected after scopolamine ointment application, and scopolamine concentrations in the plasma and salivary glands were measured. Saliva volume after application in the SSG group was significantly lower at all time points than in the non-treated group, and the change in saliva volume in the SSG group was greater than that in the SB group at all time points. This suggests that applying scopolamine ointment to the SSG strongly suppresses salivary secretion. Scopolamine concentration in the salivary glands of the SSG group was significantly higher at 9 h. The change in the efficacy of scopolamine ointment depending on the application site was due to the difference in transfer to the salivary glands. Transdermal administration of scopolamine to the skin over the salivary glands may have high efficiency in treating drooling.

Analysis of Atypical Antipsychotics-Induced Adverse Events Related to Diabetes Mellitus in Patients With Dementia Using the Japanese Adverse Drug Event Report Database.

BACKGROUND: Patients with dementia are prescribed low-dose atypical antipsychotics (AAPs) to treat psycho-behavioral symptoms. Although AAPs are known to cause diabetes mellitus-related adverse events (DMAEs), information regarding AAPs-induced DMAEs experienced by patients with dementia is lacking. OBJECTIVE: To use the Japan Adverse Drug Event Report (JADER) database to assess the onset tendencies and patterns of DMAEs attributable to AAPs prescribed to patients with dementia. METHODS: We performed an analysis using dementia cases from the JADER database that were registered from April 2004 to December 2022. Data in the JADER database are completely anonymized; thus, we did not require institutional review board approval for using the JADER database in our study. The reporting odds ratio and proportional reporting ratio (PRR) were used to assess the onset tendencies of DMAEs with AAPs. In addition, Weibull shape parameters were used to assess the patterns of DMAEs that occur with the use of AAPs. RESULTS: We identified AAPs associated with DMAEs. In particular, low doses of quetiapine showed the potential to induce DMAEs. An analysis of the onset of DMAEs showed the early failure patterns for AAPs (median onset = 38 days). CONCLUSION AND RELEVANCE: The AAPs may cause DMAEs in patients with dementia. Low doses of quetiapine may induce DMAEs. Health care workers should focus on the development of DMAEs during the early administration period of AAPs. These results may assist with the safe management of patients with dementia who use AAPs.

Multicenter prospective observational study on hospital pharmacist interventions to reduce inappropriate medications.

Background: In Japan, the involvement of hospital pharmacists in inappropriate medications (IMs) practices has not been sufficiently reported. Therefore, this prospective study described the interventions of hospital pharmacists in discontinuing inappropriate drugs or reducing drug doses. Methods: We conducted a prospective, multicenter, observational study to investigate the intervention of hospital pharmacists in inappropriate prescriptions for inpatients in September 2018. Fifty pharmacists from 45 hospitals in Japan participated in this study. IMs were defined as medications that pharmacists deemed inappropriate for patient treatment. The subjects of the study were patients who interacted with the participating pharmacists. Results: During the study period, the median number of beds in hospitals where the 50 participating pharmacists worked was 380, and the average number of beds for which the pharmacists were responsible was 49. The enrolled hospital pharmacists recommended that doctors discontinue or reduce the doses of their regular drugs for 347 out of 1,415 (24.5%) patients. Among the 391 pharmacists' recommendations to reduce IMs for 347 patients, physicians accepted 368 (94.1%) recommendations, and 523 drugs were discontinued as a result. Pharmacist intervention also led to improvements in hypnotic sedation, delirium, and hypotension. The most common reasons for IMs identified by pharmacists were "long-term administration of irresponsible or aimless medications" (44.5%), "adverse effects caused by medications" (31.5%), and "medications-mediated duplication of the pharmacological effect" (15.3%). Approximately 90% of pharmacists' suggestions to reduce medications were accepted for each reason. The average number of regular medications used by patients involved in drug reduction was 8.2, and the average number of medications reduced was 1.7. A sub-analysis showed that patients using opioids tended to take more medications, and these patients were able to reduce the amount of medications taken. Interventions by pharmacists certified in palliative pharmacies tended to reduce adverse drug events. Conclusion: This was the first multicenter prospective observational study conducted in Japan to demonstrate hospital pharmacist intervention's effectiveness in promoting appropriate prescription and, consequently, a reduction in the number of medications in use and polypharmacy.

Effect of Anticoagulant/Antifibrinolytic Combination Therapy on Enhanced Fibrinolytic-Type Disseminated Intravascular Coagulation in End-of-Life Stage Solid Tumor Patients.

Thrombotic disorders such as venous thromboembolism and disseminated intravascular coagulation (DIC) are known complications of solid tumors. To date, no reports have described the treatment of enhanced fibrinolytic-type DIC caused by end-of-life stage solid tumors. We encountered three cases of end-of-life stage solid tumors complicated by enhanced fibrinolytic-type DIC with severe bleeding symptoms. In all three cases, bleeding symptoms improved dramatically after intervention for enhanced fibrinolytic-type DIC with heparin(s) and tranexamic acid. Improvements in abnormal coagulation test results were also seen and the need for platelet concentrate transfusion and fresh frozen plasma infusion was able to be eliminated. However, one patient developed multiple cerebral infarctions. In the future, further studies to investigate the need for intervention in enhanced fibrinolytic-type DIC caused by end-of-life stage solid tumors and suitable treatment strategies are warranted.

Opioid-Related Respiratory Depression in Non-Cancer Patients, as Reported in the Japanese Adverse Drug Event Report Database.

BACKGROUND: Opioid-induced respiratory depression (RD) is a potentially life-threatening adverse drug event. This study used the Japanese Adverse Drug Event Report (JADER) database to investigate the profile of opioid-related RD in non-cancer patients. METHODS: We analyzed data recorded in the JADER database between April 2004 and February 2020, which were downloaded from the Pharmaceutical and Medical Devices Agency website. Reporting odds ratios for RD were calculated for the 20 opioids approved in Japan, and daily dose and onset time were further analyzed for opioids used in chronic non-cancer pain (CNCP). RESULTS: Among the opioids, RD adverse event signals were detected for 22 combinations of opioids and administration routes in non-cancer patients. Of these combinations, transdermal buprenorphine and oral tramadol/acetaminophen were approved for CNCP and tended to be reported more frequently in elderly patients. The median daily doses of transdermal buprenorphine and oral tramadol/acetaminophen were 10.0 and 22.5 mg of daily oral morphine equivalent doses, respectively, which are within the standard range for starting dosage. The median time-to-onset of transdermal buprenorphine and oral tramadol/acetaminophen was 6.5 and 4.0 days, respectively, and 75% of cases were reported within 20 to 40 days after the start of treatment. The hazard type for both opioids was classified as early failure. CONCLUSIONS: Our findings suggest that elderly CNCP patients should be closely monitored after the start of opioid treatment, especially during the first week and, if possible, for 1 month, even if starting doses are within ranges recommended by the manufacturer and guidelines.

Japanese Nationwide Comparative Survey of Medication Guidance Provided by Certified and Uncertified Palliative Care Pharmacists.

BACKGROUND: As members of a medical team, pharmacists are expected to provide optimal patient-centered, evidence-based pharmacotherapy. In Japan, in consideration of the importance of palliative care, a system was initiated for certifying palliative care pharmacists in 2010. However, no studies have evaluated the usefulness of board certification in palliative pharmacy. Therefore, we surveyed the status of medication guidance for the physical and psychological symptoms of patients receiving palliative care and compared the medication guidance provided by certified and uncertified pharmacists. METHODS: The survey was conducted in February and March 2022. Pharmacists registered as members of the Japanese Society of Pharmaceutical Palliative Care and Sciences were surveyed by using a web-based questionnaire and 209 pharmacists responded: the certified pharmacist group comprised 123 (58.9%) pharmacists and the uncertified pharmacist group comprised 86 (41.1%) pharmacists. RESULTS: The certified pharmacist group provided better and more frequent medication guidance, according to responses to four of the six items related to pain relief. Three items were related to non-pain symptom relief, and one of the four items was related to psychiatric symptom relief (P < 0.05). The study showed that the certified pharmacist group received a better rating than the uncertified pharmacist group for involvement in palliative pharmacotherapy leading to improvement of patient quality of life (P < 0.05). CONCLUSION: As compared with uncertified pharmacists, certified pharmacists intervened more proactively and provided a broader range of palliative care.

Multicentre prospective observational study on community pharmacist interventions to reduce inappropriate medications.

OBJECTIVES: The status of community pharmacists' involvement in inappropriate prescription practices among outpatients who visit community pharmacies has not been reported in Japan. Therefore, this study described community pharmacists' interventions aimed at the discontinuation of inappropriate drugs or the reduction of drug doses. METHODS: We conducted a multicentre prospective observational study of pharmacists' interventions on inappropriate prescriptions for outpatients during a 1-month period in September 2018. A total of 28 pharmacists from 28 community pharmacies in Japan participated in this study. We analysed cases in which pharmacists discontinued drugs or changed the doses due to drugs being inappropriate, adverse effects, duplication of pharmacological effects and drug-drug interactions. KEY FINDINGS: Community pharmacists provided interventions for 736 patients at an average of 26.2 patients per day during the study period. The pharmacists recommended that doctors discontinue inappropriate drugs or reduce the doses of regular drugs for 103 patients (13.9%). Among the 107 pharmacist recommendations to decrease inappropriate prescriptions, 83 (77.6%) were accepted, including 62 cases of discontinuation (57.9%) and 21 of drug dose reduction (19.6%). A total of 122 drugs were discontinued according to pharmacists' recommendations. In addition, pharmacists' intervention improved sleepiness, sedation and cognitive function. CONCLUSIONS: This study shows the active involvement of community pharmacists in polypharmacy by discontinuing inappropriate drugs or reducing the dose of regular drugs, which may contribute to the improvement of adverse effects among outpatients.

Diabetes Mellitus, Elevated Hemoglobin A1c, and Glycated Albumin Are Associated with the Presence of All-Cause Dementia and Alzheimer's Disease: The JPSC-AD Study.

BACKGROUND: Glucose dysmetabolism is an important risk factor for dementia. OBJECTIVE: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. METHODS: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent ß-cell function (HOMA-ß), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer's disease (AD) and vascular dementia (VaD) were investigated. RESULTS: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08-1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %-6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19-2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00-1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. CONCLUSION: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

Recombinant human erythropoietin attenuates hepatic dysfunction by suppressing hepatocellular apoptosis in lipopolysaccharide-induced disseminated intravascular coagulation in rats.

The aim of the present study was to clarify the effect of recombinant human erythropoietin (EPO) and low molecular weight heparin (LMWH) on a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC). Experimental DIC was induced by sustained infusion of 5 mg/kg LPS for 4 h. EPO or LMWH was then administered to the LPS-induced DIC model. LPS-induced consumption coagulopathy, hemostatic activation and plasma TNF elevation remained unaltered in the LPS+EPO group, except for the D-dimer levels, and these abnormalities were significantly improved in the LPS+LMWH group. Plasma alanine aminotransferase (ALT) levels were markedly reduced in the LPS+EPO group, accompanied by a significant suppression of hepatocellular apoptosis. In the LPS+LMWH group, plasma creatinine levels and glomerular fibrin deposition were significantly attenuated, along with plasma ALT levels and hepatocellular apoptosis. Thus, a single administration of EPO may improve hepatic dysfunction by primarily exerting an anti-apoptotic, not anticoagulant, effect in the LPS-induced DIC model.

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case-control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05-3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05-5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58-6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Effect of NOS Inhibitors and Anticoagulants on Nitric Oxide Production in a Tissue-factor Induced Rat DIC Model.

BACKGROUND/AIM: We examined the mechanism of nitric oxide (NO) production in a tissue-factor (TF)-induced disseminated intravascular coagulation (DIC) model in rats, using inducible nitric oxide synthase (iNOS) inhibitor (L-NIL), endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), Factor Xa inhibitor (DX-9065a), and thrombin inhibitor argatroban. MATERIALS AND METHODS: Experimental DIC was induced by sustained infusion of 3.75 U/kg TF for 4 h via the tail vein. We then investigated the effect of these four agents on TF-induced DIC. RESULTS: Administration of L-NIL or L-NAME during induction of TF-induced DIC did not affect hemostatic markers, whereas elevated plasma levels of NO metabolites (NOX) were significantly suppressed by co-administration of L-NAME. A significant increase in eNOS-mRNA expression was observed in the TF-induced DIC model. Argatroban almost completely suppressed eNOS-mRNA expression. CONCLUSION: eNOS plays an important role in the NO production in the TF-induced DIC, and thrombin is a key stimulant of eNOS-mRNA expression in this model.

[Factors Associated with Self-reported Medication Adherence in Japanese Community-dwelling Elderly Individuals: The Nakajima Study].

Medication non-adherence in the elderly population is a major problem, preventing them from obtaining optimal therapeutic effects. Identifying the factors affecting medication adherence is crucial for improving and maintaining health among the elderly population and enhance healthcare economy. The purpose of this study was to examine the prevalence of self-reported medication adherence, and identify the associated factors and the influence of health-related quality of life (HRQOL) in the Japanese community-dwelling elderly population. This cross-sectional study was part of the Nakajima study and targeted inhabitants aged ≥60 years who underwent health examinations in 2017. Data regarding medication adherence were acquired through interviews and self-administered questionnaires. Medication adherence were assessed using a visual analog scale, and HRQOL was assessed by EuroQol five-dimensional questionnaire with 3 levels. Among the 455 participants, low and high medication adherence were seen in 9.7% and 66.2% of the participants, respectively (visual analog scores <80% and ≥95%, respectively). Medication adherence was significantly lower in participants taking medications ≥3 times daily than in those taking medications once or twice daily; a regimen involving drug administration ≥3 times daily had significantly lower odds of medication adherence. The use of a drug profile book and HRQOL had significant positive association with medication adherence. Our results suggest that low dosing frequency and using a drug profile book was positively associated with medication adherence among elderly persons, which in turn could enhance their QOL.

Detailed exploration of pathophysiology involving inflammatory status and bleeding symptoms between lipopolysaccharide- and tissue factor-induced disseminated intravascular coagulation in rats.

Lipopolysaccharide (LPS) and tissue factor (TF) have frequently been used to induce disseminated intravascular coagulation (DIC) in experimental animal models. We have previously reported that the pathophysiology of DIC differs according to the inducing agents. However, inflammatory status and bleeding symptoms have not been fully compared between rat models of the two forms of DIC. We attempted to evaluate detailed characteristic features of LPS- and TF-induced DIC models, especially in regard to inflammatory status and bleeding symptoms, in addition to selected hemostatic parameters and pathologic findings in the kidneys. The degree of hemostatic activation in both types of experimental DIC was identical, based on the results of thrombin-antithrombin complex levels. Markedly elevated tumor necrosis factor, interleukin-6, and high-mobility group box-1 concentrations were observed with severe organ dysfunction and marked fibrin deposition in the kidney on administration of LPS, whereas markedly elevated D-dimer concentration and bleeding symptoms were observed with TF administration. Pathophysiology such as fibrinolytic activity, organ dysfunction, inflammation status, and bleeding symptom differed markedly between LPS- and TF-induced DIC models in rats. We, therefore, recommend that these disease models be assessed carefully as distinct entities to determine the implications of their experimental and clinical use.

Initial Serum C-reactive Protein Level as a Predictor of Increasing Serum Vancomycin Concentration During Treatment.

BACKGROUND: Vancomycin has a narrow therapeutic window, and an increase in its serum concentration-to-dose ratio during treatment can cause renal toxicity. Therefore, this study was aimed at finding a marker to identify patients at risk of increasing serum vancomycin during treatment. METHODS: This was a retrospective cohort study of patients treated with vancomycin at Kanazawa University Hospital, Japan, from April 2012 to May 2015. Spearman correlation coefficients were calculated to determine the correlations between changes in vancomycin concentration-to-dose ratio and initial values or changes in laboratory data and other parameters. In addition, a multiple regression analysis was conducted. RESULTS: One hundred ninety-nine patients for whom 2 or more points of data on therapeutic drug monitoring (TDM) of intravenous vancomycin treatment were available and did not undergo dialysis were included in the study. Changes in vancomycin concentration-to-dose ratio were associated with C-reactive protein (CRP) and sodium (Na) levels on the initial day of TDM and with changes in white blood cell count, Na, and estimated glomerular filtration rates (eGFRs). Multiple regression analysis helped identify CRP and Na levels on the initial day of TDM and change in eGFR as independent influencing variables. CONCLUSIONS: A high serum CRP level on the initial day of TDM is an independent predictor of increasing vancomycin concentration-to-dose ratio in patients receiving intravenous vancomycin treatment, even if eGFR remains unchanged.

Sarcopenia may Influence the Prognosis in Advanced Thyroid Cancer Patients Treated With Molecular Targeted Therapy.

BACKGROUND/AIM: Reportedly, sarcopenia and nutritional status are associated with prognosis in cancer patients. However, data regarding the relationship of these factors with advanced thyroid cancer patients receiving molecular targeted therapy remains scarce. Therefore, we investigated the relationship between nutritional assessment, as well as sarcopenia, and prognosis in patients with advanced thyroid cancer undergoing molecular targeted therapy. PATIENTS AND METHODS: In this retrospective study, sarcopenia and several markers of nutritional status were assessed in advanced thyroid cancer patients at the Kanazawa University Hospital, before the introduction of molecular targeted therapy. RESULTS: Advanced thyroid cancer patients with sarcopenia presented a worse prognosis than those without sarcopenia. Additionally, sarcopenia strongly correlated with several markers of nutritional status, such as albumin, prognostic nutrition index, and Glasgow prognostic score. CONCLUSION: Sarcopenia could be a prognostic factor in patients with advanced thyroid cancer receiving molecular targeted therapy.

Risk Factors for Delayed Elimination of Methotrexate in Children, Adolescents and Young Adults With Osteosarcoma.

BACKGROUND/AIM: High-dose methotrexate (HD-MTX) is pivotal chemotherapy in the treatment of patients with osteosarcoma. Blood concentrations of MTX are associated with several side effects, but there are large individual differences in the elimination of MTX. The aim of this study was to explore risk factors for delayed elimination of MTX in children, adolescents and young adults with osteosarcoma. PATIENTS AND METHODS: We conducted a retrospective study on Japanese patients with osteosarcoma who were treated with HD-MTX at Kanazawa University Hospital from April 2006 to March 2015. Risk factors for delayed elimination of methotrexate were identified by multiple logistic regression analysis. RESULTS: A total of 92 cycles of HD-MTX therapy were analyzed. Female and lower creatinine clearance (CCr) were identified as independent risk factors for delayed elimination of MTX. CONCLUSION: Knowing the factors associated with delayed elimination of MTX could lead to safer and optimized chemotherapy for patients with osteosarcoma.

Comparison of Tolerability Between 2-Weekly and 3-Weekly Docetaxel Regimen in Castration-resistant Prostate Cancer.

BACKGROUND: The tolerability of 2-weekly docetaxel at 25-35 mg/m2 for castration-resistant prostate cancer (CRPC) has not been fully evaluated. The aim of this study was to evaluate its tolerability compared to 3-weekly docetaxel at 60-75 mg/m2 in patients with CRPC. PATIENTS AND METHODS: In this retrospective study, data were compared with respect to efficacy and safety between 2-weekly and 3-weekly docetaxel regimens in patients with CRPC. RESULTS: Time to treatment failure and prostate-specific antigen (PSA) response rate did not differ significantly between the two regimens. Compared to 3-weekly administration, incidence of severe leukopenia and febrile neutropenia was significantly lower (p<0.05), and relative dose intensity was significantly higher (p<0.05) for the 2-weekly schedule. Docetaxel dosage and PSA response were identified as independent risk factors for severe leukopenia. CONCLUSION: Two-weekly treatment seems better tolerated than three-weekly treatment in Japanese patients with CRPC.