Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

BACKGROUND: Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells. METHODS: We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life. TRIALS REGISTRATION: jRCT2021220012 registered on 17 June 2022.

Assessing Heterogeneity of Treatment Effect in Real-World Data.

Increasing availability of real-world data (RWD) generated from patient care enables the generation of evidence to inform clinical decisions for subpopulations of patients and perhaps even individuals. There is growing opportunity to identify important heterogeneity of treatment effects (HTE) in these subgroups. Thus, HTE is relevant to all with interest in patients' responses to interventions, including regulators who must make decisions about products when signals of harms arise postapproval and payers who make coverage decisions based on expected net benefit to their beneficiaries. Prior work discussed HTE in randomized studies. Here, we address methodological considerations when investigating HTE in observational studies. We propose 4 primary goals of HTE analyses and the corresponding approaches in the context of RWD: to confirm subgroup effects, to describe the magnitude of HTE, to discover clinically important subgroups, and to predict individual effects. We discuss other possible goals including exploring prognostic score- and propensity score-based treatment effects, and testing the transportability of trial results to populations different from trial participants. Finally, we outline methodological needs for enhancing real-world HTE analysis.

Quality evaluation of the Japanese Adverse Drug Event Report database (JADER).

INTRODUCTION: The spontaneous adverse drug reaction (ADR) reporting system plays an important role in pharmacovigilance by providing information from clinical settings in the postmarketing environment. The Japanese Adverse Drug Event Report (JADER) database contains a portion of Japanese ADR reports, and no previous study has described the quality or characteristics of ADR reports in the JADER. OBJECTIVE: The aim of this study was to identify the characteristics of the JADER database and to evaluate the quality of ADR reports contained in the JADER using the documentation-grading scheme developed by the World Health Organization. METHODS: Of 478 508 ADR reports in the JADER, the analysis set consisted of 395 091 reports meeting inclusion criteria. An analysis was carried out to evaluate the quality of the reports according to the type of report, the type of sender, and the qualification of the reporter. Annual changes in the number of reports from medical institutions submitted by pharmacists were compared with changes in the number submitted by physicians. RESULTS: The distribution of documentation grade differed according to the type of report, the type of sender, and the qualification of the reporter. Regarding "medical institution reports", the quality of reports was similar among qualification types, while the quality of reports submitted by physicians was higher for "company reports" and "study reports" (P < .0001, respectively). CONCLUSION: Our study showed that the quality of the ADR reports in the JADER differed among the type of report, the sender of the report, and the qualification of the reporter.

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."

Identifying drug substances of screening tool for older persons' appropriate prescriptions for Japanese.

BACKGROUND: In 2015, the Japan Geriatric Society (JGS) updated "the Guidelines for Medical Treatment and its Safety in the elderly," accompanied with the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J): "drugs to be prescribed with special caution" and "drugs to consider starting." The JGS proposed the STOPP-J to contribute to improving prescribing quality; however, each decision should be carefully based on medical knowledge. The STOPP-J shows examples of commonly prescribed drug substances, but not all relevant drugs. This research aimed to identify substances using such coding, as a standardized classification system would support medication monitoring and pharmacoepidemiologic research using such health-related information. METHODS: A voluntary team of three physicians and two pharmacists identified possible approved medicines based on the STOPP-J, and matched certain drug substances to the Anatomical Therapeutic Chemical Classification (ATC) and the Japanese price list as of 2017 February. Injectables and externally used drugs were excluded, except for self-injecting insulin, since the STOPP-J guidelines are intended to cover medicines used chronically for more than one month. Some vaccines are not available in the Japanese price list since they not reimbursed through the national health insurance. RESULTS: The ATC 5th level was not available for 39 of the 235 identified substances, resulting in their classification at the ATC 4th level. Furthermore, among 26 combinations, 10 products were matched directly to the ATC 5th level of the exact substances, and others were linked to the ATC representing the combination or divided into multiple substances for classification if the combination was not listed in the ATC. CONCLUSION: This initial work demonstrates the challenge of matching ATC codes and the Japan standard commodity classification codes corresponding to STOPP-J substances. Since coding facilitates database analysis, the proposed drug list could be applied to research using large databases to examine prescribing patterns in patients older than 75 years or who are frail. Since ATC is not available for some substances, Japanese medicines need the process to be registered in the ATC for an effective screening tool to be developed for STOPP-J.

Medicine reclassification processes and regulations for proper use of over-the-counter self-care medicines in Japan.

OBJECTIVES: Japan has actively reclassified substances ranging from prescription drugs to over-the-counter (OTC) drugs in recent years. The sale of most OTC drugs was deregulated several times and pharmacists' supervision was deemed no longer mandatory. Japan established a new OTC evaluation system in 2015 to hear opinions from various stakeholders regarding medicine types to be reclassified. This study aimed to examine the new framework to identify candidate substances for reclassification. Moreover, we examined how to manage the safe, self-care use of OTC drugs in Japan. METHODS: The necessary regulatory information on OTC approvals as of January 2015 was collected using an Internet search and relevant databases. To highlight the characteristics of OTC drugs in Japan, the UK was selected as a comparison country because it too was actively promoting the reclassification of medicines from prescription to nonprescription status, and because of economic similarity. RESULTS: Japan and the UK have a risk-based classification for nonprescription medicines. Japan has made OTC drugs available with mandatory pharmacists' supervision, face-to-face with pharmacists, or online instruction, which is similar to the "pharmacy medicine" practiced in the UK. Japan recently reformed the reclassification process to involve physicians and the public in the process; some interactions were back to "prescription-only medicine" in the UK. CONCLUSION: It is expected that the opinion of marketers, medical professionals, and the public will improve the discussion that will greatly contribute to the safe use of drugs. Monitoring the new system will be noteworthy to ensure that OTC drug users are managing their self-care properly and visiting a doctor only when necessary. The supply methods are similar in Japan and the UK; however, the expected growth in the Japanese OTC market by the Cabinet and the industry is still uncertain.

Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases.

BACKGROUND: The use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection. METHODS: Two AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug-event combinations for three substances frequently recorded in both systems. RESULTS: The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37) in the JP and 3.3±3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected. CONCLUSION: The FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data.

Drug Utilization Reviews by Community Pharmacists in Japan: Identification of Potential Safety Concerns through the Brown Bag Program.

OBJECTIVES: Pharmacy-based drug utilization reviews were conducted through the Brown Bag program to understand drug-use patterns, identify potential safety concerns, and provide appropriate consultation for elderly individuals. METHODS: Community pharmacists in Hiroshima, Japan, participated in this review program from October to December 2009. Elderly individuals, 65 years or older, were recruited from community events or at pharmacies and were asked to bring all their prescription and nonprescription drugs including over-the-counter drugs and dietary supplements to the program. Pharmacists reviewed the medications and their usages and gave appropriate feedback if medications were used incorrectly, had potential interactions, or had safety concerns. The relationships among medication usage, participant responses, and potential safety concerns were analyzed by using logistic regression models. In addition, contraindications, duplicate medications, and potentially inappropriate medications were descriptively analyzed. RESULTS: Drug utilization reviews were conducted on 508 elderly participants at 177 community pharmacies. Of the 508 participants, 53% were 75 years old or older and 34% were men. Twenty-four percent of the elderly participants used prescription drugs only, and 73% used both prescription and nonprescription drugs. Pharmacists offered feedback to 250 participants (49%) concerning the risk of duplication/interaction, possible adverse drug reaction that can be averted, inappropriate/unnecessary medication, nonadherence, and overdose. Two cases of contraindicated drugs, 3 cases of duplicate medications, and 327 cases of potentially inappropriate medications were identified. CONCLUSIONS: The drug-use patterns among elderly individuals were identified. This medication review program conducted at community pharmacies was a useful approach to reduce concerns among users and prevent safety problems.

Serum elastase and antithrombin-3 levels after umbilical cord blood transplantation or bone marrow transplantation.

The severity of graft-versus-host disease (GVHD) was compared after cord blood transplantation (CBT) and bone marrow transplantation (BMT). The severity of GVHD was also analyzed in relation to serum elastase and antithrombin-3 (AT-3) levels. There was no significant difference in the average grade of acute GVHD between 49 BMT patients and 20 CBT patients (chi2-test). However, there was a lower incidence of patients without acute GVHD (grade 0) or patients with severe acute GVHD (grade 3 or 4) in CBT compared with BMT group. Linear regression analysis found no significant correlation between the serum elastase level and the grade of acute GVHD, between the serum AT-3 level and the grade of acute GVHD, or between the serum levels of elastase and AT-3 before conditioning and after engraftment. The AT-3 level after engraftment was significantly higher in the CBT group than in the BMT group and it did not fail along with the elevation of elastase in the CBT group (p < 0.01 by the Mann-Whitney U-test vs. the BMT group). In conclusion, the lower risk of severe acute GVHD in the CBT group may have been related to the smaller decrease of AT-3 after transplantation.

[A case of giant tumorous shadow by pulmonary tuberculosis].

A 63-year-old woman who had been treated for myelodysplastic syndrome had a high fever. Chest radiography and computed tomography revealed a giant tumorous shadow from the right mediastinum to the hilum. She was treated with antibiotics but with little effect. The culture of bronchial washing fluid and sputum revealed Mycobacterium tuberculosis infection. There were no malignant cells in the sputum or bronchial washing fluid. Tumor markers were within normal limits. She was treated with isoniazid, rifampicin, streptomycin and pyrazinamide. On the sixth day of treatment, high fever disappeared, and sputum culture for tuberculosis became negative after two months. The size of the mass decreased with clinical improvement. The final diagnosis was pulmonary tuberculosis with mediastinal lymphadenopathy. Since the patient was a compromised host, the giant mass was considered to be induced by atypical response to mycobacterial infection.

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation.

To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.

Heparin cofactor II as a predictor of thrombotic microangiopathy after bone marrow transplantation.

The pathogenesis of thrombotic microangiopathy (TMA) after allogeneic bone marrow transplantation (BMT) remains unclear since ADAMTS13, which is implicated in primary thrombotic thrombocytopenic purpura (TTP), has been shown to have no role in this condition. We investigated whether the onset of TMA after BMT could be predicted by measuring heparin-cofactor II (HC II), a marker for thrombosis of unknown etiology. In 30 consecutive BMT patients, the serum HC II level was measured before conditioning and one week after recovery from leukopenia. Four of the 30 patients developed TMA, and 26 did not. Before conditioning, the mean serum HC II level was 1.748 +/- 0.37 U/mL in the TMA group and 0.889 +/- 0.25 U/mL, in the non-TMA group, being higher in the former group (p < 0.01, t-test). After recovery from leukopenia, the two groups showed no significant difference of serum HC II. The HC II level at the onset of TMA was above the upper limit of normal in only one out of four patients. These results suggest that vascular endothelial damage due to chemotherapy before BMT increases the risk of TMA, and that HC II is useful for predicting the occurrence of TMA after BMT.

Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone marrow.

Reduced-intensity (RI) conditioning followed by cord blood transplantation (CBT) is a new treatment modality, but failure to engraft is a major concern. We describe 12 patients with advanced hematologic malignancies who underwent RI conditioning and CBT with a conditioning regimen consisting of 200 mg/m(2) fludarabine (Flu), 50 mg/kg cyclophosphamide (CY), and 3 Gy total body irradiation (TBI). Cyclosporin A and/or methotrexate were used for graft-versus-host disease prophylaxis. Cord blood grafts were not mismatched for more than 2 serologically defined HLA alleles but were later found by high-resolution DNA typing to be mismatched for 2 to 4 alleles in most cases. Short tandem repeat analysis of bone marrow cells at day 14 showed complete donor chimerism in 6 of the patients and mixed chimerism in 5, indicating rapid engraftment in the bone marrow, whereas the remaining patient experienced graft rejection. Neutrophil recovery was achieved at a median of day 17 (range, days 11-24) in 10 of the 11 patients with marrow chimerism at day 14. Of these 10 patients, however, transplantation-related mortality within 100 days occurred in 4 patients who showed failed platelet recovery and a lack of durable engraftment. Overall survival and disease-free survival rates were 41.7% and 33.3%, respectively. These results show that CB mismatched at 2 to 4 HLA alleles and transplanted with the Flu/CY/3 Gy TBI regimen is able to engraft in the bone marrow as early as day 14.

Prognosis value of atrial natriuretic peptide and brain natriuretic peptide for heart failure in patients undergoing allogeneic bone marrow transplantation.

It is essential to evaluate the organ function of the recipient before bone marrow transplantation (BMT). This study investigated the usefulness of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as indicators of cardiac function. Seventy-five consecutive patients undergoing allogeneic BMT were enrolled. All of them had an ejection fraction of 55% or more on echocardiography. Six of the 75 patients died of heart failure after transplantation and these 6 patients were compared with the other 69 patients to assess the prognostic value of the two natriuretic peptides. Both peptides remained normal from before conditioning until recovery from leukopenia in all 69 surviving patients. Among the 6 patients who died of heart failure, however, BNP was increased in all 6 patients and ANP was increased in five of them at an average of 43.6 +/- 16.7 days before the onset of heart failure. Monitoring of these peptides may not only be useful for assessment of cardiac function but also for predicting the occurrence of heart failure.

Serum elastase and antithrombin-3 in patients with acute graft-vs.-host disease after bone marrow transplantation.

The mechanism by which inflammatory cytokines are involved in acute graft-vs.-host disease (GVHD) after hematopoietic stem cell transplantation has only been studied recently. We focused on the changes of serum elastase and antithrombin-3 (AT-3) from before pre-treatment until the leukocyte recovery period after transplantation. We examined the correlation between these two parameters and the grade of acute GVHD, as well as the mechanism of onset. We measured the serum elastase and AT-3 levels before pre-treatment and during the leukocyte recovery period in 49 consecutive patients receiving bone marrow transplantation. The severity of acute GVHD was divided into five grades (0-4). No significant differences of pre-transplantation elastase levels were observed among the GVHD grades, but the elastase level during the leukocyte recovery period showed a significant correlation with the grade of GVHD (p < 0.01). A significant inverse correlation was also observed (p < 0.05) between the pre-transplantation level of AT-3 and the grade of GVHD, as well as a significant correlation at the time of leukocyte recovery (p < 0.0001). Furthermore, a significant correlation (p < 0.0001) was observed between the elastase and AT-3 levels during the leukocyte recovery period. These results suggest that elastase levels during the leukocyte recovery period are related to the grade of acute GVHD and the mechanism appears to include vascular endothelial injury mediated via AT-3.

Heparin-induced thrombocytopenia antibody and the pathogenesis of thrombotic microangiopathy after stem cell transplantation.

Thrombotic microangiopathy (TMA) that occurs after stem cell transplantation (SCT) is generally regarded as being different from thrombotic thrombocytopenic purpura (TTP), because it is reportedly not associated with deficiency of von Willebrand factor-cleaving protease, whereas this enzyme is deficient in TTP. However, better understanding of the pathogenesis of this condition is still required. Accordingly, we investigated the relationship between TMA occurring after SCT and heparin-induced thrombocytopenia (HIT), a condition related to low-dosed heparin therapy that features thrombocytopenia and generalized thrombotic disorders. Thirty-nine consecutive patients who underwent bone marrow transplantation were divided into a TMA group and a non-microangiopathy group (10 and 29 patients, respectively). Before SCT, the serum platelet factor 4 (PF4) levels of the TMA and non-microangiopathy groups were 0.123 +/- 0.023 and 0.132 +/- 0.025, respectively (p = NS). One week after recovery of the white blood cell count following transplantation, the TMA group (0.2902 +/- 0.0678) had a significantly higher PF4 level than the non-microangiopathy group (0.1548 +/- 0.0312) (p < 0.001, t-test). Thus, PF4 increased after engraftment of the transplanted stem cells in the patients who developed TMA. In patients who developed TMA, there was a significant correlation between the PF4 level and the grade of angiopathy according to the Zeigler grading system (p < 0.01 by linear regression analysis). These results suggest that a HIT antibody produced by donor cells may be involved in the development of TMA after SCT.