Prediction of Milk Transfer of Drugs Using Machine Learning Methods / 医薬品情報学

Objective: Currently, limited information is available on the milk transfer properties of drugs when consumed by lactating women. Therefore, we aim to construct a prediction model of milk transfer of drugs using machine learning methods.Methods: We obtained data from Hale’s Medications & Mothers’ Milk (MMM) and SciFinder®, and then constructed the datasets. The physicochemical and pharmacokinetic data were used as feature variables with M/P ratio ≥ 1 and M/P ratio < 1 as the objective variables, classified into two groups as the classification of milk transferability. In this study, analyses were conducted using machine learning methods: logistic regression, linear support vector machine (linear SVM), kernel method support vector machine (kernel SVM), random forest, and k-nearest neighbor classification. The results were compared to those obtained with the linear regression equation of Yamauchi et al. from a previous study. The analysis was performed using scikit-learn (version 0.24.2) with python (version 3.8.10).Results: Model construction and validation were performed on the training data comprising 159 drugs. The results revealed that the random forest had the highest accuracy, area under the receiver operating characteristic curve (AUC), and F value. Additionally, the results with test data A and B (n = 36, 31), which were not used for training, showed that both F value and accuracy for the random forest and the kernel method SVM exceeded those with the linear regression equation of Yamauchi et al. Conclusion: We were able to construct a predictive model of milk transferability with relatively high performance using a machine learning method capable of nonlinear separation. The predictive model in this study can be applied to drugs with unknown M/P ratios for providing a new source of information on milk transfer.

Japanese Medical Academic Organizations Surveyed on the Current Situation of Medical Information Providedto the Public on the Internet / 医薬品情報学

Objective: The internet isflooded with drug information; however, some of it isinappropriate and thisinadequate information could expose the public to health hazards. Therefore, we conducted research on the idea of transmitting drug information to the public via the internet and the current state of the information currently provided by each academic society relevant to the field of Medical Informatics.Methods: A questionnaire was mailed to the website managers for the website of 129 specialist medical societies, all members of the Japanese Association of Medical Sciences. We conducted our research between October to November 2018. We investigated each website administrator’s opinion about offering drug information for consumers via the internet and what information each academic society is currently providing.Results: The effective response rate was 43.4% (56/129 groups). Most respondents thought that drug information overflowed in the current Internet society. Moreover, more than half of the respondents thought that the quality of drug information transmitted to the public wasinadequate. Currently, 30 of the academic groupssurveyed are providing information to the public. When providing information, they did not refer to the “Drug Guide for Patients” much. More than 80% of respondents said they would cooperate with linking to the information provided to the public. However, each academic society felt there would be many problems with doing so such as the need for a system to check the contents of the information provided and a system to perform maintenance.Conclusion: The results showed that the website administrators recognized that there is a need to improve the quality of and system for providing drug information to the public. We believe that an integrated information system can be constructed by aggregating the drug information held by each academic society. However, this cannot be realized without first solving many problems.

Creating a Checklist and a Survey on Research That Used the Japanese Adverse Drug Event Report Database / 医薬品情報学

Objective: The purpose of this study was to create a checklist that summarizes checkpoints that should be noted when using the Japanese Adverse Drug Event Report database (JADER). After we created the checklist, we then used it to survey published academic papers that used JADER.Method: First, we created a draft checklist for research that uses JADER by citing the report of CIOMS working group VIII “Practical Aspects of Signal Detection in Pharmacovigilance”. Then, we conducted a pilot test and revised the draft checklist. Finally, the checklist was completed after the review by a pharmacoepidemiology expert. The checklist was applied to published academic papers that used JADER, and the fulfill rate of each checkpoints was calculated.Results: A “checklist of important points to be noted during research that uses the data mining method in JADER (mainly signal detection by disproportionality analysis)” was created. We also revealed problems with published academic papers that used JADER. For example, some researchers were thought to be inappropriately using JADER as a source of their research while others used an inappropriate version of MedDRA.Conclusion: The checklist created in this study summarizes key points that could be noted in research that uses JADER and is thought to contribute to an improvement in quality of research that uses JADER. Additionally, in our investigation of published academic papers that used JADER, we found the possibility that both the role of signal detection and the impact on analysis of JADER using the updated MedDRA version are not well understood.

Relationship between Drug-Induced Photosensitivity and Ultraviolet-Visible Absorption Spectrum and Structure / 医薬品情報学

Objective: To clarify the background difference between drug-induced photosensitivity and ultraviolet-visible absorption spectrum or structure and to construct useful information for prevention and prediction of drug-induced photosensitivity. Methods: We investigated whether, for 457 drugs for which the ultraviolet-visible absorption spectrum is listed in the Japanese Pharmacopoeia, there were absorption maxima in the UVA (320 nm or more and less than 400 nm), UVB (280 nm or more and less than 320 nm), or UVA and UVB (280 nm or more and less than 400 nm). Structure was investigated for the existence of “conjugated”, carbonyl, sulfone, nitro and fluorine. The case drug group was taken to be those drugs for which photosensitivity was listed as a side effect on the medical drug package insert. Using statistical software, SPSS statistics ® 24 (IBM), we performed univariate logistic regression analysis, and multivariate logistic regression analysis with a stepwise increment method (likelihood ratio) combining items with p＜0.2, and calculated the odds ratio (hereinafter: aOR). The significance level was taken as 0.05. Results: There were 85 drugs in the case drug group, and 372 drugs in the control drug group. As a result of multiple logistic regression analysis, in Model 1, we placed sulfone (aOR: 4.55, 95% C.I.: 2.22-9.35), fluorine (aOR: 3.66, 95% C.I.: 1.82-7.39) and nitro (aOR: 4.46, 95 % C.I.: 1.73-11.48) in this order. In Model 2, we placed sulfone (aOR: 4, 40, 95% C.I.: 2.12-9.15), fluorine (aOR: 3.81, 95% C.I.: 1.87-7.76), UVA (aOR: 2.40, 95% C.I.: 1.37-4.18) and nitro (aOR: 3.61, 95% C.I.: 1.39-9.40) in this order. Conclusion: When a drug is developed, its ultraviolet-visible absorption spectra and structure become clear, and from this information,measures can be taken which bear the potential risk of photosensitivity in mind.

Exploring the Factors That Influence Pain Relief and Bone-marrow Suppression When Strontium Chloride Is Administrated

Aim: The usefulness and safety of strontium chloride (89Sr), a radiopharmaceutical agent for painful bone metastasis, varies from patient to patient, but the reasons for why the usefulness and safety vary have not been elucidated. The purpose of this study is to explore the background factors of patients who experienced pain relief or bone-marrow suppression after 89Sr was administrated. Methods: In the cases of pain relief, we divided the results from a numeric rating scale (NRS) before and after 89Sr administration into effective and ineffective groups as outcomes. In the cases of bone-marrow suppression, we analyzed neutrophil cells, blood platelets, and hemoglobin levels, respectively, before and after 89Sr administration as outcomes. Then, we performed statistical analyses on both case groups. Results: The results showed that the background factors associated with pain relief were weight, the 89Sr dosage amount, NRS, eGFR, SCr, and Ca levels before 89Sr administration and the area of bone metastasis (number of sites reached). We found that background factors associated with bone-marrow suppression have a moderate significant correlation with hemoglobin, NRS, and SCr levels before 89Sr administration after investigating factors which influence neutropenia. In the case of thrombocytopenia, there was a moderate significant correlation with platelet counts before 89Sr administration. In the case of hypochromia, there was a moderate significant correlation with hemoglobin levels before 89Sr administration. Discussion: Our study could elucidate patient background factors associated with pain relief and bone-marrow suppression after 89Sr administration.

Association between the Current Situation of Adverse Reactions Caused by Non-prescription Drug Abuse and Patient Backgrounds / 医薬品情報学

Objective:In this study,we explored adverse reactions and patient background and performed a case/non-case study on a database of adverse reaction case reports in order aid the prevention of non-prescription drug abuse.Study Design:We conducted a case/non-case study on a database of adverse reaction case reports.Methods:We studied case reports of adverse reactions and addiction in Japan and extracted adverse reaction cases associated with taking antipyretic analgesics,antitussive drugs,antitussive expectorant drugs,hypnotic and sedative drugs,anti-anxiety drugs,and purgative drugs. We divided the extracted cases into an abuse case group (adverse reactions associated with non-prescription drug abuse,and divided its intended purpose or the purpose of abuse at the initial dose)and non-case group(other adverse reactions). We performed univariate logistic regression analysis on each item of investigation in the abuse case group and non-case group and calculated the odds ratio,p-value,and 95%confidence interval.Results:There were many abuse case reports of women 20-40 years old in the antipyretic analgesics abuse case group and many of them had liver/biliary lesions and chronic urological impairment. The most common reason reported for taking the initial dose of each drug was for its intended purpose.Discussion:It is important for pharmacists at community pharmacies and drugstores to be able to recognize the characteristics of patients who might be at risk of abuse and the adverse reactions and patient backgrounds elucidated in this study could be helpful in identifying them.

Characteristics of Adverse Events in Pregnant Women / 医薬品情報学

<b>Purpose: </b>The purpose of this study is to elucidate the characteristics of adverse events in pregnant women, the offending drugs, and patient backgrounds from reports of adverse events.  We performed a case series study.<br><b>Methods: </b>We used CARPIS, a database of adverse events and toxication reported in Japan spanning from 1987 to 2014 and created by the Drug Information Center, Meijo University.  We extracted cases of adverse events in pregnant women, their fetuses, and newborns and investigated the age, primary disease, and history of allergies of the women and the intended use of/offending drugs, therapeutic category, and names for adverse events.<br><b>Result: </b>We collected 434 cases of adverse events in pregnant women, and 251 pediatric cases with adverse events.  The most frequent offending drug in both groups was ritodrine hydrochloride.  The most frequent adverse event in pregnant women was pulmonary oedema due to the administration of ritodrine hydrochloride.  The most frequently reported adverse events in pediatric cases were transient hypothyroidism and withdrawal symptoms in newborns and birth abnormalities in fetuses and newborns, all of which were caused by drugs given for the underlying diseases of their mothers.<br><b>Discussion: </b>We elucidated serious adverse events in pregnant women caused by the administration of ritodrine hydrochloride.  Frequent factors for adverse events were the onset of physiological factors in pregnant women and complicated factors of the mechanism of action of ritodrine hydrochloride.  We need to monitor both mothers and fetuses during the drug administration.  It is suggested that adverse events in pediatric cases are associated with drugs given for underlying diseases in mothers.  Thus, it is necessary to give appropriate information and communicate the risks of taking these drugs before pregnancy.  We believe the results could be helpful in the early detection of adverse events in the future.

The Influence of Drugs Taken during Breastfeeding on Infants: Report and Analysis of Adverse Events Using FAERS / 医薬品情報学

<b>Introduction</b>: The purpose of this study is to elucidate the influence of drugs on infants and to provide information about safe drug treatments during breastfeeding using the FDA’s Adverse Event Reporting System (FAERS).<br><b>Study Design</b>: Case series based on FAERS data.<br><b>Methods: </b>We used the cleaned FAERS data in JAPIC AERS, extracted cases of adverse events from the category “neonatal exposure through breastfeeding (2000189)” in Standardized MedDRA Queries, and collected “the cases of breast-feeding infants” by system organ class, the type of adverse event, therapeutic category of first suspected drugs, and the generic name of the drugs.  We aggregated the data of the most reported cases of suspected drugs from first to fifth by the name of the adverse event.  Additionally, we investigated the properties and disposition of each suspected drug and verified the transitivity of breast milk as well.<br><b>Results: </b>Only 551 cases of breast-feeding infants (0.01%) were extracted from the data of JAPIC AERS.  The aggregated data of adverse events in terms of system organ class showed high numbers of gastrointestinal disease (such as diarrhea and vomiting) and impairment of the nervous system (such as drowsiness), and drugs which acted on the nervous system were the most suspected drugs.  There were 26 cases of adverse events associated with lamotrigine, which was the most frequently reported.<br><b>Discussion: </b>We could observe the characteristics of adverse events and suspected drugs that were shown as the influence of drugs taken during breastfeeding which were exposed to infants.  Our study showed 2 conclusions: 1) the drugs that have had adverse events frequently reported have the characteristic of facilitating the drug’s migration into breast milk, and 2) the most frequently reported cases were those in which nursing mothers or medical experts could recognize the correlation between breast milk and the adverse event(s) immediately after breast milk was given to the infant.

Analysis of Erroneously Dispensed Named Generic Drugs / 医薬品情報学

<b>Objective: </b>The purpose of this study is to investigate incidents of erroneously dispensed drugs on the assumption that the incidents stem from the similar names of the drugs.  The investigation was also conducted to prevent such dispensing incidents in the future, i.e. to search for factors that can prevent future incidents, and finally to propose a prevention plan which takes each of these factors into account.<br><b>Methods: </b>We extracted incident cases related to generic drugs reported by pharmacies in Japan and from those cases examined those that were categorized as cases of erroneously dispensed medicine.  We used this data to categorize the difference in relationship between the drugs which were supposed to be prescribed and those which were erroneously dispensed, and to analyze the association between the “Flowchart for Avoiding Confusion Errors between Similarly Named Drugs” and the name similarity index based on this flowchart.<br><b>Results: </b>The types of incident cases due to name similarities of generic drugs were categorized into specification mistakes and brand mistakes.  The edit of the name similarity index were especially important factors for dispensing incidents between generic drugs.<br><b>Conclusion: </b>This study focusing on generic drugs revealed the factors that result in dispensing incidents due to name similarity.  Further empirical studies investigating the usefulness of interventions that alter the name similarity index is required.

The Actual Status of the Provision of Drug Information in Clinical Clerkships and Development of an Online Self-Learning Tool / 医薬品情報学

<b>Objective: </b>The purpose of this study was to identify existing problems related to the provision of drug information in clinical clerkships.  In addition, we aimed to develop a self-learning tool based on our findings.<br><b>Methods: </b>We conducted a questionnaire survey on students who had completed a clinical clerkship between December 2012 and February 2013 concerning the actual status of the provision of drug information.  Based on responses received from 86 students, we then developed an online self-learning tool.  This online tool was subsequently evaluated by the same 86 students.<br><b>Results: </b>More than 20% of students surveyed reported never having made inquiries at their clerkship site; therefore, we developed an online self-learning tool for inquiry services in which students were able to learn step-by-step how to analyze, search, evaluate and provide inquiries.  A total of 89% of the students who tried this tool reported being satisfied with its use.<br><b>Conclusion: </b>Our results suggest that students in clinical clerkships lack sufficient experience regarding drug information-related inquiries.  Therefore, our online self-learning tool should be helpful in promoting understanding of how to manage such inquiries for students in clinical clerkships.

Development and Evaluation of a Self-Learning Tool for Drug Information / 医薬品情報学

<b>Objective: </b>In pharmacy school, most faculty members use generic names when discussing medicine; however, in clinical clerkships, most staff members use brand names. This sometimes leads to poor communication and understanding between the students and medical staff.  The purpose of this study was to clarify the need for a tool to improve communication and understanding in relation to drug information.  Based on the findings of this survey, our secondary aim was to develop and subsequently evaluate such a tool.<br><b>Methods: </b>To clarify the need for a self-learning tool, we conducted a questionnaire survey on 58 faculty members who teach courses on drug informatics.  Based on their responses, we then developed a self-learning tool that was subsequently evaluated by a total of 78 undergraduate students.<br><b>Results: </b>Most of the faculty agreed concerning the necessity of a self-learning tool for drug information, particularly in regard to the establishment of a more user-friendly system and reduced user fees for students.  The faculty also believed that students should be able to associate the generic drug name with various kinds of information, including its safety, efficacy, and brand name.  All students agreed that the tool was helpful, very easy to use, and could be learned during their commute to school.<br><b>Conclusion: </b>Our results suggest that most faculty members support the idea of having a tool capable of promoting a better understanding and grasp of drug information.  Therefore, our self-learning tool should be helpful in promoting increased knowledge concerning drug information for students in clinical clerkships.

Risk Factors and Subjective Symptoms of Drug-Induced Thrombocytopenia / 医薬品情報学

<b>Objective: </b>The present study investigated risk factors and subjective symptoms associated with drug-induced thrombocytopenia.<br><b>Methods: </b>We selected 361 patients with drug-induced thrombocytopenia from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 65,000 case reports of adverse drug reactions and assigned these patients to a case group.  We also randomly selected 794 cases of adverse drug reactions not associated with thrombocytopenia as a control group.<br><b>Results: </b>Data were compared between the case and control groups, and results were analyzed using logistic regression analysis.  We identified type of infection (non-viral) and renal failure as risk factors for drug-induced thrombocytopenia.  In addition, administration of carbamazepine, methotrexate, interferon alpha, ticlopidine or valproic acid significantly increased the risk of drug-induced thrombocytopenia.  Significant associations were also found between drug-induced thrombocytopenia and purpura, fever, and mucosal bleeding.<br><b>Conclusion: </b>These findings provide helpful information for early detection and prevention of thrombocytopenia as a serious adverse drug reaction.

Classification and Evaluation of Medical Terms in Briefing Papers Given to Patients about Adverse Drug Reactions / 医薬品情報学

<b>Objective: </b>Nowadays, patient-centered medical care is essential.  It is very important to use layman’s terms that patients can understand. However, most medical staff tend to use difficult medical terms.  The purpose of this study was to investigate the amount of difficult medical terms in briefing papers given to patients.<br><b>Methods: </b>We conducted a questionnaire survey on September 21, 2012 of 246 non-medical professionals in order to identify difficult medical terms used in a manual for handling disorders due to adverse drug reactions.<br><b>Result: </b>It was found that there were 387 terms of those in the manual (<i>n</i>=980) that non-medical professionals had never seen or heard before (39.5%).  There were 128 terms for which they could not correctly replace Japanese kana (phonetic) characters with kanji (pictorial) characters (13.1%).<br><b>Conclusion: </b>The results indicate that the manual has many terms that are difficult for non-medical professionals to understand.  This may hinder patients’ comprehension.  These difficult medical terms need to be replaced with layman’s terms.

The Current Status of Health Food- or Supplement-Related Adverse Health Effects / 医薬品情報学

<b>Objective: </b>Recently, use of health foods and supplements, as well as the amount of information available about them, has been steadily increasing.  Therefore, a noticeable increase in adverse drug reactions caused by health foods and supplements has also been seen.  The purpose of this study was to clarify the current status and backgrounds of patients with health food- or supplement-related adverse health effects.<br><b>Methods: </b>We selected the cases of health food- or supplement-related adverse health effects from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database, which contains over 57,000 case reports of adverse drug reactions.  We investigated the background, suspected products and adverse events in each case and conducted univariate logistic regression analysis to determine significance.<br><b>Results: </b>We obtained a total of 327 cases consisting of 103 causative products.  Women comprised 66% of study subjects and had a significant association with dietary supplements.  Patients with a history of liver disease had a significant association with liver damage caused by “Ukon,” a drink made from turmeric root and sold as an anti-hangover remedy in Japan.<br><b>Conclusion: </b>The causative products had several unique features.  This information should be utilized to prevent health food- and supplement-related adverse health effects in the future.

Analysis of Actual Pharmacist Research Activity at Japan Pharmaceutical Association (JPA) Congress of Pharmacy and Pharmaceutical Science / 医薬品情報学

<b>Objective: </b>The purposes of this study were to verify the actual state and to identify the problems associated with research activities by pharmacists.<br><b>Methods: </b>The abstracts presented at the 42nd and the 37th Japan Pharmaceutical Association (JPA) Congress of Pharmacy and Pharmaceutical Science were investigated.  They were categorized into six research types: “Outcome research”; “Intervention research”; “Observational study”; “Status report”; “Case report”; and “Other”.  They were then ranked according to evidence level, with “Outcome research” ranked the highest.  In addition, “Outcome research”, “Intervention research” and “Observational studies” were checked for whether they had structured abstracts, and form scores were awarded.<br><b>Results: </b>We found that only 0.8% of abstracts were “Outcome research”.  but the level was higher at the 42nd Congress than the 37th (<i>p</i>=0.03).  Structured abstracts were also more common at the 42nd Congress than at the 37th (<i>p</i><0.01).  However, the form scores were not significantly different between the 42nd and 37th Congresses.<br><b>Conclusions: </b>Our findings suggest that pharmacist research activities are improving, but that there is still room for further development.  The referee system and the guidelines for research design are useful methods to encourage more activity.  The target of this study was community pharmacy, and further studies are necessary for hospital pharmacy.

Development of Code System for Generic Drug Information / 医薬品情報学

<b>Objective: </b>In recent years, the Ministry of Health, Labor and Welfare has actively promoted the use of generic drugs.  However, implementation of this policy has not progressed smoothly, as information on generic drugs is poorly organized.  As a result, it is difficult for pharmacists to select the appropriate generic drugs.  Therefore, we attempted to develop a code system to organize information on generic drugs.<br><b>Methods: </b>We analyzed the guidelines used for the approval of generic drugs.  We then identified the important aspects for comparison of generic drugs and developed a code system.  Next, we tested this code system using temocapril hydrochloride tablets, which is a generic drug.<br><b>Results: </b>We were able to develop a code system for selection of generic drugs.  Furthermore, we confirmed the utility of this code system for selecting generic drugs in the case of temocapril hydrochloride tablets.<br><b>Conclusion: </b>We believe that this code system with be useful for pharmacists, but further development is necessary for other generic drugs.

Pharmacists’ Knowledge and Opinions Regarding Generic Drugs: A Survey / 医薬品情報学

<b>Objective: </b>In recent years, the Ministry of Health, Labor and Welfare has actively promoted the use of generic drugs.  However, implementation of this policy has not progressed smoothly, and generic drug companies suggest that this is because medical staff and patients are not properly informed.  We examined pharmacists’ knowledge and opinions concerning generic drugs.<br><b>Methods: </b>We conducteda questionnaire survey to determine community pharmacists’ opinions and understanding with regard to generic drugs.<br><b>Results: </b>About 90% of pharmacists were apprehensive about the use of generic drugs.  All pharmacists scored low on factual questions, answering an average of 40 % correctly.  The question about the bioequivalence evaluation method in particular was poorly answered.  However, pharmacists’ anxiety about using generic drugs was not related to their knowledge.<br><b>Conclusion: </b>Our findings suggest that community pharmacists lack sufficient knowledge about generic drugs.  It is therefore necessary to educate them on the use of generic drugs.  Also, in order to allay pharmacists’ fears, it is important to improve the comprehensiveness of information concerning generic drugs.

Evaluation of Adverse Drug Reaction Reports in Early Post-marketing Vigilance Phase / 医薬品情報学

<b>Objective: </b>The purpose of this study is to identify the problems in the adverse drug report (ADR) system in early post-marketing vigilance phase (EPM phase) in Japan.<br><b>Methods: </b>The incidence of all ADRs and the ratio of serious ADRs were compared between the new drug application phase (ND phase) and the EPM phase.  The target medicines were Moxifloxacin (Avelox®tablets, 400mg), Gatifloxacin (Gatiflo®tablets, 100mg) and Prulifloxacin (Sword®tablets, 100mg).<br><b>Results: </b>The average incidence of all ADRs in the ND phase was 100-fold greater than that in the EPM phase.  There were also 2-fold differences in the ratio of serious ADRs of individual medicines.<br><b>Conclusion: </b>There are several problems with the ADR system in the EPM phase in Japan.  It is currently possible that the implementation of EPM will vary between in individual medicines and companies.  This suggests that the present data cannot be applied universally.  Thus, there is an urgent need to standardize the implementation of EPM.