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Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population‐specific factors (e.g., more frequent use of off‐label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life‐cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post‐marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record‐linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life‐cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs. [ABSTRACT FROM AUTHOR]

Objective: Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time. Methods: A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Summary: Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting. Conclusion: Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug‐induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work‐up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) represent a significant threat to patients' safety in dentistry, necessitating proactive measures for prevention and treatment. However, identifying ADRs of dental and oral interest can be challenging, and underreporting remains a persistent issue globally. This paper illustrates a smart system to help Italian healthcare personnel, including dentists, in identifying and reporting dental and oral ADRs. This educational program is within a larger multi-regional project financed by the Italian Agency of Drugs (AIFA). The proposed system comprises a free online questionnaire on ADRs of dental interest (including specific items about awareness and attitudes), and after the free consultation of an atlas of clinical images of dental and oral ADRs linked with a digital synopsis of drugs potentially related to ADRs. This section of the project was presented in April 2023 at the 30th National Congress of the Italian College of University Professors of Dental Disciplines, and the system appears to hold tremendous potential to improve the knowledge of healthcare professionals on oral and dental ADRs. [ABSTRACT FROM AUTHOR]

The article discusses the rapid evolution of artificial intelligence (AI) and related innovative technologies in clinical pharmacy practice and education. It highlights the potential benefits of AI in enhancing patient care, optimizing therapeutic outcomes, and advancing research. The use of machine learning in clinical decision support systems, drug discovery, and medication adherence is explored. The article also mentions the emergence of large language models (LLM) and their potential applications in clinical pharmacy. Ethical considerations, such as data privacy and algorithmic bias, are emphasized. The International Journal of Clinical Pharmacy is calling for submissions on AI-based solutions and other innovative technologies in clinical pharmacy practice and research to promote excellence and better equip pharmacy practitioners. [Extracted from the article]

Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs). This article summarises a set of strategies designed to monitor and manage lorlatinib-related AEs that were agreed upon by a multidisciplinary panel of specialists in a meeting held in July 2020. Among the recommendations hereby described, special emphasis was placed on communication: prescribing physicians should inform patients and their families/caregivers about the likelihood and nature of lorlatinib AEs, encouraging them to report any symptoms, while at the same time reassuring them that most events are manageable and resolve spontaneously and have little to no interference with cancer treatment. Importantly, all patients should undergo a set of baseline assessments, including biochemical analysis, evaluation of cardiovascular risk, electrocardiogram (ECG), neurological evaluation and contrast-enhanced magnetic resonance imaging of the brain, which should be repeated regularly during lorlatinib treatment. Supportive medications to treat or relieve lorlatinib AEs were also discussed, as were the conditions requiring specialist consultations and/or adjustments in lorlatinib therapy. The overall goal of this article is to serve as a practical guide for oncologists to systematically and effectively approach lorlatinib AEs. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID‐19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off‐label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off‐label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease. [ABSTRACT FROM AUTHOR]

This document is an editorial introducing a special issue on drug toxicity. It highlights the toxic effects of various drugs, including ethanol, hydrocodone, heroin, pentylenetetrazol, metronidazole, paracetamol, paclitaxel, and tilmicosin. The editorial also discusses the protective effects of certain agents and plant extracts against drug-induced toxicity. The research articles included in the special issue cover topics such as the attenuation of alcohol dependence, the upregulation of glutamate transporters to mitigate the effects of chronic drug exposure, the use of natural polyphenols to reduce heroin-seeking behaviors, and the teratogenicity and hepatotoxicity risks associated with certain medications during pregnancy. The issue also includes a review article on the poisoning effects of Xylazine in humans. Overall, the special issue provides valuable insights into the pharmacological and toxicological nature of drugs and their potential impacts on the body. [Extracted from the article]

Introduction: The use of opioids such as morphine has anti-pain effects along with some side effects on body organs. Opioids such as morphine can be transferred from mother to child through the placenta and or breastfeeding. This study aimed to assess the effect of morphine on mineral content and histological changes of incisor teeth of rats born to morphine-addicted mothers. Methods: In this experimental animal study, 24 pregnant rats were randomly divided into 6 groups of control, morphine, zinc, vitamin D, morphine plus zinc, and morphine plus vitamin D. After completion of the breastfeeding period, two babies were randomly selected among the newborns of each mother rat. Mineral content was analyzed using the Rontec device. The obtained data were analyzed by Newman-Keuls multiple comparisons test in Prism 5. Results: Results showed a significant reduction in fluorine content in the experimental groups compared with the control group (P<0.05). The magnesium content in the experimental groups was significantly higher than that in the control group (P<0.05). Microscopic assessment of the slides showed a significantly less enamel maturation in the experimental groups compared with the control group (P<0.05). Conclusion: Morphine use by mothers decreased the fluorine content of tooth structure and retarded the maturity of the enamel of infants. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell–mediated reactions classically occur more than 6 hours after drug administration and include life‐threatening conditions such as toxic epidermal necrolysis, Stevens‐Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA‐B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA‐compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim‐sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future. [ABSTRACT FROM AUTHOR]

The article focuses on the glucocorticoids being a risk factor causing osteoporosis in patients with immune thrombocytopenia (ITP) receiving steroids. It talks about the Good Practice Paper compiled by the British Society for Haematology (BSH) consisting of guideline for the prevention of glucocorticoid-induced osteoporosis (GIO) during the treatment of patients with ITP.

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Drug hypersensitivity reactions (DHR) constitute a major and common public health problem, particularly in children. One of the most severe manifestations of DHR is anaphylaxis, which might be associated with a life‐threatening risk. During those past decades, anaphylaxis has received particularly a lot of attention and international consensus guidelines have been recently published. Whilst drug‐induced anaphylaxis is more commonly reported in adulthood, less is known about the role of drugs in pediatric anaphylaxis. Betalactam antibiotics and non‐steroidal anti‐inflammatory drugs are the most commonly involved drugs, probably related to high prescription rates. Diagnosis relies on the recognition of symptoms pattern and is based on complete allergic workup, particularly including skin tests and/or specific IgE. However, the real diagnostic value of those tests to diagnose immediate reactions in children remains not well defined for a significant number of the drugs. Generally, a drug provocation test is discussed to confirm or exclude an immediate‐onset drug‐induced hypersensitivity. Although avoidance of the incriminated drug (and related drug) is the rule, rapid desensitization is useful in selected subgroups of patients. There is a need for large, multicentric studies, to evaluate the real diagnostic value of the currently available skin tests. Moreover there is also a need to develop new diagnostic tests in the future to improve the management of these children. [ABSTRACT FROM AUTHOR]

Aims This paper discusses the application of transformational leadership to the teaching and learning of safe medication management. Background The prevalence of adverse drug events ( ADEs) and medication-related hospitalisations (one hundred thousand each year in the USA) are of concern. Evaluation This discussion is based on a narrative literature review and scrutiny of international nursing research to synthesise pedagogical strategies for the application of transformational leadership to teaching medication safety. Key issues The four elements relating transformational leadership to medication safety education are: 'Idealised influence' or role modelling, both actual and exemplary, 'Inspirational motivation' providing students with commitment to medication safety, 'Intellectual stimulation' encouraging students to value improvement and change, and 'Individualised consideration' of individual students' educational goals, practice development and patient outcomes. The model lends itself to experiential learning and a case-study approach to teaching, offering an opportunity to reduce nursing's theory-practice gap. Conclusion Transformational leadership for medication safety education is characterised by a focus on the role of nurse educators and mentors in the development of students' abilities, creation of a supportive culture, and enhancement of students' creativity, motivation and ethical behaviour. This will prepare nursing graduates with the competencies necessary to be diligent about medication safety and the prevention of errors. Implications for nursing management Teaching medication safety through transformational leadership requires the close collaboration of educators, managers and policy makers. Investigation of strategies to reduced medication errors and consequent patient harm should include exploration of the application of transformational leadership to education and its impact on the number and severity of medication errors. [ABSTRACT FROM AUTHOR]

To examine how countries differ in attitudes to adverse drug reactions by examining published scientific papers.We searched Ovid EMBASE for publications indexed by the category′therapeutic agents′, and the subcategory′adverse effects′, by country for 43 countries.We counted 1 810 202 papers world-wide regarding therapeutic agents during 14 years, of which 195 154 (10.8%) were included in the adverse effects subcategory. There were substantial differences between countries, not explained by population, economic variation, overall publication rate on therapeutic agents, or the presence of large indigenous pharmaceutical companies.Many local cultural factors influence the ratio of papers on adverse reactions to all drug effects, so it may be difficult to improve their recognition and reporting by international efforts. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbsinduced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility; however, whether women with PCOS and spontaneous or drug-induced ovulatory cycles have the same reproductive potential as non-PCOS controls is a matter of debate. In the present opinion paper, the author takes the opportunity to summarize the collective evidence supporting the hypothesis of reduced fertility potential in women with PCOS, regardless of ovulatory status, and speculate that reduced reproductive potential may be caused by altered oocytes, embryo and endometrial competence, and infertility-related co-morbidities as well as an increased risk of pregnancy complications. [ABSTRACT FROM AUTHOR]

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are musclerelated. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term "statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented. [ABSTRACT FROM AUTHOR]

Monitoring for drug-induced liver injury (DILI) via serial transaminase measurements in patients on potentially hepatotoxic medications (e.g., for HIV and tuberculosis) is routine in resource-rich nations, but often unavailable in resource-limited settings. Towards enabling universal access to affordable point-of-care (POC) screening for DILI, we have performed the first field evaluation of a paper-based, microfluidic fingerstick test for rapid, semi-quantitative, visual measurement of blood alanine aminotransferase (ALT). Our objectives were to assess operational feasibility, inter-operator variability, lot variability, device failure rate, and accuracy, to inform device modification for further field testing. The paper-based ALT test was performed at POC on fingerstick samples from 600 outpatients receiving HIV treatment in Vietnam. Results, read independently by two clinic nurses, were compared with gold-standard automated (Roche Cobas) results from venipuncture samples obtained in parallel. Two device lots were used sequentially. We demonstrated high inter-operator agreement, with 96.3% (95% C.I., 94.3–97.7%) agreement in placing visual results into clinically-defined “bins” (<3x, 3–5x, and >5x upper limit of normal), >90% agreement in validity determination, and intraclass correlation coefficient of 0.89 (95% C.I., 0.87–0.91). Lot variability was observed in % invalids due to hemolysis (21.1% for Lot 1, 1.6% for Lot 2) and correlated with lots of incorporated plasma separation membranes. Invalid rates <1% were observed for all other device controls. Overall bin placement accuracy for the two readers was 84% (84.3%/83.6%). Our findings of extremely high inter-operator agreement for visual reading–obtained in a target clinical environment, as performed by local practitioners–indicate that the device operation and reading process is feasible and reproducible. Bin placement accuracy and lot-to-lot variability data identified specific targets for device optimization and material quality control. This is the first field study performed with a patterned paper-based microfluidic device and opens the door to development of similar assays for other important analytes. [ABSTRACT FROM AUTHOR]

Background: Atypical antipsychotic medications have often been used in the treatment of behavioral and psychological symptoms of dementia (BPSD). Recently, the US Food and Drug Administration (FDA) issued new safety information concerning atypical antipsychotic drugs, indicating that their use may increase the risk of cardiovascular adverse events among elderly adults with BPSD. Based on this information, the Japanese Ministry of Health, Labor and Welfare issued a similar warning against the use of atypical antipsychotic drugs licensed in Japan. We then sought to determine whether or not the use of typical antipsychotics should be recommended to replace atypical antipsychotics. In this paper, we discuss the influence of these warnings on the withholding of use of risperidone exemplified in seven case histories. Methods: Seven inpatients who exhibited BPSD received risperidone monotherapy in our hospital. In response to the FDA notice, the atypical antipsychotics used to treat these patients were replaced with typical antipsychotic agents. Results: During the period of risperidone administration, all patients exhibited clinical improvement compared with their baseline results and showed no adverse events. Two of our seven patients developed psychotic exacerbation and exhibited extrapyramidal symptoms coinciding with the replacement of risperidone with conventional antipsychotics. Conclusion: To the best of our knowledge, this is the first clinical report on the influence of the FDA alert on the use of atypical antipsychotics for psychotic symptoms in older patients with dementia in Japan. In two of our seven BPSD cases, there was no benefit from taking conventional antipsychotics. Our results lead to the conclusion that the use of typical antipsychotics should not be recommended to replace atypical antipsychotics. Although close attention should be paid to the FDA alert, clinicians must take into consideration the balance of benefits and risks when evaluating the appropriate use of antipsychotics in older patients with dementia. [ABSTRACT FROM AUTHOR]

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies. [ABSTRACT FROM AUTHOR]

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment. [ABSTRACT FROM AUTHOR]

Background: PRO-CTCAE is a library of items that measure cancer treatment-related symptomatic adverse events (NCI Contracts: HHSN261201000043C and HHSN 261201000063C). The objective of this study is to examine the equivalence and acceptability of the three data collection modes (Web-enabled touchscreen tablet computer, Interactive voice response system [IVRS], and paper) available within the US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system.Methods: Participants (n = 112; median age 56.5; 24 % high school or less) receiving treatment for cancer at seven US sites completed 28 PRO-CTCAE items (scoring range 0-4) by three modes (order randomized) at a single study visit. Subjects completed one page (approx. 15 items) of the EORTC QLQ-C30 between each mode as a distractor. Item scores by mode were compared using intraclass correlation coefficients (ICC); differences in scores within the 3-mode crossover design were evaluated with mixed-effects models. Difficulties with each mode experienced by participants were also assessed.Results: 103 (92 %) completed questionnaires by all three modes. The median ICC comparing tablet vs IVRS was 0.78 (range 0.55-0.90); tablet vs paper: 0.81 (0.62-0.96); IVRS vs paper: 0.78 (0.60-0.91); 89 % of ICCs were ≥0.70. Item-level mean differences by mode were small (medians [ranges] for tablet vs. IVRS = -0.04 [-0.16-0.22]; tablet vs paper = -0.02 [-0.11-0.14]; IVRS vs paper = 0.02 [-0.07-0.19]), and 57/81 (70 %) items had bootstrapped 95 % CI around the effect sizes within +/-0.20. The median time to complete the questionnaire by tablet was 3.4 min; IVRS: 5.8; paper: 4.0. The proportion of participants by mode who reported "no problems" responding to the questionnaire was 86 % tablet, 72 % IVRS, and 98 % paper.Conclusions: Mode equivalence of items was moderate to high, and comparable to test-retest reliability (median ICC = 0.80). Each mode was acceptable to a majority of respondents. Although the study was powered to detect moderate or larger discrepancies between modes, the observed ICCs and very small mean differences between modes provide evidence to support study designs that are responsive to patient or investigator preference for mode of administration, and justify comparison of results and pooled analyses across studies that employ different PRO-CTCAE modes of administration.Trial Registration: NCT Clinicaltrials.gov identifier: NCT02158637. [ABSTRACT FROM AUTHOR]

This article reviews the regulatory guidelines that provide for the inclusion of recovery groups in toxicology studies, presents the challenges in the design and interpretation of nonclinical recovery studies, and summarizes the best practices for the role of an anatomic pathologist regarding toxicology studies with recovery groups. Evaluating the potential recovery of histopathologic findings induced by a biopharmaceutical requires the active participation of one or more anatomic pathologists. Their expertise is critical in risk assessment regarding the potential for recovery as well as providing scientific guidance in the design and evaluation of studies with recovery groups. [ABSTRACT FROM PUBLISHER]

The article reports that the journal "Vaccines" on July 2, 2021 retracted a peer-reviewed article after the resignations of several editors who were protesting the publication of a study one week earlier that had misused data in a Dutch vaccine adverse events registry to make the claim that COVID-19 vaccines kill. Topics covered include the background of the paper's authors, how the authors computed COVID-19 deaths prevented by vaccines and the fears of the editors who resigned.

Purpose: Rare diseases present challenges for accessing patient populations to conduct surveys. Clinical Data Research Networks (CDRNs) offer an opportunity to overcome those challenges by providing infrastructure for accessing patients and sharing data. This study aims to demonstrate the feasibility of collecting patient preference information for a rare disease in a CDRN, using idiopathic pulmonary fibrosis as proof of concept. Patients and methods: Utilizing a cohort of idiopathic pulmonary fibrosis (IPF) patients across a CDRN, a discrete choice experiment was administered via electronic and paper methods to collect patient preference information about benefits and risks of two therapeutic options. Survey data were augmented with data from electronic health records and patient-reported outcome surveys. Results: Thirty-three patients completed the preference experiment. The amount of choice attributable to a benefit of slowing of decline in lung function was 36%. Improving efficacy in terms of lung function was 2.16 times as important as improving efficacy in terms of shortness of breath. In terms of side effects, decreasing risk of gastrointestinal problems was 2.6 times as important as decreasing risk of sun sensitivity and 2.4 times as important as decreasing risk of liver injury. In terms of benefit-risk trade-offs, improving efficacy in terms of lung function was 1.6 times as important as decreasing risk of gastrointestinal problems. Conclusion: This study used IPF as a proof of concept to demonstrate the feasibility of collecting patient preference information in a CDRN. The network was advantageous to the study of patient preferences. Future research should continue to explore pathways for the collection and use of patient preference information across networks. The power of consolidated collection efforts may lead to the ability to use preference data to inform decision-making at the regional, specialty, or individual encounter level. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) are a significant problem in children, affecting one in ten children in hospital. Within the community, one in 500 children will experience an adverse drug reaction each year. Pharmacovigilance has been useful in detecting suspected ADRs. However, most ADRs are unreported and often not suspected. Education of health professionals in relation to drug toxicity improves the reporting rate of suspected ADRs. Clinical trials are useful to evaluate the efficacy of drugs. They are, however, not the best way of looking at ADRs where surveillance following the widespread use of a drug is more appropriate. Alongside work by the regulatory agencies, independent investigators have helped collate data. This information has been useful in developing guidelines to prevent further cases of drug toxicity. Greater awareness and understanding of drug toxicity in children should result in more rational prescribing. [ABSTRACT FROM AUTHOR]

The article offers information on several studies related to topics including drug effects, genetics, and bone repair. L. A. Fitzpatrick and colleagues study the effect of ronacaleret on bone mineral density (BMD) of postmenopausal women. G. H. Dolmans and colleagues discuss role of WNT signaling to Dupuytren's disease. Moreover, K. A. Alexander and colleagues report on the role of osteal macrophages (osteomacs) in the anabolic response to bone injury.

Background: Second-generation antidepressants dominate the management of major depressive disorder, dysthymia, and subsyndromal depression. Evidence on the comparative benefits and harms is still accruing. Purpose: To compare the benefits and harms of second-generation antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine) for the treatment of depressive disorders in adults. Data Sources: MEDLINE, EMBASE, PsychLit, Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007, limited to English-language articles. Reference lists of pertinent review articles were manually searched and the Center for Drug Evaluation and Research database was explored to identify unpublished research. Study Selection: Abstracts and full-text articles were independently reviewed by 2 persons. Six previous good- or fair-quality systematic reviews or meta-analyses were included, as were 155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized, controlled trials of at least 6 weeks' duration. For harms, 35 observational studies with at least 100 participants and follow- up of at least 12 weeks were also included. Data Extraction: Using a standard protocol, investigators abstracted data on study design and quality-related details, funding, settings, patients, and outcomes. Data Synthesis: If data were sufficient, meta-analyses of head-tohead trials were conducted to determine the relative benefit of response to treatment and the weighted mean differences on specific depression rating scales. If sufficient evidence was not available, adjusted indirect comparisons were conducted by using meta-regressions and network meta-analyses. Secondgeneration antidepressants did not substantially differ in efficacy or effectiveness for the treatment of major depressive disorder on the basis of 203 studies; however, the incidence of specific adverse events and the onset of action differed. The evidence is insufficient to draw conclusions about the comparative efficacy, effectiveness, or harms of these agents for the treatment of dysthymia and subsyndromal depression. Limitation: Adjusted indirect comparisons have methodological limitations and cannot conclusively rule out differences in efficacy. Conclusion: Current evidence does not warrant the choice of one second-generation antidepressant over another on the basis of differences in efficacy and effectiveness. Other differences with respect to onset of action and adverse events may be relevant for the choice of a medication. [ABSTRACT FROM AUTHOR]

I In this in vitro study, i [5] I in the USA evaluated the cytotoxic effects of amikacin on equine chondrocytes, synoviocytes, and bone marrow and adipose- derived mesenchymal stem cells (MSC). i Chondrocytes, synovial cells, and adipose and bone marrow derived MSC were harvested post-mortem from three horses with no evidence of osteoarthritis. Cell metabolism/viability was assessed by colorimetric MTT assay, and cell proliferation was assessed by live cell imaging. Amikacin at clinically applied doses induces rapid, pronounced cell death of equine joint cells and so amikacin doses currently used intra-articularly should be reconsidered. [Extracted from the article]

To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep. Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28–31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis. All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals. Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain. [ABSTRACT FROM AUTHOR]

Presents a study on rural obstetrical analgesia and anesthesia in Canada. Aim of the study; Side effects of intrathecal opiates; List of propositions and recommendations on obstetrical regional analgesia.

• Good documentation practice is the foundation for promoting medication safety in young population. • Study identified poor documentation practice through paper and electronic means of medical records. • Newly introduced electronic medical records did not improve the rates of metabolic monitoring nor the quality of documented monitoring. • Youth are at significant risk for antipsychotic induced metabolic syndrome the repercussion of which may impact years of productivity. • Potentially electronic health records could provide health workers with real-time information access, and develop accurate, relevant and structured information thereby adhering to clinical evidence. Since the development of digital records, claims have been made that they improve audits. Clinical audits play important role in evaluation of evidence-practice gaps. Antipsychotic medications are one of the commonly prescribed group of drugs in severe adverse mental conditions. Youth and young people are highly prone to develop drug induced metabolic syndrome. Present study evaluated the extent of data documentation on evidence for metabolic monitoring of antipsychotics and compared paper based to electronic records with good documentation standards. First phase of this study involved a retrospective clinical audit of paper-based documentation on the extent of documentation of weight (primary outcome); lipid and blood glucose (secondary outcomes) of youth prescribed atypical antipsychotics. This was undertaken in three public mental health clinics and a public/private developmental service in Australia based on paper-based documentation. The second phase included auditing electronic data capture from one community clinic. Evidence of documentation was compared with practice standards and published clinical audits (adherence rate benchmark: 40–60%). A total of 310 cases were assessed of which 51 and 37 cases met the eligibility criteria for paper-based and electronic based audit respectively as a component of clinical audit. Evidence of paper documentation of weight was 43% among participants and was comparable with other published clinical audits (p = 0.07) with poor monitoring rates for other blood tests. Findings revealed poor rate of documentation at 35.1% (13 cases), 5.4% (2 cases) and 8.1% (3 cases) for weight, lipid assessments and glucose monitoring, respectively based on electronic records. Present study demonstrate lack of good documentation practices on metabolic monitoring of youth prescribed antipsychotics. It appears transitioning from paper to electronic records did not impact the rate of increase in documentation of metabolic monitoring. This study recommends inclusion of e-monitoring icon with built in metabolic monitoring chart as a component of youth prescribed antipsychotic case records. Good documentation practice is a first step in determination of causality of antipsychotics induced metabolic syndrome. Appropriate strategies to a user-friendly electronic reminder system will be crucial to address on the mechanistic of documentation. [ABSTRACT FROM AUTHOR]

Background There is increasing evidence that opioids interfere with the oral bioavailability of P2Y 12 inhibitors leading to delayed onset of antiplatelet effects. Several strategies have been proposed to mitigate this interaction including utilizing alternative analgesic agents in the management of ischemic chest pain. Methods The lidocAine Versus Opioids In MyocarDial Infarction (AVOID-2) study is a phase II, pre-hospital, open-label, non-inferiority, randomized controlled trial conducted by Ambulance Victoria and Monash University in metropolitan Melbourne, Victoria, Australia. The purpose of the study is to compare the analgesic effect (reduction in pain by arrival to hospital) and safety (e.g. adverse drug reactions) (co-primary endpoints) of intravenous lidocaine versus intravenous fentanyl in 300 adult patients attended by ambulance with suspected ST-elevation myocardial infarction (STEMI). Secondary endpoints and a cardiac magnetic resonance imaging (MRI) sub-study will also compare infarct size between these two groups. Conclusions The evaluation of alternative analgesic agents in the management of acute coronary syndromes is urgently needed to manage the opioid-P2Y 12 inhibitor interaction. The results of this trial will have significant implications on the emergency management of acute coronary syndromes internationally. [ABSTRACT FROM AUTHOR]

Copyright of Malaria Journal is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Potentially inappropriate polypharmacy (PIP) is among the major factors leading to adverse drug reactions, increased healthcare costs, reduced medication adherence, and worsened patient conditions. This study aims to identify existing interventions implemented to monitor and manage polypharmacy in the Italian setting. Methods: A systematic literature review (PROSPERO: CRD42023457049) was carried out according to the PRISMA statement guidelines. PubMed, Embase, ProQuest, and Web of Science were queried without temporal constraints, encompassing all published papers until October 2023. Inclusion criteria followed the PICO model: patients with polypharmacy; interventions to monitor/manage polypharmacy regimen versus no/any intervention; outcomes in terms of intervention effectiveness and cost variation. Results: After duplicate deletion, 153 potentially relevant publications were extracted. Following abstract and full-text screenings, nine articles met the inclusion criteria. Overall, 78% (n = 7) were observational studies, 11% (n = 1) were experimental studies, and 11% (n = 1) were two-phase studies. A total of 44% (n = 4) of the studies involved patients aged ≥ 65 years, while 56% (n = 5) were disease-specific. Monitoring was the most prevalent choice of intervention (67%; n = 6). Outcomes were mainly related to levels of polypharmacy (29%; n = 6) and comorbidities (29%; n = 6), effectiveness rates (14%; n = 3), and avoidable costs (9%; n = 2). Conclusions: This review outlines that Italy is still lacking in interventions to monitor/manage PIP, addressing an unmet need in developing patient-tailored strategies for reducing health-system burden. [ABSTRACT FROM AUTHOR]

DEET (N,N-Diethyl-meta-toluamide) is considered the gold standard in mosquito repellents, not only for its effectiveness, but also for its safety. DEET has been more extensively studied for safety than any other repellent, and is accepted as completely safe when used correctly (i.e. not consumed or bathed in). Researchers studying botanical repellents, however, often paint DEET as far more toxic than it really is, falsely claiming it is a menace to the public health or even the environment. These claims are unfounded, and often the only evidence given by such publications are references to other publications also studying botanical repellents. Such publications are biased, and may be attacking DEET's excellent safety record to justify their existence and the need for their research. The inconvenient yet undisputable fact is that no botanical repellent has been proven to be as safe as DEET, and the majority never had any safety testing whatsoever. The automatic assumption that botanical repellents are safer than DEET is the 'appeal to nature fallacy,' which also drives most of the market for "natural" repellents, yet natural repellents have side effects and even a body count. Finding a botanical repellent that works as well as DEET and is equally safe is a legitimate research goal on its own, and need not be justified by fear-mongering and irrational chemophobia. Researchers studying these alternatives should strive for integrity, raising the real issue of the lack of safety testing for botanical repellents rather than denying the proven safety of DEET. [ABSTRACT FROM AUTHOR]

Ways to solve the passivation layer undercut in via hole were described in detail. By tuning the pretreatment before the passivation layer deposition, the passivation layer undercut in via hole was solved efficiently without any other side effects. Different from changing dry etching process parameters, we increasing the adhesion of the interface between metal layer and passivation layer to overcome undercut issue. [ABSTRACT FROM AUTHOR]

Background: Despite unclear evidence to support the long-term use of antipsychotics to treat challenging (problem) behaviours in people with autism in the absence of a psychiatric disorder, this practice is common. Methods: We conducted a systematic review and meta-analysis of all randomised controlled trials (RCTs) involving antipsychotics for people with autism of all ages, irrespective of the outcomes assessed. We searched seven databases and hand-searched ten relevant journals. Two authors independently screened titles, abstracts and full papers and extracted data using the Cochrane Handbook template. We conducted meta-analyses of outcomes and the rate of adverse events. Results: We included 39 papers based on 21 primary RCTs that recruited 1482 people with autism. No RCT assessed any psychiatric disorder outcome, such as psychoses or bipolar disorder. A meta-analysis of ten placebo-controlled RCTs showed a significantly improved Aberrant Behaviour Checklist-Irritability score in the antipsychotic group with an effect size of −6.45 [95% confidence interval (CI) −8.13 to −4.77] (low certainty). Pooled Clinical Global Impression data on 11 placebo-controlled RCTs showed an overall effect size of 0.84 (95% CI 0.48 to 1.21) (moderate certainty). There was a significantly higher risk of overall adverse effects (p = 0.003) and also weight gain (p < 0.00001), sedation (p < 0.00001) and increased appetite (p = 0.001) in the antipsychotic group. Conclusions: There is some evidence for risperidone and preliminary evidence for aripiprazole to significantly improve scores on some outcome measures among children with autism but not adults or for any other antipsychotics. There is a definite increased risk of antipsychotic-related different adverse effects. [ABSTRACT FROM AUTHOR]

Background Persons with HIV and tuberculosis (TB) co-infection require transaminase monitoring while on hepatotoxic medications. A novel paper-based, point-of-care transaminase test is in development at an anticipated cost of $1 per test. Methods To project long-term clinical outcomes and estimate the cost-effectiveness of using a paper-based fingerstick test to monitor for drug-induced liver injury (DILI), as compared with automated testing and with no laboratory monitoring. The design was a decision analytic model, including deterministic and probabilistic sensitivity analyses. Data sources were observational cohorts and a validation study of the paper-based test. The target population was HIV/TB co-infected persons in South Africa on antiretroviral therapy who were initiating TB therapy. Interventions: (1) clinical (no laboratory) monitoring; (2) monitoring using the paper-based test with a ≥120 IU/mL threshold for positivity; (3) monitoring using the paper-based test with a ≥200 IU/mL threshold for positivity; (4) monitoring using the paper-based test using 1 of 3 categories: <120 IU/mL, 120 to 200 IU/mL, and >200 IU/mL (“bin placement”); (5) monitoring using automated ALT testing using the same 3 categories (“automated testing”). The outcome measures were discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results The ICER of automated testing was $5180/QALY. Use of the paper-based test with the bin placement strategy was cost-effective compared with clinical monitoring alone. Conclusion At its current performance, monthly DILI monitoring by bin placement using the paper-based test was cost-effective, compared with clinical monitoring, in HIV/TB co-infected persons in South Africa. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is an adverse hepatic drug reaction that can potentially lead to life-threatening liver failure. Previously published work in the scientific literature on DILI has provided valuable insights for the understanding of hepatotoxicity as well as drug development. However, the manual search of scientific literature in PubMed is laborious and time-consuming. Natural language processing (NLP) techniques along with artificial intelligence/machine learning approaches may allow for automatic processing in identifying DILIrelated literature, but useful methods are yet to be demonstrated. To address this issue, we have developed an integrated NLP/machine learning classification model to identify DILI-related literature using only paper titles and abstracts. For prediction modeling, we used 14,203 publications provided by the Critical Assessment of Massive Data Analysis (CAMDA) challenge, employing word vectorization techniques in NLP in conjunction with machine learning methods. Classification modeling was performed using 2/3 of the data for training and the remainder for test in internal validation. The best performance was achieved using a linear support vector machine (SVM) model on the combined vectors derived from term frequency-inverse document frequency (TF-IDF) and Word2Vec, resulting in an accuracy of 95.0% and an F1-score of 95.0%. The final SVM model constructed from all 14,203 publications was tested on independent datasets, resulting in accuracies of 92.5%, 96.3%, and 98.3%, and F1-scores of 93.5%, 86.1%, and 75.6% for three test sets (T1-T3). Furthermore, the SVM model was tested on four external validation sets (V1-V4), resulting in accuracies of 92.0%, 96.2%, 98.3%, and 93.1%, and F1-scores of 92.4%, 82.9%, 75.0%, and 93.3%. [ABSTRACT FROM AUTHOR]

Papers from the 2010 American Medical Informatics Association (AMIA) Summit on Translational Bioinformatics held from March 10-12, 2010 in San Francisco, California are presented including "Mapping Transcription Mechanisms from Multimodal Genomic Data," "Using Gene Co-Expression Network Analysis to Predict Biomarkers for Chronic Lymphocytic Leukemia," and "Mining Multi-Item Drug Adverse Effect Associations in Spontaneous Reporting Systems."

An introduction is presented in which the editor discusses articles in the issue on topics including use of medication in residential aged care facilities; effect of dementia on daily life; and improvements in the care for older cognitively impaired patients with benefits for families.

Clinical Efficacy and Adverse Effects of Clobazam in Patients with Refractory Epilepsy.Purpose:A new antiepileptic drug (AED), clobazam (CLB), was introduced in Japan in 2000. In previous studies, CLB was effective in 30–80% of epilepsy patients. A retrospective study of the clinical efficacy and adverse effects of CLB was performed in patients with refractory epilepsy. The development of tolerance to CLB and related factors also was studied.Methods:Patients with refractory epilepsy who had one or more seizures per month despite treatment with three or more AEDs were included in the study. CLB was prescribed as an add-on therapy, once or twice per day. In patients who were taking other benzodiazepines (BZDs), the other BZDs were gradually tapered as the dosage of CLB was increased. The patients were followed up for>6 months.Results:Seventy-two patients were studied. Their ages ranged from 1 to 37 years (16.4± 10.2 years, mean± SD). Twenty-one patients had symptomatic generalized epilepsy (early myoclonic encephalopathy, one; West syndrome, four; Lennox–Gastaut syndrome, 12), 48 had localization-related epilepsy (cryptogenic, one), and three had severe myoclonic epilepsy in infancy. The mean minimum dosage of CLB was 0.13 mg/kg/day in patients with body weight<20 kg, or 5.3 mg/day in those with body weight of≥20 kg. The mean maximum dosage was 0.4 mg/kg/day in patients with body weight<20 kg, or 16.7 mg/day in those with body weight of≥20 kg. CLB reduced the frequency of seizures by≥50% in 48% of the subjects (18% with no seizure, 6% with 75% reduction, and 24% with 50–75% reduction). CLB was effective for both generalized epilepsy (42.5%) and focal epilepsy (50%), and especially for temporal lobe epilepsy (TLE) (60%). CLB was effective for partial seizures (55.5%), primary (57%) and secondarily generalized (40%) tonic–clonic seizures, and tonic seizures (46%). It was not effective for spasms (0), atonic seizures (0), and the majority of absence seizures (25%). CLB was effective in 10 nonresponders to clonazepam (CZP). Among the adverse effects of CLB, the incidences of somnolence, salivation, and aggressiveness were 29%, 1.3%, and 13.8%, respectively, which was lower than the incidence previously reported for patients taking CZP; and the incidence of depression was 13.8%, which was higher than that reported for patients taking CZP. Similar to several other BZDs, in some patients, tolerance to CLB developed. In 65% of patients, tolerance to CLB developed within 1 year (55% within 6 months). Tolerance was not observed in other patients who had taken CLB for>1 year. In 55% of the cases in whom tolerance to CLB developed, the frequency of seizures returned to the original frequency before starting CLB treatment, whereas in the remaining 45% of cases, the frequency of seizures increased slightly and was lower than the frequency before starting CLB treatment. The mean CLB dosage in patients in whom tolerance did not develop (16.7 mg/day) was lower than the dosage in those in whom tolerance developed (19.0 mg/day). The mean serumN-desmethyl CLB concentration in long-term users who did not develop tolerance was very high (3,071 ng/ml).Conclusions:CLB was effective for both refractory generalized and localization-related epilepsies and was especially effective for TLE. CLB was effective at a lower dosage than previously reported. The incidence of some adverse effects such as somnolence, salivation, and aggressiveness was lower for CLB than for CZP. CLB was also effective in some patients who had tolerance to other BZDs. In those who developed tolerance to CLB, tolerance appeared within 6 months in most cases. Patients who did not develop tolerance to CLB had a higher serumN-desmethyl CLB concentration, which may be an important factor. Antihistaminergic/Allergic Drug-Induced Seizures in Children at Our Outpatient Clinic.Purpose:It is well known that antihistaminergic (AH) or antiallergic (AA) drugs and theophyline (Theo) have proconvulsant effects. The North Kyushu Study Group on Pediatric Allergy reported that in children with bronchial asthma treated with and without Theo had similar prevalence of seizures of 0.42%. However, reports on this issue by pediatric neurologists are rare. Therefore we retrospectively investigated the relation between administration of AH drugs or Theo and seizure occurrence in our patients with febrile convulsions (FCs) or epilepsy.Methods:The 1,037 patients visited our outpatient neurologic clinic between January 1999 and July 2001. Among them, 158 had FCs, and 350 had epilepsy. By reviewing the clinical charts of these 508 patients, we selected those who had seizures while they were administered AH drugs or Theo for upper respiratory infection or asthma. Then we investigated the causal relation of these drugs with seizures.Results:Among 158 patients with FCs who visited our clinic many times, 17 (10.7%) had seizures while receiving AH drugs or Theo: four received Theo (2.5%; one of them received ketotifen, and another, azelastine), and 13 (8.2%) received AH or AA drugs. Among 350 patients with epilepsy, 11 (3.1%) had seizures while receiving such drugs: five received Theo (1.4%; three of them received ketotifen), and six (1.7%) received AH or AA drugs. A representative case is presented.Case IY:A 3-year-old boy (birth history: 40 weeks; 3,725 g; Apgar, 8 of 10; HIE grade 1) had a history of spastic diplegia, asthma, and atopic dermatitis. On July 15, 1995, he became febrile and asthmatic. He received some drugs and had seizures. On August 16, he visited our clinic and 200 mg of theophyline, 3 mg of pemirolast, and 3 mg of cyproheptadine were administered. He had seizures in that evening. Thereafter, 100 mg of Theo was continued, and seizures occurred every other day. On October 12, he had status epileptics. Seizures ceased after the second IV diazepam. Serum concentrations of carbamazepine (CBZ), valproic acid (VPA), and Theo were 3.5, 33.6, and 2.7μg/ml, respectively. Since October 12, Theo was stopped. Meanwhile, no seizure occurred. Pemirolast (3 mg) and cyproheptadine (3 mg) were continued, and he had seizures once a month. Since May 1996, the dose of cyproheptadine was increased to 4 mg. In August 1996, he had seizures. Pemirolast and cyproheptadine were stopped, and since then, no seizures have occurred. On June 1, 1997, Theo was again administered for severe asthmatic attacks. Serum concentrations of CBZ, VPA, and Theo were 4.8, 84.9, and 9.3μg/ml, respectively. He had seizures on June 18, 19, 20, and 21, and Theo was discontinued. Thereafter, he remained seizure free.Conclusions:Our results suggested that AH drug or Theo-related seizures occurred more frequently in FC patients than in epilepsy patients. One factor contributing to this result may be the fact that recently we (pediatric neurologists) have become aware of a risk of seizure induction by AH drugs and Theo in epilepsy patients. Some patients have no seizures while receiving these drugs. Our results suggest that Theo and some AH drugs may induce seizures, although not all patients with FC or epilepsy are sensitive to these drugs. Our study was designed with a small number of subjects. Although statistical analysis is not possible, our results may suggest that physicians must pay more attention to AH drugs than to Theo as seizure-inducing agents. A Case of Migraine-Like Headache and Metamorphopsia Caused by Epileptogenicity of an Occipital Lesion: Successful Treatment with Sumatriputan.Case Report:A 20-year-old man with a history of complex partial seizures since age 9 years had experienced some episodes of pulsatile right hemicrania followed by a visual sensation of distortion of the left part of objects (metamorphopsia). During an attack, only hemicrania improved after treatment with an analgesic, whereas metamorphopsia continued with little change. The patient was admitted to our hospital when a neuroophthalmologic examination triggered worsening of the symptoms. After hemicrania was successfully treated with sumatriptan, metamorphopsia also remitted gradually. A twilight state existed for a while after the treatment. The waking and sleeping EEGs showed occipital slow activity predominating on the right but no epileptogenic discharge. On computed tomographic (CT) scanning, right occipital cortical and subcortical calcifications were observed, and magnetic resonance imaging (MRI) showed parenchymal atrophy in the surrounding areas. Single-photon emission CT (SPECT) with[123I]IMP was performed on day 12 after admission, and right occipitotemporal hypoperfusion and ipsilateral temporal hyperperfusion were detected.Discussion:This is a case of paroxysmal metamorphopsia triggered by pulsatile hemicrania, with evidence of morphologic and functional abnormality in the occipital lobe. Sumatriptan was effective in relieving not only hemicrania but also lingering metamorphopsia. In general, patients with lesions of the occipital lobe often have elemental visual hallucinations such as light, color, lines, and circles. Conversely, distortions of objects, such as metamorphopsia in a narrow sense, usually occur in those with temporal lobe lesions. Furthermore, visual phenomena such as typical migranous aura based on the concept of spreading depression cannot continue for>60 min. The SPECT findings imply that the epileptic discharge originated from the occipital lobe and propagated toward the temporal lobe, and cells with a lower epileptogenic threshold were easily excited for a long period. We concluded that the patient was irritated by local changes of the vascular system because of the lesion, and then migraine triggered epileptogenic visual seizure. Initial Effect and Long-Term Outcome of the Combination Therapy with ACTH and Clonazepam for Patients with West Syndrome: A Further Study.Purpose:To treat West syndrome, we usually use high-dose vitamin B6 therapy at first; and if this not effective, we administer adrenocorticotropic hormone (ACTH) and clonazepam (CZP) together; and after the end of the treatment with ACTH, we continue to use CZP as maintenance therapy. In this study, we reviewed the initial effect and long-term outcome of this combination therapy with ACTH and CZP for the treatment of West syndrome.Methods:During 20 years from April 1979 to March 1999, we used combination therapy of ACTH and clonazepam to treat 41 patients. Nineteen patients were classified as having cryptogenic West syndrome, and the other 22, as symptomatic. The onset ages of West syndrome in these patients were from 3 months to 21 months (mean, 7 months). The period from disease onset to the start of treatment ranged from 12 days to 6 months (mean, 1.5 months). ACTH (0.025 mg/kg; later, 0.0125 mg/kg) was injected intramuscularly every day for the first 2 weeks, every other day for the next 2 weeks, twice a week for another 2 weeks, and once a week for the last 2 weeks. We added a daily dose of 0.025 mg/kg of CZP at the start of ACTH and doubled its dose every week in general up to the maintenance dose between 0.1 and 0.2 mg/kg/day. We continued to administer CZP after completion of the ACTH therapy.Results:For the initial effect, both the seizures and the hypsarrhythmia on EEG disappeared in 33 (80.5%) patients. In six patients, the seizures or the EEG abnormalities were improved. In two patients, both the seizures and hypsarrhythmia persisted. We analyzed the long-term outcome for 10 years by the Kaplan–Meier method. The seizure-suppression rate for cryptogenic West syndrome patients without mental retardation was 70.1% in 3 years, and no patients showed seizure recurrence thereafter. The rate for cryptogenic West syndrome patients with mental retardation was 58.3% in 5 years, and the final rate decreased to 29.2%. Half of the patients with symptomatic West syndrome showed seizure recurrence within a year, and the final suppression rate was 24.5%. To sum up the outcome for all patients, 17 (41.5%) patients showed seizures within a year. The seizure-suppression rate was 50.7% in 3 years, 43.4% in 5 years, and 29.7% in 10 years. As for the EEG findings at the final observations, the paroxysmal discharges disappeared in 11 (68.8%) of 16 patients who showed very effective short-term results and with seizures controlled in the long term. The evolving epilepsies in 17 seizure-recurrence cases included three cases of recurrence of West syndrome and eight cases of Lennox–Gastaut syndrome. As for the prognosis of mental development, among the five cryptogenic patients who had no mental retardation at onset and showed good short-term response and long-term seizure control, two patients showed normal development at older than 3 years.Conclusions:Various methods have been tried for the treatment of West syndrome in various institutions. ACTH is usually used for its treatment. Only a few studies have focused on the efficacy of CZP for West syndrome. Our combination therapy of ACTH and CZP showed effective short-term results and a good long-term outcome, except in patients with mental retardation. These results indicate that the ACTH-CZP regimen is an effective treatment for West syndrome. Intravenous Sodium Valproate in Refractory Seizures.Purpose:Valproic acid (VPA) has evolved as a major antiepileptic drug (AED) for treatment of seizures. The role of intravenous VPA (IVVPA) is still not established. Clinical and electrophysiologic evidence suggests it to be effective for status epilepticus (SE) after failure of first-line AEDs.Methods:We report our experience on use of IVVPA in 18 patients with SE with seizures of different types and etiologies. They had not responded to therapeutic regimens of oral or parenteral conventional AEDs. There were four patients each with viral encephalitis (VE) and hypoxic ischemic encephalopathy (HIE), two each with tubercular meningitis, multiple cerebral infarcts, multiple neurocysticercosis, and idiopathic generalized tonic–clonic seizures (GTCSs). There was a single patient with subacute sclerosing panencephalitis (SSPE) and right frontal hematoma seen in SE. Seizures were of different types[epilepsia partialis continua (EPC), seven; nonconvulsive SE (NCSE), two; GTCSs, three; and myoclonic SE (MSE), six].Results:IVVPA was infused at a dose of 20 mg/kg at a rate of 20 mg/min to all patients. Seizures were controlled in all except one patient within 6–14 h, without any complication or adverse effects, even in patients with cardiovascular instability. The patient who did not respond (although frequency of attacks was reduced) to IVVPA even with a dose of 35 mg/kg was an 18-year-old boy with SSPE.Conclusions:We conclude that IVVPA appears to be effective and safe when rapid control of seizures is the goal, even in elderly persons with cardiovascular instability. No intensive care monitoring is required, unlike that with conventional IV AEDs. It can be recommended as the drug of choice for EPC and HIE, which is usually refractory to oral AEDs. The possible mechanism for its efficacy when other AEDs fail may be due to its rapid penetration into brain tissue. Application of Diffusion Tensor Imaging in the Evaluation of Cerebellar Atrophy Associated with Phenytoin.Purpose:To assess the clinical usefulness of diffusion tensor imaging in the evaluation of cerebellar atrophy associated with phenytoin (PHT).Methods and Materials:Sixteen patients and sex/age-matched normal controls participated in this study. The patient groups consisted of long-standing PHT users (n= 6), olivopontocerebellar atrophy (OPCA; n= 4), autoimmune disease (n= 3), and multiple sclerosis (n= 3). All studies were performed by using a 1.5-T Philips Gyroscan Intera system. Diffusion-weighted imaging was performed by using single-shot echoplanar imaging, with navigator echo-phase correction and SENSE, along six independent axes with diffusion weighting of b= 600 s/mm2. Data were processed on a Windows-2000 PC equipped with IDL, by which vector map and functional anisotropy (FA) map were generated. FA of cerebellar peduncles and cerebellar white matter were measured and compared between PHT users and other cerebellar atrophy groups.Results:In PHT users, FA values of middle cerebellar peduncle and transverse pontine fiber were not statistically different from those of normal controls. Non-PHT cerebellar atrophy showed significantly decreased FA of middle cerebellar peduncles and transverse pontine fibers. On vector maps, these changes also were prominently represented as loss of fiber direction on color-coded images.Conclusions:The results suggest that PHT-induced cerebellar atrophy may be a direct injury to cerebellar Purkinje cells, whereas other types of cerebellar atrophy may be induced by deterioration of efferent fibers to the cerebellum from the brainstem. Diffusion tensor imaging is useful in the differential diagnosis of cerebellar atrophy associated with PHT. Fanconi Syndrome Caused by Valproic Acid: Report of Four Severely Disabled Children.Background:Fanconi syndrome (FS) includes rickets associated with multiple defects of the proximal renal tubules and is characterized by generalized aminoaciduria, glycosuria, and proteinuria, resulting in metabolic acidosis, hypophosphatemia, and hypokalemia. Although the exact mechanism remains unknown, valproic acid (VPA) has been reported as a rare cause of FS. We have recently encountered four severely disabled children in whom FS developed after prolonged administration of VPA.Case Report:Case 1: This 4-year-old boy with microcephalus experienced seizures at age 2 months, and VPA was therefore started. He was bedridden. At age 2 years 7 months, hypokalemia of unknown origin developed. At age 4 years 2 months, routine laboratory examinations disclosed metabolic acidosis, hypophosphatemia, hypouricemia, and proteinuria. VPA was replaced by zonisamide (ZNS), and sodium citrate, phosphate supplementation, and vitamin D3 were added. Two months after the discontinuation of VPA, the urinary abnormalities disappeared. Case 2: This 8-year-old girl had West syndrome at age 3 months, and oral administration of VPA was started. She had spastic quadriplegia and was fed with a nasogastric tube. At age 8 years, the laboratory findings were compatible with FS. Immediate correction of the metabolic acidosis was started. VPA was stopped, and sodium citrate, vitamin D3, and phosphate supplement were administered. She regained normal renal functions within 2 months after the VPA therapy was stopped. Case 3: This severely disabled 14-year-old girl was treated with VPA from age 7 years. At age 13 years, she sometimes had a fever of unknown origin. Routine laboratory examinations revealed metabolic acidosis, hypophosphatemia, hypouricemia, proteinuria, glycosuria, generalized hyperaminoaciduria, and renal tubular dysfunction. A renal biopsy revealed interstitial nephritis without immune deposits. VPA was replaced by ZNS, and alkalization therapy was started. After discontinuation of VPA, she had no further febrile episodes. One year later, her laboratory data became almost normal except for the hypouricemia. Case 4: This 2-year-old girl had West syndrome at age 8 months, and VPA was started. She had spastic quadriplegia. At age 2 years, she was admitted to our hospital because of pneumonia. The laboratory findings on admission were compatible with FS. She was hypouricemic and hypokalemic, associated with metabolic acidosis. She exhibited proteinuria and increased FEUA. VPA was stopped, and vitamin D3 was administered. Her laboratory data became normal within 1 month after the discontinuation of VPA.Discussion:These four patients showed both clinical and biochemical evidence of FS. The reversion to normal of all clinical evidence of proximal tubular dysfunction after the cessation of VPA therapy is supportive evidence of a close relation between VPA and renal involvement. Although VPA has known adverse effects, renal effects are relatively uncommon. A direct effect of VPA on the mitochondria of the proximal tubules or interstitial nephritis caused by drug hypersensitivity was suspected to be the major mechanism causing VPA-induced FS. It is interesting that almost all reported patients with VPA-associated FS have been severely disabled and in a bedridden state, like our four patients. Although the relation between FS and a bedridden state remains unclear, a bedridden state may be a risk factor for FS in children with epilepsy taking VPA. We must pay attention to FS in children with epilepsy treated with VPA, especially in the severely disabled. [ABSTRACT FROM AUTHOR]