Foreword: Lithium: A review of its adverse effects, toxicity and discontinuation.

Immunotherapy is rapidly evolving secondary to the advent of newer immunotherapeutic agents and increasing approval of the current agents by the United States Food and Drug Administration to treat a wide spectrum of cancers. Immunotherapeutic agents have gained immense popularity due to their tumor-specific action. Immunotherapy is slowly transforming into a separate therapeutic entity, and the fifth pillar of management for cancers alongside surgery, radiotherapy, chemotherapy, and targeted therapy. However, like any therapeutic entity it has its own adverse effects. With the increasing use of immuno-therapeutic agents, it is vital for physicians to acquaint themselves with these adverse effects. The aim of this review is to investigate the common systemic adverse effects and toxicities associated with the use of different classes of immunotherapeutic agents. We provide an overview of potential adverse effects and toxicities associated with different classes of immunotherapeutic agents organized by organ systems, as well as an extensive discussion of the current recommendations for treatment and clinical trial data. As we continue to see increasing usage of these agents in clinical practice, it is vital for physicians to familiarize themselves with these effects.

Drug-induced toxicity related proteins (DITRPs) are proteins that mediate adverse drug reactions (ADRs) or toxicities through their binding to drugs or reactive metabolites. Collection of these proteins facilitates better understanding of the molecular mechanisms of drug-induced toxicity and the rational drug discovery. Drug-induced toxicity related protein database (DITOP) is such a database that is intending to provide comprehensive information of DITRPs. Currently, DITOP contains 1501 records, covering 618 distinct literature-reported DITRPs, 529 drugs/ligands and 418 distinct toxicity terms. These proteins were confirmed experimentally to interact with drugs or their reactive metabolites, thus directly or indirectly cause adverse effects or toxicities. Five major types of drug-induced toxicities or ADRs are included in DITOP, which are the idiosyncratic adverse drug reactions, the dose-dependent toxicities, the drug-drug interactions, the immune-mediated adverse drug effects (IMADEs) and the toxicities caused by genetic susceptibility. Molecular mechanisms underlying the toxicity and cross-links to related resources are also provided while available. Moreover, a series of user-friendly interfaces were designed for flexible retrieval of DITRPs-related information. The DITOP can be accessed freely at http://bioinf.xmu.edu.cn/databases/ADR/index.html. Supplementary data are available at Bioinformatics online.

Chinese herbal medicines for unexplained recurrent miscarriage.

Acarbose treatment in liver disease: Cognitive or glycemic control?

Chapter 37 - Adverse effects, side effects and toxicity of select phytochemicals: A review of clinical studies

Herbal medicaments are in common use. In general, the judicious use of carefully selected and prepared herbal medications seems to cause few adverse effects and may be beneficial. However, toxic effects of these products have been reported with increasing frequency. Infants and children may be even more susceptible to some of the adverse effects and toxicity of these products because of differences in physiology, immature metabolic enzyme systems, and dose per body weight. Although information promoting the use of herbal medicine is widespread, true evidence-based information about the efficacy and safety of herbal medications is limited. Although the most conservative approach is to recommend against use of herbal medicine until such evidence is available, some patients are not receptive to this approach. A reasonable approach for health care providers may be to follow such use closely, assist in herbal therapeutic decisions, and monitor for adverse effects and interactions. This manuscript discusses general concepts about herbal medicines, public health implications, and a framework for mechanisms of adverse effects from the use of botanicals. Adverse effects and toxicity of selected herbal products, including Chinese herbal medicines, are presented. The authors propose a risk reduction approach in which physicians actively seek information about the use of complementary or alternative medicine while taking medical histories.

Background: Currently, there is a great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidio-lex®, a purified CBD medicine formulated for oral administration for the treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization considers rescheduling can-nabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s effi-cacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake.Methods: Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit.Results: CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nerv-ous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormal-ities, diarrhea, fatigue, vomiting, and somnolence.Conclusion: CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.

The study aimed to identify the increasing health challenges posed by the rapid emergence of novel psychoactive substances (NPS) compounds. The research employed a multifaceted approach, integrating advanced computational techniques such as the Maestro Schrödinger 12.8 software suite, admeSAR, Protox II, Guasar toxicity modeling and molecular docking. A diverse dataset comprising chemical structures, hysicochemical properties, and toxicity data for known NPS compounds was curated and used to develop predictive models for various adverse health effects, including neurotoxicity, cardiotoxicity, hepatotoxicity, and reproductive toxicity. Key findings from the study revealed significant correlations between chemical structural features and toxicological endpoints, enabling the identification of structural alerts and toxicophores associated with NPS-induced adverse effects. Moreover, the study investigated the impact of metabolic pathways and bioactivation processes on NPS toxicity, providing insights into the potential formation of reactive metabolites and their contribution to adverse health outcomes. Overall, this research contributes to advancing the field of predictive toxicology and provides valuable tools for assessing the health risks associated with NPS consumption. The findings underscore the importance of integrating computational approaches into regulatory decision-making processes and public health policies to effectively mitigate the adverse effects of NPS on individuals and communities.

The fluoroquinolone class of antibacterial agents are among the most frequently prescribed drugs, with utility in a broad range of bacterial infections. Although very useful agents, the fluoroquinolones as a class are associated with a number of adverse events, some with considerable clinical significance. In the past 15-20 years, tolerability concerns have led to restrictions on the use of the fluoroquinolones and, in some instances, the withdrawal of agents from the market. This review focuses on the safety and tolerability of levofloxacin, a third-generation fluoroquinolone, relative to other fluoroquinolones. A literature search was performed of the MEDLINE database encompassing the dates 1980-2009, using as keywords the drug names levofloxacin and concurrently marketed fluoroquinolones combined with the words 'safety', 'adverse effect' or 'adverse drug reaction', or the name of the specific adverse effect. Adverse events commonly associated with the fluoroquinolones include gastrointestinal and CNS toxicity (most frequently headache and dizziness), as well as other adverse events including ECG abnormalities (for example QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, and hepatic toxicity. Package inserts for the fluoroquinolones in Europe and the US contain warnings regarding these risks. US package inserts also carry 'black-box' warnings regarding the risk of tendon rupture and joint disorders with these agents; however, there is a substantial body of evidence to indicate that there are marked differences in the tolerability profiles of the individual agents within the fluoroquinolone class. These differences may be explained, at least in part, by structural differences: all fluoroquinolones share a basic quinolone core, with differences in specific side chains underlying the adverse event relationships. Furthermore, many of the fluoroquinolone-associated adverse effects and toxicities occur more frequently in patients with pre-existing risk factors, or in certain subpopulations. Notably, package inserts for the fluoroquinolones carry warnings regarding use in the elderly, paediatric patients and patients with pre-existing, or factors predisposing to, seizure disorders. Because of this, many adverse reactions with these agents could be prevented by improving patient screening and education. The recent withdrawal of gatifloxacin due to dysglycaemia makes it timely to review the safety and tolerability of the individual agents in this class. Overall, it appears that levofloxacin is relatively well tolerated, with low rates of clinically important adverse events such as CNS toxicity, cardiovascular toxicity and dysglycaemia.

Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides

Chapter 3 - Implant metals and their potential toxicity

There has been an increase in the number of oral antineoplastic medications approved by the US Food and Drug Administration (FDA). In 2011 it was estimated that 25% of the nearly 400 cancer chemotherapy medications in the pipeline were oral agents.1 It now appears that patients prefer the oral antineoplastic agents to their injectable counterparts, although they are not without numerous concerns, including adverse effects, toxicities, and potential nonadherence.2 As with most oral medications, there are also concerns regarding drug-drug, drug-food, drug-supplement, and drug-herbal interactions. Without proper pharmacist counseling, these interactions can lead to reduced efficacy, therapeutic failure, and extra toxicities.2 These medications are also costly and they generally need to be obtained from a specialty pharmacy. In many cases, the patient has no personal relationship with the site of medication dispensing. The 10 most common adverse drug reactions related to antineoplastic therapy are constipation, nausea with or without vomiting, fatigue, alopecia, drowsiness, myelosuppression, anorexia, dermatological effects, mucositis, and diarrhea.3 The newer oral antineoplastic agents list these potential adverse effects, and they also have their own set of adverse effects, such as complex skin reactions and rashes and hand-foot syndrome. All these adverse effects have been on the rise since the introduction of these drugs.2 There is also increasing evidence that many patients prescribed oral antineoplastic agents often discontinue them or are nonadherent with their dosing schedule for a variety of reasons including adverse effects, toxicities, and an overall lack of education and/or knowledge regarding the medications.4–8 These issues represent significant wastes in health care dollars. The issues of adverse effects, discontinuation, and nonadherence need to be addressed. Health care technology for the production and delivery of cancer chemotherapeutics has made significant advancements in recent years, most of which have been focused on the institutional settings. Computerized order entry has been shown to decrease the overall rate of medication errors within the hospital.9 An electronic medication administration record is an organized way to map an individual patient’s medications and any special administration requirements, and it aids in the delivery of the drug to the patient in a safe and timely manner.9 Finally, barcoded medication administration helps to ensure that the correct medication is delivered to the correct patient; it works hand-in-hand with the electronic medication administration record.9 All of these systems work together to help minimize medication-related errors in the hospital setting, but what happens when the patient leaves the hospital on an oral-based cancer chemotherapy regimen? Strategies implemented in the past have had some success in maintaining patient adherence to their oral antineoplastic medications, such as providing only a small number of pills at each dispensing.10 Another way to monitor patients outside of the clinic, which may be just as effective, is by telepharmacy, which is a form of remote pharmacy services.9 Traditionally, this system was used to verify in-patient prescription orders, to ensure the proper preparation of medications when the normal institutional pharmacy staff was unavailable, and to provide services in remote areas with limited access to pharmacists, but it has now spread to more diverse niches. The telepharmacy system has been shown to be an effective way to monitor patients who need more one-on-one contact, such as those with chronic obstructive pulmonary disease.11 One study showed that 90% of patients participating in the telepharmacy program reported an overall satisfaction with the intervention as well as improved inhaler usage.11 If this system can work for one chronic disease state, is it an option for oncology patients to ensure they take their medications as well as report any unusual symptoms, adverse effects, or toxicities? If this system does work, it would be a cost-effective way to continuously monitor oncology patients. With the use of online systems such as OutcomesMTM (http://www.outcomesmtm.com/) and Mirixa (http://www.mirixa.com/), these encounters can be easily documented and, in some cases, the pharmacist, pharmacy, and/or the institution can be reimbursed for those services provided. The prescribing and monitoring of oral antineoplastic medications will be a large issue as we move into the future of the treatment of cancer. These medications are extremely expensive, as is the overall care for patients with cancer. There is a need for effective ways to ensure oncology patients are taking their medications and are able to report any problems they may be experiencing in order to provide the best and most cost-efficient care possible.

Diphenhydramine (Benadryl) is a first-generation antihistamine that is primarily used to treat allergic reactions including anaphylaxis, urticaria, and allergic rhinitis. Despite its availability as an over-the-counter medication, adverse physiologic effects and toxicity may occur with its use especially when administered rapidly via the intravenous route or when administered in large or excessive doses. The development and history of diphenhydramine is presented, its physiologic effects and clinical uses outlined, previous reports of clinically significant and potentially life-threatening adverse effects reviewed, and options to limit these effects discussed.

Atypical antipsychotic medications (second-generation antipsychotics) have been increasingly used in the treatment of a number of psychotic disorders since their introduction in 1988, with the newest medication introduced in 2002. Justification for their use includes claims of equal or improved antipsychotic activity over first-generation antipsychotics, increased tolerability, and decreased side effects. However, there are still significant adverse effects and toxicities with this class of medications. Toxicologic exposures and fatalities associated with atypical antipsychotics continue to increase in the United States, with 32,422 exposures and 72 deaths in 2003. There have also been Food and Drug Administration warnings in the past year about how some atypical antipsychotics have been marketed to minimize the potentially fatal risks and claiming superior safety to other atypical antipsychotics without adequate substantiation, indicating the toxicologic potential of these agents may be underestimated. Continued research to evaluate adverse effects and tolerability of atypical antipsychotics compared with first-generation antipsychotics and each other is reviewed. This article also reviews the pharmacodynamics, pharmacokinetics, and drug interactions with these medications. New therapeutic monitoring recommendations for this class of medications have also been proposed. Finally, clinical toxicity in overdose and management are reviewed. While new atypical antipsychotic medications may have a safer therapeutic and overdose profile than first-generation antipsychotic medications, many adverse and toxic effects still need to be considered in therapeutic monitoring and overdose management.

Urothelial carcinoma (UC) occupies a high incidence among all the genitourinary malignancies. Immune checkpoint inhibitors (ICIs), as alternative treatments of metastatic urothelial carcinoma (mUC), have been applied in the treatment of mUC after chemotherapy failure, with comparable efficacy and safety. ICIs can enhance anti-tumor T cell reactivity and promote immune control over the cancerous cells by blocking cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination of PD-1 and PD-L1. In the treatment of urothelial carcinoma, ICIs show obvious advantage and can enhance survival rates. However, their adverse effects are gradually manifested with increasing clinical applications. Therefore, we review the adverse effects and toxicity of ICIs in patients with UC, aiming to provide sound theoretical references and therapeutic strategies for their clinical application.