How does pharmacological and toxicological knowledge evolve? A case study on hydrogen cyanide in German pharmacology and toxicology textbooks from 1878 to 2020.

Little is known about how pharmacological and toxicological knowledge evolves. The aim of this study was to investigate the changes in the presentation of the poison hydrogen cyanide in sixteen German-language pharmacology and toxicology textbooks from 1878 to 2020. The categories of structure, molecular mechanism of action, occurrence, effects, resorption, areas of application, lethal dose, acute symptoms of intoxication, treatment of hydrogen cyanide poisoning, and recommended therapeutic preparations were evaluated. The knowledge on the structure, lethal dosage, and occurrence of hydrogen cyanide has remained constant. In contrast, knowledge on molecular mechanism of action and recommended preparations of the poison has changed dramatically. Until 1944, the binding of hydrogen cyanide to hemoglobin was considered the mechanism of action, whereas from 1951 onwards, the interaction of hydrogen cyanide with the Fe3+ of cytochrome oxidase was described. The number of preparations containing hydrogen cyanide decreased into obsolescence until 1951. The areas of application of hydrogen cyanide also show a change, as from 1919 onwards, mainly industrial areas of application of the poison are described instead of medical ones, and from 1951 onwards, criminalistic areas of application are also mentioned. Thus, pharmacological and toxicological knowledge develops non-linearly, molecular mechanism and uses being the most dynamic areas, whereas the knowledge about hydrogen cyanide's chemical structure, lethal dose, and occurrence remained constant. Older pharmacology and toxicology textbooks were better than newer ones at discussing changes in scientific concepts. Pharmacology and toxicology textbooks also mostly failed to discuss the misuse of hydrogen cyanide (Zyklon B) during the Nazi regime, missing an important opportunity to showcase the ethical responsibility of pharmacology and toxicology. Thus, future pharmacology and toxicology textbooks should improve on discussing the development of pharmacological and toxicological concepts and the ethical responsibility of the discipline.

The effect of cannabis edibles on driving and blood THC.

BACKGROUND: Cannabis has been shown to impact driving due to changes produced by delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis. Current legal thresholds for blood THC while driving are based predominantly on evidence utilizing smoked cannabis. It is known that levels of THC in blood are lower after eating cannabis as compared to smoking yet the impact of edibles on driving and associated blood THC has never been studied. METHODS: Participants drove a driving simulator before and after ingesting their preferred legally purchased cannabis edible. In a counterbalanced control session, participants did not consume any THC or cannabidiol (CBD). Blood was collected for measurement of THC and metabolites as well as CBD. Subjective experience was also assessed. RESULTS: Participants consumed edibles with, on average, 7.3 mg of THC, which is less than the maximum amount available in a single retail package in Ontario, providing an ecologically valid test of cannabis edibles. Compared to control, cannabis edibles produced a decrease in mean speed 2 h after consumption but not at 4 and 6 h. Under dual task conditions in which participants completed a secondary task while driving, changes in speed were not significant after the correction for multiple comparison. No changes in standard deviation of lateral position (SDLP; 'weaving'), maximum speed, standard deviation of speed or reaction time were found at any time point or under either standard or dual task conditions. Mean THC levels were significantly increased, relative to control, after consuming the edible but remained relatively low at approximately 2.8 ng/mL 2 h after consumption. Driving impairment was not correlated with blood THC. Subjective experience was altered for 7 h and participants were less willing/able to drive for up to 6 h, suggesting that the edible was intoxicating. INTERPRETATION: This is the first study of the impact of cannabis edibles on simulated driving. Edibles were intoxicating as revealed by the results of subjective assessments (VAS), and there was some impact on driving. Detection of driving impairment after the use of cannabis edibles may be difficult.

Curcumae Radix: A Review of Traditional Use, Phytochemistry, Pharmacology, Toxicology and Quality Control.

Curcumae Radix (CuR) is a traditional Chinese medicine that has been used in China for more than 1,000 years. It has the traditional efficacy of activating blood and relieving pain, promoting qi and relieving depression, clearing heart and cooling blood, and promoting gallbladder and removing jaundice. Based on this, many domestic and foreign scholars have conducted systematic studies on its chemical composition, pharmacological effects, toxicity and quality control. Currently, 250 compounds, mainly including terpenoids and curcuminoids, have been isolated and identified from CuR, which has pharmacological activities, including antitumor, anti-inflammatory and analgesic, antidepressant, hepatoprotective, hemostatic, hematopoietic, and treatment of diabetes mellitus. In modern clinical practice, CuR is widely used in the treatment of tumors, breast hyperplasia, hepatitis, and stroke. However, the generation of toxicity and clinical application of CuR and Caryophylli Flos, the determination of the concoction process of artifacts, the determination of specific Quality Marker, and the establishment of the quality control system of CuR, are problems that need to be solved urgently at present.

Pharmacological and toxicological studies of a novel goserelin acetate extended-release microspheres in rats.

LY01005 is an investigational new drug product of goserelin acetate which is formulated as extended-release microspheres for intramuscular injection. To support the proposed clinical trials and marketing application of LY01005, pharmacodynamics, pharmacokinetics and toxicity studies were performed in rats. In the pharmacological study in rats, LY01005 induced an initial supra-physiological level increase of testosterone at 24 h post-dosing which then rapidly fell to castration level. The potency of LY01005 was comparable to the comparator Zoladex® but its effect lasted longer and more stable. A single-dose pharmacokinetics study in rats demonstrated that the Cmax and AUClast of LY01005 increased in a dose-proportional manner in the range of 0.45-1.80 mg/kg and the relative bioavailability was 101.0% between LY01005 and Zoladex®. In the toxicity study, almost all of the positive findings of LY01005 in rats including the changes in hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, progestin) and in reproductive system (uterus, ovary, vagina, cervix uteri, mammary gland, testis, epididymis and prostate) were related to the direct pharmacological effects of goserelin. Mild histopathological changes in foreign body removal reaction induced by excipient were also observed. In conclusion, LY01005 displayed a sustained-release profile of goserelin, and exerted a continuous efficacy in vivo in animal models, which had a comparable potency but with a more sustained effect than that of Zoladex®. The safety profile of LY01005 was largely the same with Zoladex®. These results strongly support the planned LY01005 clinical trials.

Non-clinical pharmacology and toxicology studies of bevacizumab biosimilar LY01008.

LY01008 was a biosimilar of Avastin® developed by Shandong Boan Biotechnology. To support the clinical trial and marketing application of LY01008 as a biosimilar, a series of non-clinical pharmacodynamics (PD), pharmacokinetics (PK), and toxicological studies have been conducted. The PD study results showed that LY01008 had similar pharmacodynamic effects with Avastin in VEGF (vascular endothelial growth factor) binding activity, inhibitory effect on angiogenesis and vascular permeability, and anti-tumor activities in nude mouse models alone or combined with chemotherapeutic agents. PK study showed that LY01008 had similar PK parameters with Avastin at the same doses, and the relative bioavailability of LY01008 was 111.4%. The maximum tolerated dose of LY01008 in the single-dose toxicity study of cynomolgus monkeys was greater than 258 mg/kg. LY01008 had no effects on central nervous system, cardiovascular system and respiratory system in cynomolgus monkeys. LY01008 had no hemolytic effect in vitro and no local irritation in cynomolgus monkeys. The immunogenicity of LY01008 was no higher than that of Avastin in cynomolgus monkeys. In the one-month multiple-dose toxicity study in cynomolgus monkeys, the toxicokinetics profiles of LY01008 was similar with Avastin, the characteristics of the toxic reactions were the same and the extent was similar between LY01008 and Avastin, and no new toxic reactions were observed on LY01008. In conclusion, LY01008 had a good safety profile, and was biosimilar with Avastin in the comparative studies of pharmacodynamics, pharmacokinetics, toxicokinetics and toxicology, which supported the clinical trial and marketing application of LY01008 as a biosimilar of Avastin.

Advanced applications of mass spectrometry imaging technology in quality control and safety assessments of traditional Chinese medicines.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicines (TCMs) have made great contributions to the prevention and treatment of human diseases in China, and especially in cases of COVID-19. However, due to quality problems, the lack of standards, and the diversity of dosage forms, adverse reactions to TCMs often occur. Moreover, the composition of TCMs makes them extremely challenging to extract and isolate, complicating studies of toxicity mechanisms. AIM OF THE REVIEW: The aim of this paper is therefore to summarize the advanced applications of mass spectrometry imaging (MSI) technology in the quality control, safety evaluations, and determination of toxicity mechanisms of TCMs. MATERIALS AND METHODS: Relevant studies from the literature have been collected from scientific databases, such as "PubMed", "Scifinder", "Elsevier", "Google Scholar" using the keywords "MSI", "traditional Chinese medicines", "quality control", "metabolomics", and "mechanism". RESULTS: MSI is a new analytical imaging technology that can detect and image the metabolic changes of multiple components of TCMs in plants and animals in a high throughput manner. Compared to other chemical analysis methods, such as liquid chromatography-mass spectrometry (LC-MS), this method does not require the complex extraction and separation of TCMs, and is fast, has high sensitivity, is label-free, and can be performed in high-throughput. Combined with chemometrics methods, MSI can be quickly and easily used for quality screening of TCMs. In addition, this technology can be used to further focus on potential biomarkers and explore the therapeutic/toxic mechanisms of TCMs. CONCLUSIONS: As a new type of analysis method, MSI has unique advantages to metabolic analysis, quality control, and mechanisms of action explorations of TCMs, and contributes to the establishment of quality standards to explore the safety and toxicology of TCMs.

Pharmacotherapy Update and Review for Family Medicine Residents Using Jeopardy-Style Game.

Introduction: Pharmacotherapy is an important, required aspect of family medicine residency training. MedEdPORTAL has very limited pharmacotherapy content that is targeted to a graduate medical education audience. Methods: I implemented a Jeopardy-style game during a 1-hour didactic session to actively engage the family medicine residents. The game focused on reinforcing guidelines and teaching new medications. I created a session-specific evaluation tool to assess the residents' enjoyment of and learning from the activity. Results: Twenty-six family medicine residents participated in the session, working in groups of three or four. I evaluated the session using the session-specific evaluation tool and a standard didactics evaluation. Twenty-three of 26 residents completed the session-specific evaluation; all 26 completed the standard evaluation. All the residents agreed or strongly agreed that the session was enjoyable, an opportunity for learning, and something they would look forward to in the future. All the residents also agreed that the information presented applied to clinical practice. Comments primarily focused on the difficulty of the questions and the enjoyment of the session. Discussion: Based upon the results of the evaluations and comments, the residents felt the session was a valuable opportunity for learning. The session could be easily implemented by other family medicine or internal medicine programs. The tool can and should be updated as required to remain accurate and current.

What You Need to Know About Cannabis: An Evidence-Based Crash Course for Mental Health Trainees.

Introduction: Although increasing numbers of states are legalizing cannabis for both medical and recreational purposes, health care providers and students report low comfort levels and limited knowledge regarding cannabis, highlighting current deficits in medical training. Methods: We developed a structured cannabis curriculum for a general psychiatry residency program at the University of Colorado. In constructing our curriculum, we initially surveyed advanced psychiatry residents and attending psychiatrists in the university outpatient clinic regarding attitudes and approaches to psychiatric patients using cannabis. Prior to implementation in the following year's core curriculum for first-year postgraduates (PGY 1s), pretest assessments evaluated PGY 1s' attitudes towards cannabis use and identified learning expectations, challenges, and confidence levels. After the seminars were completed, residents provided posttest assessments and general course evaluations. Utilizing initial survey information, we constructed a Marijuana and Medicine introduction curriculum for psychiatry PGY 1s. Topics included strains and formulations, pharmacokinetics, the endocannabinoid system, local Colorado laws, monitoring, evidence regarding use in psychiatric disorders, use in pregnancy, and ethical issues. These topics were covered via case-based discussion, interactive quizzes, direct instruction, and facilitated discussion. Results: Posttest assessments indicated improvement in trainees' confidence and knowledge base and requests for additional instruction on topics such as adolescent use. Discussion: The positive posttest assessments support the value of incorporating a cannabis curriculum into psychiatric training. Now in its second year, the course has been expanded to 4 hours. As cannabis is medicalized, it is increasingly important that psychiatrists be able to knowledgably counsel their patients.

Pharmacology, Pharmacotherapy, and Pharmacopolicy Through an Evidence-Based Medicine: A Novel Approach for First-Year Medical Students.

Introduction: As evidenced by student performance on various assessments, pharmacotherapy remains a comparative weakness in undergraduate medical education, with several institutions developing novel strategies for students to apply these principles in a practical setting. Medical curricula have recently prioritized group-learning modalities and evidence-based medicine education. However, these principles have yet to impact pharmacology education. We developed and implemented an evidence-based, group-learning exercise for first-year medical students focusing on pharmacology through the practical lens of pharmacotherapy and pharmacopolicy. Methods: First-year medical students in different groups were assigned a particular medication and, during an in-class session, were encouraged to meet with other representatives assigned the same drug to interpret the provided package insert and any online information. Students then reconvened with their groups to engage in collaborative teaching about each assigned drug before completing a group quiz using online resources. Facilitators reviewed the group quiz and allowed time for student questions. Results: For 180 participants, the average group-quiz score was 86%, ranging from 68% to 100%. Student-reported satisfaction with the activity in meeting its preset objectives averaged 3.7 on a 5-point scale, with 5 being most positive. Discussion: Overall, this activity effectively integrates principles of pharmacotherapy and pharmacopolicy into a group-based, evidence-based exercise. Limitations of the activity include the number of possible example drugs and the amount of material covered in a given time frame. However, the activity lends itself to the role of an introductory session in a longer curriculum centered on clinical-applied pharmacology and evidence-based practice.

Celastrol: Progresses in structure-modifications, structure-activity relationships, pharmacology and toxicology.

Celastrol, a principal bioactive ingredient of Tripterygium wilfordii Hook F, has gained extensive exploration due to its unique structure features and multiple promising biological activities. This review will focus on the structural modifications, structure-activity relationships, pharmacology, and toxicology of celastrol in the past ten years. We hope this review would be helpful to get a better grasp of the progresses in the field and provide constructive suggestions for the further study of celastrol.

Analysis of the progress and research hotspots of “Pharmacology and Toxicology” in Chinese universities based on the databases / 中国药科大学学报

@#This paper using ESI,JCR,InCites,and WoS database,the data of Pharmacology and Toxicology were retrieved,and the development status of domestic universities was analyzed by using bibliometrics,statistics and other analysis methods. Taking Chinese universities ranked in the top 100 of ESI as an example,the multi-index status of the subject was analyzed in detail,and the publication category,citation of the highly cited papers in domestic universities were analyzed emphatically on journals,publishing institutions and teams,research frontiers and hot spots,etc. In order to provide data and decision-making references for the construction and development of Pharmacology and Toxicology,the domestic research status and frontier hot spots of Pharmacology and Toxicology were summarized.

Research Progress of Houpo Wenzhongtang / 中国实验方剂学杂志

Houpo Wenzhongtang was contained in Neiwaishang bianhuolun.It was composed of seven medicinal materials of Magnoliae Officinalis Cortex(processed with ginger),Citri Reticulatae Pericarpium(remove white sac),Glycyrrhizea Radix et Rhizoma(processed with honey),Alpiniae Katsumadai Semen,Poria,Aucklandiae Radix and Zingiberis Rhizoma.It was a classic prescription for treatment of deficient cold of spleen and stomach,distention of chest and abdomen,autumn and winter guest cold crime stomach and feel pain at times by LI Dongyuan,who was a famous doctors in Jin-Yuan dynasties.It has been included in the Catalogue of Ancient Classical Prescription(The First Batch) issued by the State Administration of Traditional Chinese Medicine in 2018.This paper systematically reviewed the relevant research progress of Houpo Wenzhongtang from the aspects of famous doctors' theory,usage and dosage,chemical composition,quality analysis,pharmacology and toxicology,clinical application in database,and to provide a reference for further exerting the clinical application of this classical prescription.

Pharmaceuticals and modern statecraft in South Africa: the cases of opium, thalidomide and contraception.

This article provides a history of three pharmaceuticals in the making of modern South Africa. Borrowing and adapting Arthur Daemmrich's term 'pharmacopolitics', we examine how forms of pharmaceutical governance became integral to the creation and institutional practices of this state. Through case studies of three medicaments: opium (late 19th to early 20th century), thalidomide (late 1950s to early 1960s) and contraception (1970s to 2010s), we explore the intertwining of pharmaceutical regulation, provision and consumption. Our focus is on the modernist imperative towards the rationalisation of pharmaceutical oversight, as an extension of the state's bureaucratic and ideological objectives, and, importantly, as its obligation. We also explore adaptive and illicit uses of medicines, both by purveyors of pharmaceuticals, and among consumers. The historical sweep of our study allows for an analysis of continuities and changes in pharmaceutical governance. The focus on South Africa highlights how the concept of pharmacopolitics can usefully be extended to transnational-as well as local-medical histories. Through the diversity of our sources, and the breadth of their chronology, we aim to historicise modern pharmaceutical practices in South Africa, from the late colonial era to the Post-Apartheid present.

PIM-Check: development of an international prescription-screening checklist designed by a Delphi method for internal medicine patients.

OBJECTIVES: Potentially inappropriate medication (PIM) occurs frequently and is a well-known risk factor for adverse drug events, but its incidence is underestimated in internal medicine. The objective of this study was to develop an electronic prescription-screening checklist to assist residents and young healthcare professionals in PIM detection. DESIGN: Five-step study involving selection of medical domains, literature review and 17 semistructured interviews, a two-round Delphi survey, a forward/back-translation process and an electronic tool development. SETTING: 22 University and general hospitals from Canada, Belgium, France and Switzerland. PARTICIPANTS: 40 physicians and 25 clinical pharmacists were involved in the study.Agreement with the checklist statements and their usefulness for healthcare professional training were evaluated using two 6-point Likert scales (ranging from 0 to 5). PRIMARY AND SECONDARY OUTCOME MEASURES: Agreement and usefulness ratings were defined as: >65% of the experts giving the statement a rating of 4 or 5, during the first Delphi-round and >75% during the second. RESULTS: 166 statements were generated during the first two steps. Mean agreement and usefulness ratings were 4.32/5 (95% CI 4.28 to 4.36) and 4.11/5 (4.07 to 4.15), respectively, during the first Delphi-round and 4.53/5 (4.51 to 4.56) and 4.36/5 (4.33 to 4.39) during the second (p<0.001). The final checklist includes 160 statements in 17 medical domains and 56 pathologies. An algorithm of approximately 31 000 lines was developed including comorbidities and medications variables to create the electronic tool. CONCLUSION: PIM-Check is the first electronic prescription-screening checklist designed to detect PIM in internal medicine. It is intended to help young healthcare professionals in their clinical practice to detect PIM, to reduce medication errors and to improve patient safety.

Research progress and clinical application of α-asarone injection / 中国比较医学杂志

Objective To understand the current state of research and clinical application of α-asarone injection.Method Literature search was conducted and the pharmacology, toxicology, preparation, clinical application and adverse reactions of α-asarone were reviewed.Results α-asarone injection has strong relieving effects on cough and asthma, but the quality of production is varying, adverse reactions are often reported, and the toxicological effects need to be further investigated.Conclusions α-asarone injection has a certain clinical effect, but the reports of related adverse reactions are gradually increased.Its toxicity remains to be further studied, and the product quality standard system and instructions need also to be further improved.

Scientific Knowledge and Technology, Animal Experimentation, and Pharmaceutical Development.

Human discovery of pharmacologically active substances is arguably the oldest of the biomedical sciences with origins >3500 years ago. Since ancient times, four major transformations have dramatically impacted pharmaceutical development, each driven by advances in scientific knowledge, technology, and/or regulation: (1) anesthesia, analgesia, and antisepsis; (2) medicinal chemistry; (3) regulatory toxicology; and (4) targeted drug discovery. Animal experimentation in pharmaceutical development is a modern phenomenon dating from the 20th century and enabling several of the four transformations. While each transformation resulted in more effective and/or safer pharmaceuticals, overall attrition, cycle time, cost, numbers of animals used, and low probability of success for new products remain concerns, and pharmaceutical development remains a very high risk business proposition. In this manuscript we review pharmaceutical development since ancient times, describe its coevolution with animal experimentation, and attempt to predict the characteristics of future transformations.

Age matters: Developmental stage of Danio rerio larvae influences photomotor response thresholds to diazinion or diphenhydramine.

Because basic toxicological data is unavailable for the majority of industrial compounds, High Throughput Screening (HTS) assays using the embryonic and larval zebrafish provide promising approaches to define bioactivity profiles and identify potential adverse outcome pathways for previously understudied chemicals. Unfortunately, standardized approaches, including HTS experimental designs, for examining fish behavioral responses to contaminants are rarely available. In the present study, we examined movement behavior of larval zebrafish over 7 days (4-10 days post fertilization or dpf) during typical daylight workday hours to determine whether intrinsic activity differed with age and time of day. We then employed an early life stage approach using the Fish Embryo Test (FET) at multiple developmental ages to evaluate whether photomotor response (PMR) behavior differed with zebrafish age following exposure to diazinon (DZN), a well-studied orthophosphate insecticide, and diphenhydramine (DPH), an antihistamine that also targets serotonin reuptake transporters and the acetylcholine receptor. 72h studies were conducted at 1-4, 4-7 and 7-10dpf, followed by behavioral observations using a ViewPoint system at 4, 7 and 10dpf. Distance traveled and swimming speeds were quantified; nominal treatment levels were analytically verified by isotope-dilution LC-MSMS. Larval zebrafish locomotion displayed significantly different (p<0.05) activity profiles over the course of typical daylight and workday hours, and these time of day PMR activity profiles were similar across ages examined (4-10dpf). 10dpf zebrafish larvae were consistently more sensitive to DPH than either the 4 or 7dpf larvae with an environmentally realistic lowest observed effect concentration of 200ng/L. Though ELS and FET studies with zebrafish typically focus on mortality or teratogenicity in 0-4dpf organisms, behavioral responses of slightly older fish were several orders of magnitude more sensitive to DPH. Our observations highlight the importance of understanding the influence of time of day on intrinsic locomotor activity, and the age-specific hazards of aquatic contaminants to fish behavior.