Potential Adverse Drug Effects Research Articles

Foundational model aided automatic high-throughput drug screening using self-controlled cohort study.

Developing medicine from scratch to governmental authorization and detecting adverse drug reactions (ADR) have barely been economical, expeditious, and risk-averse investments. The availability of large-scale observational healthcare databases and the popularity of large language models offer an unparalleled opportunity to enable automatic high-throughput drug screening for both repurposing and pharmacovigilance. To demonstrate a general workflow for automatic high-throughput drug screening with the following advantages: (i) the association of various exposure on diseases can be estimated; (ii) both repurposing and pharmacovigilance are integrated; (iii) accurate exposure length for each prescription is parsed from clinical texts; (iv) intrinsic relationship between drugs and diseases are removed jointly by bioinformatic mapping and large language model - ChatGPT; (v) causal-wise interpretations for incidence rate contrasts are provided. Using a self-controlled cohort study design where subjects serve as their own control group, we tested the intention-to-treat association between medications on the incidence of diseases. Exposure length for each prescription is determined by parsing common dosages in English free text into a structured format. Exposure period starts from initial prescription to treatment discontinuation. A same exposure length preceding initial treatment is the control period. Clinical outcomes and categories are identified using existing phenotyping algorithms. Incident rate ratios (IRR) are tested using uniformly most powerful (UMP) unbiased tests. We assessed 3,444 medications on 276 diseases on 6,613,198 patients from the Clinical Practice Research Datalink (CPRD), an UK primary care electronic health records (EHR) spanning from 1987 to 2018. Due to the built-in selection bias of self-controlled cohort studies, ingredients-disease pairs confounded by deterministic medical relationships are removed by existing map from RxNorm and nonexistent maps by calling ChatGPT. A total of 16,901 drug-disease pairs reveals significant risk reduction, which can be considered as candidates for repurposing, while a total of 11,089 pairs showed significant risk increase, where drug safety might be of a concern instead. This work developed a data-driven, nonparametric, hypothesis generating, and automatic high-throughput workflow, which reveals the potential of natural language processing in pharmacoepidemiology. We demonstrate the paradigm to a large observational health dataset to help discover potential novel therapies and adverse drug effects. The framework of this study can be extended to other observational medical databases.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic param- eters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treat- ment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide prac- tical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic parameters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide practical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

[Translated article] Therapeutic Drug Monitoring of antibiotic and antifungical drugs in paediatric and newborn patients. Consensus Guidelines of the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Paediatric Infectious Diseases (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host.In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals—usually used off-label in paediatrics—to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.

Using a Patient Portal to Screen Patients for Symptoms After Starting New Medications.

Conduct systematic proactive pharmacovigilance screening for symptoms patients experienced after starting new medications using an electronic patient portal. We aimed to design and test the feasibility of the system, measure patient response rates, provide any needed support for patients experiencing potentially drug-related problems, and describe types of symptoms and problems patients report. We created an automated daily report of all new prescriptions, excluding likely non-new and various over-the-counter meds, and sent invitations via patient portal inviting patients to inquire if they had started the medication, and if "yes," inquire if they had they experienced any new symptoms that could be potential adverse drug effects. Reported symptoms were classified by clinical pharmacists using SOC MeDra taxonomy, and patients were offered follow-up and support as desired and needed. Of 11,724 included prescriptions for 9360 unique patients, 2758 (29.4%) patients responded. Of 2616 unique medication starts, patients reported at least 1 new symptom that represented a potential adverse drug reaction (ADR) in 678/2616 (25.9%). Nearly one-third of those experiencing new symptoms (30.3%) reported 2 or more new symptoms after initiating the drug. GI disorders accounted for 30% of the total reported ADRs. Systematic portal-based surveillance for potential adverse drug reactions was feasible, had higher response rates than other methods (such as automated interactive phone calling), and uncovered rates of potential ADRs (roughly 1 in 4 patients) consistent with other methods/studies.

DIGEP-Pred 2.0: A web application for predicting drug-induced cell signaling and gene expression changes.

The analysis of drug-induced gene expression profiles (DIGEP) is widely used to estimate the potential therapeutic and adverse drug effects as well as the molecular mechanisms of drug action. However, the corresponding experimental data is absent for many existing drugs and drug-like compounds. To solve this problem, we created the DIGEP-Pred 2.0 web application, which allows predicting DIGEP and potential drug targets by structural formula of drug-like compounds. It is based on the combined use of structure-activity relationships (SARs) and network analysis. SAR models were created using PASS (Prediction of Activity Spectra for Substances) technology for data from the Comparative Toxicogenomics Database (CTD), the Connectivity Map (CMap) for the prediction of DIGEP, and PubChem and ChEMBL for the prediction of molecular mechanisms of action (MoA). Using only the structural formula of a compound, the user can obtain information on potential gene expression changes in several cell lines and drug targets, which are potential master regulators responsible for the observed DIGEP. The mean accuracy of prediction calculated by leave-one-out cross validation was 86.5 % for 13377 genes and 94.8 % for 2932 proteins (CTD data), and it was 97.9 % for 2170 MoAs. SAR models (mean accuracy-87.5 %) were also created for CMap data given on MCF7, PC3, and HL60 cell lines with different threshold values for the logarithm of fold changes: 0.5, 0.7, 1, 1.5, and 2. Additionally, the data on pathways (KEGG, Reactome), biological processes of Gene Ontology, and diseases (DisGeNet) enriched by the predicted genes, together with the estimation of target-master regulators based on OmniPath data, is also provided. DIGEP-Pred 2.0 web application is freely available at https://www.way2drug.com/digep-pred.

Acceptance of Mass Drug Administration for Prophylaxis against Lymphatic Filariasis in a Tribal Endemic Area: A Descriptive Cross-sectional Study.

India is at a critical stage to eliminate filariasis. Uncovering the factors governing may help taking appropriate measures to achieve the goal. This study evaluated the acceptance of "mass drug administration" (MDA) for prophylaxis against filariasis and the factors facilitating and interfering with it. A cross-sectional study was conducted in a tribal endemic area of India from May 2022 to October 2022. A validated 29-item self-administered questionnaire was used to collect the data. Items were grouped under "knowledge," "social processes," "think and feel," "practical factors," and "motivation/hesitancy" domains. Of 101 participants, majority were aware of the disease (92.1%), its vector (74.3%), at least one disability caused (87.2%), and governmental scheme of MDA (69.3%). Two-thirds never received and 85.1% did not receive MDA within 1 year. 68.3% refused of distribution of MDA to their doorstep. Majority were concerned for getting MDA for self and their family/friends; however, 49.5% showed inability to take independent decision. More than 30% disagreed to get MDA had it been available. The region with the highest concerns for adverse drug effects showed minimum MDA consumption than others (P < 0.05). MDA acceptance/consumption was significantly associated with knowledge about disability caused, distribution of drugs by a health-care representative to doorstep, behavior of the representative, and concerns about potential adverse drug effects. MDA coverage was inadequate in the study population. Level of knowledge, practical difficulties in getting drugs, inapt thinking/concerns, motivation, awareness about disabilities caused, door-to-door drug distribution, and behavior of health-care representative(s), were identified as factors significantly affecting acceptance of MDA.

Pluripotent stem cells for target organ developmental toxicity testing.

Prenatal developmental toxicity research focuses on understanding the potential adverse effects of environmental agents, drugs, and chemicals on the development of embryos and fetuses. Traditional methods involve animal testing, but ethical concerns and the need for human-relevant models have prompted the exploration of alternatives. Pluripotent stem cells (PSCs) are versatile cells with the unique ability to differentiate into any cell type, serving as a foundational tool for studying human development. Two-dimensional (2D) PSC models are often chosen for their ease of use and reproducibility for high-throughput screening. However, they lack the complexity of an in vivo environment. Alternatively, three-dimensional (3D) PSC models, such as organoids, offer tissue architecture and intercellular communication more reminiscent of in vivo conditions. However, they are complicated to produce and analyze, usually requiring advanced and expensive techniques. This review discusses recent advances in the use of human PSCs differentiated into brain and heart lineages and emerging tools and methods that can be combined with PSCs to help address important scientific questions in the area of developmental toxicology. These advancements and new approach methods align with the push for more relevant and predictive developmental toxicity assessment, combining innovative techniques with organoid models to advance regulatory decision-making.

Anti-Infective Therapy in Pregnant Women and Children: Current Shortcomings and Potential Pitfalls

Pregnant women and children are kept under special group of patients that needs extra efforts while selecting drug therapy for this group of patients. The use of anti-infective medicines in pregnant women and children has several limitations because of altered pharmacokinetics and pharmacodynamics of anti-infectives in these groups of patients, which is poorly understood, and optimal dosage regimes have yet to be established. This simply suggest that when drug therapy is suggested early in life the medication's perceived possible harmful effects and long term impact on pregnancy and the growing foetus must be taken into consideration. In this special group of populations, these limitations prohibit the recruitment of these categories of patients in clinical research and hence hamper the approval of novel anti-infective medications. Consequently, drug selection in these patients becomes a challenge and poses chances of enhanced risk of potential adverse drug effects and toxicity. In this review we provide some particular instances of the existing shortcomings and current pitfalls of anti-infective medicine usage in pregnant women as well as children.

Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.

Knowledge4COVID-19: A semantic-based approach for constructing a COVID-19 related knowledge graph from various sources and analyzing treatments’ toxicities

In this paper, we present Knowledge4COVID-19, a framework that aims to showcase the power of integrating disparate sources of knowledge to discover adverse drug effects caused by drug–drug interactions among COVID-19 treatments and pre-existing condition drugs. Initially, we focus on constructing the Knowledge4COVID-19 knowledge graph (KG) from the declarative definition of mapping rules using the RDF Mapping Language. Since valuable information about drug treatments, drug–drug interactions, and side effects is present in textual descriptions in scientific databases (e.g., DrugBank) or in scientific literature (e.g., the CORD-19, the Covid-19 Open Research Dataset), the Knowledge4COVID-19 framework implements Natural Language Processing. The Knowledge4COVID-19 framework extracts relevant entities and predicates that enable the fine-grained description of COVID-19 treatments and the potential adverse events that may occur when these treatments are combined with treatments of common comorbidities, e.g., hypertension, diabetes, or asthma. Moreover, on top of the KG, several techniques for the discovery and prediction of interactions and potential adverse effects of drugs have been developed with the aim of suggesting more accurate treatments for treating the virus. We provide services to traverse the KG and visualize the effects that a group of drugs may have on a treatment outcome. Knowledge4COVID-19 was part of the Pan-European hackathon#EUvsVirus in April 2020 and is publicly available as a resource through a GitHub repository and a DOI.

Effect of drugs on fertility in male dogs: A review.

The aim of this literature review was to present and discuss the available data on the positive and negative effects of drugs on male dog fertility. Apart from information on hormones and anti-hormonal agents, there is still only little information available regarding the effect of other drugs on sexual function and fertility in male dogs. A negative impact on fertility in male dogs has been reported for vincristine, cyclophosphamide, tetracycline and ketoconazole. However, preclinical safety studies of drugs for human use indicated that spermatogenesis in dogs may be sensitive to a wide variety of drugs. Thus, potential adverse effects of drugs on fertility should always be considered before their use in stud dogs. Also, in cases of reduced fertility or infertility in male dogs, previous medical treatment should be taken into account as a possible cause. In most cases, the effects of drugs on sexual function and spermatogenesis are reversible after the discontinuation of the drug. Further studies on the effects of drugs on male dog fertility are needed.

PH-guided fluorescent sensing probe for the discriminative detection of Cl− and Br− in human serum

The fluctuation of the halide ion concentration in human serum is of a high clinical implication. The measurement of Cl− in human serum samples is important because Cl− is a major constituent of human serum and certain Cl− levels are indicators of many acute diseases. Real-time monitoring of Br− levels in human serum samples from patients ingesting Br− salt-based antiepileptic drugs is important to regulate potential adverse drug effects. In this study, we developed a fluorescent probe for the discriminative sensing of Cl− and Br− using a naphthalimide–benzimidazole conjugate-based Ag+ complex (L1-Ag+ complex) by exploiting the strong interaction between Ag+ and halide ions with selectivity control by pH variation. The probe exhibited a dual function of detecting Cl− and Br− at pH levels of 4.5 and 8.0, respectively. Under this two pH conditions, the probe showed a high sensitivity (limit of detection (LOD) = 43 and 5 μM for Cl− and Br−, respectively) and selectivity toward Cl− and Br−. Importantly, the probe could be applied in the quantification of Cl− and Br− levels in human serum samples under two conditions: Cl− in normal human serum and Br− in the serum-mimicking that of epileptic patients during medication.

Impairment of LA strain and LV myocardial work in Ph+ Chronic myeloid leukaemia patients treated with TKis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Worsening of cardiac function with increased arrhythmic risk is common in cancer patients undergoing chemotherapy. Impaired LV Global Longitudinal Strain (GLS) in these patients despite preserved ejection fraction is a common issue. Recently, myocardial work by speckle-tracking echocardiography has been used to overcome GLS limitations in various conditions, but little is known about its usefulness in the detection of cardiac toxicity. Moreover, left atrial (LA) toxicity may occur early in the course of cancer therapy. The main aim of the study was to assess the cardiotoxic effects of tyrosine kinase inhibitors (TKIs) on patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) by using novel echocardiographic tools as myocardial work and atrial strain analysis. Methods We retrospectively enrolled Ph+ CML patients treated with TKIs followed at the cardio-oncology outpatient clinic of our hospital from December 2018 to March 2019 who underwent clinical evaluation with ECG and echocardiogram (TTE) before and after one year of treatment with TKIs. Healthy subjects were enrolled in the control group matched for gender, age and cardiovascular risk factors. Myocardial work was derived from the strain-pressure relation, integrating in its calculation the non-invasive arterial pressure. LA longitudinal strain (reservoir, conduit and booster) was obtained from an optimized apical 4-chamber view of the LA. Results The study recruited 32 patients in Ph+ CML group and 32 healthy controls. 39% of patients were treated with Imatinib, 29.3% with Nilotinib, 4.9% with Dasatinib and 4.9% with Ponatinib. Main results are detailed in the Table 1. At one-year follow-up there was a significant reduction compared to baseline in Global Constructive Work (2555.22 ± 564.33 vs 2119.31 ± 700.19; p = 0.0001), Global Work Efficiency (96.13 ± 1.90 vs 94.00 ± 2.96; p = 0.002) and Global Work Index (2340.75 ± 579.57 vs 1938.46 ± 680.23; p = 0.001), and a non-significant reduction in Global Wasted Work (p = 0.393). Regarding left atrial strain analysis at the one-year follow-up there was a statistically significant reduction in LA contractile strain (booster= 14.63 ± 1.408 vs 12.38 ± 1.581; p= 0.018). LA contractile strain reduction was also observed in the comparison with controls (12.38 ± 2.99 vs 14.91 ± 3.09; p = 0.009). Any other significant difference was detected between baseline and FU TTE data in the Ph+ CML group. Conclusions New imaging methods for the study of cardiotoxicity provide an additional tool for early prediction of potential adverse effects of antineoplastic drugs. TKIs therapy leads to an impairment of atrial contractility, which can be detected by atrial strain e myocardial work analysis. Abstract table 1 Abstract figure 1

710 Advanced echocardiographic analysis to identify cardiac toxicity after TKI exposure in patients with CML

Abstract Aims Worsening of cardiac function with increased arrhythmic risk is common in cancer patients undergoing chemotherapy. Impaired LV global longitudinal strain (GLS) in these patients despite preserved ejection fraction is a common issue. Recently, myocardial work by speckle-tracking echocardiography has been used to overcome GLS limitations in various conditions, but little is known about its usefulness in the detection of cardiac toxicity. Moreover, left atrial (LA) toxicity may occur early in the course of cancer therapy. The main aim of the study was to assess the cardiotoxic effects of tyrosine kinase inhibitors (TKIs) on patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) by using novel echocardiographic tools as myocardial work and atrial strain analysis. Methods and results We retrospectively enrolled Ph+ CML patients treated with TKIs followed at the cardio-oncology outpatient clinic of our hospital from December 2018 to March 2019 who underwent clinical evaluation with ECG and echocardiogram (TTE) before and after 1 year of treatment with TKIs. Healthy subjects were enrolled in the control group matched for gender, age and cardiovascular risk factors. Myocardial work was derived from the strain-pressure relation, integrating in its calculation the non-invasive arterial pressure. LA longitudinal strain (reservoir, conduit, and booster) was obtained from an optimized apical 4-chamber view of the LA. The study recruited 32 patients in Ph+ CML group and 32 healthy controls. 39% of patients were treated with Imatinib, 29.3% with Nilotinib, 4.9% with Dasatinib and 4.9% with Ponatinib. Main results are detailed in Table 1. At 1-year follow-up there was a significant reduction compared to baseline in global constructive work (2555.22 ± 564.33 vs. 2119.31 ± 700.19; P = 0.0001), global work efficiency (96.13 ± 1.90 vs. 94.00 ± 2.96; P = 0.002), and global work index (2340.75 ± 579.57 vs. 1938.46 ± 680.23; P = 0.001), and a non-significant reduction in global wasted work (P = 0.393). Regarding left atrial strain analysis at the 1-year follow-up there was a statistically significant reduction in LA contractile strain (booster= 14.63 ± 1.408 vs. 12.38 ± 1.581; P = 0.018). LA contractile strain reduction was also observed in the comparison with controls (12.38 ± 2.99 vs. 14.91 ± 3.09; P = 0.009). Any other significant difference was detected between baseline and FU TTE data in the Ph+ CML group. Conclusions New imaging methods for the study of cardiotoxicity provide an additional tool for early prediction of potential adverse effects of antineoplastic drugs. TKIs therapy leads to an impairment of atrial contractility, which can be detected by atrial strain e myocardial work analysis.

CE: Hypertensive Emergencies: A Review.

While acute blood pressure elevations are commonly seen in the ED, not all require emergency treatment. True hypertensive emergencies are characterized by a rapid elevation in blood pressure to a level above 180/120 mmHg and are associated with acute target organ damage, which requires immediate hospitalization for close hemodynamic monitoring and IV pharmacotherapy. Recognizing the clinical signs and symptoms of hypertensive emergency, which may vary widely depending on the target organ involved, is critical. High blood pressure levels that produce no signs or symptoms of target organ damage may be treated without hospitalization through an increase in or reestablishment of previously prescribed oral antihypertensive medication. However, all patients presenting with blood pressure this high should undergo evaluation to confirm or rule out impending target organ damage, which differentiates hypertensive emergency from other hypertensive crises and is vital in facilitating appropriate emergency treatment. Drug therapy for hypertensive emergency is influenced by end-organ involvement, pharmacokinetics, potential adverse drug effects, and patient comorbidities. Frequent nursing intervention and close monitoring are crucial to recuperation. Here, the authors define the spectrum of uncontrolled hypertension; discuss the importance of distinguishing hypertensive emergencies from hypertensive urgencies; and describe the pathophysiology, clinical manifestations, and management of hypertensive emergencies.

Kaempferol Alleviates Murine Experimental Colitis by Restoring Gut Microbiota and Inhibiting the LPS-TLR4-NF-κB Axis.

Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)–dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration via increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of IL-1β, IL-6, and TNF-α and downregulated transcription of an array of inflammatory signaling molecules, while it increased IL-10 mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the Firmicutes to Bacteroidetes ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as Prevotellaceae and Ruminococcaceae; and reducing the richness of Proteobacteria in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.

Drug Residues in Foods of Animal Origin and Their Impact on Human Health: Review

The safety of human food is threatened by various agents including pathogenic microorganisms, and antimicrobial agents. Antibiotics are natural products of a micro-organism, or similar semi-synthetic products that inhibit the growth or destroy microorganisms. Residues of veterinary medicines are defined as pharmacologically active substances, principles, or degradation products and their metabolites, which remain in foodstuffs obtained from animals that have been administered the veterinary medicine. The most common causes for the presence of antibiotic residues in food of animal origin are violation of withdrawal periods, overdosing of antibiotics and use of inaccurate routes of administration of drugs. Drug residues concentrations vary from tissue to tissue and are generally observed to be higher in tissues of storage such as body fat or in organs that actively metabolize and excrete them. Probably the most common way milk is contaminated by penicillin is through intra-mammary infusion of the drug in the treatment of mastitis. The presence of antibiotics or their metabolites in food is potentially hazardous to health as it may cause allergic reactions in people and antibiotic resistance in pathogenic microorganisms. Some antibiotics like streptomycin, neomycin and gentamicin has been reported to cause damage to the kidney and to hearing. Allergic reaction to the human body mostly resulted from β-Lactam antibiotics. Anaphylactic reactions are reported to result from consumption of beef or pork containing penicillin. Drugs in which their residues induce cancer in humans or consumers are: nitrofurans, nitroimdazoles, etc. Antibiotics are invariably administered to dairy cattle, but their indiscriminate use, without adequate technical and veterinary control, can lead to a series of negative consequences at all levels of the dairy productive chain. Many antibacterial and anticoccidial drugs are licensed for use in poultry for treatment of enteric and respiratory disease. Potential adverse effects of drugs that appear as residues in food animals are: carcinogenic, allergic, toxic, neurologic disorder and microbiological effects. Keywords: Drugs, Drug residue, Food, Human DOI: 10.7176/FSQM/108-02 Publication date: May 31 st 2021

Drug safety in hospitalized patients with tuberculosis: Drug interactions and adverse drug effects.

Hospitalized patients with tuberculosis (TB) are prescribed with drugs having high risk of potential drug-drug interactions (pDDIs) and adverse drug effects (ADEs). To explore the adverse effects of anti-tuberculosis (anti-TB) drugs and the prevalence and predictors of pDDIs in hospitalized patients with TB. Clinical profiles of 436TB patients were reviewed for adverse effects induced by anti-TB drugs and screened for pDDIs using Micromedex-DrugReax. Prevalence and severity levels of pDDIs were reported. Odds ratios for predictors were calculated using logistic regression analysis. Of total 436 patients, adverse effects of anti-TB drugs were found in 36%. ADEs were highly prevalent in patients with high doses of anti-TB drugs. Hepatotoxicity, neuropathy, insomnia, arthralgia, psychosis, hematological alterations, skin rashes, red color stool, diplopia, and photophobia were the identified ADEs. All drugs types- and anti-TB drugs-pDDIs were reported in 78.2% and 55.7%, respectively. Major-pDDIs of anti-TB drugs were identified in 55.5%. Total 1090 anti-TB drugs pDDIs were found, among them, 55.6% were of major- and 40.5% were of moderate-severity. Significant association was observed for the pDDIs with≥7 prescribed medicines (P<0.001). Potential adverse outcomes of the most frequent interactions were hepatotoxicity, decreased drug's effectiveness, QT-interval prolongation, nephrotoxicity, and gastrointestinal ulceration. Patients with TB present with a considerable number of clinically important pDDIs and ADEs (particularly hepatotoxicity). TB patients should be monitored for adverse effects of anti-TB drugs. Attention should be given to major-pDDIs. Patients more at risk to interactions should be identified and monitored for related adverse outcomes.

Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS.

Lung transplantation is a potentially life-saving therapy for patients with terminal respiratory illnesses. Long-term survival is limited by the development of a variety of opportunistic infections and rejection. Optimal means of differential diagnosis of infection and rejection have not been established. With these challenges in mind, we tried to use transbronchial lung biopsy (TBLB) rapid on-site cytological evaluation (ROSE), metagenomic next-generation sequencing (mNGS), and routine histologic examination to timely distinguish infection and rejection, and accurately detect etiologic pathogens. We reviewed the medical records of all patients diagnosed with infection or rejection by these means from December 2017 to September 2018 in our center. We identified seven recipients whose clinical course was complicated by infection or rejection. Three patients were diagnosed with acute rejection, organizing pneumonia, and acute fibrinoid organizing pneumonia, respectively. Four of the seven patients were diagnosed with infections, including Pneumocystis carinii pneumonia, cytomegalovirus, Aspergillus, and bacterial pneumonia. These patients recovered after proper treatment. TBLB + ROSE + mNGS might be a good method to accurately detect etiologic pathogens, which may help us to facilitate the use of targeted and precision medicine therapy in postoperative complications and avoid unnecessary potential adverse effects of drugs.