Anticancer Res. 2023 Mar;43(3):1377-1384. doi: 10.21873/anticanres.16286.

ABSTRACT

BACKGROUND/AIM: This study aimed to assess the clinical impact of lenvatinib after disease progression on atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC).

PATIENTS AND METHODS: A total of 14 patients who received lenvatinib after failure of atezolizumab plus bevacizumab and all patients were classified as having a Barcelona Clinic Liver Cancer stage C. Six patients had macrovascular invasion, and a liver occupation rate of >50% was reported in seven patients. The Kaplan-Meier method was performed to analyze the cumulative survival, while log-rank test was used to detect the differences. The dose of lenvatinib was determined based on body weight.

RESULTS: The participants' responses to lenvatinib treatment were as follows: 21.4% achieved partial response (PR), while 35.7% had a stable disease, with a disease control rate of 57.1%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 8.3 months, respectively; the median PFS and OS were 6.7 months and 10.5 months in the PR group. No significant difference was observed in the median PFS and OS between patients with and without macrovascular invasion or liver occupation rate of >50%. Most of the adverse events (AEs) were categorized as grade 1-2; all patients tolerated the AEs, and no drug-related mortality was reported. Additionally, half of the population underwent subsequent therapy after progression on lenvatinib treatment.

CONCLUSION: Lenvatinib is effective and can be safely used as second-line systemic therapy after progression on atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice.

PMID:36854513 | DOI:10.21873/anticanres.16286

J Cancer Res Clin Oncol. 2023 Feb 28. doi: 10.1007/s00432-023-04630-4. Online ahead of print.

ABSTRACT

PURPOSE: Clinical pharmacy can reduce drug-related iatrogenesis by improving the management of adverse effects of drugs, limiting drug-drug interactions, and improving patient adherence. Given the vulnerability of cancer patients and the toxicity of injectable anticancer drugs, clinical pharmacy service (CPS) could provide a significant clinical benefit in cancer care. This review aims to synthesize existing evidence on clinical pharmacy's impact on patients treated with intravenous anticancer drugs.

METHODS: A comprehensive search was performed in the PubMed/Medline database from January 2000 to December 2021, associating the keywords: clinical pharmacy, pharmaceutical care, pharmacist, oncology, and chemotherapy. To be eligible for inclusion, studies have to report clinical pharmaceutical services for patients treated with intravenous chemotherapy with a clinical and/or economic impact.

RESULTS: Forty-one studies met the selection criteria. Various CPS were reported: medication reconciliation, medication review, and pharmaceutical interview with patient. There was a lack of randomized study (n = 3; 7.3%). In one randomized controlled trial, pharmaceutical intervention significantly improved quality of life of patients receiving pharmaceutical care during injectable anticancer drugs courses. Economical results appear to show positive impact of clinical pharmacy with cost savings reported from 3112.87$ to 249 844€. Although most studies were non-comparative, they highlighted that clinical pharmacy tend to limit chemotherapy side effects and drug-related problems, improve quality of life and satisfaction of patients and healthcare professional, and a positive economic impact.

CONCLUSION: Clinical pharmacy can reduce adverse drug events in cancer patients. More robust and economic evaluations are still required to support its development in everyday practice.

PMID:36853384 | DOI:10.1007/s00432-023-04630-4

J Korean Med Sci. 2023 Feb 27;38(8):e56. doi: 10.3346/jkms.2023.38.e56.

ABSTRACT

BACKGROUND: Adverse drug reactions (ADRs) are escalating, and their socioeconomic burden is increasing. However, large-scale prospective studies investigating ADRs during hospitalization are rare in Korea. We prospectively investigated the incidence, characteristics, and economic burden of ADRs in hospitalized patients based on electronic medical records (EMRs).

METHODS: Among patients admitted to three hospitals from October 2016 to October 2017, 5,000 patients were randomly selected and prospectively observed during hospitalization. Research nurses monitored and detected patients who had symptoms, signs, or laboratory findings suspicious for ADRs using an EMR-based detection protocol. Next, allergy and ADR specialists reviewed the medical records to determine the relationship between adverse reactions and drugs. Cases in which a causal relationship was certain, probable/likely, or possible were included in the ADR cases. Clinically meaningful ADR cases or those leading to prolonged hospitalization were defined as significant ADRs.

RESULTS: ADRs occurred in 510 (10.2%) patients. The mean length of hospital stay was approximately 5 days longer in patients with ADRs. Opioids accounted for the highest percentage of total ADRs. Significant ADRs were observed in 148 (3.0%) patients. Antibiotics accounted for the highest percentage of significant ADRs. Drug hypersensitivity reactions (DHRs) occurred in 88 (1.8%) patients. Antibiotics accounted for the highest percentage of DHRs. The average medical expenses for one day of hospitalization per patient were highest in significant ADRs, followed by non-significant ADRs, and non-ADRs.

CONCLUSION: ADRs in hospitalized patients are an important clinical issue, resulting in a substantial socioeconomic burden. EMR-based strategy could be a useful tool for ADR monitoring and early detection.

PMID:36852852 | DOI:10.3346/jkms.2023.38.e56

Drug Dev Ind Pharm. 2023 Feb 28:1-12. doi: 10.1080/03639045.2023.2183724. Online ahead of print.

ABSTRACT

OBJECTIVE: The present work provides characterization of rheological properties of a new bentonite-based thixotropic gel emulsion nasal spray (AM-301), its nasal residence time, distribution, safety and tolerability.

SIGNIFICANCE: The nasal epithelium is a portal of entry for allergens and primary infection by airborne pathogens. Non-pharmacological interventions, which enhance physical and biological barriers, protect against allergens and pathogens without drug-related side effects. AM-301 has shown promising efficacy and safety in the nasal epithelium against viruses (in vitro) and pollen (clinical).

METHODS: Technical part (i) spray characterization was performed with a validated droplet size distribution method; evaluation of the rheological properties of the formulation was performed by a validated amplitude sweep method and a validated oscillation, rotation, oscillation; Clinical part (ii) nasal and oropharyngeal endoscopy were used to provide a semi-quantitative evaluation of distribution and residence time of fluorescein-labelled AM-301 in the nose and oropharynx of healthy volunteers; (iii) tolerability and safety.

RESULTS: (i) The non-Newtonian rheological properties of the formulation allow AM-301 to be sprayed and then to revert to a gel to prevent run-off from the nasal cavity; (ii) the formulation remains on the inferior turbinate, septum and oropharynx of volunteers for up to 210 min and on the middle turbinate for up to 60 min; two nasal sprays provide no substantial benefit over a single application with regards to coverage or retention; (iii) the spray is well tolerated.

CONCLUSIONS: Single dose spray delivery of AM-301 provides extended coverage of the nasal mucosa up to the inferior turbinates.

PMID:36852769 | DOI:10.1080/03639045.2023.2183724

Hepatol Res. 2023 Feb 28. doi: 10.1111/hepr.13895. Online ahead of print.

ABSTRACT

AIM: To compare patient characteristics and outcomes between the overall and Japanese populations of GLIMMER.

METHODS: GLIMMER was a multicenter, double-blind, randomized, placebo-controlled, Phase 2b study evaluating linerixibat for the treatment of pruritus in patients with primary biliary cholangitis (PBC).

RESULTS: A total of 147 patients were randomized in the GLIMMER overall population with 38 patients comprising the Japanese population. Demographics and baseline clinical characteristics were similar across treatment groups and between both populations. A reduction in mean worst daily itch score from baseline to Week 16 (primary endpoint) was seen in all groups, with the largest reduction observed with linerixibat 40 mg twice daily (BID; -2.92 [95% CI: -5.07, -0.76] and -2.86 [95% CI: -3.76, -1.95] for Japanese and overall populations, respectively). The highest proportion of responders was generally in the 40 mg BID group in both populations regardless of the responder definition applied. Improvements in health-related quality of life were generally consistent in both populations. In the Japanese and overall populations, on-treatment drug-related adverse events were reported in 25% and 19% of patients in the placebo group and 0-86% and 31-78% of patients in the linerixibat groups, respectively. Consistent with the mechanism of action, the most common events were gastrointestinal in nature. Effects of linerixibat on pharmacodynamic biomarkers favored BID dosing.

CONCLUSIONS: Therapeutic responses and safety of linerixibat were consistent between the Japanese and overall populations of GLIMMER. Linerixibat may provide an effective treatment option for cholestatic pruritus in patients with PBC. This article is protected by copyright. All rights reserved.

PMID:36852705 | DOI:10.1111/hepr.13895

Drug Deliv. 2023 Dec;30(1):2184307. doi: 10.1080/10717544.2023.2184307.

ABSTRACT

Rheumatoid arthritis (RA), a systemic autoimmune disease that dramatically affects patients' quality of life. Given the intricacy of RA's pathophysiology, no single treatment can completely halt the disease progression. Here, we attempted to treat RA holistically and synergistically by co-delivering methotrexate (MTX), a standard slow-acting anti-rheumatic drug, and phenethyl isothiocyanate (PEITC), a bioactive phytochemical, using a sodium alginate (SA)-pluronic F127 (PF-127) in situ hydrogel formulation. Therefore, in the current study, the co-delivery of MTX and PEITC in the nanoparticulate form could help enhance stability and solubility and facilitate greater penetration in the target arthritic tissues. The fabricated MTX NP and PEITC NE were found to have a minimum particle size, PDI, and good zeta potential. Results from in vitro release studies showed that MTX and PEITC were simultaneously released from the DD NP HG matrix over 6-7 days through diffusion and erosion mechanisms. An intra-articular (IA) injection of DD NP HG dramatically reduced chronic inflammation in adjuvant-induced arthritis (AIA) rats, delayed the onset of bone erosion, significantly reduced synovitis, and down-regulated the inflammatory cytokine expression. Most notably, the co-delivery strategy almost entirely restored the morphological features of the ankle joints of RA rats. The hepatic and renal function tests indicated good biological safety for DD NP HG in RA conditions. Taken together, these findings indicated that DD NP HG could achieve good anti-inflammatory activity and reverse cartilage disruption through a synergistic effect between two nanoparticulate forms of MTX and PEITC, which can effectively improve the drawbacks of their free forms.

PMID:36852696 | DOI:10.1080/10717544.2023.2184307

JAMA Netw Open. 2023 Feb 1;6(2):e230803. doi: 10.1001/jamanetworkopen.2023.0803.

ABSTRACT

IMPORTANCE: The US leads the world in the raw number of incarcerated persons as well as the rate of incarceration, with detrimental effects on individual-, family-, community-, and population-level health; as such, federal research has a critical role in documenting and addressing the health-related impacts of the US criminal legal system. How often incarceration-related research is funded at the National Institutes of Health (NIH), National Science Foundation (NSF), and US Department of Justice (DOJ) levels has a direct association with the public attention given to mass incarceration as well as the efficacy of strategies to mitigate negative effects and poor health related to incarceration.

OBJECTIVE: To understand how many incarceration-related projects have been funded at the NIH, NSF, and DOJ.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used public historical project archives to search for relevant incarceration-related keywords (eg, incarceration, prison, parole) since January 1, 1985 (NIH and NSF), and since January 1, 2008 (DOJ). Quotations and Boolean operator logic were used. All searches and counts were conducted and double verified by 2 coauthors between December 12 and 17, 2022.

MAIN OUTCOMES AND MEASURES: Number and prevalence of funded projects related to incarceration and prison keywords.

RESULTS: The term incarceration resulted in 3540 of 3 234 159 total project awards (0.11%) and prisoner-related terms resulted in 11 455 total project awards (0.35%) across the 3 federal agencies since 1985. Nearly a tenth of all projects funded at NIH since 1985 related to education (256 584 [9.62%]) compared with only 3373 projects (0.13%) that related to criminal legal or criminal justice or correctional system and 18 projects (0.0007%) that related to incarcerated parents. Only 1857 (0.07%) of all NIH-funded projects have been funded related to racism since 1985.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found that a very low number of projects about incarceration have historically been funded at the NIH, DOJ, and NSF. These findings reflect a dearth of federally funded studies investigating the effects of mass incarceration or intervention strategies to mitigate adverse effects. Given the consequences of the criminal legal system, it is undoubtedly time for researchers, and our nation, to invest more resources into studying whether this system should be maintained, the intergenerational effects of mass incarceration, and strategies to best mitigate its impact on public health.

PMID:36848087 | PMC:PMC9972190 | DOI:10.1001/jamanetworkopen.2023.0803

Pharmacol Res Perspect. 2023 Apr;11(2):e01067. doi: 10.1002/prp2.1067.

ABSTRACT

Protein kinase inhibitors (PKIs) used in oncology can induce severe and even fatal hepatotoxicity. Several PKIs are registered within a certain class to target a specific kinase. No systematic comparison of the reported hepatotoxicity and clinical guidance for monitoring and management of hepatotoxic events between the various PKI summaries of product characteristics (SmPC) is yet available. A systematic analysis of data on 21 hepatotoxicity parameters obtained from the SmPCs and European public assessment reports (EPARs) of European Medicines Agency-approved antineoplastic PKIs (n = 55) has been conducted. The median reported incidence (range) of all grades of aspartate aminotransferase (AST) elevations was 16.9% (2.0%-86.4%) for PKI monotherapy, with 2.1% (0.0%-10.3%) being grade 3/4 and for all grades alanine aminotransferase (ALT) elevations 17.6% (2.0%-85.5%), with 3.0% (0.0%-25.0%) being grade 3/4. Fatalities due to hepatotoxicity were reported for 22 out of 47 PKIs (monotherapy) and for 5 out of 8 PKIs (combination therapy). A maximum grade of grade 4 and grade 3 hepatotoxicity was reported for 45% (n = 25) and 6% (n = 3), respectively. Liver parameter monitoring recommendations were present in 47 of the 55 SmPCs. Dose reductions were recommended for 18 PKIs. Discontinuation was recommended for patients meeting Hy's law criteria (16 out of 55 SmPCs). Severe hepatotoxic events are reported in approximately 50% of the analyzed SmPCs and EPARs. Differences in the degree of hepatotoxicity are apparent. Although liver parameter monitoring recommendations are present in the vast majority of the analyzed PKI SmPCs, the clinical guidance for hepatotoxicity was not standardized.

PMID:36846954 | DOI:10.1002/prp2.1067

Pan Afr Med J. 2022 Jul 20;42:218. doi: 10.11604/pamj.2022.42.218.32239. eCollection 2022.

ABSTRACT

INTRODUCTION: even though Highly Active Antiretroviral Therapy (HAART) is effective in managing Human Immuno-deficiency Virus (HIV) infection, it is not without its adverse drug effects (ADE) and or adverse drug reactions (ADRs). The study of ADRs associated with HAART in hospitals and clinics is crucial in gauging the burden of the severity of morbidity and mortality in such facilities, hence the reporting of such ADRs is important.

METHODS: the study was divided into 2 phases: the 1st phase entailed collecting data from HIV infected patients using a questionnaire on ADR experienced, whilst the 2nd phase was a retrospective analysis of respective patients´ medical files to record if an ADR was experienced. Three antiretroviral clinics linked to public sector facilities in EThekwini Metro, Kwa-Zulu Natal were the study sites.

RESULTS: seventy-two percent of patients reported at least one ADR after HAART initiation. Skin rash (11%) was the most commonly stated ADR by patients, whilst anemia (29%) and cardiovascular disease (23%) were the most commonly recorded ADRs on the patients´ medical files. Of those patients who reported ADRs, 57% were on the first line regimen consisting of Tenofovir, Emtricitabine and Efavirenz. Thirty-six patients reported that they were admitted to hospitals due to ADRs, however none resulted in death. These ADRs were experienced by patients on different regimens, with 10 admissions from the same regimen.

CONCLUSION: adverse drug reactions were experienced by South African patients, however the reporting of ADRs by patients were inconsistent with what was recorded on their medical files.

PMID:36845236 | PMC:PMC9949296 | DOI:10.11604/pamj.2022.42.218.32239

Front Immunol. 2023 Feb 9;14:1030810. doi: 10.3389/fimmu.2023.1030810. eCollection 2023.

ABSTRACT

OBJECTIVE: This study aimed to investigate the Coronavirus disease 2019 (COVID-19) vaccination rate, reasons for vaccine hesitancy and clinical effects on patients with Takayasu's arteritis (TAK).

METHODS: A web-based survey was administered to a TAK cohort established by the Department of Rheumatology, Zhongshan Hospital through WeChat in April, 2022. Responses from a total of 302 patients were received. The Sinovac or Sinopharm inactivated vaccination rate, side effects, and vaccine hesitancy reasons were analyzed. In addition, disease flare, new disease onset, and changes of immune-related parameters after vaccination were analyzed in vaccinated patients.

RESULTS: Among 302 patients, 93 (30.79%) received the inactivated COVID-19 vaccination. Among the 209 unvaccinated patients, the most common reason for hesitancy were concern about side effects (136, 65.07%). Vaccinated patients had a longer disease duration (p = 0.08) and lower use of biologic agents (p < 0.001); 16 (17.20%) of the 93 vaccinated patients developed side effects, and most of them were mild; 8 (8.60%) developed disease flares or new-onset disease 12-128 days post-vaccination and 2 (2.15%) developed serious adverse effects (vision defect and cranial infarction). Immune-related parameters of 17 patients indicated decreases in IgA and IgM after vaccination (p < 0.05). Eighteen (19.35%) of the 93 vaccinated patients were diagnosed post-vaccination.These patients had a significantly higher percentage of CD19+ B cells at disease onset (p < 0.05) than the unvaccinated patients diagnosed at the same time.

CONCLUSION: The vaccination rate was low in TAK, which was mainly caused by concerns about negative effects of vaccination on their disease. An acceptable safety profile was observed in vaccinated patients. The risk of disease flare associated with COVID-19 vaccination warrants further investigation.

PMID:36845121 | PMC:PMC9946967 | DOI:10.3389/fimmu.2023.1030810

Drug Ther Bull. 2023 Feb 27:dtb-2023-000011. doi: 10.1136/dtb.2023.000011. Online ahead of print.

ABSTRACT

Overview of: Pham C, Le K, Draves M, et al Assessment of FDA-approved drugs not recommended for use or reimbursement in other countries, 2017-2020. JAMA Intern Med 2023. doi:10.1001/jamainternmed.2022.6787. [Epub ahead of print 13 Feb 2023].

PMID:36849223 | DOI:10.1136/dtb.2023.000011

Z Gerontol Geriatr. 2023 Feb 27. doi: 10.1007/s00391-023-02173-4. Online ahead of print.

ABSTRACT

BACKGROUND: From a geriatric perspective, the use of antipsychotic drugs (AP) is associated with significant risks in addition to their known effects. These include unfavorable interactions with geriatric syndromes, such as immobility and risk of falling, and potentially increased mortality, at least in certain patient groups. With reference to this the current state of knowledge on treatment with AP in older people with schizophrenia spectrum disorders is summarized with a focus on the typical multimorbidity of geriatric patients.

METHODS: Narrative review with special consideration of guidelines and consensus papers from German speaking countries and a PubMed-supported literature search for current systematic reviews and meta-analyses.

RESULTS: Antipsychotic agents are an essential part of a comprehensive treatment concept for schizophrenia with well-documented evidence. In geriatric patients adaptations under gerontopharmacological aspects are necessary. A sufficient data basis for evidence-based recommendations for the treatment of multimorbid and frail geriatric patients does not exist.

CONCLUSION: An effective and as safe as possible treatment with AP requires a careful risk-benefit assessment, combined with an individual adaptation regarding the substance applied, dose and treatment duration in an interdisciplinary/multiprofessional context.

PMID:36847861 | DOI:10.1007/s00391-023-02173-4

Zh Nevrol Psikhiatr Im S S Korsakova. 2023;123(2):73-82. doi: 10.17116/jnevro202312302173.

ABSTRACT

OBJECTIVE: To evaluate the efficacy of Ipigrix in the complex treatment of patients with dorsalgia (DA) of the lumbosacral spine based on the results of the DORISS observational non-interventional multicenter study.

MATERIAL AND METHODS: Overall 3563 patients with verified diagnoses of DA at 200 clinical centers within the Russian Federation who received comparable baseline therapy according to nosological standards were examined, some of them additionally received oral or staggered treatment with Ipigrix. Baseline therapy for DA was given to 376 patients (treatment group 1), combination of baseline with oral Ipigrix was given to 1026 patients (group 2), and combination with staggered prescription of ipidacrine - to 2161 (group 3). Secondary endpoint of the study included analysis of the improvement of clinical symptoms, values of pain NRS and DN4 scales together with Roland-Morris questionnaire during the period of observation depending on the therapy with an assessment of its safety.

RESULTS: The results of the analysis of covariance allowed to exclude the influence of confounders (age and initial indicators of the utilized scales) on DA outcomes and demonstrated the greatest pain reduction in patients who additionally received Ipigrix via the staggered scheme. The inter-group comparison aligned by pseudorandomization showed statistically significant benefits of combined therapy regardless of the type of Ipigrix administration concerning main vertebral syndrome manifestations, sensory and motor disturbances, relief of pain, as well as neuropathic symptoms, improvement of neurophysiological parameters and restoration of life functioning without serious drug related adverse events.

CONCLUSION: Ipigrix (ipidacrine) can be considered an effective and safe adjuvant analgesic in the treatment of DA.

PMID:36843462 | DOI:10.17116/jnevro202312302173

Medicina (Kaunas). 2023 Feb 14;59(2):364. doi: 10.3390/medicina59020364.

ABSTRACT

Since vaccines are in fact manufactured chemical compounds such as drugs, the appearance of side effects following their use is not surprising. Similarly, as the main goal of vaccines is to stimulate the immune system bringing out the production of protective antibodies, autoimmune-related side effects as a consequence of increased immune activity do not seem irrational. Fortunately, the rate of such side effects is low; however, the importance of reporting adverse events following vaccinations, understanding the mechanisms behind their appearance, making early diagnosis, and appropriate treatment cannot be overemphasized. In fact, autoimmune-related side effects of vaccines, particularly those based on adjuvants, were reported long before the introduction of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Nevertheless, ASIA gathered and united the side effects of vaccines under one title, a step which helped organize the research and call for better immune stimulators than adjuvants. New technologies and methods of making vaccines were clearly noticed during the pandemic of COVID-19 after the introduction of mRNA-based vaccines. In our current paper, we introduce the notion of side effects to vaccines, particularly those of autoimmune nature, the mechanisms of ASIA, and the main vaccines linked with the syndrome including the recent COVID-19 vaccines. The transition from side effects to ASIA is the main idea behind our work.

PMID:36837564 | PMC:PMC9966463 | DOI:10.3390/medicina59020364

Int J Mol Sci. 2023 Feb 18;24(4):4116. doi: 10.3390/ijms24044116.

ABSTRACT

Analysis platforms to predict drug-induced seizure liability at an early phase of drug development would improve safety and reduce attrition and the high cost of drug development. We hypothesized that a drug-induced in vitro transcriptomics signature predicts its ictogenicity. We exposed rat cortical neuronal cultures to non-toxic concentrations of 34 compounds for 24 h; 11 were known to be ictogenic (tool compounds), 13 were associated with a high number of seizure-related adverse event reports in the clinical FDA Adverse Event Reporting System (FAERS) database and systematic literature search (FAERS-positive compounds), and 10 were known to be non-ictogenic (FAERS-negative compounds). The drug-induced gene expression profile was assessed from RNA-sequencing data. Transcriptomics profiles induced by the tool, FAERS-positive and FAERS-negative compounds, were compared using bioinformatics and machine learning. Of the 13 FAERS-positive compounds, 11 induced significant differential gene expression; 10 of the 11 showed an overall high similarity to the profile of at least one tool compound, correctly predicting the ictogenicity. Alikeness-% based on the number of the same differentially expressed genes correctly categorized 85%, the Gene Set Enrichment Analysis score correctly categorized 73%, and the machine-learning approach correctly categorized 91% of the FAERS-positive compounds with reported seizure liability currently in clinical use. Our data suggest that the drug-induced gene expression profile could be used as a predictive biomarker for seizure liability.

PMID:36835526 | PMC:PMC9963992 | DOI:10.3390/ijms24044116

Int J Mol Sci. 2023 Feb 16;24(4):4013. doi: 10.3390/ijms24044013.

ABSTRACT

Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [-]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [-] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [-] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.

PMID:36835425 | PMC:PMC9968093 | DOI:10.3390/ijms24044013

Int J Mol Sci. 2023 Feb 14;24(4):3791. doi: 10.3390/ijms24043791.

ABSTRACT

Drug-induced liver injury, also known as drug-induced hepatotoxicity (DILI), is a major cause of medicine withdrawal (prescription or over-the-counter) from the market [...].

PMID:36835204 | PMC:PMC9961832 | DOI:10.3390/ijms24043791

Int J Mol Sci. 2023 Feb 7;24(4):3291. doi: 10.3390/ijms24043291.

ABSTRACT

Lipid-lowering therapies are widely used to prevent the development of atherosclerotic cardiovascular disease (ASCVD) and related mortality worldwide. "Omics" technologies have been successfully applied in recent decades to investigate the mechanisms of action of these drugs, their pleiotropic effects, and their side effects, aiming to identify novel targets for future personalized medicine with an improvement of the efficacy and safety associated with the treatment. Pharmacometabolomics is a branch of metabolomics that is focused on the study of drug effects on metabolic pathways that are implicated in the variation of response to the treatment considering also the influences from a specific disease, environment, and concomitant pharmacological therapies. In this review, we summarized the most significant metabolomic studies on the effects of lipid-lowering therapies, including the most commonly used statins and fibrates to novel drugs or nutraceutical approaches. The integration of pharmacometabolomics data with the information obtained from the other "omics" approaches could help in the comprehension of the biological mechanisms underlying the use of lipid-lowering drugs in view of defining a precision medicine to improve the efficacy and reduce the side effects associated with the treatment.

PMID:36834701 | PMC:PMC9960554 | DOI:10.3390/ijms24043291

Int J Environ Res Public Health. 2023 Feb 20;20(4):3725. doi: 10.3390/ijerph20043725.

ABSTRACT

Adverse drug reaction (ADR) severity levels are mainly rated by healthcare professionals (HCPs), but patient ratings are limited. This study aimed to compare patient-rated and pharmacist-rated ADR severity levels and determined methods employed for ADR management and prevention by patients and HCPs. A cross-sectional survey was conducted in outpatients visiting two hospitals. Patients were asked about ADR experiences using a self-administered questionnaire, and additional information was retrieved from the medical records. In total, 617 out of 5594 patients had experienced ADRs (11.0%), but 419 patients were valid (68.0%). Patients commonly reported that their ADR severity level was moderate (39.4%), whereas pharmacists rated the ADRs as mild (52.5%). There was little agreement between patient-rated and pharmacist-rated ADR severity levels (κ = 0.144; p < 0.001). The major method of ADR management by physicians was drug withdrawal (84.7%), while for patients, it was physician consultation (67.5%). The main methods for ADR prevention by patients and HCPs were carrying an allergy card (37.2%) and recording drug allergy history (51.1%), respectively. A higher level of ADR bothersomeness was associated with higher ADR severity levels (p < 0.001). Patients and HCPs rated ADR severity and used ADR management and prevention methods differently. However, patient rating of ADR severity is a potential signal for severe ADR detection of HCPs.

PMID:36834422 | PMC:PMC9959449 | DOI:10.3390/ijerph20043725

Int J Environ Res Public Health. 2023 Feb 18;20(4):3639. doi: 10.3390/ijerph20043639.

ABSTRACT

There is no published evidence on the possible differences in multimorbidity, inappropriate prescribing, and adverse outcomes of care, simultaneously, from a sex perspective in older patients. We aimed to identify those possible differences in patients hospitalized because of a chronic disease exacerbation. A multicenter, prospective cohort study of 740 older hospitalized patients (≥65 years) was designed, registering sociodemographic variables, frailty, Barthel index, chronic conditions (CCs), geriatric syndromes (GSs), polypharmacy, potentially inappropriate prescribing (PIP) according to STOPP/START criteria, and adverse drug reactions (ADRs). Outcomes were length of stay (LOS), discharge to nursing home, in-hospital mortality, cause of mortality, and existence of any ADR and its worst consequence. Bivariate analyses between sex and all variables were performed, and a network graph was created for each sex using CC and GS. A total of 740 patients were included (53.2% females, 53.5% ≥85 years old). Women presented higher prevalence of frailty, and more were living in a nursing home or alone, and had a higher percentage of PIP related to anxiolytics or pain management drugs. Moreover, they presented significant pairwise associations between CC, such as asthma, vertigo, thyroid diseases, osteoarticular diseases, and sleep disorders, and with GS, such as chronic pain, constipation, and anxiety/depression. No significant differences in immediate adverse outcomes of care were observed between men and women in the exacerbation episode.

PMID:36834333 | PMC:PMC9964600 | DOI:10.3390/ijerph20043639