Pol Merkur Lekarski. 2023;51(3):189-193. doi: 10.36740/Merkur202303101.

ABSTRACT

OBJECTIVE: Aim: Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease resulting in cognitive impairment, physical disabilities, and neurological symptoms. Ocrelizumab is an effective drug used in MS treatment. However, it causes a risk of hepatitis B reactivation in anti-HBc positive patients. We describe the impact of entecavir and tenofovir on HBV reactivation during treatment with ocrelizumab.

PATIENTS AND METHODS: Materials and methods: Our study included eight patients (aged 18-70 years) with positive anti-HBc antibodies who were diagnosed with MS based on the 2017 McDonald criteria. The subjects were treated with ocrelizumab and were given anti-HBV prophylaxis with nucleoside analogs. The mean time from the beginning of therapy with nucleoside analogs to the initiation of ocrelizumab treatment was 27.5 days. Patients were administered ocrelizumab and none of them was diagnosed with HBV reactivation.

RESULTS: Results: None of the laboratory parameters worsened. No severe adverse effects were observed. These results suggest that entecavir and tenofovir are effective in HBV reactivation prophylaxis. Additionally, positive anti-HBc antibodies do not rule out treatment with ocrelizumab.

CONCLUSION: Conclusions: In patients with positive anti-HBc antibodies, nucleoside analogs, such as entecavir or tenofovir, should be administered before ocrelizumab administration to reduce the risk of viral reactivation. Further studies on simultaneous treatment with ocrelizumab and nucleoside analogs are required to confirm our findings.

PMID:37589101 | DOI:10.36740/Merkur202303101

Reg Anesth Pain Med. 2023 Aug 17:rapm-2023-104873. doi: 10.1136/rapm-2023-104873. Online ahead of print.

NO ABSTRACT

PMID:37591616 | DOI:10.1136/rapm-2023-104873

Immunotherapy. 2023 Aug 17. doi: 10.2217/imt-2022-0290. Online ahead of print.

ABSTRACT

Background: The infliximab biosimilar CT-P13 was approved in Thailand in 2015. Methods: This open-label, multicenter, post-marketing surveillance study evaluated the safety (events of special interest [ESIs]; primary end point) and effectiveness of 46 weeks of CT-P13 treatment according to routine practice in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA), with 1 year follow-up post-treatment. Results: 30 patients were enrolled (16 RA, 8 AS and 6 PsA). Infections were the most frequently reported study drug-related ESIs (2 RA and 2 AS). One patient with RA and one with PsA experienced infusion-related reactions. No cases of tuberculosis, malignancy (as expected, given 1 year follow-up), or drug-induced liver disease were reported. Disease activity improved across indications. Conclusion: CT-P13 was well tolerated and effective across indications.

PMID:37589164 | DOI:10.2217/imt-2022-0290

J Hematol Oncol. 2023 Aug 17;16(1):96. doi: 10.1186/s13045-023-01490-w.

ABSTRACT

BACKGROUND: About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells.

METHODS: This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1-5: single dose of 0.5 mg/m2, 1.5 mg/m2, 5 mg/m2, 15 mg/m2, 45 mg/m2; cohort 6: 15 mg/m2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow.

RESULTS: Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses.

CONCLUSIONS: FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254).

PMID:37587502 | PMC:PMC10433561 | DOI:10.1186/s13045-023-01490-w

J Transl Med. 2023 Aug 16;21(1):549. doi: 10.1186/s12967-023-04400-3.

ABSTRACT

BACKGROUND: Bladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.

METHODS: To examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.

RESULTS: JorA inhibited the proliferation of MIBC cells, and the IC50 of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in "cancer-related pathways" and "EGFR-related signaling pathways", which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were - 8.153 and - 7.264 kcal/mol, respectively).

CONCLUSIONS: The marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.

PMID:37587470 | DOI:10.1186/s12967-023-04400-3

BMC Complement Med Ther. 2023 Aug 16;23(1):288. doi: 10.1186/s12906-023-04110-9.

ABSTRACT

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been well defined as a common chronic liver metabolism disorder. Statins as a first-line therapeutic treatment had some side effects. Here, we found that Fumigaclavine C (FC) was collected from endophytic Aspergillus terreus via the root of Rhizophora stylosa (Rhizophoraceae), had potential anti-adipogenic and hepatoprotective effects both in vitro and in vivo without obvious adverse side effects. However, the mechanisms of the prevention and management of FC for hepatic steatosis are incompletely delineated.

METHODS: The pharmacodynamic effects of FC were measured in high-fat diet (HFD)-induced obese mice. Liver index and blood biochemical were examined. Histopathological examination in the liver was performed by hematoxylin & eosin or oil red O. The levels of serum TG, TC, LDL-c, HDL-c, FFA, T-bili, ALT, AST, creatinine, and creatine kinase were estimated via diagnostic assay kits. The levels of hepatic lipid metabolism-related genes were detected via qRT-PCR. The expression levels of hepatic de novo lipogenesis were quantitated with Western blot analysis. RESULTS: FC-treatment markedly reduced hepatic lipid accumulation in HFD-induced obese mice. FC significantly attenuated the hepatic lipid metabolism and ameliorated liver injury without obvious adverse side effects. Moreover, FC also could dose-dependently modulate the expressions of lipid metabolism-related transcription genes. Mechanically, FC notably suppressed sterol response element binding protein-1c mediated de novo lipogenesis via interfering with the RhoA/ROCK signaling pathway by decreasing the levels of geranylgeranyl diphosphate and farnesyl diphosphate.

CONCLUSIONS: These findings suggested that FC could improve hepatic steatosis through inhibiting de novo lipogenesis via modulating the RhoA/ROCK signaling pathway.

PMID:37587459 | DOI:10.1186/s12906-023-04110-9

Cad Saude Publica. 2023 Aug 11;39(7):e00145922. doi: 10.1590/0102-311XEN145922. eCollection 2023.

ABSTRACT

Exposure to ambient air pollution increases mortality and morbidity, leading disabilities, and premature deaths. Air pollution has been identified as a leading cause of global disease burden, especially in low- and middle-income countries in 2015 (Global Burden of Diseases, Injuries and Risk Factors Study, 2015). This study explores the relation between mortality rates and particulate matter (PM) concentrations in the 50 Spanish regions for the period 2002-2017. Moreover, we estimated the premature deaths due to PM in Spain according to welfare and production losses in 2017. Random-effects models were developed to evaluate the relation between mortality rates and PM concentrations. The economic cost of premature deaths was assessed using the Willingness to Pay approach to quantify welfare losses and the Human Capital method to estimate production losses. PM10 concentrations are positively related to mortality due to respiratory diseases and stroke. Based on 10,342 premature deaths in 2017, losses in welfare amount to EUR 36,227 million (3.1% of Spanish GDP). The economic value of current and future production losses reached EUR 229 million (0.02% of GDP). From a social perspective, air pollution is a public health concern that greatly impacts health and quality of life. Results highlight the need to implement or strengthen regulatory, fiscal, and health public policies to substantially benefit the population's health by reducing their exposure to air pollution.

PMID:37585903 | DOI:10.1590/0102-311XEN145922

J Med Internet Res. 2023 Aug 16;25:e45146. doi: 10.2196/45146.

ABSTRACT

BACKGROUND: Methylphenidate is an effective first-line treatment for attention-deficit/hyperactivity disorder (ADHD). However, many adverse effects of methylphenidate have been recorded from randomized clinical trials and patient-reported outcomes, but it is difficult to determine abuse from them. In the context of COVID-19, it is important to determine how drug use evaluation, as well as misuse of drugs, have been affected by the pandemic. As people share their reasons for using medication, patient sentiments, and the effects of medicine on social networking services (SNSs), the application of machine learning and SNS data can be a method to overcome the limitations. Proper machine learning models could be evaluated to validate the effects of the COVID-19 pandemic on drug use.

OBJECTIVE: To analyze the effect of the COVID-19 pandemic on the use of methylphenidate, this study analyzed the adverse effects and nonmedical use of methylphenidate and evaluated the change in frequency of nonmedical use based on SNS data before and after the outbreak of COVID-19. Moreover, the performance of 4 machine learning models for classifying methylphenidate use based on SNS data was compared.

METHODS: In this cross-sectional study, SNS data on methylphenidate from Twitter, Facebook, and Instagram from January 2019 to December 2020 were collected. The frequency of adverse effects, nonmedical use, and drug use before and after the COVID-19 pandemic were compared and analyzed. Interrupted time series analysis about the frequency and trends of nonmedical use of methylphenidate was conducted for 24 months from January 2019 to December 2020. Using the labeled training data set and features, the following 4 machine learning models were built using the data, and their performance was evaluated using F-1 scores: naïve Bayes classifier, random forest, support vector machine, and long short-term memory.

RESULTS: This study collected 146,352 data points and detected that 4.3% (6340/146,352) were firsthand experience data. Psychiatric problems (521/1683, 31%) had the highest frequency among the adverse effects. The highest frequency of nonmedical use was for studies or work (741/2016, 36.8%). While the frequency of nonmedical use before and after the outbreak of COVID-19 has been similar (odds ratio [OR] 1.02 95% CI 0.91-1.15), its trend has changed significantly due to the pandemic (95% CI 2.36-22.20). Among the machine learning models, RF had the highest performance of 0.75.

CONCLUSIONS: The trend of nonmedical use of methylphenidate has changed significantly due to the COVID-19 pandemic. Among the machine learning models using SNS data to analyze the adverse effects and nonmedical use of methylphenidate, the random forest model had the highest performance.

PMID:37585250 | DOI:10.2196/45146

Sci Rep. 2023 Aug 16;13(1):13338. doi: 10.1038/s41598-023-40004-z.

ABSTRACT

Drug-induced liver injury induced by already approved substances is a major threat to human patients, potentially resulting in drug withdrawal and substantial loss of financial resources in the pharmaceutical industry. Trovafloxacin, a broad-spectrum fluoroquinolone, was found to have unexpected side effects of severe hepatotoxicity, which was not detected by preclinical testing. To address the limitations of current drug testing strategies mainly involving 2D cell cultures and animal testing, a three-dimensional microphysiological model of the human liver containing expandable human liver sinusoidal endothelial cells, monocyte-derived macrophages and differentiated HepaRG cells was utilized to investigate the toxicity of trovafloxacin and compared it to the structurally-related non-toxic drug levofloxacin. In the model, trovafloxacin elicited vascular and hepatocellular toxicity associated with pro-inflammatory cytokine release already at clinically relevant concentrations, whereas levofloxacin did not provoke tissue injury. Similar to in vivo, cytokine secretion was dependent on a multicellular immune response, highlighting the potential of the complex microphysiological liver model for reliably detecting drug-related cytotoxicity in preclinical testing. Moreover, hepatic glutathione depletion and mitochondrial ROS formation were elucidated as intrinsic toxicity mechanisms contributing to trovafloxacin toxicity.

PMID:37587168 | DOI:10.1038/s41598-023-40004-z

Epileptic Disord. 2023 Aug 16. doi: 10.1002/epd2.20146. Online ahead of print.

ABSTRACT

OBJECTIVE: Eslicarbazepine acetate (ESL) is a once-daily oral antiseizure medication. Its safety and tolerability from clinical trials have been mostly confirmed by real-world data. The main purpose of this report is to provide an overview of the safety profile of ESL in the United Kingdom (UK) and Republic of Ireland (ROI).

METHODS: Safety data was obtained from UK and ROI post-marketing sources (October 2009 - April 2022) by the Marketing Authorisation Holder. All individual reports were included in the Argus SafetyTM database. All adverse events (AEs) were coded using MedDRA® version 24.1. Only valid cases (meeting the minimum pharmacovigilance reporting requirements) were included.

RESULTS: During 13 years of ESL marketing, with cumulative estimated exposure of 2 210 395 patients-years, 183 reports were received. A total of 402 AEs were reported for the 155 valid cases. The most common reported AEs (≥6% of total reported), per System Organ Class (SOC), were: Nervous System Disorders (23.4%), Injury, Poisoning and Procedural Complications (18.9%), General Disorders and Administration Site Conditions (12.9%), Psychiatric Disorders (12.7%) and Gastrointestinal Disorders (6.7%). The most frequently reported (≥2% of total reported) AEs were: seizures (4.5%), hyponatremia (4.2%), dizziness (2.7%), rash, fatigue (2.5% each) and somnolence (2.0%). Seven percent of AEs lead to treatment discontinuation. Twenty-six percent of cases were classified as serious (including six fatal cases).

SIGNIFICANCE: The current analysis supports the known safety profile of ESL, as generally well-tolerated with most AEs being non-serious. The most common AEs were considered either expected according to the disease itself or to the reference safety information. ESL continues to be a relevant medication in the treatment of partial (focal-onset) epilepsy, as also confirmed by the 2022 NICE guidelines.

PMID:37584596 | DOI:10.1002/epd2.20146

Pak J Pharm Sci. 2023 May;36(3):713-721.

ABSTRACT

In both developed and developing nations, the rising prevalence of adverse drug reactions (ADRs) and underreporting of ADRs in pharmacovigilance centers have become major problems. The goal of this study was to access the overall knowledge, attitude and practices toward pharmacovigilance and ADRs reporting among Albanian healthcare professionals. A cross-sectional questionnaire-based study was conducted from December 2021 to February 2022 including physicians, community pharmacists and nurses in Tirana, Albania. There were distributed a total of 511 questionnaires to healthcare professionals, where 410 of them were returned, resulting in an 80.23 percent response rate. Physicians and pharmacists compare to nurses had better knowledge about pharmacovigilance and its main purpose. Pharmacists had better knowledge regarding the establishment of the pharmacovigilance law (67.62%) and how to report ADRs (51.43%), Of all, 85.42% of physicians, 74.29% of pharmacists and 40.38% of nurses resulted had a positive attitude towards ADR reporting as a professional obligation, as well as 57.29% of physicians, 58.57% of pharmacists and 22.12% (p < 0.05) of nurses, declared that they have reported ADRs. Only physicians have reported ADRs to the national pharmacovigilance center. The findings of this study show that most of the healthcare professionals in Tirana do not have a thorough understanding of pharmacovigilance techniques.

PMID:37580918

Radiology. 2023 Aug;308(2):e223135. doi: 10.1148/radiol.223135.

ABSTRACT

Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

PMID:37581502 | DOI:10.1148/radiol.223135

Redox Rep. 2023 Dec;28(1):2220531. doi: 10.1080/13510002.2023.2220531.

ABSTRACT

Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling 'mitocans' such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues.Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX).Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A.Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

PMID:37581329 | DOI:10.1080/13510002.2023.2220531

Ghana Med J. 2022 Dec;56(4):239-245. doi: 10.4314/gmj.v56i4.2.

ABSTRACT

OBJECTIVE: The study assessed willingness to accept the COVID-19 vaccine among out-patient department (OPD) attendants in the Bono Region in Ghana.

DESIGN: This was an analytical cross-sectional study.

SETTING: The study was conducted at the Wenchi Methodist Hospital (WMH) OPD, Bono Region, Ghana. The region had not yet been earmarked for vaccination at the time of the study.

PARTICIPANTS: Three hundred and twenty-five (325) participants aged ≥18 years, accessing care at the OPD of WMH and willing to give informed consent, were interviewed.

MAIN OUTCOME MEASURES: The proportion of participants willing to accept the COVID-19 vaccine and its determinants.

RESULTS: Of 325 participants interviewed, 32 (9.8%) had been vaccinated already. 82.6% (242/293) indicated COVID-19 vaccine acceptance among the unvaccinated. The major reason for vaccine acceptance was "it could protect against COVID-19" (96.7%, 234/242). "Fear of vaccine side effects and "perception of not being susceptible to COVID-19" were among the reasons for vaccine refusal. Perceived susceptibility to COVID-19 (AOR 4.09, 95% CI 1.79, 9.34), knowledge of COVID-19 and COVID-19 vaccine (AOR 3.62, 95% CI 1.14, 11.46) and willingness to pay for the vaccine (AOR 5.20, 95% CI 2.49, 10.43) were associated with vaccine acceptance.

CONCLUSIONS: Adequate knowledge of COVID-19 and the vaccine may drive vaccine acceptance in the study area and possibly other areas in Ghana. Campaign messages aimed at increasing COVID-19 vaccine coverage must emphasise its safety, likely side effects and management in order to help rid the population of misconceptions.

FUNDING: None indicated.

PMID:37575629 | PMC:PMC10416289 | DOI:10.4314/gmj.v56i4.2

Front Immunol. 2023 Jul 27;14:1237361. doi: 10.3389/fimmu.2023.1237361. eCollection 2023.

ABSTRACT

Malignant tumors have a unique tumor microenvironment (TME), which includes mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), and high glutathione (GSH) levels, among others. Recently, TME regulation approaches have attracted widespread attention in cancer immunotherapy. Nanoparticles as drug delivery systems have ability to modulate the hydrophilicity of drugs to affect drug uptake and efflux in tumor. Especially, the metal nanoparticles have been extensive applied for tumor immunotherapy due to their unique physical properties and elaborate design. However, the potential deficiencies of metal nanoparticles due to their low biodegradability, toxicity and treatment side effects restrict their clinical application. In this review, we briefly introduce the feature characteristics of the TME and the recent advances in tumor microenvironment responsive metal nanoparticles for tumor immunotherapy. In addition, nanoparticles could be combined with other treatments, such as chemotherapy, radiotherapy and photodynamic therapy also is presented. Finally, the challenges and outlook for improving the antitumor immunotherapy efficiency, side effect and potential risks of metal nanoparticles has been discussed.

PMID:37575228 | PMC:PMC10413122 | DOI:10.3389/fimmu.2023.1237361

Eur J Hosp Pharm. 2023 Aug 14:ejhpharm-2023-003793. doi: 10.1136/ejhpharm-2023-003793. Online ahead of print.

ABSTRACT

BACKGROUND: Due to staffing constraints, several hospitals have defined targeting strategies for pharmacist-led medication order review, leaving non-targeted patients exposed to potential harmful drug-related problems (DRPs). Using targeting criteria to stratify medication order review level (level 1 (L1): orders, basic patient characteristics; level 2 (L2) or comprehensive medication order review: orders, patient characteristics, medical records, laboratory results) could make it possible to save time and increase the overall number of medication order reviews. This study aims to define targeting criteria to stratify medication order review level and estimate the time saved for the performance of additional medication order reviews.

METHOD: This retrospective single-centre study included all medication order reviews performed in 2020; DRPs were collected to assess the medication order review level required to detect them. Logistic regressions were performed to define patient characteristics associated with L2. These targeting criteria were applied to the cohort to estimate the time saved and the number of additional medication order reviews which could have been performed using this approach.

RESULTS: 2478 DRPs were reported; 54.2% (1343/2748) could have been detected using an L1 medication order review (representing 48.2% of the patients (829/1721)). L2 medication order reviews were significantly associated with age ≥65 years, male, and renal clearance <60 mL/min (OR≥75yo=1.79; OR65-74yo=1.74; ORfemale=0.74; OR30-59mL/min=1.67; OR<30mL/min=2.62; p<0.05). Sex being a confounding factor, only age and renal clearance were used as targeting criteria. The time saved was estimated at 274 hours per year, leading to an additional 1720 medication order reviews (54 hospital beds).

CONCLUSION: The proposed approach would maintain a satisfying level of safety and quality for patients, by performing an L2 medication order review for targeted patients based on age and renal clearance, while improving medication order review coverage with an L1 medication order review for non-targeted patients, using the available workforce.

PMID:37580118 | DOI:10.1136/ejhpharm-2023-003793

J Clin Transl Hepatol. 2023 Oct 28;11(5):1239-1245. doi: 10.14218/JCTH.2022.00067S. Epub 2023 Apr 28.

ABSTRACT

Drug-induced liver injury (DILI) is a major cause of acute liver injury, liver failure, and liver transplantation worldwide. In recent years, immune checkpoint inhibitors have become widely used. This has led to an increase in DILI, for which pathophysiology and management methods differ significantly from the past. As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase, information about a DILI is becoming more valuable. DILI is classified into two types according to its etiology: intrinsic DILI, in which the drug or its metabolites cause liver damage that is dose-dependent and predictable; and idiosyncratic DILI, in which liver damage is also dose-independent but unpredictable. In addition, depending on the course of the disease, chronic DILI or drug-induced autoimmune hepatitis may be present. The number of DILI cases caused by antimicrobial agents is decreasing, whereas that caused by drugs for malignant tumors and health foods is increasing. The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI. Liver injury is a type of immune-related adverse event. The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular, but mixed type and bile stasis have also been reported. Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury. Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration; however, mycophenolate mofetil may be considered if the disease is refractory to steroids.

PMID:37577239 | PMC:PMC10412691 | DOI:10.14218/JCTH.2022.00067S

Cureus. 2023 Jul 12;15(7):e41781. doi: 10.7759/cureus.41781. eCollection 2023 Jul.

ABSTRACT

Immune checkpoint inhibitors (ICIs) as standard of care have revolutionized the treatment of patients with metastatic melanoma. The combination of nivolumab and ipilimumab improves treatment efficacy and prolongs survival compared to monotherapy alone. However, combination therapy is also associated with an increased incidence of adverse events. We report an uncommon yet important case of multi-organ failure in a patient following a single dose of nivolumab plus ipilimumab. A 60-year-old male with a history of ulcerative colitis in remission and metastatic melanoma was admitted on February 25, 2021, for presumed sepsis, after presenting with neutropenic fever. His brain metastases were previously resected on January 14, 2021, and he was started on dexamethasone 4 mg BID for six weeks. On February 11, 2021, he received one dose of nivolumab plus ipilimumab, per the CheckMate-067 protocol. He presented 14 days later with fever, diarrhea, pancytopenia, renal failure, drug-induced hepatitis, and myocarditis. The infectious workup was negative. His neutropenia responded to growth factors. He was diagnosed with interstitial nephritis due to immunotherapy and treated with corticosteroids. His symptoms resolved with concomitant improvement of his renal, hepatic, and cardiac function. He was discharged home in a stable condition. Although these specific immune-related adverse events (irAEs) are uncommon and rarely occur simultaneously, ICIs can trigger non-specific immune system activation, resulting in widespread inflammatory effects. Since irAEs can lead to multi-organ failure, as evidenced in this case, early recognition and institution of high-dose steroids are critical to preventing rapid deterioration. Given that ICI therapy is the standard of care for several cancers and is often studied in clinical trials, increased education on irAE toxicity and updated algorithms on the management of febrile cancer patients are warranted.

PMID:37575835 | PMC:PMC10419328 | DOI:10.7759/cureus.41781

Cureus. 2023 Jul 10;15(7):e41647. doi: 10.7759/cureus.41647. eCollection 2023 Jul.

ABSTRACT

Introduction Multiple risk factors, such as human immunodeficiency virus (HIV) infection and immunosuppressive therapies, increase the odds of latent tuberculosis infection (LTBI) reactivation and progression to active tuberculosis. A six-to-nine-month preventive treatment with isoniazid (INH) decreases the risk of LTBI reactivation, but its effectiveness can be limited by its long duration and adverse events (AEs), including liver toxicity. Due to comorbidities and polypharmacy, people living with HIV (PLHIV) may be at increased risk of INH-associated AEs. Our study aimed to assess the prevalence of AEs among patients receiving INH treatment for LTBI, to identify risk factors for their occurrence, and to evaluate whether PLHIV have higher odds of developing INH-associated AEs. Methods We conducted a single-center retrospective case-control study, including 130 outpatients with LTBI treated with INH between July 2019 and March 2022. Participants who developed AE (cases) were compared to controls, and a subgroup of PLHIV was compared to HIV-negative participants. Demographics, socioeconomic variables, comorbidities, and clinical variables were compared between study groups. Patient data were obtained from institutional electronic medical records, and outcomes were measured at regularly scheduled appointments. Results We included 130 participants, of which 54 were PLHIV. The PLHIV subgroup was significantly younger (p = 0.01) and demonstrated significantly higher prevalences of chronic liver disease, previous viral hepatitis, daily alcohol consumption, and intravenous drug use (IDU). One-third of the participants had an AE (45 cases, 34.6%), with liver toxicity being the most common (22.3%). Participants who developed AEs were significantly older (p = 0.030) and had a higher prevalence of economic hardship (p = 0.037), as well as higher scores of the Charlson comorbidity index (p = 0.002) than the controls. INH withdrawal occurred in 17 participants (13.1%) and was mainly associated with liver toxicity (p < 0.01) and gastrointestinal symptoms (p = 0.022). In the adjusted effect model, an age ≥ 65 years, economic hardship, and excessive alcohol consumption were significantly associated with higher odds of AEs, while HIV infection decreased the odds by 68.4% (p = 0.033). Conclusions In our study, INH-associated AEs were common, with liver toxicity being the most frequent. Older age, economic hardship, and excessive alcohol consumption increased the odds of INH-associated AEs, while PLHIV had lower odds of developing INH-associated AEs, even when adjusting for other variables in the multivariate analysis. Further studies should be conducted to assess if these results are replicable in a larger population and in different settings.

PMID:37575717 | PMC:PMC10412740 | DOI:10.7759/cureus.41647

J Ethnopharmacol. 2023 Aug 10:117022. doi: 10.1016/j.jep.2023.117022. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Chemotherapy is a common cancer treatment strategy. However, its effectiveness is constrained by toxicity and adverse effects. The Lamiaceae herb Salvia miltiorrhiza Bunge has a long history of therapeutic use in the treatment of blood stasis illnesses, which are believed by traditional Chinese medicine to be connected to cancer.

AIM OF THE STUDY: This review summarized the common toxicity of chemotherapy and the potential chemo-adjuvant effect and mechanisms of active ingredients from S. miltiorrhiza, hoping to provide valuable information for the development and application of S. miltiorrhiza resources.

MATERIALS AND METHODS: The literatures were retrieved from PubMed, Web of Science, Baidu Scholar and Google Scholar databases from 2002 to 2022. The inclusion criteria were studies reporting that S. miltiorrhiza or its constituents enhanced the efficiency of chemotherapy drugs or reduced the side effects.

RESULTS: Salvianolic acid A, salvianolic acid B, salvianolic acid C, rosmarinic acid, tanshinone I, tanshinone IIA, cryptotanshinone, dihydrotanshinone I and miltirone are the primary adjuvant chemotherapy components of S. miltiorrhiza. The mechanisms mainly involve inhibiting proliferation, metastasis, and angiogenesis, inducing apoptosis, regulating autophagy and tumor microenvironment. In addition, they also improve chemotherapy drug-induced side effects.

CONCLUSIONS: The bioactive compounds of S. miltiorrhiza are shown to inhibit proliferation, metastasis, and angiogenesis, induce apoptosis and autophagy, regulate immunity and tumor microenvironment when combined with chemotherapy drugs. However, further clinical studies are required to validate the current studies.

PMID:37572929 | DOI:10.1016/j.jep.2023.117022