Clin Infect Dis. 2022 Sep 27:ciac643. doi: 10.1093/cid/ciac643. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.

METHODS: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.

RESULTS: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults.

CONCLUSIONS: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. Clinical Trials Registration. NCT03129646.

PMID:36164254 | DOI:10.1093/cid/ciac643

CMAJ. 2022 Sep 26;194(37):E1288. doi: 10.1503/cmaj.220835.

NO ABSTRACT

PMID:36162843 | DOI:10.1503/cmaj.220835

Oxid Med Cell Longev. 2022 Sep 16;2022:7138194. doi: 10.1155/2022/7138194. eCollection 2022.

ABSTRACT

Naringin is a dihydroflavone which was found in citrus fruits. Previous studies have indicated the antiapoptotic, antioxidative stress, and anti-inflammatory effects of naringin. It can improve many common diseases, including fibrosis or hepatotoxicity, cardiovascular disease, and diabetes. Acetaminophen (APAP) is a frequently used painkiller, and hepatotoxic side effects limit its use. The purpose of the current examination is to find the impact of naringin on APAP-induced hepatic injury. Firstly, we pretreated mice model groups with naringin. Then, the liver injury model was established by injecting intraperitoneally into mice with APAP. After the mice were euthanized, we obtained serum and liver tissue samples from the mice. Finally, these samples were analyzed using a metabolomics approach to find the underlying mechanism of the effects of naringin on APAP-induced liver injury and provide a new treatment strategy for APAP-induced liver injury. Our data indicate that naringin significantly improves APAP-induced liver injury in mice and reduces the expression levels of liver injury markers in a dose-dependent manner. Furthermore, analysis of differential metabolites in mice with liver injury showed that naringin reduced APAP-induced hepatotoxicity due to reversing multiple metabolite expression levels and the rescue of energy, amino acid, and purine metabolism.

PMID:36160708 | PMC:PMC9507767 | DOI:10.1155/2022/7138194

Rev Med Chil. 2022 Apr;150(4):431-438. doi: 10.4067/S0034-98872022000400431.

ABSTRACT

BACKGROUND: Tocilizumab (TCZ) is a new therapeutic alternative for severe cases of COVID-19 pneumonia.

AIM: To evaluate the cumulative incidence (CI) of suspected adverse drug reactions (ADR) from TCZ in adult patients with COVID-19.

MATERIAL AND METHODS: An active pharmacological surveillance protocol was carried out in patients older than 18 years old, who received at least one dose of TCZ between May and August 2020 at a clinical hospital. Non-infectious ADRs were categorized according to the Common Terminology Criteria for Adverse Events and the development of infection was classified as present or absent. Causality and preventability of ADRs were determined with the Naranjo Algorithm and the modified Schumock & Thornton criteria, respectively.

RESULTS: The CI of ADRs caused by TCZ was 69.6% (95% confidence intervals (CI): 63.5-76.6). A rise in alanine and aspartate aminotransferases and the development of infections were the most frequent adverse events. Seventy-four percent were considered mild in severity. Sixty two percent of suspected non-infectious ADRs were classified as probable and all the infectious events as Possible. Of the ADRs observed, 33% were preventable.

CONCLUSIONS: The occurrence of ADRs after the use of TCZ is frequent, of mild severity, and in one third of the cases, preventable. We suggest monitoring blood count, liver function tests and ruling out infection prior to TCZ administration.

PMID:36155752 | DOI:10.4067/S0034-98872022000400431

Cancer Immunol Immunother. 2022 Sep 26. doi: 10.1007/s00262-022-03295-1. Online ahead of print.

ABSTRACT

BACKGROUND: Drug-induced acute pancreatitis (AP) is uncommon and pancreatic involvement due to immune checkpoint inhibitors (ICI) in published reports relied on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). CTCAE definition of AP differs from the revised Atlanta classification diagnostic criteria. This study aims to classify the spectrum of pancreatic involvement in patients receiving ICI therapy into categories built on the revised Atlanta classification.

METHODS: A retrospective cohort study of cancer patients receiving cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors between 2011 and 2020. Pancreas-specific immune-related adverse events (irAEs) were categorized into AP and pancreatic injury.

RESULTS: Forty-seven patients on ICI therapy met selection criteria. Twenty patients (43%) had AP, while 27 (57%) had pancreatic injury. Fifteen patients (75%) developed mild AP. Five patients progressed to pancreatic atrophy, and two patients (4%) developed exocrine pancreatic insufficiency. In both groups, most patients received nivolumab therapy (70% vs. 67%, p = 0.08) with no difference in mean number of nivolumab doses (9 vs. 10, p = 0.69). There was no correlation between the mean number of nivolumab or pembrolizumab doses and AP events (OR 0.94, p = 0.26, and OR 0.98, p = 0.86), but the duration of ICI therapy was significantly related to pancreatic atrophy (OR 1.01, p = 0.05; 95% CI 1.00-1.02).

CONCLUSION: Based on the novel classification, majority of pancreatic irAEs were classified as asymptomatic pancreatic injury but with some risk of pancreatic atrophy. This classification can help in assessing patterns of pancreatic involvement, pathogenesis, and treatment decisions.

PMID:36161510 | DOI:10.1007/s00262-022-03295-1

Cureus. 2022 Sep 8;14(9):e28948. doi: 10.7759/cureus.28948. eCollection 2022 Sep.

ABSTRACT

We report a case of a 64-year-old female with a past medical history of invasive right breast adenocarcinoma presented with diffuse hyperpigmentation of her skin after admission to the hospital for an infected breast implant. She had no recollection of a similar cutaneous reaction in her past. The patient had been on a chronic regimen of anastrozole and abemaciclib for her metastatic breast cancer. A punch biopsy revealed results were highly suspicious for a drug-induced hyperpigmentation reaction. After a thorough review of the patient's current and past medication lists, it was determined that her abemaciclib was the most likely culprit of her hyperpigmentation. This case is significant because of the rarity of this possible specific cutaneous reaction to abemaciclib. The literature that exists on cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6) is minimal. And so, the importance of shedding light on its possible cutaneous side effects is not only helpful for clinician diagnosis but also essential for patients to make informed decisions. To our knowledge, there is no other published literature on likely abemaciclib-induced hyperpigmentation.

PMID:36159365 | PMC:PMC9484784 | DOI:10.7759/cureus.28948

BMJ Open. 2022 Sep 23;12(9):e061774. doi: 10.1136/bmjopen-2022-061774.

ABSTRACT

OBJECTIVES: This study aims to develop and validate a novel implicit tool to assist clinicians in resource-limited settings to promptly assess suitability for modification of solid oral dosage forms (SODFs) during medication prescribing, review and/or administration for patients with dysphagia.

DESIGN: Literature review and a group discussion were conducted to elicit items for the construction of the INappropriate solid oral dosaGE form modification aSsessmenT (INGEST) algorithm. For its validation, inter-rater reliability among three independent users was evaluated. Accuracy of users' ratings was also evaluated against the screening results using the Don't Rush to Crush handbook.

SETTING AND PARTICIPANTS: Three pharmacists were involved in the development and another three were involved in the validation of the INGEST algorithm using anonymised medication records of 50 patients in a nursing home and a hospital ward; only SODFs that were modified prior to administration were evaluated.

RESULTS: Following literature review, considerations included by consensus in the INGEST algorithm were the presence of special coating or modified release characteristics of the SODF medications, hazardous nature and taste of the active ingredients, manufacturer's advice and use of tube feeding. Of the 381 SODF medications evaluated, 26 (6.8%) were identified by at least one pharmacist to be inappropriate for modification. Gwet's AC among the three pharmacists in identifying SODF medications inappropriate for modification was 0.75 (p<0.001, 95% CI 0.63 to 0.87), and 0.80 (p<0.001, 95% CI 0.71 to 0.89) in identifying SODF medications appropriate for modification, suggesting substantial inter-rater agreement. Overall accuracy of each pharmacist's ratings was high, ranging from 93.7% to 95.6%.

CONCLUSIONS: The implicit INGEST algorithm has potential for use by clinicians in nursing home and hospital settings for determining suitability of SODF medications for modification. Further studies should be conducted to assess its external validity and utilisation in daily practice for improving clinical outcomes for patients with SODF dysphagia.

PMID:36153038 | PMC:PMC9511581 | DOI:10.1136/bmjopen-2022-061774

BMJ Open. 2022 Sep 23;12(9):e062589. doi: 10.1136/bmjopen-2022-062589.

ABSTRACT

OBJECTIVES: To describe the distribution of costs based on potentially inappropriate prescribing (PIP) and adverse drug reaction (ADR) status in terms of total direct costs and costs caused by ADRs, among older adults.

DESIGN: A retrospective cohort study was conducted among older adults, identified from a random sample of the general Swedish population. PIP was identified based on the Screening Tool of Older Persons' Prescriptions (STOPP) criteria and ADRs were identified using the Howard criteria. Causality between PIP and ADRs was evaluated using Hallas' criteria. Prevalence-based direct healthcare costs were calculated for the 3-month study period, including the total cost for healthcare and drugs, and the cost caused by ADRs.

SETTING: All care levels, including primary care, other outpatient care and inpatient care.

PARTICIPANTS: 813 adults ≥65 years.

PRIMARY OUTCOME MEASURES: The prevalence and cost of PIP and ADRs.

RESULTS: Total direct cost for persons with PIP was approximately twice the total cost of those without PIP (€1958 (€1428-€2616) vs €881 (€817-€1167), p=0.0020). The costs caused by ADRs was 10 times higher among persons with PIP, compared with those without PIP (€270 (€86-€545) vs €27 (€10-€61), p=0.047). For persons with ADRs caused by PIP, total direct costs were €4646 (€2617-€7931). This group represented 8% of the study population and used 25% of the costs. The main cost driver in all studied patient groups was healthcare contacts.

CONCLUSIONS: Older persons with PIP and ADRs had high healthcare costs, particularly when ADRs were caused by PIP. Since these costs appear to be substantial, the potential savings by preventing their occurrence may, to a certain degree, cover the added cost of such activities. Further studies should be undertaken to provide further evidence on the costs of PIP, ADRs and ADRs caused by PIP.

PMID:36153031 | PMC:PMC9511550 | DOI:10.1136/bmjopen-2022-062589

Rev Fac Cien Med Univ Nac Cordoba. 2022 Sep 16;79(3):241-247. doi: 10.31053/1853.0605.v79.n3.35443.

ABSTRACT

INTRODUCTION: Numerous medicines have been withdrawn from the market because of the risks of serious adverse effects. The objective of this study was to identify in the Argentine pharmaceutical market (APM) the presence of medicines withdrawn in other countries due to safety problems, to analyze the information on their risks and to propose recommendations.

METHOD: observational, descriptive study that explored the presence in the APM, until May 2021, of 462 medicines withdrawn in other countries. Those medicines on this list that are present in the APM and that are not currently authorized in countries with high sanitary surveillance were studied.

RESULTS: 17 medicines are still present in the APM, one over-the-counter. The package insert for 11 of the 17 medicines does not mention the adverse effects that led to their withdrawal. It was considered that the permanence in the APM of 16 of them should be reassessed.

CONCLUSIONS: recommendations are made on actions to be taken by the regulatory authorities with the 17 medicines already present in the APM.

PMID:36149072 | DOI:10.31053/1853.0605.v79.n3.35443

Pharmacoepidemiol Drug Saf. 2022 Sep;31 Suppl 2:3-678. doi: 10.1002/pds.5518.

NO ABSTRACT

PMID:36148859 | DOI:10.1002/pds.5518

Int J Mol Sci. 2022 Sep 19;23(18):10948. doi: 10.3390/ijms231810948.

ABSTRACT

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.

PMID:36142866 | PMC:PMC9502843 | DOI:10.3390/ijms231810948

Biosensors (Basel). 2022 Sep 3;12(9):718. doi: 10.3390/bios12090718.

ABSTRACT

An in vitro human renal proximal tubule model that represents the proper transporter expression and pronounced epithelial polarization is necessary for the accurate prediction of nephrotoxicity. Here, we constructed a high-throughput human renal proximal tubule model based on an integrated biomimetic array chip (iBAC). Primary human renal proximal tubule epithelial cells (hRPTECs) cultured on this microfluidic platform were able to form a tighter barrier, better transporter function and more sensitive nephrotoxicity prediction than those on the static Transwell. Compared with the human immortalized HK2 model, the hRPTECs model on the chip gained improved apical-basolateral polarization, barrier function and transporter expression. Polymyxin B could induce nephrotoxicity not only from the apical of the hRPTECs, but also from the basolateral side on the iBAC. However, other chemotherapeutic agents, such as doxorubicin and sunitinib, only induced nephrotoxicity from the apical surface of the hRPTECs on the iBAC. In summary, our renal proximal tubule model on the chip exhibits improved epithelial polarization and membrane transporter activity, and can be implemented as an effective nephrotoxicity-screening toolkit.

PMID:36140103 | PMC:PMC9496563 | DOI:10.3390/bios12090718

Sleep Med Clin. 2022 Sep;17(3):471-484. doi: 10.1016/j.jsmc.2022.06.011. Epub 2022 Sep 8.

ABSTRACT

Undesirable side effects of insomnia and/or sleepiness may occur with many prescribed drugs, psychotropics as well as non-psychotropics. These central nervous system effects can be explained by the interactions of the drug with any of the numerous neurotransmitters and receptors that are involved in sleep and wakefulness. Also a close - sometimes bidirectional - relationship between disease and (disturbed) sleep/wakefulness is often present e.g. in chronic pain; drug effects may lead this vicious circle in both ways. Besides the importance for health and quality of life, effects on sleep or waking function can be a potential source of non-compliance.

PMID:36150808 | DOI:10.1016/j.jsmc.2022.06.011

Int J Nanomedicine. 2022 Sep 16;17:4307-4319. doi: 10.2147/IJN.S370194. eCollection 2022.

ABSTRACT

INTRODUCTION: Compared to intravenous administration, intratumoral drug administration enables the direct delivery of drugs to tumors and mitigates the systemic absorption of drugs and associated drug-induced side effects. However, intratumoral drug administration presents several challenges. The high interstitial fluid pressure (IFP) of the tumor prevents the retention of drugs within the tumor; thus, significant amounts of the drugs are absorbed systemically through the bloodstream or delivered to non-target sites. To solve this problem, in this study, a drug-enclosed needle-type starch implant was developed that can overcome IFP and remain in the tumor.

METHODS: Injectable needle-type starch implants (NS implants) were prepared by starch gelatinization and drying. The structure, cytotoxicity, and anticancer effects of the NS implants were evaluated. Biodistribution of NS implants was evaluated in pork (in vitro), dissected liver (ex vivo), and 4T1 tumors in mice (in vivo) using a fluorescence imaging device.

RESULTS: The prepared NS implants exhibited a hydrogel structure after water absorption. NS implants showed effective cytotoxicity and anticancer effects by photothermal therapy (PTT). The NS implant itself has sufficient strength and can be easily injected into a desired area. In vivo, the NS implant continuously delivered drugs to the tumor more effectively and uniformly than conventional hydrogels and solutions.

CONCLUSION: This study demonstrated the advantages of needle-type implants. An injectable NS implant can be a new formulation that can effectively deliver drugs and exhibit anticancer effects.

PMID:36147547 | PMC:PMC9488191 | DOI:10.2147/IJN.S370194

Pharmaceutics. 2022 Aug 23;14(9):1755. doi: 10.3390/pharmaceutics14091755.

ABSTRACT

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D &lt; 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist's perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.

PMID:36145503 | DOI:10.3390/pharmaceutics14091755

Antioxidants (Basel). 2022 Sep 9;11(9):1780. doi: 10.3390/antiox11091780.

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. However, FDA-approved electrophilic Nrf2 activators cause irreversible alkylation of cysteine residues in various cellular proteins resulting in side effects. We propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. This review presents the current knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD.

PMID:36139853 | DOI:10.3390/antiox11091780

Am J Nurs. 2022 Oct 1;122(10):20-21. doi: 10.1097/01.NAJ.0000890208.43509.40.

ABSTRACT

The Food and Drug Administration (FDA) is warning that an increased risk of death is possible with the use of duvelisib (Copiktra) compared with the monoclonal antibody ofatumumab in the treatment of chronic lymphocytic leukemia. Serious adverse effects also appear to be more likely with duvelisib use.Nurses should monitor for adverse effects and report them to the FDA's MedWatch program.

PMID:36136021 | DOI:10.1097/01.NAJ.0000890208.43509.40

Rev Assoc Med Bras (1992). 2022 Aug;68(8):979-981. doi: 10.1590/1806-9282.20220643.

NO ABSTRACT

PMID:36134822 | DOI:10.1590/1806-9282.20220643

Cell Rep Med. 2022 Sep 20;3(9):100748. doi: 10.1016/j.xcrm.2022.100748.

ABSTRACT

Endometriosis is a chronic pain condition affecting 1 in 10 women. There is an unmet need for better medical treatments for endometriosis. We spotlight trials of a single preparation combined HRT-GnRH antagonist (Relugolix) by Giudice et al.,1 for endometriosis-associated pain.

PMID:36130483 | DOI:10.1016/j.xcrm.2022.100748

Nursing. 2022 Oct 1;52(10):56-61. doi: 10.1097/01.NURSE.0000872476.95884.05.

ABSTRACT

PURPOSE: To determine the incidence of and predictors for serious opioid-related adverse drug events (ORADEs) in postoperative inpatients.

METHODS: A retrospective cohort study design of serious ORADEs in surgical inpatients between 2015 and 2017, who were abstracted from the electronic health record, in an 800-bed academic medical health center.

RESULTS: A total of 27,942 surgery patients met the inclusion criteria. Of those, 25,208 patients (90%) were exposed to opioids after surgery. A total of 25,133 (99.7%) patients exposed to opioids did not experience a serious ORADE while 75 (0.3%) patients did experience a serious ORADE and required naloxone. The predictors for ORADEs include age (OR = 1.040, P-value < .0001); gender (OR = 0.394, P-value = .0006); psychiatric disorder (OR = 4.440, CI: 2.435, 8.095); morphine level with respect to hydrocodone-acetaminophen (OR = 5.841, P-value = .0384); and were almost six times more likely to experience a serious ORADE when morphine is prescribed and 4.44 times more likely in patients with a psychiatric disorder (P-value < .0001).

CONCLUSION: Once a baseline incidence is known, predictors for serious ORADEs in surgical inpatients are useful in guiding medical-surgical nurses' opioid safety practices, with more frequent focused respiratory assessments before opioid dosing and closer monitoring when opioids are prescribed postoperatively, especially in higher-risk surgical inpatients.

PMID:36129510 | DOI:10.1097/01.NURSE.0000872476.95884.05