J Investig Med. 2024 Apr 10:10815589241247796. doi: 10.1177/10815589241247796. Online ahead of print.

ABSTRACT

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both SSRI antidepressants, inhibit the NLRP3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and the incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs (VA) healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by ICD-9-CM or ICD-10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR=0.62, 95% CI=(0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.

PMID:38597272 | DOI:10.1177/10815589241247796

J Pediatr Pharmacol Ther. 2024 Apr;29(2):119-129. doi: 10.5863/1551-6776-29.2.119. Epub 2024 Apr 8.

ABSTRACT

OBJECTIVE: Care coordination for children and youth with special health care needs and medical complexity (CYSHCN-CMC), especially medication management, is difficult for providers, parents/caregivers, and -patients. This report describes the creation of a clinical pharmacotherapy practice in a pediatric long-term care facility (pLTCF), application of standard operating procedures to guide comprehensive medication management (CMM), and establishment of a collaborative practice agreement (CPA) to guide drug therapy.

METHODS: In a prospective case series, 102 patients characterized as CYSHCN-CMC were included in this pLTCF quality improvement project during a 9-month period.

RESULTS: Pharmacists identified, prevented, or resolved 1355 drug therapy problems (DTP) with an average of 13 interventions per patient. The patients averaged 9.5 complex chronic medical conditions with a -median length of stay of 2815 days (7.7 years). The most common medications discontinued due to pharmacist assessment and recommendation included diphenhydramine, albuterol, sodium phosphate enema, ipratropium, and metoclopramide. The average number of medications per patient was reduced from 23 to 20. A pharmacoeconomic analysis of 244 of the interventions revealed a monthly direct cost savings of $44,304 ($434 per patient per month) and monthly cost avoidance of $48,835 ($479 per patient per month). Twenty-eight ED visits/admissions and 61 clinic and urgent care visits were avoided. Hospital -readmissions were reduced by 44%. Pharmacist recommendations had a 98% acceptance rate.

CONCLUSIONS: Use of a CPA to conduct CMM in CYSHCN-CMC decreased medication burden, resolved, and prevented adverse events, reduced health care-related costs, reduced hospital readmissions and was well-accepted and implemented collaboratively with pLTCF providers.

PMID:38596413 | PMC:PMC11001202 | DOI:10.5863/1551-6776-29.2.119

Cureus. 2024 Mar 9;16(3):e55865. doi: 10.7759/cureus.55865. eCollection 2024 Mar.

ABSTRACT

Clozapine has become a widely popular and effective medication in the treatment of refractory schizophrenia and refractory bipolar disorder. Although the use of clozapine proves to be an effective resort, it has to be closely monitored due to its narrow therapeutic range and multiple dangerous adverse effects. In rare cases, clozapine has been known to cause an antagonistic myoclonic jerk that leads to knee buckling. Here, we present the case of a 29-year-old female who is being treated for schizoaffective disorder, bipolar, manic type, who reported two instances of knee buckling associated with falls while taking clozapine.

PMID:38595866 | PMC:PMC11002468 | DOI:10.7759/cureus.55865

J Oncol Pharm Pract. 2024 Apr 9:10781552241229662. doi: 10.1177/10781552241229662. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer patients are at a significantly increased risk of drug-related problems due to multiple drugs. An inclusive review of drug-related problems would offer an approach for healthcare providers to decrease the frequency of drug-related problems in cancer patients. The purpose of this study was to assess all characteristic components of drug-related problems in cancer patients, and explore actions taken to resolve the detected drug-related problems the results could be used as a baseline for epidemiology and potential related risk factors for drug-related problems in cancer patients.

METHODS: The present systematic review was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search consisted of studies listed from January 2015 and up to May 2023. A systematic review was carried out using an electronic database with a combination of Medical subject Headings of key words Medical Subject Heading terms.

RESULTS: This evaluation included 17 studies from 11 different nations having 11 prospective and 6 retrospective studies. Pharmaceutical Care Network Europe classification system is the most commonly used to classify the drug-related problems. The prevalence of drug-related problems varied from 9.6% to 92.8%. The key predictors of the drug-related problems were age, polypharmacy, multiple comorbidities, and the stage of the disease.

CONCLUSION: Drug-related problems are significantly more common among cancer patients. The age, polypharmacy, multiple comorbidities, and the stage of the malignancy all enhance the risk of acquiring drug-related problems. This review raises awareness of drug-related problems, encourages their early detection, and emphasizes the necessity for framing effective drug-related problem management strategies which will enhance patient care.

PMID:38594941 | DOI:10.1177/10781552241229662

Front Immunol. 2024 Mar 15;15:1348189. doi: 10.3389/fimmu.2024.1348189. eCollection 2024.

ABSTRACT

Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer.

PMID:38590525 | PMC:PMC11000233 | DOI:10.3389/fimmu.2024.1348189

Drug Ther Bull. 2024 Apr 9:dtb-2024-000021. doi: 10.1136/dtb.2024.000021. Online ahead of print.

NO ABSTRACT

PMID:38594060 | DOI:10.1136/dtb.2024.000021

Transl Androl Urol. 2024 Mar 31;13(3):433-441. doi: 10.21037/tau-24-96. Epub 2024 Mar 25.

ABSTRACT

BACKGROUND: ARASENS has demonstrated the efficacy and safety for darolutamide (DARO) with androgen deprivation therapy (ADT) plus docetaxel in metastasis hormone-sensitive prostate cancer (mHSPC). There is a lack of reports for DARO with ADT in mHSPC though the regimen is used in clinical from time to time. Moreover, recent studies have supported the importance of early and rapid prostate-specific antigen (PSA) reduction, which correlates with reduced disease progression and improved survival in patients with mHSPC. This study aims to evaluate PSA reduction as a primary endpoint for DARO with ADT in the treatment of mHSPC and to evaluate the real-world short-term PSA control of DARO with ADT from two leading medical centers in China.

METHODS: We retrospectively reviewed the clinical records of patients with mHSPC receiving ADT and DARO (600 mg, b.i.d.). The collection of data spanned from March 1, 2022, to July 31, 2023. The main observation indicators were PSA level and drug-related adverse events (AE) after medication. PSA levels were closely monitored prior to treatment initiation and at 2-week intervals, as well as at 1, 3, and 6 months after the initiation of treatment. We also conducted an analysis to determine the proportion of patients achieving a PSA reduction of 50% or more (PSA50) and 90% or more (PSA90) as well as the percentage of patients with a notable decrease in PSA level to 0.2 ng/mL and PSA nadir of ≤0.02 ng/mL.

RESULTS: Fifty-one patients were included in the study, with a median age of 73 years. At diagnosis of HSPC, the majority of patients had a Gleason score ≥8 (n=40, 78.40%) and a median baseline PSA level of 88 ng/mL. Approximately 45.1% (n=23) of patients had a Charlson Comorbidity Index over 1 and were receiving one or more nontumor-related treatments. The median follow-up time was 9.3 months (range, 1.16-15.8 months). The median reductions in PSA levels compared to baseline were 84.37%, 91.48%, 94.67% and 99.81% at 2 weeks, 1 month, 3 months and 6 months after administration of DARO with ADT, respectively. The median time to PSA50, PSA90, significant PSA reduction (PSA <0.2 ng/mL), and PSA nadir (PSA <0.02 ng/mL) was 0.97, 1.27, 1.98, and 2.08 months, respectively. AE mainly included fatigue (two patients) and arm pain (one patient), all of which were grade I or II AE. No grade III or AE were observed.

CONCLUSIONS: For treating prostate cancer, DARO with ADT has good early efficacy, demonstrating prompt and substantial control of PSA levels, with a favorable safety profile.

PMID:38590967 | PMC:PMC10999023 | DOI:10.21037/tau-24-96

Cureus. 2024 Mar 8;16(3):e55819. doi: 10.7759/cureus.55819. eCollection 2024 Mar.

ABSTRACT

Amiodarone is a commonly used antiarrhythmic used to treat atrial fibrillation and ventricular tachycardias. While this agent can present with pulmonary, thyroid, and hepatic side effects, it can also, less commonly cause neurologic toxicity, particularly optic neuropathy. Optic neuropathy can manifest as acute vision loss. The management of amiodarone-associated optic neuropathy (AAON) includes early recognition of symptom manifestation so that the medication can be discontinued promptly. Here, we describe a case of a 64-year-old male who developed acute onset complete left-sided vision loss after initiation of amiodarone.

PMID:38590471 | PMC:PMC10999886 | DOI:10.7759/cureus.55819

Cureus. 2024 Mar 6;16(3):e55666. doi: 10.7759/cureus.55666. eCollection 2024 Mar.

ABSTRACT

Immune-related adverse events (IrAEs) involving the bladder are seldom reported and tend to be overlooked by oncologists. Cystitis caused by immune checkpoint inhibitors (ICIs) is rarely reported, with only four documented instances in the literature, of which just one case is attributed to pembrolizumab. We present a rare occurrence of pembrolizumab-induced hemorrhagic cystitis in a 71-year-old male with stage II-b lung adenocarcinoma with an chronic indwelling Foley catheter. He presented with persistent hematuria despite the completion of a course of antibiotics for a urinary infection; a cystoscopic examination was also normal. Drug-induced cystitis was suspected and the patient was treated with prednisone as well as temporary discontinuation of pembrolizumab, which was followed by an improvement of symptoms.

PMID:38586668 | PMC:PMC10997305 | DOI:10.7759/cureus.55666

EClinicalMedicine. 2024 Jan 8;68:102364. doi: 10.1016/j.eclinm.2023.102364. eCollection 2024 Feb.

ABSTRACT

BACKGROUND: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery.

METHODS: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833.

FINDINGS: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population).

INTERPRETATION: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned.

FUNDING: Renibus Therapeutics, Inc.

PMID:38586479 | PMC:PMC10994969 | DOI:10.1016/j.eclinm.2023.102364

Korean J Fam Med. 2024 Apr 5. doi: 10.4082/kjfm.23.0220. Online ahead of print.

ABSTRACT

Medication review is an intervention with the potential to reduce drug-related problems (DRPs) in the elderly. This study aimed to determine the effect of pharmacists' medication reviews on geriatric patients. This study accessed two online databases, MEDLINE Complete and Scopus, and examined all studies published in English between 2019 and 2023, except for reviews. The studies included (1) participants over 65 years of age and (2) medication reviews conducted by pharmacists. The titles, abstracts, and full texts were reviewed for data extraction to determine whether the studies satisfied the inclusion and exclusion criteria. Forty-four of the initial 709 articles were included in this study. The articles included discussions on the incidence rates of DRPs and potentially inappropriate medications (PIMs) (n=21), hospitalization (n=14), medication adherence (n=9), quality of life (QoL) (n=8), and falls (n=7). Pharmacist medication reviews were associated with a reduced incidence of DRPs and PIMs, and improved adherence to medications. Patients' overall QoL is also increasing. However, pharmacist medication reviews were not strongly associated with decreased hospitalization or falls. A pharmacist's medication review may be a feasible intervention for reducing the incidence rates of DRPs and PIMs, regardless of whether it is performed as a sole intervention or supplemented with other interventions. The intervention was also effective in increasing medication adherence and QoL.

PMID:38583876 | DOI:10.4082/kjfm.23.0220

Inquiry. 2024 Jan-Dec;61:469580241246464. doi: 10.1177/00469580241246464.

ABSTRACT

The concept of pharmacovigilance (PV) is currently highlighted after emergency authorization and worldwide distribution of the urgently launched COVID-19 novel vaccinations. As they typically serve as the initial point of patient contact for medication-related issues, understanding the knowledge, perspectives, and attitudes of community pharmacists in PV and reporting adverse drug reactions (ADRs) is crucial to improving the healthcare system and public health policies. However, previous studies in Jordan have not focused entirely on community pharmacists. This study aimed to assess community pharmacists' knowledge, perspectives, and attitudes on PV and ADRs reporting in Jordan. The applied methodology in this study was based on a cross-sectional study design using a validated questionnaire distributed to a convenient sample of Jordanian community pharmacists. Seventeen questions were designed from different pieces of literature relating to knowledge, perspectives, and attitudes of PV among community pharmacists. Descriptive statistics (frequencies and percentages) were used to report the results data. The study questionnaire was completed by 180 of 325 community pharmacists willing to participate (a response rate of 55.4%). Of them (n = 132, 73%) were aware of the concept of PV. Additionally (n = 84, 47%) of the community pharmacists would use the concept and policy of PV in their everyday work. Nevertheless, only (n = 36, 20.0%) of the community pharmacists thought an ADR should be reported if seen, and approximately 120 pharmacists (67.0%) believed it was essential to report ADRs as patient health matters. Although community pharmacists in Jordan showed a considerable awareness level of PV, they demonstrated a low level of its application. Thus, ADR reporting is not considered a mainstay among them, and the implementation of PV is not yet addressed. The results from this study shed light on community pharmacists' perceptions and attitudes regarding ADR reporting and PV.

PMID:38581250 | PMC:PMC10999125 | DOI:10.1177/00469580241246464

Food Chem Toxicol. 2024 Apr 4:114636. doi: 10.1016/j.fct.2024.114636. Online ahead of print.

ABSTRACT

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity. Diabetes models displayed changes in hepatic metabolizing enzymes, transporters, and glomerular filtration rates (GFR), leading to variability in drug responses and susceptibility to toxicity. Animal models of advanced age exhibited impairment of drug metabolism and kidney function, thereby reducing the drug-metabolizing capacity and clearance. Along with changes in hepatic metabolic enzymes, animal models of metabolic syndrome-related hypertension showed renal dysfunction, resulting in a reduced GFR and urinary excretion of drugs. Taken together, underlying diseases can induce dysfunction of organs involved in the ADME of drugs, ultimately affecting toxicity. Therefore, the use of animal models of representative underlying diseases in nonclinical toxicity studies can be considered to improve the predictability of drug side effects before clinical trials.

PMID:38582343 | DOI:10.1016/j.fct.2024.114636

Prim Care Companion CNS Disord. 2024 Mar 28;26(2):23cr03658. doi: 10.4088/PCC.23cr03658.

NO ABSTRACT

PMID:38579255 | DOI:10.4088/PCC.23cr03658

Indian J Med Res. 2024 Feb 1;159(2):143-152. doi: 10.4103/ijmr.ijmr_2507_21. Epub 2024 Apr 4.

ABSTRACT

BACKGROUND OBJECTIVES: Expenditure on healthcare is a major concern in the geriatric age group. The current study was carried out to assess the expenditure patterns on medicines utilized in geriatric inpatients.

METHODS: An observational study was conducted on 1000 geriatric inpatients, aged ≥60 yr, admitted to the medicine unit. Data were collected regarding demographic characteristics, prescribed medicines, expenditure incurred on medicines, appropriateness of medicines prescribed and adverse drug reactions (ADRs). Appropriateness of the prescribed medicines was determined using the American Geriatrics Society 2015 Updated Beers Criteria.

RESULTS: Geriatric inpatients comprised 41.3 per cent of the total individuals admitted in the ward during the study period. A total of 8366 medicines were prescribed in 127 formulations. The total expenditure on prescribed medicines was INR 1,087,175 with a per capita expenditure of INR 1087.17. Parenteral medicines accounted for 91 per cent of the expenditure on medicines. Maximum expenditure (70%) was incurred on 11.9 per cent of the medicines prescribed. The per capita expenditure was significantly higher in individuals with comorbidities (P=0.03) and those who had a longer duration of hospital stay (P<0.0001). About 28.1 per cent prescriptions were inappropriate. ADRs (140) were observed in 139 (13.9%) inpatients. Individuals with inappropriate medicines prescriptions and ADRs had a longer duration of hospital stay and more number of medicines prescribed.

INTERPRETATION CONCLUSIONS: Comorbidities, prolonged hospitalization, polypharmacy, inappropriate medicines and parenteral medicines being prescribed contribute to increased expenditure on medicines in geriatric inpatients. In view of the rising number of geriatric inpatients, there is a need to frame a drug policy for them along with surveillance of expenditure on prescribed medicines. This needs to be treated as a priority.

PMID:38577855 | DOI:10.4103/ijmr.ijmr_2507_21

Eur J Hosp Pharm. 2024 Apr 5:ejhpharm-2023-004048. doi: 10.1136/ejhpharm-2023-004048. Online ahead of print.

ABSTRACT

OBJECTIVES: Haemodynamic changes following intravenous acetaminophen are well studied in adults. Limited data are published in critically ill paediatric patients, especially from the Middle East. We aim to investigate haemodynamic effects and incidence of hypotension with intravenous acetaminophen in critically ill children, with a focus on understanding factors influencing these effects.

METHODS: We retrospectively reviewed patients who received intravenous acetaminophen between July and December 2022. A haemodynamic event was defined as drop of >15% in systolic blood pressure (SBP) or mean arterial blood pressure (MAP) within 120 min after drug administration. Hypotension was defined as either drop in SBP below the 5th percentile for age, or a haemodynamic event associated with tachycardia, increased lactate or treatment with fluid/vasopressors. Logistic regression was performed to quantify relationships between patients' characteristics and the occurrence of haemodynamic event and hypotension.

RESULTS: A haemodynamic event was observed in 50/156 patients (32%) post-acetaminophen. Mean MAP (SD) before and after acetaminophen was 69.6 mm Hg (14.8) and 67.4 mm Hg (13.9), respectively (p=0.001). Mean SBP (SD) before and after acetaminophen was 95.4 mm Hg (18.2) and 92.8 mm Hg (19.2), respectively (p=0.006). Baseline MAP, median (interquartile range (IQR)) was 76.0 (64.0-85.3) and 66.0 (57.0-74.5) in patients with and without haemodynamic events, respectively (p=0.004). Only 38/156 patients (24%) met the definition for hypotension. Baseline MAP, median (IQR) was 62.0 (51.8-79.0) in patients with, and 68.5 (62.0, 79.3) in patients without hypotension (p=0.036). Baseline shock, vasoactives, mechanical ventilation and paediatric sequential organ failure assessment were not significantly associated with hypotension. Only MAP was found to be associated with both haemodynamic event (adjusted odds ratio (AOR) 1.05, 95% CI 1.02-1.10) and hypotension (AOR 1.06, 95% CI 1.02-1.10) even after controlling for other confounders.

CONCLUSIONS: Administration of intravenous acetaminophen in critically ill children can lead to haemodynamic changes, including clinically significant hypotensive events.

PMID:38580429 | DOI:10.1136/ejhpharm-2023-004048

Drug Ther Bull. 2024 Apr 5:dtb-2024-000020. doi: 10.1136/dtb.2024.000020. Online ahead of print.

NO ABSTRACT

PMID:38580400 | DOI:10.1136/dtb.2024.000020

J Bone Miner Res. 2024 Apr 5:zjae057. doi: 10.1093/jbmr/zjae057. Online ahead of print.

ABSTRACT

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

PMID:38578978 | DOI:10.1093/jbmr/zjae057

J Immunotoxicol. 2024 Dec;21(1):2332177. doi: 10.1080/1547691X.2024.2332177. Epub 2024 Apr 5.

ABSTRACT

Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.

PMID:38578203 | DOI:10.1080/1547691X.2024.2332177

Cancer Rep (Hoboken). 2024 Apr;7(4):e2028. doi: 10.1002/cnr2.2028.

ABSTRACT

BACKGROUND: Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only.

CASE: Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly.

CONCLUSION: The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.

PMID:38577842 | DOI:10.1002/cnr2.2028