Front Pharmacol. 2022 Feb 15;13:765905. doi: 10.3389/fphar.2022.765905. eCollection 2022.

ABSTRACT

The second-generation antipsychotic drugs are widely used in the field of psychiatry, for an expanding number of different conditions. While their clinical efficacy remains indispensable, many of the drugs can cause severe metabolic side-effects, resulting in an increased risk of developing cardiometabolic disorders. The physiological basis of these side-effects remains an ongoing area of investigation. In the present study, we examined the potential role of peripheral catecholamines in antipsychotic-induced glucose intolerance. Adult female rats were acutely treated with either the first-generation antipsychotic drug haloperidol (0.1, 0.5 or 1 mg/kg) or the second-generation drugs risperidone (0.25, 1.0 or 2.5 mg/kg), olanzapine (1.5, 7.5 or 15 mg/kg) or clozapine (2, 10 or 20 mg/kg) or vehicle. Fasting glucose levels were measured and then animals were subjected to the intraperitoneal glucose tolerance test. Levels of peripheral norepinephrine, epinephrine and dopamine were concurrently measured in the same animals 75, 105 and 135 min after drug treatment. All antipsychotics caused glucose intolerance, with strongest effects by clozapine > olanzapine > risperidone > haloperidol. Plasma catecholamines were also increased by drug treatment, with greatest effects for norepinephrine and epinephrine caused by clozapine > risperidone > olanzapine > haloperidol. Importantly, there were strong and statistically significant associations between norepinephrine/epinephrine levels and glucose intolerance for all drugs. These findings confirm that increases in peripheral catecholamines co-occur in animals that exhibit antipsychotic-induced glucose intolerance, and these effects are strongly associated with each other, providing further evidence for elevated catecholamines as a substrate for antipsychotic metabolic side-effects.

PMID:35242029 | PMC:PMC8886888 | DOI:10.3389/fphar.2022.765905

Hepatol Commun. 2022 Mar 3. doi: 10.1002/hep4.1926. Online ahead of print.

ABSTRACT

The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single-arm open-label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per-protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug-related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

PMID:35238498 | DOI:10.1002/hep4.1926

Front Genet. 2022 Feb 14;13:832890. doi: 10.3389/fgene.2022.832890. eCollection 2022.

ABSTRACT

PEG-Asparaginase (also known as Pegaspargase), along with glucocorticoids (predominantly prednisolone or dexamethasone) and other chemotherapeutic agents (such as cyclophosphamide, idarubicin, vincristine, cytarabine, methotrexate and 6-mercaptopurine) is the current standard treatment for acute lymphoblastic leukaemia in both children and adults. High doses of PEG-asparaginase are associated with side effects such as hepatotoxicity, pancreatitis, venous thrombosis, hypersensitivity reactions against the drug and severe hypertriglyceridemia. We report a case of a 28-year-old male who was normolipidemic at baseline and developed severe hypertriglyceridemia (triglycerides of 1793 mg/dl) following treatment with PEG-asparaginase for acute lymphoblastic leukaemia. Thorough genetic analysis was conducted to assess whether genetic variants could suggest a predisposition to this drug-induced metabolic condition. This genetic analysis showed the presence of a rare heterozygous missense variant c.11G > A-p.(Arg4Gln) in the APOC3 gene, classified as a variant of uncertain significance, as well as its association with four common single nucleotide polymorphisms (SNPs; c.*40C > G in APOC3 and c.*158T > C; c.162-43G > A; c.-3A > G in APOA5) related to increased plasma triglyceride levels. To our knowledge this is the first case that a rare genetic variant associated to SNPs has been related to the onset of severe drug-induced hypertriglyceridemia.

PMID:35237305 | PMC:PMC8882989 | DOI:10.3389/fgene.2022.832890

Clin Infect Dis. 2022 Mar 2:ciac130. doi: 10.1093/cid/ciac130. Online ahead of print.

ABSTRACT

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term non-inferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CAR).

METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48; Snapshot, intention-to-treat-exposed population, 5% non-inferiority margin).

RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n=246) or continue CAR (n=247). At Week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating non-inferiority (adjusted difference, -0.8%; 95% CI, -2.4%, 0.8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through Week 48 but comparable post-Week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers.

CONCLUSIONS: Switching to DTG/3TC was non-inferior to continuing CAR for maintaining virologic suppression at Week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC.

PMID:35235656 | DOI:10.1093/cid/ciac130

J Psychopharmacol. 2022 Mar 2:2698811221077196. doi: 10.1177/02698811221077196. Online ahead of print.

ABSTRACT

BACKGROUND: Psychotropic medications are essential in the treatment of mental illness. Unfortunately, these medications are associated with side effects that may reduce adherence to treatment and quality of life. Therefore, systematic screening for side effects is fundamental to optimize treatment with psychotropic medications. Self-report of side effects is a practical alternative to time-consuming clinical assessments. We developed the Aarhus Side effect Assessment Questionnaire (ASAQ) in an attempt to strike the balance between extensive coverage of side effects and reasonable application time.

AIM: The aim of the study was to validate the ASAQ using the clinician-rated Udvalg for Kliniske Undersøgelser (UKU) Side Effect Scale as gold standard reference.

METHODS: A total of 122 inpatients and outpatients-mainly with psychotic (39%) and affective disorders (43%)-receiving treatment with psychotropic medication completed the ASAQ and the World Health Organization-Five Well-Being Index (WHO-5) and were subsequently rated on the UKU by trained raters.

RESULTS: Using the UKU as the gold standard reference, the ASAQ demonstrated sensitivity values >75% for 77% of its 30 items (ranging from 37% for cutaneous disturbances to 98% for increased sweating) and specificity values >75% for 47% of its 30 items (ranging from 28% for reduced sleep to 98% for micturition disturbances). While 17% of the participants considered discontinuing their medication, 24% had recently refrained from taking their medication as prescribed. A negative correlation was found between the ASAQ and the WHO-5 and total scores (Pearson's correlation coefficient = -0.44).

CONCLUSIONS: The self-reported ASAQ seems to be a sensitive tool for detecting side effects of psychotropic medications.

PMID:35234056 | DOI:10.1177/02698811221077196

JBRA Assist Reprod. 2022 Mar 2. doi: 10.5935/1518-0557.20210108. Online ahead of print.

ABSTRACT

OBJECTIVE: Infertility, defined as the inability to conceive after one year of intercourse without the use of contraception, affects 15% of couples. Many factors, such as genitourinary tract infections, endocrine disorders, immunological factors and drug-related injuries, affect the male reproductive system and cause infertility. Due to men's fear of infertility, it is very important to pay attention to medicinal plants that are effective in male fertility. Therefore, the aim of this study was to evaluate the medicinal plants that affect sperm and testosterone production in men.

METHODS: In this review, we used the following search terms, consisting of herbal medicine, traditional medicine, traditional therapies, sperm, testosterone, testicles and Iran were used to retrieve the relevant articles published in the journals indexed in the Information Sciences Institute, Science Direct, PubMed, Scopus, PubMed Central and Scientific Information Databases. We searched and used papers published between 2000 and 2020. Then, we analyzed the eligible papers. We collected and analyzed 35 papers from the databases. We selected only the articles about herbs that affect sperm and testosterone production.

RESULTS: Based on the results, herbs Apium graveolens, Cinnamomum camphora, Cornus mas, Satureja khuzestanica, Withania somnifera, Fumaria parviflora, zingiber officinale, cinnamomum zeylanicum and Phoenix dactylifera are used in the male reproductive system.

CONCLUSIONS: Plants can probably be useful in increasing fertility due to their antioxidant power and low side effects.

PMID:35234023 | DOI:10.5935/1518-0557.20210108

J Med Imaging Radiat Oncol. 2022 Mar 1. doi: 10.1111/1754-9485.13391. Online ahead of print.

ABSTRACT

Oncology care has significantly changed with the emergence of immunotherapy agents, in particular immune checkpoint inhibitors (ICIs). This has had an immediate effect on imaging, with different radiological tumour responses to treatment compared with conventional chemotherapies, and novel imaging findings due to complications caused by these agents (referred to as immune-related adverse effects, irAEs). Some of the more common irAEs may be familiar, but as the use of ICIs increases to a wider variety of cancers, these complications, and in particular, the less common irAEs, will be encountered more frequently on imaging. It will be increasingly important to be familiar with these uncommon irAEs, particularly since they can be difficult to recognise and distinguish from metastatic disease. The aim of this pictorial essay was to describe and illustrate imaging findings that may be encountered related to uncommon but important irAEs as a result of treatment with immune checkpoint inhibitors.

PMID:35233953 | DOI:10.1111/1754-9485.13391

Expert Opin Drug Saf. 2022 Mar 2. doi: 10.1080/14740338.2022.2047177. Online ahead of print.

ABSTRACT

BACKGROUND: Second-generation triazoles including posaconazole are efficacious for prophylaxis and salvage treatment of life-threatening invasive fungal diseases but have been associated with hepatic adverse events (AEs). This report evaluated hepatic AEs in posaconazole-treated patients.

RESEARCH DESIGN AND METHODS: Hepatobiliary AEs with posaconazole exposure in the company's global safety database were analyzed to characterize underlying medical conditions and concomitant drug exposure.

RESULTS: As of October 2019, 516 cases (168 from clinical trials, 348 from postmarketing use) containing 618 hepatobiliary AEs were reported regardless of causality. Frequently reported terms were hyperbilirubinemia, hepatic failure, and hepatic function abnormal (clinical trials reports) and hepatotoxicity, hepatocellular injury, and hepatic function abnormal (postmarketing reports). Cases reporting concurrent medications associated with drug-induced liver injury (DILI) included 8% with verified severe DILI (vMost-DILI) concern, 24% with verified mild to moderate DILI (vLess-DILI) concern, and 37% received both vMost-DILI and vLess-DILI-concern medications in the DILIrank data set.

CONCLUSIONS: Use of concomitant medications with known risks for hepatic injury appears to be an important contributor for the development of hepatotoxicity in patients treated with posaconazole.

PMID:35232318 | DOI:10.1080/14740338.2022.2047177

Int J Hematol. 2022 Feb 28. doi: 10.1007/s12185-022-03304-0. Online ahead of print.

ABSTRACT

The prognosis of patients with chronic myeloid leukemia (CML) has improved dramatically since the development of tyrosine kinase inhibitors (TKIs). Three second-generation TKIs, including bosutinib, are currently approved for treatment of CML, and show a faster and deeper clinical response than imatinib. Common adverse events (AEs) of bosutinib are diarrhea and hepatic toxicity; however, lung complications are rare. Here, we report two cases of bosutinib-induced severe lung injury, along with a literature review. The events of these cases occurred at early time points and severity was extremely high, requiring high-flow oxygen and steroid treatments. Compared to previously reported cases, the prevalence and severity of the damage may vary among different ethnicities. However, bosutinib-induced lung injury can cause life-threatening complications. In conclusion, patients treated with bosutinib should be monitored carefully to mitigate serious drug-induced lung injury.

PMID:35229254 | DOI:10.1007/s12185-022-03304-0

J Med Syst. 2022 Feb 28;46(4):18. doi: 10.1007/s10916-022-01808-0.

ABSTRACT

We describe the technological development of a web platform named CHRONIC-PHARMA that integrates three prescription support tools for patients with chronic diseases: Anticholinergic Burden Calculator (ABC), LESS-CHRON criteria and TRIGGER-CHRON. They focus on the optimization and evaluation of pharmacotherapy in patients with chronic diseases, resulting in a useful, single platform that can facilitate the review of pharmacotherapy and improve the safety of chronically ill patients. This is achieved by estimating and reducing the anticholinergic risk (ABC), detecting opportunities for deprescribing drugs and monitoring its success (LESS-CHRON criteria), as well as calculating the risk of adverse drug events (TRIGGER-CHRON). The platform is freely accessible online ( https://chronic-pharma.com/ ) as well as through a mobile application, and therefore easily accessible among the healthcare community.

PMID:35226192 | DOI:10.1007/s10916-022-01808-0

Afr Health Sci. 2021 Sep;21(3):1027-1039. doi: 10.4314/ahs.v21i3.10.

ABSTRACT

BACKGROUND: Despite close to two decades of antiretroviral therapy (ART) in Nigeria, data on late on-onset ART-associated adverse drug reactions (ADRs) are sparse.

OBJECTIVES: To describe early and late-onset ADRs and compare their incidence in an outpatient HIV positive Cohort on ART.

METHOD: We described the incidence of clinical ADRs identified and documented in an outpatient clinic cohort of HIV-positive patients treated between June 2004 and December 2015 at a tertiary health facility in Nigeria. Incidence rates of ADRs during the first and subsequent years of ART were compared.

RESULTS: of the 13,983 patients' data analyzed, 9317 were females (66%), and those in the age bracket of 25 to 45 years made up 78% of the studied population. During 52,411 person-years (py) of ART, 1485 incident ADRs were recorded; Incidence rate (IR) 28.3 (95% confidence interval [CI] 26.9:29.8) ADRs per 1000 person-years (py) of ART. The IR of ADRs was about two times higher in the first year of ART compared to subsequent years of treatment; crude incidence rate ratio (IRR) 1.77 (95% CI 1.59:1.97). Anemia, hypersensitivity reactions, and nervous system disorders had 7, 23, and 5 times higher incidence, respectively, in the first year of therapy, compared to subsequent years.

CONCLUSION: The first year of ART is the period of highest risk of ADRs. Individual and programmatic treatment success in resource-limited settings requires strategies for early identification and management of ADR during the period of greatest risk of ADRs.

PMID:35222564 | PMC:PMC8843256 | DOI:10.4314/ahs.v21i3.10

Australas J Ageing. 2022 Feb 28. doi: 10.1111/ajag.13046. Online ahead of print.

ABSTRACT

OBJECTIVE: To map explicit screening tools to identify potentially inappropriate medication (PIMs), and the characteristics and limitations of these tools. Including PIMs-interactions, therapeutic alternatives and the clinical management of PIMs.

METHODS: A systematic scoping review was conducted in PubMed and Scopus (until May 2021). The number of PIMs listed as essential drugs was identified in Model List of Essential Medicines by the World Health Organization (WHO) and National List of Essential Medicines (Brazil). In addition to reporting the therapeutic alternatives and clinical management proposed by explicit screening tools to identify PIMs, we suggested our own alternatives for the PIMs most frequently reported.

RESULTS: Fifty-eight tools reported 614 PIMs and 747 PIMs-interactions. Limited overlap between the tools was observed: 123 (69.1%) of 178 therapeutic alternatives proposed by the tools were considered inappropriate by other tools, and 222 (36.1%) of the 614 PIMs identified were named as being inappropriate only once. Only 21 tools were developed by a Delphi panel technique associated with systematic review. The PIMs listed as essential medication in Brazil and by the WHO were 30.6% and 23.3% of the total reported, respectively. For the most-cited PIMs, such as non-steroidal anti-inflammatory drugs, tricyclic antidepressants and benzodiazepines, we suggested the use of non-opioid and opioid analgesics; agomelatine, bupropion or moclobemide; and melatonin, respectively.

CONCLUSIONS: The next stages in the development of explicit screening tools to identify PIMs include achieving more consensus between them and improving their applicability across countries. Further, it is recommended that tools include PIMs risks and advice on therapeutic alternatives.

PMID:35226786 | DOI:10.1111/ajag.13046

Ocul Immunol Inflamm. 2022 Feb 28:1-3. doi: 10.1080/09273948.2022.2042316. Online ahead of print.

ABSTRACT

PURPOSE: COVID-19 vaccines are currently undergoing long-term safety monitoring, including for ocular side effects. Uveitis following vaccination has been described previously with other vaccines and warrants evaluation for COVID-19 vaccines, especially given their widespread use.

CASE REPORTS: We present two cases of patients who developed anterior uveitis following the Moderna COVID-19 vaccine, as reported to the National Registry for Drug-Induced Ocular Side Effects. We also summarize reports of anterior uveitis following COVID-19 vaccination as reported to the World Health Organization global database of individual case safety reports.

CONCLUSIONS: Based on the temporal pattern of ocular inflammation following vaccine delivery in these cases, an association may be present between uveitis and COVID-19 vaccination. Further investigation to explore this association is warranted to guide patient care.

PMID:35226563 | DOI:10.1080/09273948.2022.2042316

J Investig Med High Impact Case Rep. 2022 Jan-Dec;10:23247096221077836. doi: 10.1177/23247096221077836.

ABSTRACT

Many pediatric rheumatic diseases can be safely managed with biologic therapy. Severe allergic reactions to these medications are uncommon. We report the case of a 2-year-old male with systemic-onset juvenile idiopathic arthritis and secondary macrophage activation syndrome (MAS), whose treatment was complicated by severe allergic reactions to biologics, including drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity reaction (DIHR) likely due to anakinra, and anaphylactoid reaction to intravenous tocilizumab. These required transition to canakinumab, cyclosporine, and corticosteroids, with later development of interstitial lung disease and MAS flare needing transition from canakinumab to tofacitinib, which led to disease control. Whether lung disease is a manifestation of DRESS/DIHR to canakinumab remains unclear. High index of suspicion of hypersensitivity reactions for timely diagnosis and drug discontinuation is critical, especially in patients with active disease who might be at increased risk of these adverse events.

PMID:35225032 | DOI:10.1177/23247096221077836

Brief Bioinform. 2022 Feb 28:bbac016. doi: 10.1093/bib/bbac016. Online ahead of print.

ABSTRACT

Accurate identification of drug-target interactions (DTIs) plays a crucial role in drug discovery. Compared with traditional experimental methods that are labor-intensive and time-consuming, computational methods are more and more popular in recent years. Conventional computational methods almost simply view heterogeneous networks which integrate diverse drug-related and target-related dataset instead of fully exploring drug and target similarities. In this paper, we propose a new method, named DTIHNC, for $\mathbf{D}$rug-$\mathbf{T}$arget $\mathbf{I}$nteraction identification, which integrates $\mathbf{H}$eterogeneous $\mathbf{N}$etworks and $\mathbf{C}$ross-modal similarities calculated by relations between drugs, proteins, diseases and side effects. Firstly, the low-dimensional features of drugs, proteins, diseases and side effects are obtained from original features by a denoising autoencoder. Then, we construct a heterogeneous network across drug, protein, disease and side-effect nodes. In heterogeneous network, we exploit the heterogeneous graph attention operations to update the embedding of a node based on information in its 1-hop neighbors, and for multi-hop neighbor information, we propose random walk with restart aware graph attention to integrate more information through a larger neighborhood region. Next, we calculate cross-modal drug and protein similarities from cross-scale relations between drugs, proteins, diseases and side effects. Finally, a multiple-layer convolutional neural network deeply integrates similarity information of drugs and proteins with the embedding features obtained from heterogeneous graph attention network. Experiments have demonstrated its effectiveness and better performance than state-of-the-art methods. Datasets and a stand-alone package are provided on Github with website https://github.com/ningq669/DTIHNC.

PMID:35224614 | DOI:10.1093/bib/bbac016

Clin J Pain. 2022 Feb 28. doi: 10.1097/AJP.0000000000001028. Online ahead of print.

ABSTRACT

OBJECTIVES: This study investigated whether a new sustained-release (SR) pregabalin formulation is non-inferior to immediate-release (IR) pregabalin in alleviating peripheral neuropathic pain in Korean patients.

METHODS: This was a randomized, double-blind, active-controlled phase 3 study of patients with diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN) from 41 sites in South Korea in 2017-2018. Eligible patients were randomized (1:1) to receive once-daily SR pregabalin or twice-daily IR pregabalin (150-600▒mg/d) in a double-dummy manner for 12 weeks according to a stratified permuted block randomization scheme. The primary endpoint was the daily pain rating scale (DPRS) score at the end of treatment, averaged from the last seven available scores.

RESULTS: A total of 319 of 371 (86.0%) randomized patients completed the 12-week treatment (SR pregabalin: n=154; IR pregabalin: n=165; per protocol set: n=296). The least square (LS) mean difference between both groups for the primary endpoint was 0.06 (SE 0.19); (95% CI -0.31 to 0.42), with the lower limit of the CI above the pre-specified margin (-0.78; P-value for non-inferiority <0.0001). Drug-related treatment-emergent adverse events (TEAEs) were comparable between both groups. The incidence of drug-related TEAEs leading to treatment discontinuation was low (SR pregabalin: 2.7%; IR pregabalin: 1.1%). No serious drug-related TEAEs or deaths occurred.

DISCUSSION: The results demonstrate that the new once-daily SR pregabalin formulation is non-inferior to twice-daily IR pregabalin in reducing peripheral neuropathic pain, and is well tolerated in Korean patients with DPN or PHN after 12 weeks of treatment. Trial registration: ClinicalTrials.gov (identifier NCT02985216).

PMID:35220330 | DOI:10.1097/AJP.0000000000001028

Int J Mol Sci. 2022 Feb 14;23(4):2105. doi: 10.3390/ijms23042105.

ABSTRACT

The use of in silico toxicity prediction methods plays an important role in the selection of lead compounds and in ADMET studies since in vitro and in vivo methods are often limited by ethics, time, budget and other resources. In this context, we present our new web tool VenomPred, a user-friendly platform for evaluating the potential mutagenic, hepatotoxic, carcinogenic and estrogenic effects of small molecules. VenomPred platform employs several in-house Machine Learning (ML) models developed with datasets derived from VEGA QSAR, a software that includes a comprehensive collection of different toxicity models and has been used as a reference for building and evaluating our ML models. The results showed that our models achieved equal or better performance than those obtained with the reference models included in VEGA QSAR. In order to improve the predictive performance of our platform, we adopted a consensus approach combining the results of different ML models, which was able to predict chemical toxicity better than the single models. This improved method was thus implemented in the VenomPred platform, a freely accessible webserver that takes the SMILES (Simplified Molecular-Input Line-Entry System) strings of the compounds as input and sends the prediction results providing a probability score about their potential toxicity.

PMID:35216217 | PMC:PMC8877213 | DOI:10.3390/ijms23042105

ESMO Open. 2022 Feb 23;7(2):100404. doi: 10.1016/j.esmoop.2022.100404. Online ahead of print.

ABSTRACT

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs.

OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients.

METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events.

RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis.

CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

PMID:35219244 | DOI:10.1016/j.esmoop.2022.100404

J Investig Med. 2022 Feb 25:jim-2021-001968. doi: 10.1136/jim-2021-001968. Online ahead of print.

ABSTRACT

Domperidone is an effective antiemetic used worldwide, but there have been reports of possible cardiotoxicity. Our goal was to explore the cardiac safety and clinical efficacy of long-term domperidone, titrated as high as 120 mg/day, in patients not responding or unable to tolerate other therapies for gastroparesis (GP).This retrospective cohort study was conducted at a single tertiary care academic center. We objectively assessed the safety and efficacy of domperidone through questionnaires, clinical follow-up and frequent ECGs as mandated by the Food and Drug Administration. We excluded patients with a history of dangerous arrhythmias, prolonged QTc, clinically significant electrolyte disturbances, gastrointestinal hemorrhage or obstruction, presence of a prolactinoma, pregnant or breastfeeding females, or allergy to domperidone. A total of 21 patients met the inclusion criteria for eligibility in this study (52.4% white, 42.9% Hispanic; mean age 50.1 years; 90.5% female). The mean duration of domperidone therapy was 52.3 (range 16-97) months with a mean highest dose of 80 mg/day (range 40-120 mg). Two patients (9.5%) taking 120 mg/day experienced asymptomatic meaningful QTc prolongation (>450 ms in males, >470 ms in females). One-third of patients had asymptomatic non-meaningful QTc prolongation. Palpitations or chest pain was reported in 19% of patients without ECG abnormalities or adverse cardiac events. The mean severity of vomiting and nausea was improved by 82% and 55%, respectively.Long-term treatment with high doses of domperidone (40-120 mg/day) improved GP symptoms in patients previously refractory to other medical therapies and with a satisfactory cardiovascular risk profile.

PMID:35217570 | DOI:10.1136/jim-2021-001968

Sci Rep. 2022 Feb 24;12(1):3124. doi: 10.1038/s41598-022-07164-w.

ABSTRACT

We conducted a multicenter prospective study on whether a comprehensive geriatric assessment (CGA) can predict the adverse events (AEs) of chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients aged ≥ 65 years with newly diagnosed DLBCL underwent a pretreatment baseline CGA consisting of six assessment tools: activities of daily living (ADL), instrumental ADL (IADL), mood, nutritional status, comorbidities, and cognitive function. An attending physician chose each patient's treatment but was blind to CGA results. Patients were grouped as "dependent" or "independent" according to the CGA. The primary endpoint was to evaluate the association between chemotherapy-induced grade 3-4 toxicity and CGA. Of 86 patients, 78 completed the designated CGA. The median age was 79 years (65-89). Seventy-two patients were treated with a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP-like) regimen, and six were treated with low-toxicity regimens. Forty-one patients were classified as dependent and 37 as independent. In multivariate analysis, an impairment of IADL was independently associated with grade 3-4 leukopenia (odds ratio [OR] 0.63; 95% confidence interval [CI] 0.43-0.92, p = 0.017) and anemia (OR 0.67; 95% CI 0.50-0.90, p = 0.008). The presence of a comorbidity was also associated with grade 3-4 non-hematological toxicity (OR 2.17; 95% CI 1.37-3.43, p = 0.001). The 4-year survival rate tended to be longer in the independent (72.7%) compared to dependent (56.9%) group. Overall, a CGA may be a useful tool for predicting serious AEs associated with chemotherapy in elderly patients with DLBCL.

PMID:35210509 | PMC:PMC8873456 | DOI:10.1038/s41598-022-07164-w