J Chem Inf Model. 2021 Nov 22;61(11):5386-5394. doi: 10.1021/acs.jcim.1c00733. Epub 2021 Nov 10.

ABSTRACT

In silico assessment of drug toxicity is becoming a critical step in drug development. Conventional ligand-based models are limited by low accuracy and lack of interpretability. Further, they often fail to explain cellular mechanisms underlying structure-toxicity associations. We addressed these limitations by incorporating target profile as an intermediate connecting structure to toxicity. To accommodate for high-dimensional feature space, we developed a pipeline named TargetTox that can identity a subset of predictive features. We implemented TargetTox to study 569 targets and 815 adverse events. The features identified by TargetTox comprise less than 10% of the original feature space; nevertheless, they accurately predicted binding outcomes for 377 targets and toxicity outcomes for 36 adverse events. We demonstrated that predictive targets tend to be differentially expressed in the tissue of toxicity. We also rediscovered key cellular functions associated with cardiotoxicity from the predictive targets, as well as markers of skin and liver diseases. Furthermore, we found evidence supporting diagnostic and therapeutic applications of some predictive targets in hepatotoxicity and nephrotoxicity. Our findings highlighted the critical role of predictive targets in cellular mechanisms leading to toxicity. In general, our study improved the interpretability of toxicity prediction without sacrificing accuracy. Our novel pipeline may benefit future studies of high-dimensional data sets.

PMID:34757743 | DOI:10.1021/acs.jcim.1c00733

Enferm Clin (Engl Ed). 2021 Nov-Dec;31(6):363-370. doi: 10.1016/j.enfcle.2020.10.011. Epub 2021 Mar 18.

ABSTRACT

OBJECTIVE: This study aimed to gain knowledge of the nurses' involvement in the spontaneous report of suspected adverse drug reactions (ADR) in the Spanish Pharmacovigilance System for Medicinal Products for Human Use (SEFV-H), describing the principal characteristics of the reported cases, identifying points of improvement.

METHODS: A descriptive observational retrospective study was based on the data from FEDRA, the database created by the SEFV-H. The sample taken was the spontaneous adverse drug reactions reported to SEFV-H by nurses during the first 6 months of the 2018.

RESULTS: Complete data was provided by 6,370 suspicions of ADR reported to SEFV-H by all healthcare professionals. Only 4,8% of the samples were taken by nurses, 62,7% came from medical centers. The majority of the ADR were not considered a serious disease (78%). The most frequently adverse drug reactions reported by nurses were local reactions. The patients most involved were children and vaccines were the most reported drugs (58,3%), followed by the intravenous contrast agents used in diagnostic tests.

CONCLUSIONS: Nurses report very few cases to SEFV-H and are mostly related to the administration of vaccines and are sent by nurses working in the out-of-hospital setting. Most cases are not serious and usually report known adverse reactions to the suspected drug. This observed under-notification raises the need to promote increased pharmacovigilance training among these notifying nurses so that they can continue to report, and also for those who do not do so in their daily practice, so that they can begin to do so.

PMID:34756240 | DOI:10.1016/j.enfcle.2020.10.011

J Geriatr Cardiol. 2021 Oct 28;18(10):783-795. doi: 10.11909/j.issn.1671-5411.2021.10.003.

ABSTRACT

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) significantly reduce the risk of cardiovascular (CV) and renal adverse events in patients with diabetes mellitus, heart failure (HF) and/or chronic kidney disease. We performed a meta-analysis to explore the impact of several different SGLT2i on all-cause mortality, CV mortality, HF hospitalizations and the combined outcome CV death/HF hospitalization in HF patients across the spectrum of left ventricular ejection fraction (LVEF) phenotypes.

METHODS: A systematic search in MEDLINE database and Cochrane library through March 2021 was performed without limitations. Randomized clinical trials that provided data about the impact of SGLT2i on all-cause mortality, CV mortality, HF hospitalizations or the combined outcome of CV death/HF hospitalization in HF patients were included. A random effects model was used for calculating the effect estimates.

RESULTS: Nine studies (n = 16,723 patients, mean age: 65.9 years, males: 70.7%) were included in the quantitative synthesis. Compared to placebo, SGLT2i use was associated with 14% lower risk of all-cause mortality [hazard ratio (HR) = 0.86, 95% CI: 0.78-0.94,I 2 = 0, P = 0.0008], 32% lower risk of HF hospitalizations (HR = 0.68, 95% CI: 0.62-0.74,I 2 = 0, P < 0.001), 14% lower risk of CV mortality (HR = 0.86, 95% CI: 0.77-0.95, I 2 = 0, P = 0.003) and 26% lower risk of CV death/HF hospitalization (HR = 0.74, 95% CI: 0.68-0.80,I 2 = 0, P < 0.001). Regarding the safety outcomes, our data revealed no significant differences between SGLT2i and placebo groups in drug related discontinuations, amputations, severe hypoglycemia, hypotension, volume depletion, ketoacidosis and genital infections. By contrast, a protective role of SGLT2i against placebo was found for serious adverse events and acute kidney injury.

CONCLUSIONS: In patients with HF, regardless of LVEF phenotype, all SGLT2i had an excellent safety profile and significantly reduced the risk of all-cause mortality, CV mortality, HF hospitalizations and CV deaths/HF hospitalizations compared to placebo.

PMID:34754290 | PMC:PMC8558745 | DOI:10.11909/j.issn.1671-5411.2021.10.003

Eur J Hosp Pharm. 2021 Nov 9:ejhpharm-2021-003062. doi: 10.1136/ejhpharm-2021-003062. Online ahead of print.

ABSTRACT

OBJECTIVES: Levetiracetam is an anticonvulsive drug increasingly used in paediatric populations. Ontogenesis may alter its pharmacokinetics, demanding dose individualisation of levetiracetam in paediatric populations. We therefore aimed to explore levetiracetam pharmacokinetics and to propose its optimal dosing in the paediatric population.

METHODS: Individual levetiracetam pharmacokinetic parameters were calculated based on therapeutic drug monitoring data, using a one-compartmental model, and regression models were used to explore possible covariates.

RESULTS: 56 patients aged from 47 days to 18 years were included in the analysis. The median (IQR) volume of distribution and clearance of levetiracetam were 0.7 (0.58-0.85) L/kg and 0.123 (0.085-0.167) L/hour/kg, respectively. Levetiracetam pharmacokinetics were influenced by postnatal age, body size descriptors and renal functional status.

CONCLUSIONS: Based on observed relationships, an individualised loading dose of 26.2 mg/kg body weight and maintenance dose of 20.7 mg/mL/min of estimated glomerular filtration rate were calculated as optimal. Since we observed increased levetiracetam clearance in association with valproate co-medication, caution should be used when combining these two drugs.

PMID:34753796 | DOI:10.1136/ejhpharm-2021-003062

BMC Anesthesiol. 2021 Nov 9;21(1):275. doi: 10.1186/s12871-021-01501-8.

ABSTRACT

BACKGROUND: Opioids are currently prescribed for chronic non-cancer pain (CNCP), and some patients use opioids continuously for long-term treatment. Stakeholders' awareness about long-term opioid therapy is essential for improving the safety and effectiveness of pain treatment. The purpose of this study is to explore the perspectives of pain specialists, patients, and family caregivers about long-term opioid use in CNCP management.

METHODS: This study was a qualitative study and adhered to the COREQ guidelines. Pain specialists (n = 12), patients (n = 14), and family members (n = 9) were recruited to the study by purposive sampling at the Pain Clinic of Ramathibodi Hospital. Semi-structured interviews were recorded, verbatim transcribed, conceptually coded, and analyzed using Atlas.ti 8.0.

RESULTS: All groups of participants described opioids as non-first-line drugs for pain management. Opioids should be prescribed only for severe pain, when non-opioid pharmacotherapy and non-pharmacological therapies are not effective. Patients reported that the benefits of opioids were for pain relief, while physicians and most family members highlighted that opioid use should improve functional outcomes. Physicians and family members expressed concerns about opioid-related side effects, harm, and adverse events, while patients did not. Patients confirmed that they would continue using opioids for pain management under supervision. However, physicians stated that they would taper off or discontinue opioid therapy if patients' pain relief or functional improvement was not achieved. Both patients and family members were willing to consider non-pharmacological therapies if potential benefits existed. Patient education, doctor-patient/family relationships, and opioid prescription policies were proposed to enhance CNCP management.

CONCLUSION: Long-term opioid therapy for CNCP may be beneficial in patients who have established realistic treatment goals (for both pain relief and functional improvement) with their physicians. Regular monitoring and evaluation of the risks and benefits, adverse events, and drug-related aberrant behaviors are necessary. Integrated multimodal multidisciplinary therapies and family member collaborations are also important for improving CNCP management.

PMID:34753421 | DOI:10.1186/s12871-021-01501-8

J Infus Nurs. 2021 Nov-Dec 01;44(6):331-338. doi: 10.1097/NAN.0000000000000446.

ABSTRACT

Teprotumumab was the first and only medication approved by the US Food and Drug Administration for the treatment of thyroid eye disease in January 2020. Thyroid eye disease is a complex autoimmune inflammatory disease that can be sight-threatening, debilitating, and disfiguring to affected patients. Although biologic therapies are a preferred treatment option for many complex immunologic and oncologic conditions, their use in ophthalmology and endocrinology may be more novel. The goals of this article are to introduce this new therapeutic option; discuss its mechanism of action, indications for use, administration protocol, infusion precautions, and informed consent; and review common side effects and management.

PMID:34753152 | DOI:10.1097/NAN.0000000000000446

Br J Dermatol. 2021 Nov 8. doi: 10.1111/bjd.20880. Online ahead of print.

ABSTRACT

BACKGROUND: HSP90 is a downstream regulator of tumor necrosis factor α (TNFα) and interleukin (IL)-17A signaling and may therefore serve as a novel target in the treatment of psoriasis.

OBJECTIVE: This phase 1b proof-of-concept study was undertaken to evaluate the safety and efficacy of a novel HSP90 inhibitor (RGRN-305) in the treatment of plaque psoriasis.

METHODS: An open-label, single-arm, dose-selection, single-center proof-of-concept study. Patients with plaque psoriasis were treated with 250 mg or 500 mg RGRN-305 daily for 12 weeks. Efficacy was evaluated clinically using Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Physician Global Assessment (PGA) scores and by Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8, and 12 weeks after treatment start were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, ECG, and physical examinations.

RESULTS: Six of the eleven patients completing the study responded to RGRN-305 with a PASI improvement between 71% and 94%, whereas five patients were considered nonresponders with a PASI response < 50%. No severe adverse events were reported. Four of seven patients treated with 500 mg RGRN-305 daily experienced a mild to moderate exanthematous drug induced eruption due to study treatment. Two patients chose to discontinue the study due to this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNFα, and IL-17A signaling pathways and normalization of both histological changes and psoriatic lesion gene expression profiles in patients responding to treatment.

CONCLUSION: Treatment with RGRN-305 showed an acceptable safety, especially in the low-dose group, and was associated with clinically meaningful improvement in a subset of patients with plaque psoriasis, indicating that HSP90 may serve as a novel future target in psoriasis treatment.

PMID:34748646 | DOI:10.1111/bjd.20880

J Cyst Fibros. 2021 Nov 3:S1569-1993(21)02104-4. doi: 10.1016/j.jcf.2021.10.002. Online ahead of print.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, Trikafta) is the newest Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drug approved by the Food and Drug Administration. Post-marketing reports with earlier CFTR modulators suggest these medications can impact mood, and in clinical trials an adverse effect of headache was reported with all currently approved CFTR modulators. However, there are no other documented reports of mental status changes during clinical trials or in post-marketing reports with elexacaftor/tezacaftor/ivacaftor. In this case series, we describe 6 patients who reported "mental fogginess" or other mental status changes shortly after initiation of this drug. The mechanism of this patient-reported side effect is still unclear. All patients noticed a change within the first 3 months of therapy. The management differed in each case, with all four cystic fibrosis (CF) care teams utilizing a patient-centered decision-making approach to address this concern.

PMID:34742667 | DOI:10.1016/j.jcf.2021.10.002

Health Technol Assess. 2021 Nov;25(60):1-72. doi: 10.3310/hta25600.

ABSTRACT

BACKGROUND: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children.

OBJECTIVES: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia.

DESIGN: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland.

SETTING: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards.

PARTICIPANTS: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge.

INTERVENTIONS: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio.

MAIN OUTCOME MEASURES: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication.

RESULTS: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms.

LIMITATIONS: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children.

CONCLUSIONS: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms.

FUTURE WORK: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing.

TRIAL REGISTRATION: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.

FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.

PMID:34738518 | DOI:10.3310/hta25600

BMC Ophthalmol. 2021 Nov 4;21(1):386. doi: 10.1186/s12886-021-02147-3.

ABSTRACT

BACKGROUND: Indapamide, a sulfonamide diuretic used to treat hypertension, has been reported to have ocular side effects of acute angle-closure glaucoma, transient myopia and choroidal effusion whose immediate etiology is uncertain. This report aims to clarify the nature of indapamide-induced edema of the entire eyeball using multimodal imaging.

CASE PRESENTATION: A 60-year-old woman who was following a long-term carbohydrate-restricted diet and receiving oral treatment for hypertension was referred to our department for eye pain. Indapamide (1 mg daily) was prescribed for uncontrolled hypertension 5 days before her visit; she took the medication for only 3 days and then stopped due to dry eye. However, she began to feel eye pain the day after her last dose, and the pain gradually intensified. She experienced no decrease in visual acuity at the initial visit; however, an extremely shallow anterior chamber was observed in both eyes, along with a slight increase in intraocular pressure. For differential diagnosis, ocular manifestations were evaluated with wide-field fundus photography, optical coherence tomography (OCT) of both anterior and posterior segments, fluorescein / indocyanine green angiography, ultrasound biomicroscopy and head magnetic resonance, showing edema of the entire eyeball. Treatment with tropicamide and phenylephrine hydrochloride drops resulted in rapid recovery of the anterior chamber depth and disappearance of the choroidal effusion within 3 days.

CONCLUSIONS: Multimodal imaging is useful for diagnosing drug-induced choroidal effusion by evaluating ocular conditions before and after treatment.

PMID:34736431 | DOI:10.1186/s12886-021-02147-3

Anticancer Res. 2021 Nov;41(11):5827-5834. doi: 10.21873/anticanres.15401.

ABSTRACT

BACKGROUND/AIM: Recently, the number of patients with cancer receiving outpatient chemotherapy using oral anticancer drugs has increased, but the currently available outpatient cancer chemotherapy is not safer than that available before. The present study aimed to identify risk factors associated with unplanned acute care (UAC) requiring outpatient chemotherapy-related consultation and hospitalisation.

PATIENTS AND METHODS: We conducted a case- control study among 1,674 patients who received oral anticancer drug treatment either alone or in combination with injectable anticancer drugs at National Cancer Center Hospital East, Japan, between December 1, 2014, and November 30, 2015.

RESULTS: Body mass index (BMI) was identified as a risk factor for UAC during chemotherapy. Patients with a BMI of <18.5 kg/m2, classified as underweight according to the World Health Organization classification of nutritional status, had a significantly higher risk of UAC.

CONCLUSION: A low BMI immediately before the occurrence of chemotherapy-related UAC is a risk factor for adverse effects; therefore, underweight patients need more careful monitoring and supportive care.

PMID:34732458 | DOI:10.21873/anticanres.15401

Psychiatr Serv. 2021 Nov 1;72(11):1362. doi: 10.1176/appi.ps.721105.

NO ABSTRACT

PMID:34734754 | DOI:10.1176/appi.ps.721105

Psychiatr Serv. 2021 Nov 1;72(11):1361-1362. doi: 10.1176/appi.ps.721104.

NO ABSTRACT

PMID:34734752 | DOI:10.1176/appi.ps.721104

Eur J Med Chem. 2021 Oct 9;227:113909. doi: 10.1016/j.ejmech.2021.113909. Online ahead of print.

ABSTRACT

O6-Methylguanine-DNA-methyltransferase (MGMT) is a key DNA repair enzyme involved in chemoresistance to DNA-alkylating anti-cancer drugs such as Temozolomide (TMZ) through direct repair of drug-induced O6-methylguanine residues in DNA. MGMT substrate analogues, such as O6-benzylguanine (BG), efficiently inactivate MGMT in vitro and in cells; however, these drugs failed to reach the clinic due to adverse side effects. Here, we designed hybrid drugs combining a BG residue covalently linked to a DNA-interacting moiety (6-chloro-2-methoxy-9-aminoacridine). Specifically, two series of hybrids, encompassing three compounds each, were obtained by varying the position of the attachment point of BG (N9 of guanine vs. the benzyl group) and the length and nature of the linker. UV/vis absorption and fluorescence data indicate that all six hybrids adopt an intramolecularly stacked conformation in aqueous solutions in a wide range of temperatures. All hybrids interact with double-stranded DNA, as clearly evidenced by spectrophotometric titrations, without intercalation of the acridine ring and do not induce thermal stabilization of the duplex. All hybrids, as well as the reference DNA intercalator (6-chloro-2-methoxy-9-aminoacridine 8), irreversibly inhibit MGMT in vitro with variable efficiency, comparable to that of BG. In a multidrug-resistant glioblastoma cell line T98G, benzyl-linked hybrids 7a-c and the N9-linked hybrid 19b are moderately cytotoxic (GI50 ≥ 15 μM after 96 h), while N9-linked hybrids 19a and 19c are strongly cytotoxic (GI50 = 1-2 μM), similarly to acridine 8 (GI50 = 0.6 μM). Among all compounds, hybrids 19a and 19c, similarly to BG, display synergic cytotoxic effect upon co-treatment with subtoxic doses of TMZ, with combination index (CI) values as low as 0.2-0.3. In agreement with in vitro results, compound 19a inactivates cellular MGMT but, unlike BG, does not induce significant levels of DNA damage, either alone or in combination with TMZ, as indicated by the results of γH2AX immunostaining experiments. Instead, and unlike BG, compound 19a alone induces significant apoptosis of T98G cells, which is not further increased in a combination with TMZ. These results indicate that molecular mechanisms underlying the cytotoxicity of 19a and its combination with TMZ are distinct from that of BG. The strongly synergic properties of this combination represent an interesting therapeutic opportunity in treating TMZ-resistant cancers.

PMID:34731767 | DOI:10.1016/j.ejmech.2021.113909

Acta Med Port. 2021 Nov 3. doi: 10.20344/amp.16762. Online ahead of print.

NO ABSTRACT

PMID:34731595 | DOI:10.20344/amp.16762

Ann Indian Acad Neurol. 2021 Jul-Aug;24(4):501-505. doi: 10.4103/aian.AIAN_925_20. Epub 2021 Jun 17.

ABSTRACT

PURPOSE: While two-thirds of epilepsy patients can become seizure free on medical treatment, poor adherence to medication is a major problem to sustained remission and functional restoration. The aim of this study was to assess the prevalence and associated factors of antiepileptic drug (AED) non-adherence.

METHODS: We conducted a subgroup analysis based on results that emerged from a single center, cross-sectional study. Patients who were 18 years or older were included. The 4-item Morisky Medication Adherence Scale was used to measure adherence to AED (s). Multivariable logistic regression analysis was used to predict factors associated with AED non-adherence.

RESULTS: A total of 268 patients fulfilled inclusion criteria and were included in this subgroup analysis. Among the participants, 81 (30%) were non-adherent to medication. Three factors associated with non-adherence were AED polytherapy [OR: 4.5 (2.1-9.5) P = 0.001], drug related adverse events [OR: 3.9 (2.1-7.3) P = 0.001], and treatment duration exceeding 3 years [OR: 2.6 (1.3-5.0) P = 0.003].

CONCLUSION: About one-third patients were not compliant with their medication. If the treatment of patients is restricted to monotherapy as far as possible and patients are educated about duration of treatment and possible adverse effects of AEDs, non-adherence may be reduced.

PMID:34728941 | PMC:PMC8513971 | DOI:10.4103/aian.AIAN_925_20

Curr Rheumatol Rev. 2021 Nov 1. doi: 10.2174/1573397117666211102094330. Online ahead of print.

ABSTRACT

Nowadays, tumor necrosis factor alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, among them, drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone, was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti-Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

PMID:34727862 | DOI:10.2174/1573397117666211102094330

Cancer. 2021 Nov 2. doi: 10.1002/cncr.34005. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical benefit of cusatuzumab, a CD70-directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL).

METHODS: In this cohort expansion of the ARGX-110-1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed.

RESULTS: The most common adverse events included infusion-related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1-3) were reported in 11 patients; 1 of these (vasculitis) was considered drug-related. For 8 of the 11 patients receiving 1 mg/kg, anti-drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses.

CONCLUSIONS: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.

PMID:34726773 | DOI:10.1002/cncr.34005

J Clin Pharm Ther. 2021 Nov 2. doi: 10.1111/jcpt.13565. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Newborns, particularly preterm babies, are prone to vascular vasospasm and thromboembolism. Differences in the haemostatic system, small vessel diameter and presence of any serious diseases are predisposing causes of thromboembolic disease in newborns. The lack of randomized controlled studies on the management of vasospasm and thromboembolism exacerbates the problem. We present a case series of the successful and safe use of PTX for the treatment of vasospasm and thrombosis in neonates.

METHODS: The study was conducted in the Bezmialem Vakif University Hospital Neonatal Intensive Care Unit (NICU). A retrospective chart review was performed on consecutive patients treated for vascular spasm and thrombosis. Nine patients diagnosed with vasospasm or thrombosis were enrolled in the study.

RESULTS: Five patients had arterial injuries. Six patients were premature, and five patients were diagnosed with thrombosis by using Doppler ultrasonography (US). The drug was diluted with 5% dextrose and administered intravenously at a dose of 5 mg/kg/h over six hours, ranging from 1 to 5 days. No drug-related side effects were observed. All babies recovered, and no amputation was performed.

WHAT IS NEW AND CONCLUSION: PTX may be an alternative treatment for vascular vasospasm and thromboembolism with fewer side effects than anticoagulant and thrombolytic agents in neonates. Starting PTX in the early stages of vascular insult may prevent the development of vasospasm and thromboembolism and thus limb ischaemia.

PMID:34726284 | DOI:10.1111/jcpt.13565

Int J Clin Pract. 2021 Nov 1:e15001. doi: 10.1111/ijcp.15001. Online ahead of print.

ABSTRACT

OBJECTIVE: Warfarin-induced skin necrosis (WSN) is a rare (0.0.1-0.1%) and severe adverse reaction. The clinical characteristics of this reaction and its mortality rate have not been explored in a large population. Therefore, we present the case of a Peruvian patient who developed WSN and perform a systematic review of case reports of WSN.

METHODS: A systematic search was performed using the Pubmed / Medline, Scopus, Web of Science, and Embase databases. Patient clinical data were collected and extracted from every case report. Furthermore, we analyzed the factors associated with mortality due to WSN using the Poisson regression model with robust variations, obtaining risk ratios (RR) and their respective confidence intervals (95% CI).

RESULTS: We identified 90 case reports that included a total of 111 patients with WSN (mean age 52.5 years), 20.72% of whom died of complications due to WSN. Being male (RR: 2.87; 95% CI 1.21 - 6.83) and having three or more affected regions (RR: 6.81; 95% CI 2.62 - 17.74) were associated with an increased risk of death caused by WSN.

CONCLUSION: This systematic review identified 90 case reports of WSN with three or more affected body regions. Male sex was associated with an increased risk of death. Further studies are needed to analyze and confirm these results.

PMID:34725899 | DOI:10.1111/ijcp.15001