Lancet Oncol. 2022 Apr;23(4):540-552. doi: 10.1016/S1470-2045(22)00061-4.

ABSTRACT

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.

METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.

FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).

INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

FUNDING: Bayer Healthcare Pharmaceuticals.

PMID:35358455 | DOI:10.1016/S1470-2045(22)00061-4

J Chem Inf Model. 2022 Mar 31. doi: 10.1021/acs.jcim.1c01414. Online ahead of print.

ABSTRACT

Despite the potency of most first-line anti-cancer drugs, nonadherence to these drug regimens remains high and is attributable to the prevalence of "off-target" drug effects that result in serious adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea. Some anti-cancer drugs are converted by liver uridine 5'-diphospho-glucuronosyltransferases through homeostatic host metabolism to form drug-glucuronide conjugates. These sugar-conjugated metabolites are generally inactive and can be safely excreted via the biliary system into the gastrointestinal tract. However, β-glucuronidase (βGUS) enzymes expressed by commensal gut bacteria can remove the glucuronic acid moiety, producing the reactivated drug and triggering dose-limiting side effects. Small-molecule βGUS inhibitors may reduce this drug-induced gut toxicity, allowing patients to complete their full course of treatment. Herein, we report the discovery of novel chemical series of βGUS inhibitors by structure-based virtual high-throughput screening (vHTS). We developed homology models for βGUS and applied them to large-scale vHTS against nearly 400,000 compounds within the chemical libraries of the National Center for Advancing Translational Sciences at the National Institutes of Health. From the vHTS results, we cherry-picked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds that exhibited positive inhibitory activity in a follow-up βGUS biochemical assay in vitro. Our findings correspond to a hit rate of 24% and could inform the successful downstream development of a therapeutic adjunct that targets the human microbiome to prevent SAEs associated with first-line, standard-of-care anti-cancer drugs.

PMID:35357819 | DOI:10.1021/acs.jcim.1c01414

Respirol Case Rep. 2022 Mar 23;10(4):e0938. doi: 10.1002/rcr2.938. eCollection 2022 Apr.

ABSTRACT

The Pfizer-BioNTech mRNA vaccine (BNT162b2) is an effective and well-tolerated coronavirus disease 2019 (COVID-19) vaccine. However, rare adverse events have been reported. We report two cases of COVID-19 mRNA vaccine-related interstitial lung disease (ILD). A 67-year-old man and a 70-year-old man with underlying ILD presented to our hospital with a few days of fever and respiratory symptoms after receiving the BNT162b2 vaccine. Drug-related pneumonitis due to the COVID-19 mRNA vaccine was diagnosed. One case was diagnosed with lymphocytic alveolitis by bronchoalveolar lavage fluid and transbronchial lung cryobiopsy. Both patients were successfully treated with corticosteroids, and they attended outpatient clinics thereafter. Although the safety and efficacy of COVID-19 vaccines have been established, further studies are needed to estimate long-term data and reports of rare adverse reactions. We present the clinical course of two cases, review previously published case reports on COVID-19 mRNA vaccine-related ILD and discuss the relevant findings.

PMID:35355663 | PMC:PMC8942814 | DOI:10.1002/rcr2.938

Clin Pharmacol Drug Dev. 2022 Mar 30. doi: 10.1002/cpdd.1090. Online ahead of print.

ABSTRACT

Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. We evaluated the role of hepatic impairment on daprodustat pharmacokinetics, pharmacodynamics, and tolerability. Participants with mild (Child-Pugh Class A, score 5-6) and moderate (Child-Pugh Class B, score 7-9) hepatic impairment and matched healthy controls were administered single 6-mg doses of daprodustat. Exposure parameters were determined for daprodustat and its six metabolites. Comparisons resulted in 1.5- and 2.0-fold higher daprodustat Cmax and area under the curve (AUC) exposures in participants with mild and moderate hepatic impairment, respectively, versus controls; Cmax in mild hepatic impairment was comparable to controls. Similarly, aligned with parent drug, unbound daprodustat Cmax and AUC exposures increased 1.6- to 2.3-fold in hepatic-impaired participants versus controls, and metabolite exposures were 1.2- to 2.0-fold higher in participants with hepatic impairment. Erythropoeitin (EPO) baseline-corrected AUC exposures were between 0.3-fold lower and 2.2-fold higher in matched controls versus hepatic-impaired participants. No serious or study drug-related adverse events were reported. Daprodustat exposure was increased in participants with moderate and mild hepatic impairment compared with matched controls; however, no meaningful differences in EPO were observed and no new safety concerns were identified (ClinicalTrials.gov: NCT03223337).

PMID:35355447 | DOI:10.1002/cpdd.1090

Org Biomol Chem. 2022 Mar 31. doi: 10.1039/d2ob00260d. Online ahead of print.

ABSTRACT

Hydrazide drugs can cause severe drug-induced liver injury owing to the enzymatic release of N2H4 in the liver. Also, changes in cellular viscosity are associated with liver damage. Thus, simultaneous monitoring of changes in N2H4 levels and viscosity can be used to evaluate the side effects of hydrazide drugs. Herein, we firstly reported a near-infrared fluorescent probe (FNN), which contains 1,8-naphthalimide as the fluorophore and a chalcone moiety as the responsive receptor, for sensitively detecting intracellular viscosity and N2H4. FNN showed a fast 'turn-on' fluorescence response to N2H4 with excellent selectivity. Additionally, FNN could selectively track viscosity without interference from polarity, pH, and other active species. Furthermore, imaging experiments suggested that FNN could be successfully applied in living cells and zebrafish larvae and embryos, which is of great importance for effectively assessing the degree of liver injury.

PMID:35355037 | DOI:10.1039/d2ob00260d

Eur J Hosp Pharm. 2022 Mar 30:ejhpharm-2021-003087. doi: 10.1136/ejhpharm-2021-003087. Online ahead of print.

ABSTRACT

OBJECTIVES: Identifying instances where medications have been discontinued due to an adverse/allergic reaction however the patients' allergy status has not been updated appropriately. Data were evaluated in an established electronic prescribing and medicines administration system within a medium-sized teaching hospital.

METHODS: Details of all medications stopped due to allergic reaction over a 3-year period were extracted from the electronic prescribing system. The instances where the discontinued medication was not included in the patients' allergy status were investigated further. Patient records were explored to determine whether genuine reactions had occurred.

RESULTS: 434 medications were discontinued due to drug allergy over the time period. Of these, 26 cases were identified where a documented drug reaction had not been added to the patients' inpatient allergy history.

CONCLUSIONS: Electronic systems provide a wealth of information which can be analysed to identify gaps in processes and systems. This information can be leveraged to improve these systems and subsequently improve patient safety.

PMID:35354592 | DOI:10.1136/ejhpharm-2021-003087

Psychiatr Danub. 2021 Spring-Summer;33(Suppl 4):1038-1042.

ABSTRACT

Psychopharmacotherapy does not stand alone. The act of prescribing involves much more than solely choosing "best" medication. It seems that somewhere in the process of trying to objectify and scientify our therapy, we have neglected an important and effective dimensions of it. Psychopharmacology should consider much more than just biological dimension of drugs. Psychological, social and behavioral factors that influence drug metabolism, efficacy and side-effects are largely overlooked. Obviously, the subtext of information provided by the medical professional inevitably contains suggestion. Important part of that subtext is consisted in way we think of it, we talk of it and we perform that information. Defining of preformative and performative psychopharmacotherapy was atempted as well as desciption of narrative creative person-centered psychopharmacotherapy. Studies that indicate that medicines (SSRI) do not work on its own but as amplifier of the influence of the living conditions on mood are provided. Undirected susceptibility to change hypothesis which request acknowledging the importance of social, psychological, environmental factors to explain such the mechanisms underlying the recovery from the disease is explained. Understanding the role of medicines (SSRIs) as amplifier of the influence of the living conditions on mood represents a critical step in developing a creative, person-centered psychopharmacotherapy aimed at better matching patients with treatment and avoiding potential harmful consequences.

PMID:35354168

Acad Med. 2022 Apr 1;97(4):517. doi: 10.1097/ACM.0000000000004585.

NO ABSTRACT

PMID:35353735 | DOI:10.1097/ACM.0000000000004585

Age Ageing. 2022 Mar 1;51(3):afac045. doi: 10.1093/ageing/afac045.

ABSTRACT

AIM: Cardiovascular disease (CVD) is common amongst frail older people. The evidence base for CVD commonly excludes older adults with multimorbidity or chronic conditions. Most cardiovascular drugs have the potential to lower blood pressure (BP) and therefore cause medication-related harm (MRH). We aimed to identify key clinical and sociodemographic characteristics associated with MRH in older people taking BP-lowering drugs for whatever indication they were prescribed.

METHODS: The PRIME (prospective study to develop a model to stratify the risk of MRH in hospitalised elderly patients in the UK) study investigating the incidence and cost of MRH in older people across Southern England. Adults ≥65 years were recruited from five teaching hospitals at hospital discharge and followed up for 8 weeks. Telephone interviews with study participants, review of primary care records and hospital readmissions were undertaken to identify MRH. PRIME study participants taking BP-lowering drugs (as defined by National Institute for Health and Care Excellence hypertension guidelines) were included in this analysis.

RESULTS: One hundred and four (12%) study patients experienced a total of 153 MRH events associated with BP-lowering drugs. Patients on four BP-lowering drugs were five times more likely to experience MRH compared to those taking one medication (OR 4.96; 95%CI 1.63-15.13; P = 0.01). Most MRH events were classified 'serious' (80%, n = 123), requiring dose change or treatment cessation. Almost half of MRH were potentially preventable (49%, n = 75).

CONCLUSION: Polypharmacy from BP-lowering drugs in older people is associated with preventable harm. Decisions around cardiovascular risk reduction should be carefully considered in view of MRH arising from BP-lowering drugs.

PMID:35352796 | PMC:PMC8966023 | DOI:10.1093/ageing/afac045

BMC Infect Dis. 2022 Mar 29;22(1):306. doi: 10.1186/s12879-022-07288-4.

ABSTRACT

BACKGROUND: Checkpoints inhibitors (CPIs) are increasingly used for the treatment of several malignancies. The most common side effects are Immune Related Adverse Events, while infectious complications are rare, especially cerebral nocardiosis.

CASE PRESENTATION: Here, we report the first clinical case of a cerebral nocardiosis revealed after seizure in a patient treated by pembrolizumab for a metastatic lung cancer, in the absence of any additional immunosuppressive therapy or risk factors for cerebral nocardiosis. The extended evaluation including a brain CT-scan did not reveal any lesion before pembrolizumab. Nevertheless, the 3-month delay between the start of Pembrolizumab and the diagnosis of cerebral nocardiosis suggests that the infection occurred prior to the CPI. Unfortunately, the patient died during treatment for cerebral nocardiosis, while the lung cancer tumor mass had decreased by 80% after the sixth cycle of pembrolizumab.

CONCLUSIONS: This case report emphasizes that clinicians should consider diagnoses other than metastasis in a patient with a brain mass and metastatic cancer treated with CPI, such as opportunistic infections or IRAE.

PMID:35351017 | DOI:10.1186/s12879-022-07288-4

Pharmacology. 2022 Mar 30:1-9. doi: 10.1159/000522396. Online ahead of print.

ABSTRACT

BACKGROUND: Botulinum toxin type A (BTA) has a wide range of clinical applications, and its use in improving aesthetics is one of them. The aim of this study was to better assess the efficacy and safety of BTA in patients with facial scars.

SUMMARY: We extracted the data of the visual analog scale (VAS) score, Vancouver scar scale (VSS) score, scar width, observer scar assessment scale (OSAS), patient scar assessment scale (PSAS), and/or drug-related adverse events. Five studies provided the data of VAS score, and the results showed that the VAS score in the BTA group was significantly higher than that in the control group. Three randomized controlled trials (RCTs) reported the VSS score. A statistically significant difference exists between the BTA group and the control group. Three RCTs reported the scar width after BTA treatment. A more favorable change was found in the BTA group with scar width even without statistical significance. Data about the OSAS and PSAS scores were available in two trials. There was no significant difference in OSAS and PSAS scores between the BTA group and the control group. Only three studies recorded three slight adverse events. There were no reports of severe complications. In conclusions, this study demonstrated that BTA has the potential to improve facial scars with an acceptable safety profile.

PMID:35354154 | DOI:10.1159/000522396

JAMA Netw Open. 2022 Mar 1;5(3):e224492. doi: 10.1001/jamanetworkopen.2022.4492.

ABSTRACT

IMPORTANCE: Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking.

OBJECTIVE: To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China.

DESIGN, SETTING, AND PARTICIPANTS: This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020.

INTERVENTIONS: Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone.

MAIN OUTCOMES AND MEASURES: Complete or partial response rate at week 24 (prespecified).

RESULTS: A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs.

CONCLUSIONS AND RELEVANCE: In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02457221.

PMID:35353167 | DOI:10.1001/jamanetworkopen.2022.4492

Open Forum Infect Dis. 2022 Feb 9;9(4):ofac067. doi: 10.1093/ofid/ofac067. eCollection 2022 Apr.

ABSTRACT

BACKGROUND: In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine.

METHODS: LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312.

RESULTS: Of 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA ≥50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%).

CONCLUSIONS: Oral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1.

PMID:35350172 | PMC:PMC8946678 | DOI:10.1093/ofid/ofac067

Anticancer Res. 2022 Apr;42(4):2105-2111. doi: 10.21873/anticanres.15692.

ABSTRACT

BACKGROUND/AIM: We investigated whether coronavirus disease 2019 (COVID-19) vaccination and its adverse events would cause cancer treatment of patients with urological cancer to be postponed or changed.

PATIENTS AND METHODS: We collected COVID-19 vaccination information including adverse events from the medical records of 214 patients with urological cancer receiving cancer drug therapy.

RESULTS: The cancer types were renal cancer in 40 cases (18.7%), upper urinary tract cancer in 10 cases (4.7%), bladder cancer in 21 cases (9.8%), prostate cancer in 140 cases (65.4%), and others in 3 cases (1.4%). Of the 214 patients, 178 (83.2%) had received the second dose of the vaccine. Out of 180 vaccinated patients, some adverse events were observed in 69 (38.3%). Vaccination rates for males and females were 85.4% (169/198) and 68.8% (11/16), respectively, and were not significantly different (p=0.081). The incidence of adverse events was significantly higher in females [72.7% (8/11)] than in males [36.1% (61/169)]; p=0.015. Treatment was modified in 11 vaccinated patients; postponed or changed at the discretion of the attending physician in 8 cases, skipped at the discretion of the patient in 1 case, and postponed due to side effects of the immune checkpoint inhibitor in 1 case. Treatment for one patient with upper urinary tract cancer on pembrolizumab was postponed for three weeks due to adverse events of the vaccine.

CONCLUSION: Only 0.6% of the adverse events of the vaccine required postponement of treatment, suggesting that vaccination is safe even during cancer drug therapy.

PMID:35347034 | DOI:10.21873/anticanres.15692

J Asthma. 2022 Mar 29:1-13. doi: 10.1080/02770903.2022.2056048. Online ahead of print.

ABSTRACT

Introduction: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma.Methods: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks.Results: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication).Conclusions: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed.

PMID:35348408 | DOI:10.1080/02770903.2022.2056048

Cureus. 2022 Feb 23;14(2):e22540. doi: 10.7759/cureus.22540. eCollection 2022 Feb.

ABSTRACT

Belimumab is a B-cell depletion therapy that has emerged as an effective and safe treatment option for Systemic Lupus Erythematosus (SLE), but ongoing phase IV trials continue to report its common and rare adverse effects. Our case report seeks to add data to the existing literature on the safety profile of belimumab. We report an interesting and complicated case of a 30-year-old female with a 12-year history of SLE and multiple treatment failures who developed acute pancreatitis in the context of the initiation of belimumab. The temporal link between the two events made us undertake a review of literature on the efficacy and safety of belimumab. We used PubMed and Medline to shortlist eight studies that included phase III parent and extension clinical trials of belimumab that had been conducted in the past 10 years and illustrated the results in a tabulated form. The United States Food and Drug Administration has approved belimumab as a safe and effective treatment option for SLE. The BLISS-52, BLISS-76, and BLISS-SC trials along with their extension trials showed that SRI (SLE Responder Index) was higher in the patient cohorts that were treated with IV (intravenous) or SC (subcutaneous) belimumab. According to the website "eHealthMe.com", which tracks the incidence of adverse events from drugs by allowing people to report events, 14100 people reported side effects when taking belimumab and among them, 29 people (0.21%) reported acute pancreatitis. Time on belimumab when patients had acute pancreatitis was 1-2 years for 52% of the patients and 1-6 months for 40% of the patients; 96% of the patients were females. The age group at which it was most reported was 40-49 years. Additional data is needed to enable a better characterization of the pathophysiology and nature of acute pancreatitis as a possible side effect of belimumab.

PMID:35345744 | PMC:PMC8956404 | DOI:10.7759/cureus.22540

Zhongguo Zhong Yao Za Zhi. 2022 Mar;47(5):1184-1189. doi: 10.19540/j.cnki.cjcmm.20211122.202.

ABSTRACT

Since the pathogenesis of depression is complicated, the therapeutic effects of western medicine are poor accompanied by severe side effects. Chinese medicine has unique advantages in the treatment based on syndrome differentiation and contains many effective components against depression, including flavonoids, terpenes, phenylpropanoids, quinones, and alkaloids. These chemical components can delay the course of the disease, improve the curative effect, and reduce side effects of western medicine by regulating the biochemical abnormalities of monoamine neurotransmitters, brain tissue protein content, and internal environment as well as energy metabolism to make the treatment of Chinese medicine highlighted and recognized. This study systematically reviewed the effective components and mechanisms of anti-depressive Chinese medicine to inspire the rational development and utilization of new Chinese medicines against depression.

PMID:35343143 | DOI:10.19540/j.cnki.cjcmm.20211122.202

Indian J Cancer. 2022 Mar;59(Supplement):S1-S10. doi: 10.4103/ijc.ijc_1374_21.

ABSTRACT

BACKGROUND: A Phase IV, single-arm study was conducted to assess the safety of osimertinib in Indian patients with epidermal growth factor receptor (EGFR) T790M mutation-positive stage IV non-small cell lung cancer (NSCLC).

METHODS: Enrolled patients received 80 mg osimertinib for six cycles or until disease progression or unacceptable toxicity or withdrawal. Primary safety variables included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation/interruption/change (D/I/C) of drug dose, and AEs of special interest (AESIs). AEs were summarized by the percentage of patients experiencing at least one occurrence of each event.

RESULTS: Of the 60 enrolled patients (median age 58 [range: 34-81] years; 51.7% women) at eight sites, nine patients were discontinued prematurely due to disease progression (n = 7) and death (n = 2); median (range) duration of treatment was 126 (1-134) days. Median age of patients was 58 (34-81) years; 51.7% (n = 31) were women; 86.7% (n = 52) were nonsmokers; and most of them (98.3%) had adenocarcinoma. About 75% (n = 45) of patients experienced any of the TEAEs, with the most frequent being fatigue and creatine phosphokinase (CPK) increase (n = 6, 10% each). TEAEs in 11 (18.3%) patients were judged as study treatment related, with CPK increase being the most common (n = 4, 6.7%). TEAEs led to D/I/C of drug dose in eight (13.3%) patients, with one being study treatment related. Nine (15%) patients had AESIs of dyspnea (n = 6), chest pain (n = 2), and cardiorespiratory arrest (n = 1); two of them had a fatal outcome. One AESI (mild dyspnea) was considered study drug related. TEAEs of grade ≥3 were reported in seven (11.7%) patients, including dyspnea in two (3.3%), followed by diarrhea, mucosal inflammation, cardiorespiratory arrest, and others (n = 1, 1.7% each). None of the SAEs and fatal events were considered as study treatment related. Seven (11.7%) patients had abnormal electrocardiogram (ECG; not clinically significant) at the end of the study.

CONCLUSION: Our study confirms the favorable safety profile of osimertinib without any new safety concerns in Indian patients with EGFR T790M mutation-positive stage IV NSCLC.

CLINICALTRIALS.GOV IDENTIFIER: NCT03853551.

PMID:35343187 | DOI:10.4103/ijc.ijc_1374_21

J Eur Acad Dermatol Venereol. 2022 Mar 28. doi: 10.1111/jdv.18100. Online ahead of print.

ABSTRACT

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction generally accompanied by skin manifestations as the first and most frequent symptoms. However, skin manifestations and associated clinical features of DRESS have not been fully explored and evaluated.

OBJECTIVES: This study aimed to describe the skin manifestations of DRESS in detail and analyze their association with demographic characteristics and extra-cutaneous clinical features.

METHODS: We conducted this retrospective study on patients with DRESS diagnosed between September 2009 and August 2021 at three medical institutes and validated using the RegiSCAR score. Data regarding demographics, skin manifestations, and clinical characteristics were retrieved through thorough chart reviews.

RESULTS: Among 182 potential cases of DRESS, the validated 125 cases were analyzed. A widespread rash extending over more than 50% of the body surface area was observed in 122 patients (97.6%) and typical facial edema was experienced by 67 patients (53.6%). Polymorphous maculopapules were the most common rash morphology (106, 84.8%): specifically, exfoliative (59, 47.2%), urticarial (57, 45.6%), and purpuric forms (39, 31.2%) were common. Mucosal involvement was observed in 41 patients (32.8%). Patients with carboxamide antiepileptics (carbamazepine and oxcarbazepine) experienced more edema (P = .014) and typical facial edema than those with allopurinol (P = .021). The RegiSCAR score was higher in patients with purpura (P < .01).

CONCLUSIONS: Skin manifestations of DRESS exhibit a wide range of skin lesions and can vary according to the culprit drugs. Early suspicion and prompt intervention are needed to improve prognosis.

PMID:35342995 | DOI:10.1111/jdv.18100

J Clin Pharmacol. 2022 Mar 27. doi: 10.1002/jcph.2052. Online ahead of print.

ABSTRACT

Treatment of acute lymphoblastic leukemia has changed since introducing the asparaginase drug and its pegylated form, i.e., pegasparaginase. Several trials have demonstrated a clear advantage in using this drug in adolescents and young adults, up to 60 years. However, this drug possesses a unique plethora of side effects, spanning from pancreatitis to coagulopathy, including hepatotoxicity. This could be of mild intensity but can lead to life-threatening sequelae, up to death. Here, we report a case of a 59 years old patient affected by acute lymphoblastic leukemia, who eventually died cause of pegasparaginase-related hepatotoxicity. A review of the available literature will be provided, including epidemiology, pathophysiology and possible therapeutic interventions. In the end, an analysis of the Italian pharmacovigilance database will be presented, where hepatotoxicity has been reported in 32 cases (10% of reported adverse events, including 3 deaths related to drug-induced liver damage). This article is protected by copyright. All rights reserved.

PMID:35342960 | DOI:10.1002/jcph.2052