Cancer Inform. 2022 Mar 22;21:11769351221085064. doi: 10.1177/11769351221085064. eCollection 2022.

ABSTRACT

OBJECTIVE: In recent years, natural language processing (NLP) techniques have progressed, and their application in the medical field has been tested. However, the use of NLP to detect symptoms from medical progress notes written in Japanese, remains limited. We aimed to detect 2 gastrointestinal symptoms that interfere with the continuation of chemotherapy-nausea/vomiting and diarrhea-from progress notes using NLP, and then to analyze factors affecting NLP.

MATERIALS AND METHODS: In this study, 200 patients were randomly selected from 5277 patients who received intravenous injections of cytotoxic anticancer drugs at Kagawa University Hospital, Japan, between January 2011 and December 2018. We aimed to detect the first occurrence of nausea/vomiting (Group A) and diarrhea (Group B) using NLP. The NLP performance was evaluated by the concordance with a review of the physicians' progress notes used as the gold standard.

RESULTS: Both groups showed high concordance: 83.5% (95% confidence interval [CI] 74.1-90.1) in Group A and 97.7% (95% CI 91.3-99.9) in Group B. However, the concordance was significantly better in Group B (P = .0027). There were significantly more misdetection cases in Group A than in Group B (15.3% in Group A; 1.2% in Group B, P = .0012) due to negative findings or past history.

CONCLUSION: We detected occurrences of nausea/vomiting and diarrhea accurately using NLP. However, there were more misdetection cases in Group A due to negative findings or past history, which may have been influenced by the physicians' more frequent documentation of nausea/vomiting.

PMID:35342285 | PMC:PMC8943584 | DOI:10.1177/11769351221085064

J Immunol Res. 2022 Mar 16;2022:4713684. doi: 10.1155/2022/4713684. eCollection 2022.

ABSTRACT

Helicobacter pylori as a class I carcinogen is correlated with a variety of severe gastroduodenal diseases; therefore, H. pylori eradication has become a priority to prevent gastric carcinogenesis. However, due to the emergence and spread of multidrug and single drug resistance mechanisms in H. pylori, as well as serious side effects of currently used antibiotic interventions, achieving successful H. pylori eradication has become exceedingly difficult. Recent studies expressed the intention of seeking novel strategies to improve H. pylori management and reduce the risk of H. pylori-associated intestinal and extragastrointestinal disorders. For which, vitamin supplementation has been demonstrated in many studies to have a tight interaction with H. pylori infection, either directly through the regulation of the host inflammatory pathways or indirectly by promoting the host immune response. On the other hand, H. pylori infection is reported to result in micronutrient malabsorption or deficiency. Furthermore, serum levels of particular micronutrients, especially vitamin D, are inversely correlated to the risk of H. pylori infection and eradication failure. Accordingly, vitamin supplementation might increase the efficiency of H. pylori eradication and reduce the risk of drug-related adverse effects. Therefore, this review aims at highlighting the regulatory role of micronutrients in H. pylori-induced host immune response and their potential capacity, as intrinsic antioxidants, for reducing oxidative stress and inflammation. We also discuss the uncovered mechanisms underlying the molecular and serological interactions between micronutrients and H. pylori infection to present a perspective for innovative in vitro investigations, as well as novel clinical implications.

PMID:35340586 | PMC:PMC8942682 | DOI:10.1155/2022/4713684

Cureus. 2022 Feb 9;14(2):e22042. doi: 10.7759/cureus.22042. eCollection 2022 Feb.

ABSTRACT

Clopidogrel is an antiplatelet drug used for secondary prevention of myocardial infarction, and it is also used in patients with cerebrovascular ischemia. Patients with acute myocardial infarction tend to be on dual antiplatelet therapy for 12 months followed by aspirin lifelong to prevent the risk of stent thrombosis. The most common side effects of clopidogrel are bleeding, neutropenia, and rash; however, arthritis is also one of the rare side effects. We present a case of a 53-year-old patient who had a recent myocardial infarction and was commenced on dual antiplatelet therapy in the form of aspirin and clopidogrel. He started to have severe joint pain, particularly in his knees and shoulders, and was not able to mobilize anymore only three weeks after starting the medications. His clopidogrel was stopped and the patient showed dramatic improvement within three to four days after discontinuation with complete resolution one week later.

PMID:35340484 | PMC:PMC8914393 | DOI:10.7759/cureus.22042

Sensors (Basel). 2022 Mar 16;22(6):2310. doi: 10.3390/s22062310.

ABSTRACT

Multisensor information fusion brings challenges such as data heterogeneity, source precision, and the merger of uncertainties that impact the quality of classifiers. A widely used approach for classification problems in a multisensor context is the Dempster-Shafer Theory. This approach considers the beliefs attached to each source to consolidate the information concerning the hypotheses to come up with a classifier with higher precision. Nevertheless, the fundamental premise for using the approach is that sources are independent and that the classification hypotheses are mutually exclusive. Some approaches ignore this premise, which can lead to unreliable results. There are other approaches, based on statistics and machine learning techniques, that expurgate the dependencies or include a discount factor to mitigate the risk of dependencies. We propose a novel approach based on Bayesian net, Pearson's test, and linear regression to adjust the beliefs for more accurate data fusion, mitigating possible correlations or dependencies. We tested our approach by applying it in the domain of adverse drug reactions discovery. The experiment used nine databases containing data from 50,000 active patients of a Brazilian cancer hospital, including clinical exams, laboratory tests, physicians' anamnesis, medical prescriptions, clinical notes, medicine leaflets packages, international classification of disease, and sickness diagnosis models. This study had the hospital's ethical committee approval. A statistically significant improvement in the precision and recall of the results was obtained compared with existing approaches. The results obtained show that the credibility index proposed by the model significantly increases the quality of the evidence generated with the algorithm Random Forest. A benchmark was performed between three datasets, incremented gradually with attributes of a credibility index, obtaining a precision of 92%. Finally, we performed a benchmark with a public base of heart disease, achieving good results.

PMID:35336480 | PMC:PMC8949085 | DOI:10.3390/s22062310

Medicina (Kaunas). 2022 Mar 17;58(3):438. doi: 10.3390/medicina58030438.

ABSTRACT

Polypharmacy of psychotropic medications predisposes older adults to adverse drug events (ADEs). One contributing factor is inhibition of metabolic pathways between substrates (competitive inhibition) or between substrates and inhibitors of the same cytochrome P450 (CYP450) isoforms. The purpose of this case report is to demonstrate observed sedation and difficulty concentrating from augmentation therapy for resistant major depressive disorder (MDD) and to highlight the value of clinical tools to identify opportunities for treatment optimization to reduce ADEs. The pharmacist identified significant medication burden and competitive inhibition of drug metabolism in the CYP450 system during a telehealth medication therapy management consultation with a 69-year-old male. The pharmacist recommended clinical monitoring and communicated concerns about medication-induced sedation, difficulty concentrating, and other medication-related problems (MRP) to providers. Several recommendations were implemented which helped improved patient's outcomes. Individualizing MDD pharmacotherapy based on pharmacokinetic and pharmacodynamic drug interactions and geriatric dosage considerations may lead to better outcomes and tolerability among older adults.

PMID:35334614 | PMC:PMC8953614 | DOI:10.3390/medicina58030438

Pharmaceuticals (Basel). 2022 Feb 28;15(3):298. doi: 10.3390/ph15030298.

ABSTRACT

Drug-related adverse events or adverse drug reactions (ADRs) are currently partially or substantially under-reported. ADR reporting systems need to expand their focus to include sex- and gender-related factors in order to understand, prevent, or reduce the occurrence of ADRs in all people, particularly women. This scoping review describes adverse drug reactions reported to international pharmacovigilance databases. It identifies the drug classes most commonly associated with ADRs and synthesizes the evidence on ADRs utilizing a sex- and gender-based analysis plus (SGBA+) to assess the differential outcomes reported in the individual studies. We developed a systematic search strategy and applied it to six electronic databases, ultimately including 35 papers. Overall, the evidence shows that women are involved in more ADR reports than men across different countries, although in some cases, men experience more serious ADRs. Most studies were conducted in higher-income countries; the terms adverse drug reactions and adverse drug events are used interchangeably, and there is a lack of standardization between systems. Additional research is needed to identify the relationships between sex- and gender-related factors in the occurrence and reporting of ADRs to adequately detect and prevent ADRs, as well as to tailor and prepare effective reporting for the lifecycle management of drugs.

PMID:35337096 | DOI:10.3390/ph15030298

Int J Environ Res Public Health. 2022 Mar 10;19(6):3264. doi: 10.3390/ijerph19063264.

ABSTRACT

BACKGROUND: Monitoring of adverse drug reactions (ADRs) to antimicrobials is important, as they can cause life-threatening illness, permanent disabilities, and death. We assessed country-wide ADR reporting on antimicrobials and their outcomes.

METHODS: A cross-sectional study was conducted using individual case safety reports (ICSRs) entered into the national pharmacovigilance database (VigiFlow) during 2017-2021.

RESULTS: Of 566 ICSRs, inconsistent reporting was seen, with the highest reporting in 2017 and 2019 (mass drug campaigns for deworming), zero reporting in 2018 (reasons unknown), and only a handful in 2020 and 2021 (since COVID-19). Of 566 ICSRs, 90% were for antiparasitics (actively reported during mass campaigns), while the rest (passive reporting from health facilities) included 8% antibiotics, 7% antivirals, and 0.2% antifungals. In total, 90% of the reports took >30 days to be entered (median = 165; range 2-420 days), while 44% had <75% of all variables filled in (desired target = 100%). There were 10 serious ADRs, 18 drug withdrawals, and 60% of ADRs affected the gastrointestinal system. The patient outcomes (N-566) were: recovered (59.5%), recovering (35.5%), not recovered (1.4%), death (0.2%), and unknown (3.4%). There was no final ascertainment of 'recovering' outcomes.

CONCLUSIONS: ADR reporting is inconsistent, with delays and incomplete data. This is a wake-up call for introducing active reporting and setting performance targets.

PMID:35328953 | PMC:PMC8952810 | DOI:10.3390/ijerph19063264

Int J Nanomedicine. 2022 Mar 17;17:1185-1201. doi: 10.2147/IJN.S345505. eCollection 2022.

ABSTRACT

INTRODUCTION: Metformin hydrochloride (metformin HCL), a first-line drug treating diabetes type II, was known to cause severe gastritis, so seeking a non-oral dosage form was the new trend. Bilosomes are bilayer nano-vesicles of non-ionic surfactants embodying bile salts. In our study, bilosomes were investigated as an acceptable novel carrier for active targeting transdermal delivery of metformin HCL, circumventing its side effects.

METHODS: Twelve bilosome formulations were prepared with solvent evaporation method with slight modification according to a 31.22 full factorial design, and the optimized formulation was determined using Design -Expert 13 software (Stat-Ease, Inc., Minneapolis, Minnesota, USA) studying the effect of surfactant and bile salt types on the entrapment efficiency (EE), vesicle size (VS), polydispersity index (PDI), zeta potential (ZP), percentage of drug released within 24 h (R), and flux of drug permeated within 6 h (Jss) of vesicles. In addition, the optimized formulation was further evaluated to Fourier-transform infrared spectroscopy (FTIR), deformability index (DI), and transmission electron microscope (TEM) to ensure bilosomes formation, elasticity, and spherical shape, respectively.

RESULTS: The resulting vesicles publicized EE from 56.21% to 94.21%, VS from 183.64 to 701.8 nm, PDI values oscillating between 0.33 and 0.53, ZP (absolute value) from 29 to 44.2 mV, biphasic release profile within 24 h from 60.62 and up to 75.28%, and permeation flux enhancement (198.79-431.91 ng cm -2 h-1) in comparison with the non-formulated drug (154.26 ng cm -2 h-1). Optimized formulation was found to be F8 with EE = 79.49%, VS = 237.68 nm, ZP = 40.9 mV, PDI = 0.325, R = 75.28%, Jss = 333.45 ng cm-2 h-1 and DI = 6.5 with spherical self-closed non-aggregated vesicles and non-superimposed bands of its components in the FTIR.

CONCLUSION: Overall results showed that bilosome incorporation of metformin HCL improved permeation and offered a new nano-carrier for active transdermal delivery.

PMID:35330695 | PMC:PMC8938169 | DOI:10.2147/IJN.S345505

Brain Behav. 2022 Mar 25:e2555. doi: 10.1002/brb3.2555. Online ahead of print.

ABSTRACT

OBJECTIVE: To report side effect frequency and severity in patients with major depressive disorder (MDD) receiving escitalopram and aripiprazole adjunctive therapy and to examine whether pretreatment anxious depression is associated with the number and presence of specific side effects.

METHODS: 188 of the 211 trial participants provided information on side effects during treatment with escitalopram (10-20 mg) for 8 weeks, and nonresponders received further augmentation on aripiprazole (2-10 mg) adjunctive therapy for another 8 weeks, whereas responders remained on escitalopram. Participants completed the Toronto Side Effects Scale at weeks 2, 4, 10, and 12. Covariate-adjusted negative binomial regression and Wilcoxon tests examined the association between anxious depression (GAD-7 ≥ 10) and number of side effects. Covariate-adjusted logistic regression and chi-square tests explored the association between anxious depression and specific side effects.

RESULTS: For both therapies, the most frequent side effects were also the most severe. They mostly related to the central nervous system (CNS) (i.e., drowsiness and nervousness). Between baseline and week 2, the number of side effects participants experienced (incidence rate ratio [IRR] = 1.38, p = .010) or had trouble with (IRR = 1.34, p = .026) was significantly higher among those with anxious depression for escitalopram but not adjunctive aripiprazole. Further, odds of experiencing and having trouble with nervousness and agitation were also significantly higher in anxious depression for escitalopram only (p < .05).

CONCLUSION: Patients on escitalopram and aripiprazole adjunctive therapy may experience and have trouble with CNS side effects. Pretreatment anxious depression may predispose escitalopram recipients with MDD to developing side effects, especially those related to anxiety.

PMID:35333448 | DOI:10.1002/brb3.2555

Eur J Hosp Pharm. 2022 Mar 24:ejhpharm-2021-003199. doi: 10.1136/ejhpharm-2021-003199. Online ahead of print.

ABSTRACT

PURPOSE: To define the signals that a new artificial intelligence (AI) system must emit to improve adverse drug events (ADEs) management in oral antineoplastic agents (OAA).

METHODS: A multidisciplinary group of experts in patient safety was set up to define what signals the new AI system must emit to improve ADEs management in OAAs. The baseline data for the new AI system were generated through an observational and ambispective study carried out in a university hospital. All patients who met the inclusion criteria were selected consecutively every working day for 6 months. The ADEs were collected by interview and by the review of health records. The ADEs were categorised according to how they could be detected: patient, analysis, examination.

RESULTS: The group defined what signals the AI system must emit to improve ADEs management in OAAs: a signal to educate the patient when the possible ADEs were categorised as patient, a signal as a reminder to request a blood test or a microbiological culture when the possible ADEs were categorised as analysis, and a signal as a reminder for the necessity of a clinical examination when the possible ADEs were categorised as examination. A total of 1652 ADEs were reported in the interviews (ADE-interview) with the pharmacist, and doctors noted 1989 ADEs in the health record (ADE-HR). The most frequent ADEs were identified in the patient category.

CONCLUSION: This study opens a new way for better management of ADEs and is the first step in the development of a future technology, which will improve the quality of life of patients.

PMID:35332064 | DOI:10.1136/ejhpharm-2021-003199

Antioxidants (Basel). 2022 Feb 24;11(3):452. doi: 10.3390/antiox11030452.

ABSTRACT

The world has faced the challenges of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) for the last two years, first diagnosed at the end of 2019 in Wuhan and widely distributed worldwide. As a result, the WHO has proclaimed the illness brought on by this virus to be a global pandemic. To combat COVID-19, researcher communities continuously develop and implement rapid diagnoses, safe and effective vaccinations and other alternative therapeutic procedures. However, synthetic drug-related side effects and high costs have piqued scientists' interest in natural product-based therapies and medicines. In this regard, antiviral substances derived from natural resources and some medicines have seen a boom in popularity. For instance, algae are a rich source of compounds such as lectins and sulfated polysaccharides, which have potent antiviral and immunity-boosting properties. Moreover, Algae-derived compounds or metabolites can be used as antibodies and vaccine raw materials against COVID-19. Furthermore, some algal species can boost immunity, reduce viral activity in humans and be recommended for usage as a COVID-19 preventative measure. However, this field of study is still in its early stages of development. Therefore, this review addresses critical characteristics of algal metabolites, their antioxidant potential and therapeutic potential in COVID-19.

PMID:35326102 | DOI:10.3390/antiox11030452

Am J Emerg Med. 2022 Mar 10;55:147-151. doi: 10.1016/j.ajem.2022.03.008. Online ahead of print.

ABSTRACT

BACKGROUND: Tizanidine's potent muscle relaxant properties and short onset of action makes it desirable for pain management. However, concomitant use of tizanidine with ciprofloxacin, a strong inhibitor of the P450-CYP1A2 cytochrome metabolic pathway of tizanidine, can result in increased tizanidine plasma levels and associated adverse outcomes, particularly hypotension. The aim of this study was to assess the risk of hypotension with coadministration of tizanidine and ciprofloxacin.

METHODS: An observational nested cohort study of patients 18 years or older on tizanidine was conducted using data from electronic health records from 2000 to 2018 in the US. We estimated the prevalence and risk of hypotension associated with the DDI between tizanidine and ciprofloxacin using multivariable logistic regression models.

RESULTS: Our analysis included 70,110 encounters of patients on tizanidine across 221 hospitals. Most encounters included females (65.7%), whites (82.4%), with an average age of 56 years (SD 14.9) and an Elixhauser comorbidity index mean of 1.6 (SD 2.3). Ciprofloxacin was co-administered with tizanidine in 2487 encounters (3.6%). Compared to patients who did not receive ciprofloxacin, co-administration of tizanidine and ciprofloxacin was associated with an increased likelihood of hypotension (adjusted odds ratio: 1.43, 95% Confidence Intervals:1.25-1.63, p-value<0.001).

CONCLUSIONS: Our findings suggest that the concomitant use of tizanidine and ciprofloxacin is associated with an elevated risk of hypotension. The prevalence of co-administration of drugs with a documented interaction highlights the need for continuous education across providers to avoid the incidence of DDI related adverse events and further complications and to improve patient outcomes.

PMID:35325788 | DOI:10.1016/j.ajem.2022.03.008

Expert Opin Drug Saf. 2022 Mar 24. doi: 10.1080/14740338.2022.2058487. Online ahead of print.

ABSTRACT

INTRODUCTION: The antiseizure medication phenytoin has been associated with changes in the cerebellum, cerebellar signs, and permanent cerebellar damage. We have systematically reviewed the clinical and radiological features, and the correlation between them.

AREAS COVERED: We identified sixty case reports and case series of the effects of phenytoin on the cerebellum by searching Medline and Embase and relevant reference lists. The reports described 92 [median 1, range 1-5] cases, documented median age 28 [2.7-78] years. Eighty-one cases described one or more clinical sign of ataxia (present in 96%), dysarthria (63%), and nystagmus (70%). The neurological outcome (in 76 cases): 10 (13%) recovered by 12 months; 55 (72%) suffered residual disability; and 11 (14%) died. Median serum phenytoin concentration (48 cases) was 50 (interquartile range 31-66) mg/L; only three values were below 20 mg/L. The radiological findings included cerebellar atrophy in 41 of 61 patients (67%) with at least one scan.

EXPERT OPINION: Evidence mainly comes from case reports, and is inevitably biased. Most patients with cerebellar dysfunction have phenytoin concentrations above the reference range. Clinical signs of ataxia can persist without radiological evidence of cerebellar atrophy, and cerebellar atrophy is seen without any clinical evidence of cerebellar dysfunction.

PMID:35325581 | DOI:10.1080/14740338.2022.2058487

Rev Med Chil. 2021 Sep;149(9):1258-1266. doi: 10.4067/S0034-98872021000901258.

ABSTRACT

BACKGROUND: Patients hospitalized in intensive care units (ICU) are at higher risk of having adverse drug reactions (ADR).

AIM: To determine risk factors for ADR, through intensive pharmacological surveillance at the ICU.

PATIENTS AND METHODS: An observational, descriptive and prospective study was made, determining risk parameters in patients who experienced ADR.

RESULTS: Eighty-five patients were surveilled and 24 (28%) had an ADR. A total of 48 drugs responsible for at least one ADR were identified. Seventy-three percent ADR were moderate and 27% were severe. The clinical variables significantly associated with ADR were a history of allergies, a high body mass index, the reason for admission, an APACHE II score ≥ 14 points, the use of invasive mechanical ventilation and more than seven days of hospitalization. The pharmacological variables associated with ADR were polypharmacy and medication associations and combinations.

CONCLUSIONS: The identified risk factors have a great impact on pharmacokinetic and pharmacodynamic parameters, and should be considered to avoid the appearance of ADR.

PMID:35319678 | DOI:10.4067/S0034-98872021000901258

N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022.

ABSTRACT

BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.

METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.

RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.

CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).

PMID:35320644 | DOI:10.1056/NEJMoa2115022

Pan Afr Med J. 2022 Jan 17;41:41. doi: 10.11604/pamj.2022.41.41.32191. eCollection 2022.

ABSTRACT

Secukinumab, an anti-IL-17 monoclonal antibody, has been used to treat psoriasis and psoriatic arthritis since 2015. Several adverse events were reported, such as diarrhea, upper respiratory tract infection, middle ear infection, and neutropenia. Here we report a probable case of autoimmune hemolytic anemia in a 39 years old male with psoriasis and psoriatic arthritis treated with secukinumab. Hemolytic anemia detected after first maintenance dose after completion of induction dose of secukinumab. The patient also had other comorbids, soft tissue infection that also predisposed to autoimmune hemolytic anemia, but secukinumab is still a possible etiology for drug-induced autoimmune hemolytic anemia based on Naranjo´s score. The patient decided to continue secukinumab treatment, interestingly hemoglobin levels improved.

PMID:35317476 | PMC:PMC8917466 | DOI:10.11604/pamj.2022.41.41.32191

Invest New Drugs. 2022 Mar 21. doi: 10.1007/s10637-022-01235-5. Online ahead of print.

ABSTRACT

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p < 0.005) and lactate (0.61, p < 0.005) in the DCA group. Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT. Trial registration number: NCT01386632, Date of Registration: July 1, 2011.

PMID:35312941 | DOI:10.1007/s10637-022-01235-5

Eur Radiol. 2022 Mar 21. doi: 10.1007/s00330-022-08637-2. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intra-arterial (IA) administration of ioversol.

METHODS AND MATERIALS: A systematic literature search was performed (1980-2021) and studies documenting IA use of ioversol, and reporting safety outcomes were selected. Key information on study design, patients' characteristics, indication, dose, and type of safety outcome were extracted.

RESULTS: Twenty-eight studies (including two pediatric studies) with 8373 patients exposed to IA ioversol were selected. Studies were highly heterogenous in terms of design, PC-AKI definition, and studied population. PC-AKI incidence after coronary angiography was 7.5-21.9% in a general population, 4.0-26.4% in diabetic patients, and 5.5-28.9% in patients with chronic kidney disease (CKD). PC-AKI requiring dialysis was rare and reported mainly in patients with severe CKD. No significant differences in PC-AKI rates were shown in studies comparing different iodinated contrast media (ICM). Based on seven studies of ioversol clinical development, the overall ADR incidence was 1.6%, comparable to that reported with other non-ionic ICM. Pediatric data were scarce with only one study reporting on PC-AKI incidence (12%), and one reporting on ADR incidence (0.09%), both after coronary angiography.

CONCLUSIONS: After ioversol IA administration, PC-AKI incidence was highly variable between studies, likely reflecting the heterogeneity of the included study populations, and appeared comparable to that reported with other ICM. The rate of other ADRs appears to be low. Well-designed studies are needed for a better comparison with other ICM.

KEY POINTS: • PC-AKI incidence after IA administration of ioversol appears to be comparable to that of other ICM, despite the high variability between studies. • The need for dialysis after IA administration of ioversol is rare. • No obvious difference was found regarding the safety profile of ioversol between IA and IV administration.

PMID:35312791 | DOI:10.1007/s00330-022-08637-2

Eur Radiol. 2022 Mar 21. doi: 10.1007/s00330-022-08636-3. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the incidence of adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs) and post-contrast acute kidney injury (PC-AKI), after intravenous (IV) administration of ioversol.

MATERIALS AND METHODS: A systematic literature search (1980-2021) of studies documenting IV use of ioversol and presence or absence of ADRs, HSRs, or PC-AKI was performed. Key information including patients' characteristics, indication and dose of ioversol, safety outcome incidence, intensity and seriousness were extracted.

RESULTS: Thirty-one studies (> 57,000 patients) were selected, including 4 pediatric studies. The incidence of ADRs in adults was reported in 12 studies from ioversol clinical development with a median (range) of 1.65% (0-33.3%), and 3 other studies with an incidence between 0.13 and 0.28%. The incidence of HSRs (reported in 2 studies) ranged from 0.20 to 0.66%, and acute events (4 studies) from 0.23 to 1.80%. Severe reactions were rare with a median (range) of 0 (0-4%), and none were reported among pediatric patients. The incidence of ADRs and HSRs with ioversol, especially those of severe intensity, was among the lowest in studies comparing different iodinated contrast media (ICM) of the same class. PC-AKI incidence was variable (1-42% in 5 studies); however, ioversol exposure per se did not increase the incidence.

CONCLUSIONS: When administered by the IV route, ioversol has a good safety profile comparable to that of other ICM within the same class, with a low incidence of severe/serious ADRs overall, and particularly HSRs. PC-AKI incidence does not seem to be increased compared to patients who did not receive ioversol. Further well-designed studies are warranted to confirm these results.

KEY POINTS: • Ioversol has a good safety profile in adult and pediatric patients when IV administered. • ADR and HSR incidence with ioversol, especially those of severe intensity, was among the lowest compared to other ICM. • IV administration of ioversol per se did not increase PC-AKI incidence.

PMID:35312790 | DOI:10.1007/s00330-022-08636-3

Front Pharmacol. 2022 Mar 4;12:794054. doi: 10.3389/fphar.2021.794054. eCollection 2021.

ABSTRACT

Background: The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults. Objective: This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs) safety, tolerability, and immunogenicity of single ascending subcutaneous injections of QX002N in healthy Chinese volunteers. Methods: A total of 65 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled, single ascending dose phase I study (10-320 mg). Ten subjects were allocated to each cohort (containing 8 subjects treated with QX002N and 2 with placebo), except cohort 1 (only 4 subjects treated with QX002N and 1 with placebo). The studies on PKs, PDs, tolerability, and immunogenicity of QX002N were performed. Results: Our study showed that QX002N injection was well tolerated, without deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). Neither more frequency nor high severity of the drug-related adverse reaction was observed with increasing QX002N dose. The TEAEs in all subjects were considered Grades 1-2 (CTCAE 5.0) except for one case of Grade 3 (hypertriglyceridemia). Tmax of QX002N was obtained from 168 to 240 h across the dose range after administration. The Cmax and area under the curve of QX002N increased in proportion to dose, and showed linear PKs. Anti-drug antibody positivity was detected in one (1.9%) subject after drug administration. Conclusion: QX002N was well tolerated in our study. Based on the PKs and safety results of QX002N, 80 mg is recommended as the effective dose for a future phase Ib study. Clinical Trial Registration: https://www.chinadrugtrials.org.cn/, identifier ChiCTR1900023040.

PMID:35310892 | PMC:PMC8931745 | DOI:10.3389/fphar.2021.794054