scholarly journals Data-driven methodology for discovery and response to pulmonary symptomology in hypertension through statistical learning and data mining: Application to COVID-19 related pharmacovigilance

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xuan Xu ◽  
Jessica Kawakami ◽  
Nuwan Indika Millagaha Gedara ◽  
Jim Riviere ◽  
Emma Meyer ◽  
...  
Keyword(s):  
Empirical Bayes ◽  
Quantitative Methods ◽  
Randomized Clinical Trials ◽  
Geometric Mean ◽  
Single Agent ◽  
Adverse Event Reporting System ◽  
Antihypertensive Agents ◽  
Drug Event ◽  
Antithrombotic Agents ◽  
Drug Classes

Background: Potential therapy and confounding factors including typical co‐administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials.Methods: Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System. 134 antihypertensive drugs out of 1151 drugs were filtered and then evaluated using the Empirical Bayes Geometric Mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs (pADE). Afterward, the Graphical Least Absolute Shrinkage and Selection Operator (GLASSO) captured drug associations based on pADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO.Results: Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pADEs. Macitentan and bosentan were associates with 64% and 56% of pADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy.Conclusions: We consider pADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high-risk for COVID-19. We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pADE profiles affecting outcomes in acute respiratory illness.Funding: GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.

scholarly journals Data-driven methodology for discovery and response to pulmonary symptomology in hypertension through AI and machine learning: Application to COVID-19 related pharmacovigilance

2021 ◽  
Author(s):  
Xuan Xu ◽  
Jessica Kawakami ◽  
Nuwan Indika Millagaha Gedara ◽  
Jim Riviere ◽  
Emma Meyer ◽  
...  
Keyword(s):  
High Risk ◽  
Signal Detection ◽  
Quantitative Methods ◽  
Randomized Clinical Trials ◽  
Single Agent ◽  
Respiratory Illness ◽  
Detection Methods ◽  
Drug Event ◽  
Increased Risk ◽  
Medical Histories

Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. In this study, we implemented adaptive signal detection approaches to correct spurious association, hidden factors, and confounder misclassification when the covariates are unknown or unmeasured on medications affecting the renin-angiotensin system (RAS), potentially creating an increased risk of life-threatening outcomes in high-risk patients. We consider pulmonary ADE (pADE) profiles in a long-standing group of therapeutics, RAS-acting agents, in patients with hypertension associated with high-risk for COVID-19. Using these techniques, we confirmed our hypothesis that drugs from the same drug class could have very different pADE profiles affecting outcomes in acute respiratory illness. Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pADEs. Macitentan and bosentan were associates with 64% and 56% of pADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by our signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy.

scholarly journals Kidney Injury Following Ibuprofen and Acetaminophen: A Real-World Analysis of Post-Marketing Surveillance Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi-hui Shao ◽  
Xue-dong Yin ◽  
Hong-xia Liu ◽  
Bin Zhao ◽  
Jian-quan Huang ◽  
...  
Keyword(s):  
Real World ◽  
Empirical Bayes ◽  
Geometric Mean ◽  
Adverse Event Reporting System ◽  
Young Patients ◽  
Kidney Injury ◽  
Reporting Odds Ratio ◽  
Middle Aged ◽  
Aged Patients ◽  
Post Marketing Surveillance

Background: Although kidney injury has been reported as a serious adverse effect in patients treated with ibuprofen or acetaminophen (APAP), there are still few real-world studies to compare the specific differences in the adverse effects of nephrotoxicity.Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected kidney injury after using ibuprofen and APAP based on the FDA’s Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of ibuprofen-associated kidney injury and APAP-associated kidney injury were also investigated.Results: 2,453 reports of ibuprofen-associated kidney injury and 1,288 reports of APAP-associated kidney injury were identified. Ibuprofen appeared to affected more middle-aged patients than elderly ones (27.76 vs 16.53%) while APAP appeared to affected more young patients than middle-aged patients (45.24 vs 29.10%) and elderly patients were fewer (13.99%). Compared to ibuprofen, APAP had the higher association with renal injury based on the higher reporting odds ratio (ROR = 2.45, 95% two-sided CI = 2.36–2.56), proportional reporting ratio (PRR = 2.39, χ2 = 2002.94) and empirical Bayes geometric mean (EBGM = 2.38, 95% one-sided CI = 2.3). In addition, APAP-associated kidney injury had earlier onset (32.74 vs 115.82 days, p < 0.0001) and a higher fatality rate (44.43 vs 7.36%, p < 0.001) than those of ibuprofen-associated kidney injury.Conclusion: The analysis of FAERS data provides a more accurate profile on the incidence and prognosis of kidney injury after ibuprofen and acetaminophen treatment, enabling continued surveillance and timely intervention in patients at risk of kidney injury using these drugs.

scholarly journals Molecular Initiating Events Associated with Drug-Induced Liver Malignant Tumors: An Integrated Study of the FDA Adverse Event Reporting System and Toxicity Predictions

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 944
Author(s):  
Kota Kurosaki ◽  
Yoshihiro Uesawa
Keyword(s):  
Adverse Event ◽  
Reporting System ◽  
Malignant Tumors ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Drug Event ◽  
Drug Induced ◽  
Event Reporting ◽  
Nonalcoholic Fatty Liver ◽  
Drug Classes

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure–activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.

Zidovudine and Didanosine Combination Therapy in Children With Human Immunodeficiency Virus Infection

PEDIATRICS ◽  
1994 ◽  
Vol 93 (2) ◽  
pp. 316-322 ◽  
Author(s):  
Robert N. Husson ◽  
Brigitta U. Mueller ◽  
Maureen Farley ◽  
Linda L. Lewis ◽  
Frank M. Balis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Antiviral Activity ◽  
Hiv Infection ◽  
Geometric Mean ◽  
Single Agent ◽  
Nucleoside Analogues ◽  
Hematologic Toxicity ◽  
Immunodeficiency Virus

Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to <31 pg/mL (P < .001). The geometric mean titer of HIV in plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001). Conclusions. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection.

Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Oncology ◽  
2021 ◽  
Author(s):  
Aya Satoki ◽  
Mayako Uchida ◽  
Masaki Fujiwara ◽  
Yoshihiro Uesawa ◽  
Tadashi Shimizu
Keyword(s):  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Cardiac Failure ◽  
Tumor Lysis Syndrome ◽  
Adverse Event Reporting System ◽  
Japanese Patients ◽  
Comprehensive Analysis ◽  
Drug Event ◽  
Lung Disorder ◽  
Time To Onset

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

Interchangeability of Haemophilus influenzae Type b vaccines in the Primary Series: Evaluation of a Two-dose Mixed Regimen

PEDIATRICS ◽  
1996 ◽  
Vol 98 (5) ◽  
pp. 898-904 ◽  
Author(s):  
Kathleen M. Bewley ◽  
Joel G. Schwab ◽  
Gerard A. Ballanco ◽  
Robert S. Daum
Keyword(s):  
Haemophilus Influenzae ◽  
Randomized Clinical Trials ◽  
Geometric Mean ◽  
Serum Antibody ◽  
Area Under The Curve ◽  
Haemophilus Influenzae Type ◽  
Antibody Concentration ◽  
Haemophilus Influenzae Type B ◽  
Type B ◽  
Series Evaluation

Objective. To evaluate two- or threedose "mixed" regimens of Haemophilus influenzae type b conjugate vaccines in the priming series. Design. Two randomized clinical trials with 140 and 181 infants, respectively. Setting. Private practices in New Orleans and Chicago. Methods. In trial I, infants received one of four regimens. Two were recommended regimens for polyribosylribitol phosphate (PRP)—meningococcal protein conjugate (M) and PRP—tetanus toxoid conjugate (T). Two mixed regimens consisted of M at 2 months followed by two doses of T or PRP—diphtheria toxoid conjugate (D) at 4 and 6 months. Trial II consisted of three groups. Two were recommended regimens for M and T. The third was a two-dose mixed regimen consisting of M at 2 months and T at 4 months. Parents were interviewed and instructed to record side effects after each vaccination. Serum was assayed for H influenzae type b anticapsular antibody (anti-PRP). Results. Minor differences in safety profiles likely reflected α error. In trial I, M (lot 0884T, one of several known to have had decreased immunogenicity), probably primed for substantial increase in serum antibody when D or T was given at 4 and 6 months. In trial II, infants who received the two-dose mixed regimen (M from immunogenic lot 0116W at 2 months and T at 4 months) had a significantly higher mean area under the curve than recipients of the three-dose TIT regimen when antibody concentration was plotted against age, although the geometric mean anti-PRP antibody concentration for the MT-recipients was significantly lower at 7 months. Conclusions. M used in trial I may have primed infants despite poor immunogenicity. The two-dose mixed regimen (MT-) in trial II produced a mean anti-PRP antibody concentration with higher sustained anti-PRP concentrations from 2 to 7 months, as judged by the area under the curve, but a lower mean anti-PRP antibody concentration at 7 months.

scholarly journals Combining antiplatelet and anticoagulant therapy in cardiovascular disease

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 642-648
Author(s):  
Geoffrey D. Barnes
Keyword(s):  
Randomized Clinical Trials ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Thrombotic Event ◽  
Bleeding Risk ◽  
Antithrombotic Agents ◽  
Thrombotic Risk ◽  
Coronary Syndrome ◽  
Combined Use ◽  
Life Threatening

Abstract Up to 10% of the >3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.

scholarly journals Emerging Drug Classes and Their Potential Use in Hypertension

Hypertension ◽  
2019 ◽  
Vol 74 (5) ◽  
pp. 1075-1083 ◽  
Author(s):  
Michel Azizi ◽  
Patrick Rossignol ◽  
Jean-Sébastien Hulot
Keyword(s):  
Blood Pressure ◽  
Antihypertensive Drugs ◽  
Generic Drugs ◽  
Antihypertensive Agents ◽  
Uncontrolled Hypertension ◽  
Blood Pressure Lowering ◽  
Receptor Antagonists ◽  
Drug Classes ◽  
Pressure Lowering ◽  
Potential Use

Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure–lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure–lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.

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