[Is shorter really better?]

Rev Med Interne. 2020 Jan;41(1):1-2

Authors: Dinh A

PMID: 31791647 [PubMed - indexed for MEDLINE]

Atractylenolides, essential components of Atractylodes-based traditional herbal medicines: antioxidant, anti-inflammatory and anticancer properties.

Eur J Pharmacol. 2020 Nov 18;:173735

Authors: Bailly C

Abstract
The rhizome of the plant Atractylodes macrocephala Koidz is the major constituent of the Traditional Chinese Medicine Baizhu, frequently used to treat gastro-intestinal diseases. Many traditional medicine prescriptions based on Baizhu and the similar preparation Cangzhu are used in China, Korea and Japan as Qi-booster. These preparations contain atractylenolides, a small group of sesquiterpenoids endowed with antioxidant and anti-inflammatory properties. Atractylenolides I, II and III also display significant anticancer properties, reviewed here. The capacity of AT-I/II/IIII to inhibit cell proliferation and to induce cancer cell death have been analyzed, together with their effects of angiogenesis, metastasis, cell differentiation and stemness. The immune-modulatory properties of ATs are discussed. AT-I has been tested clinically for the treatment of cancer-induced cachexia with encouraging results. ATs, alone or combined with cytotoxic drugs, could be useful to treat cancers or to reduce side effects of radio and chemotherapy. Several signaling pathways have been implicated in their multi-targeted mechanisms of action, in particular those involving the central regulators TLR4, NFκB and Nrf2. A drug-induced reduction of inflammatory cytokines production (TNFα, IL-6) also characterizes these molecules which are generally weakly cytotoxic and well tolerated in vivo. Inhibition of Janus kinases (notably JAK2 and JAK3 targeted by AT-I and AT-III, respectively) has been postulated. Information about their metabolism and toxicity are limited but the long-established traditional use of the Atractylodes and the diversity of anticancer effects reported with AT-I and AT-III should encourage further studies with these molecules and structurally related natural products.

PMID: 33220271 [PubMed - as supplied by publisher]

Ethosuximide induced macroglossia and oropharyngeal edema.

Int J Pediatr Otorhinolaryngol. 2020 Nov 15;:110498

Authors: Shang H, Glaun M, Ongkasuwan J

Abstract
Acute macroglossia and laryngeal edema are rare adverse side effects that can cause life-threatening airway obstruction. We report a case of acute macroglossia that began after initiation of ethosuximide in a 15-year-old female with severe medically refractory epilepsy. Macroglossia worsened over the next two weeks of ethosuximide administration, preventing extubation. Macroglossia and laryngeal edema improved upon ethosuximide wean, and completely resolved after discontinuation. The patient was extubated successfully, with precautionary nasal trumpet placement and dexamethasone administration prior to extubation. In medically complex patients on multiple pharmacologic agents, anti-epileptic drugs should be suspected as a possible cause of acute macroglossia.

PMID: 33218689 [PubMed - as supplied by publisher]

Skin changes in hairy cell leukemia.

Ann Hematol. 2020 Nov 20;:

Authors: Robak E, Jesionek-Kupnicka D, Robak T

Abstract
Skin lesions have been reported in about 10-12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.

PMID: 33216198 [PubMed - as supplied by publisher]

A Review of Antipsychotics and Priapism.

Sex Med Rev. 2020 Nov 16;:

Authors: Hwang T, Shah T, Sadeghi-Nejad H

Abstract
INTRODUCTION: Pharmacologically induced priapism is now the most common cause of priapism, with approximately 50% of drug-related priapism being attributed to antipsychotic usage. The majority of pharmacologic priapism is believed to result in ischemic priapism (low flow), which may lead to irreversible complications, such as erectile dysfunction. It is imperative that prescribing physicians be aware of potentially inciting medications.
OBJECTIVES: To identify medications, specifically antipsychotics, associated with priapism and prolonged erections and understand the rates and treatment of these side effects.
METHODS: A PubMed search of all articles available on the database relating to priapism, prolonged erections, and antipsychotics was performed.
RESULTS: Various typical and atypical antipsychotic drugs (APDs) have been implicated in pharmacologically induced priapism. In addition to dopaminergic and serotoninergic receptors, APDs have affinities for a wide array of other receptors in the central nervous system, including histaminergic, noradrenergic, and cholinergic receptors. Although the exact mechanism is unknown, the most commonly proposed mechanism of priapism associated with APDs is α-adrenergic blockade in the corpora cavernosa of the penis. Priapism appears in only a small fraction of men using medications with α1-receptor-blocking properties, indicating differential sensitivities to the α-blocking effect among men, and/or additional risk factors that may contribute to the development of priapism. The best predictor for the subsequent development of priapism is a past history of having prolonged and painless erections. The acute management algorithm of APD-induced priapism is the same as for other causes of low-flow priapism.
CONCLUSION: Clinicians should educate patients treated with antipsychotics about the potential for priapism and its sequelae including permanent erectile dysfunction. Appropriate patient education will raise awareness, encourage early reporting, and help reduce the long-term consequences associated with priapism through early intervention. Hwang T, Shah T,Sadeghi-NejadH. A Review of Antipsychotics and Priapism. Sex Med Rev 2020;XX:XXX-XXX.

PMID: 33214060 [PubMed - as supplied by publisher]

Latest Evidence Regarding the Effects of Photosensitive Drugs on the Skin: Pathogenetic Mechanisms and Clinical Manifestations.

Pharmaceutics. 2020 Nov 17;12(11):

Authors: Lozzi F, Di Raimondo C, Lanna C, Diluvio L, Mazzilli S, Garofalo V, Dika E, Dellambra E, Coniglione F, Bianchi L, Campione E

Abstract
Photosensitivity induced by drugs is a widely experienced problem, concerning both molecule design and clinical practice. Indeed, photo-induced cutaneous eruptions represent one of the most common drug adverse events and are frequently an important issue to consider in the therapeutic management of patients. Phototoxicity and photoallergy are the two different pathogenic mechanisms involved in photosensitization. Related cutaneous manifestations are heterogeneous, depending on the culprit drug and subject susceptibility. Here we report an updated review of the literature with respect to pathogenic mechanisms of photosensitivity, clinical manifestations, patient management, and prediction and evaluation of drug-induced photosensitivity. We present and discuss principal groups of photosensitizing drugs (antimicrobials, nonsteroidal anti-inflammatory drugs, anti-hypertensives, anti-arrhythmics, cholesterol, and glycemia-lowering agents, psychotropic drugs, chemotherapeutics, etc.) and their main damage mechanisms according to recent evidence. The link between the drug and the cutaneous manifestation is not always clear; more investigations would be helpful to better predict drug photosensitizing potential, prevent and manage cutaneous adverse events and find the most appropriate alternative therapeutic strategy.

PMID: 33213076 [PubMed]

The efficacy and adverse effects of PARP inhibitor combined with chemotherapy compared with chemotherapy alone in the treatment of cancer patient: A protocol for systematic review.

Medicine (Baltimore). 2020 Nov 06;99(45):e23040

Authors: Zhao S, Fang T, Yao L, Zheng Y, Zhang L, Zhu K

Abstract
BACKGROUND: There search of PARP inhibitors has made great breakthroughs and progress. Become a new type of medicine for cancer treatment,bringing hope to more advanced cancer patients.The purpose of this systematic review is to evaluate the clinical efficacy and adverse effects of PARP inhibitorscombined with chemotherapy and chemotherapy alone in the treatment of cancer patients.
METHODS: We searched the following 4 databases, including: PubMed, EMBASE, Web of Science, and Cochrane Library. The search will also be conducted at the clinical trial centers: ClinicalTrials.gov, ISRCTN Registry, WHO International Clinical Trials Registration Platform. The search date is as of September 22, 2020. There is no language restriction during this search, and the latest documents are kept updated through settings. The subject search terms were identified as "PARP Inhibitor", "Neoplasms" and "Dug therapy". The Phase 2 and Phase 3 clinical trials comparing PARP inhibitor combined with chemotherapy and chemotherapy alone were included. The results include overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse events. Two researchers separately completed the article inclusion, data extraction and quality evaluation of this study. The assessment of the risk of bias and data will be conducted using Review Manager.
ETHICS AND DISSEMINATION: All articles are published and do not require the approval of the ethics committee and the signed informed consent form. The results of this systematic review will be published through peer-reviewed publications.
REGISTERED: Registered on INPLASY and the registration number is INPLASY202090087.

PMID: 33157956 [PubMed - indexed for MEDLINE]

Adverse Effects of Low-Dose Methotrexate.

Ann Intern Med. 2020 07 21;173(2):166-167

Authors: Robey RB, Block CA

PMID: 32687752 [PubMed - indexed for MEDLINE]

Adverse Effects of Low-Dose Methotrexate.

Ann Intern Med. 2020 07 21;173(2):167

Authors: Solomon DH, Sparks JA

PMID: 32687751 [PubMed - indexed for MEDLINE]

Factors Affecting Prescriber Implementation of Computer-Generated Medication Recommendations in the SENATOR Trial: A Qualitative Study.

Drugs Aging. 2020 09;37(9):703-713

Authors: Dalton K, O'Mahony D, Cullinan S, Byrne S

Abstract
BACKGROUND: The SENATOR trial intervention included the provision of computer-generated medication recommendations to physician prescribers caring for hospitalised older adults (≥ 65 years), with the aim of reducing in-hospital adverse drug reactions. Interim data analysis during the trial revealed that the prescriber implementation rates of the computer-generated STOPP/START recommendations were lower than expected across all six trial sites.
AIM: The aim of this qualitative study was to identify the factors affecting prescriber implementation of the medication recommendations in the SENATOR trial.
METHODS: Semi-structured interviews were conducted with trial researchers and physician prescribers who were provided with SENATOR recommendations. Content analysis was used to identify the most relevant domains from the Theoretical Domains Framework (TDF) that affected recommendation uptake.
RESULTS: Ten trial researchers and fourteen prescribers were interviewed across the six trial sites. Eight TDF domains were found to be most relevant in affecting prescriber implementation: 'environmental context and resources', 'goals', 'intentions', 'knowledge', 'beliefs about consequences', 'memory, attention and decision processes', 'social/professional role and identity', and 'social influences'. Interviewees felt that there was often a disconnect between the time prescribers were reviewing the patient and the point at which the recommendations were provided. However, when recommendations were reviewed, prescriber inertia was highly pervasive, with a particular reluctance to make pharmacotherapy changes outside their own specialty. Implementation was facilitated by recommendations reaching a 'decision-maker', but this was often not possible as the software could not evaluate the entire clinical context of patients, and thus frequently produced recommendations of low clinical relevance.
CONCLUSION: This study has demonstrated that the clinical relevance of the SENATOR prescribing recommendations was a significant factor affecting their implementation. Whilst software refinement will be necessary to improve the quality of recommendations, future interventions will need to be multifaceted to overcome the complex prescriber specialty culture within the acute hospital environment.

PMID: 32681402 [PubMed - indexed for MEDLINE]

A reactive oxygen species-responsive antioxidant nanotherapy for the treatment of drug-induced tissue and organ injury.

Biomater Sci. 2020 Nov 19;:

Authors: Li C, Hu Y, Nie Q, Chen S, Li G, Li L, Chen S, Tang B, Zhang J

Abstract
Drug-induced tissue injury has become a growing public health problem. Gastrointestinal injury and liver dysfunction are the most common side effects related to drug therapies, resulting in high morbidity and mortality in recent years. The overproduction of reactive oxygen species (ROS) is critically involved in the pathogenesis of drug-induced tissue injury. Consequently, antioxidant therapy represents a very promising strategy for the treatment of drug-induced tissue injury. Herein, a multifunctional antioxidant nanotherapy (TON) is engineered from a cyclodextrin-derived ROS-responsive material and a radical scavenger tempol, and is capable of eliminating a broad spectrum of ROS. After oral administration, TON can passively accumulate in the inflamed gastrointestinal tissues in mice with indomethacin-induced gastrointestinal injury. Correspondingly, TON shows superior efficacy in two representative murine models of indomethacin-induced gastrointestinal injury and acetaminophen-induced hepatic injury via attenuating oxidative stress and mitigating inflammatory responses. Additionally, preliminary in vitro and in vivo experiments demonstrate the good safety profile of TON. Consequently, the ROS-responsive antioxidant nanotherapy TON is promising for the treatment of drug-induced tissue and organ injury.

PMID: 33211787 [PubMed - as supplied by publisher]

Pharmaceutical Care in Sports.

Pharmacy (Basel). 2020 Nov 16;8(4):

Authors: Bomfim JHGG

Abstract
Pharmaceutical care in sports is a new field of work to clinical pharmacists, focused on promoting pharmacotherapeutic follow up and clinical services to athletes, physical activity practitioners and enthusiasts of any sports modality. A broad range of pharmaceuticals, dietary supplements and herbal drugs have been used historically as performance promoters, doping or ergogenic aids. In this context, the role of pharmacists in prevent adverse events, drug interactions or any drug related problems, as doping issues, was described. Its actions can be important to contribute with a multi professional clinical health team, leading athletes to use these resources in a rational way, promoting and optimizing the therapeutic when its necessary.

PMID: 33207610 [PubMed]

A Review of the Mechanisms and Clinical Implications of Precision Cancer Therapy-Related Toxicity: A Primer for the Radiologist.

AJR Am J Roentgenol. 2020 09;215(3):770-780

Authors: Thomas R, Howard SA, Laferriere SL, Braschi-Amirfarzan M

Abstract
OBJECTIVE. The purpose of this review is to elucidate the mechanisms, types, and clinical significance of molecular targeted therapy (MTT) and immune checkpoint inhibitors (ICIs) and their related toxicity, emphasizing the radiologic manifestations. CONCLUSION. The related toxicities of MTT and ICIs can have acute, recurrent, chronic, and delayed presentations. These toxicities may serve as markers of response and survival. By understanding the clinical significance of drug toxicities, radiologists can play an important role in personalized cancer therapy.

PMID: 32755160 [PubMed - indexed for MEDLINE]

Drugs to Treat Depression.

J Psychosoc Nurs Ment Health Serv. 2020 Jul 01;58(7):5-7

Authors:

PMID: 32602928 [PubMed - indexed for MEDLINE]

Anticholinergic, anti-depressant and other medication use is associated with clinically relevant oesophageal manometric abnormalities.

Aliment Pharmacol Ther. 2020 06;51(11):1130-1138

Authors: Moosavi S, Woo M, Jacob DA, Pradhan S, Wilsack L, Buresi M, Gupta M, Al-Awadh Y, Li D, Andrews CN

Abstract
BACKGROUND: Medications can affect gastrointestinal tract motility. However, their effects on oesophageal motility in particular are often not as widely known or may be underestimated.
AIM: To review the effect of existing medication use on high-resolution oesophageal manometry (HRM) in a 'real-world' setting.
METHODS: Adult patients with upper gut symptoms and normal endoscopy or imaging who had HRM over a 22-month period were analysed. Achalasia and major disorders of peristalsis were excluded. All medications taken within 24 hours of the procedure were prospectively recorded and compared with HRM results, controlling for age, gender and proton pump inhibitor use.
RESULTS: A total of 502 patients (323 female, mean age 51) were recruited. Of these, 41.2% had normal oesophageal HRM, while 41.4% had ineffective oesophageal motility (IOM) and 7.6% had oesophagogastric junction outflow obstruction (OGJOO). Serotonin/norepinephrine reuptake inhibitors (SNRI) and opioids were associated with significantly higher resting lower oesophageal sphincter pressure. Benzodiazepines and opioids were associated with elevated integrated relaxation pressure. SNRI and inhaled beta-agonists were associated with increased distal contractile index, whereas calcium channel blockers were associated with a lower distal contractile index. Odds ratio of being on anticholinergics was higher in IOM patients vs normal (3.6, CI 1.2-10.8). Odds ratio for anticholinergics, inhaled beta-agonists, anticonvulsants, SNRIs and opioids (trend) were all > 3 for OGJOO patients vs normal.
CONCLUSION: Many medication classes are associated with abnormal HRM variables and diagnoses such as OGJOO and IOM; some of these associations are probably causal. These possible links should be taken into consideration during manometry interpretation.

PMID: 32383253 [PubMed - indexed for MEDLINE]

Pharmacogenomics at the center of precision medicine: challenges and perspective in an era of Big Data.

Pharmacogenomics. 2020 01;21(2):141-156

Authors: Primorac D, Bach-Rojecky L, Vađunec D, Juginović A, Žunić K, Matišić V, Skelin A, Arsov B, Boban L, Erceg D, Ivkošić IE, Molnar V, Ćatić J, Mikula I, Boban L, Primorac L, Esquivel B, Donaldson M

Abstract
Pharmacogenomics (PGx) is one of the core elements of personalized medicine. PGx information reduces the likelihood of adverse drug reactions and optimizes therapeutic efficacy. St Catherine Specialty Hospital in Zagreb/Zabok, Croatia has implemented a personalized patient approach using the RightMed® Comprehensive PGx panel of 25 pharmacogenes plus Facor V Leiden, Factor II and MTHFR genes, which is interpreted by a special counseling team to offer the best quality of care. With the advent of significant technological advances comes another challenge: how can we harness the data to inform clinically actionable measures and how can we use it to develop better predictive risk models? We propose to apply the principles artificial intelligence to develop a medication optimization platform to prevent, manage and treat different diseases.

PMID: 31950879 [PubMed - indexed for MEDLINE]

Drug-Related Problems Increase Healthcare Costs for People Living with Dementia.

J Alzheimers Dis. 2020;73(2):791-799

Authors: Wohlgemuth A, Michalowsky B, Wucherer D, Eichler T, Thyrian JR, Zwingmann I, Rädke A, Hoffmann W

Abstract
BACKGROUND: Drug-related problems (DRP) are common in the elderly population, especially in people living with dementia (PwD). DRP are associated with adverse outcomes that could result in increased costs.
OBJECTIVE: The objective of the study was to analyze the association between DRP and healthcare costs in PwD.
METHODS: The analysis was based on the cross-sectional data of 424 PwD. Compliance, adverse effects, and drug administration of prescribed and over-the-counter drugs taken were assessed. DRP were identified and classified by pharmacists using an adapted German version of "PIE-Doc®". Healthcare utilization was assessed retrospectively used to calculated costs from a public payer perspective using standardized unit costs. The associations between DRP and healthcare costs were analyzed using multiple linear regression models.
RESULTS: 394 PwD (93%) had at least one DRP. An inappropriate drug choice was significantly associated with increased total costs (b = 2,718€; CI95% 1,448-3,988) due to significantly higher costs for hospitalization (b = 1,936€; 670-3,202) and for medications (b = 417€; 68-765). Problems with medication dosage and drug interactions were significantly associated with higher medication costs (b = 679€; 31-1,328; and b = 630€; 259-1,001, respectively).
CONCLUSIONS: DRP could significantly lead to adverse outcomes for PwD and healthcare payers, reflected by a higher hospitalization and costs, respectively. Further research is needed to clarify on interventions and approaches efficiently avoiding DRP and on the effect on patient-reported and economic outcomes.

PMID: 31884468 [PubMed - indexed for MEDLINE]

Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity.

Mult Scler Relat Disord. 2020 Jan;37:101468

Authors: Juto A, Fink K, Al Nimer F, Piehl F

Abstract
BACKGROUND: Rituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity are limited. The objective here was therefore to determine the rate and cause of RTX treatment interruptions and responses to subsequent DMTs in a large single centre cohort addressing also the hypothesis that there would not be rebound activity after discontinuation of RTX, regardless of reason for discontinuation and irrespective of subsequent treatments.
METHODS: A retrospective observational study of all relapsing-remitting MS (RRMS) patients having received at least one dose of RTX at the Karolinska University Hospital from 2009 to 2018 and having either stopped treatment or had more than one year since last RTX infusion, as identified in the Swedish MS registry with additional data derived from clinical charts.
RESULTS: As of February 2018, we identified 808 patients ever treated with RTX out of 1513 RRMS patients with current or previous DMT, 92 (11%) had terminated RTX; 27 (29%) stopped RTX due to pregnancy, 26 (28%) due to adverse events, 23 (25%) for other reasons, 9 (10%) due to stable disease and the remaining 7 (8%) due to lack of effect. The cohort of 92 patients was followed until April 2019, when 34 had restarted RTX, 27 switched DMT, 24 remained without DMT and 7 were lost to follow up. Of the 7 patients terminating RTX due to lack of effect, 4 started ofatumumab, 2 had autologous hematopoietic stem cell transplantation and 1 was lost to follow up. In all of the 92 patients, after initial RTX discontinuation, only 3 patients had relapses and 4 had new T2 lesions (one of which had both). Gadolinium was administered in 78% of follow up magnetic resonance imaging (MRI) with no enhancing lesions found (mean MRI follow up from RTX discontinuation 29 months, range 7-92 months, n = =77).
CONCLUSION: Findings are consistent with a low rate of RTX interruptions, with pregnancy and adverse events as most frequent reasons. A small proportion of patients switched due to breakthrough disease in context of incomplete B-lymphocyte depletion. Signs of ongoing disease activity in the remaining group was low regardless of whether a new DMT was started. These findings are consistent with a long acting effect of RTX in RRMS and absence of rebound disease activity phenomena upon stopping therapy.

PMID: 31683231 [PubMed - indexed for MEDLINE]

Safety profile of subcutaneous trastuzumab in patients with HER2-positive early breast cancer: The French HERmione non-interventional prospective study.

Breast. 2020 Feb;49:1-7

Authors: Jacquin JP, Uwer L, Savignoni A, Ferrero JM, Lortholary A, Solub D, Delaporte F, Chalabi N, Pibre S, Belkacemi Y

Abstract
OBJECTIVES: HERmione study was conducted to assess, in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC), the safety profile of subcutaneous (SC) formulation of trastuzumab in real-life in France.
MATERIALS AND METHODS: This prospective, non-interventional study included 511 patients planned to be treated in both neoadjuvant and adjuvant settings with a follow-up of 12 months maximum in 101 sites. The safety analyses concerned 505 patients. Primary endpoint was the description of systemic safety and local tolerability of the SC trastuzumab.
RESULTS: The median age of patients was 58 years. Over the study, 2449 adverse events (AEs) occurred in 422 (83.6%) patients (asthenia, arthralgia, radiation skin injury, myalgia, hot flush and diarrhea in ≥10% of patients): 92 AEs (3.8%) were grade ≥3 (radiation skin injury in 1.8% of patients and febrile neutropenia in 1.4% of patients), 76 (3.1%) were serious (mainly febrile neutropenia in 1.4% of patients) and 336 (13.7%) were treatment-related (mainly injection site pain in 9.1% of patients). Congestive Heart Failure occurred in 58 (11.5%) patients and was related to treatment in 4.6% of patients. Only 34 AEs (1.4%) in 27 (5.4%) patients led to permanent treatment discontinuation. One death was assessed as not treatment-related. Quality of life (QoL) analyses showed no deterioration of global health status.
CONCLUSION: The HERmione study showed that, in a real-life setting, the safety of SC trastuzumab administered in HER2-positive eBC patients is consistent with data reported from previous clinical trials, without new safety concerns or QoL deterioration.

PMID: 31670262 [PubMed - indexed for MEDLINE]

Investigational treatments for COVID-19 may increase ventricular arrhythmia risk through drug interactions.

CPT Pharmacometrics Syst Pharmacol. 2020 Nov 17;:

Authors: Varshneya M, Irurzun-Arana I, Campana C, Dariolli R, Gutierrez A, Pullinger TK, Sobie EA

Abstract
Many drugs that have been proposed for treatment of COVID-19 are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here we explored the potential effects on cardiac electrophysiology of 4 drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PK) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both pharmacokinetic and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that females with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared with diseased males or healthy individuals of either sex. Statistical analysis of population simulations revealed the molecular factors that certain females with heart failure especially susceptible to arrhythmias. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.

PMID: 33205613 [PubMed - as supplied by publisher]