ABSTRACT
In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
ABSTRACT
Coronavirus disease (COVID-19) is an infectious disease caused by coronavirus. Devel-oping specific drugs for inhibiting replication and viral entry is crucial. Several clinical trial studies are underway to evaluate the efficacy of anti-viral drugs for COVID-19 patients. Nanomedicine formulations can present a novel strategy for targeting the virus life cycle. Nano-drug delivery systems can modify the pharmacodynamics and pharmacokinetics properties of anti-viral drugs and reduce their adverse effects. Moreover, nanocarriers can directly exhibit anti-viral effects. A number of nanocarriers have been studied for this purpose, including liposomes, dendrimers, exosomes and decoy nanoparticles (NPs). Among them, decoy NPs have been considered more as nanodecoys can efficiently protect host cells from the infection of SARS-CoV-2. The aim of this review article is to highlight the probable nanomedicine therapeutic strategies to develop anti-viral drug delivery systems for the treatment of COVID-19.Copyright © 2023 Bentham Science Publishers.
ABSTRACT
Objective: The COVID-19 pandemic, which started in Wuhan, China and affected the whole world, still represents a unique global challenge with its contagiousness and lethality. The symptoms of COVID-19 patients may differ depending on the severity of the disease. According to the report published by the Ministry of Health Coronavirus Research Advisory Board on the diagnosis, treatment and control of COVID-19, drug combination therapy (hydroxychloroquine, lopinavir / ritonavir and favipiravir) is recommended by health authorities. Drug-drug interaction is a possible situation as a result of simultaneous use of these drugs, which are metabolized by cytochrome P 450 enzymes (CYP), which are mostly found in the liver, with some other drugs. In this review, we aimed to show the pharmacokinetic drug-drug interactions of the drugs used in the treatment of COVID-19, especially by indicating the metabolism pathways. Result and Discussion: The COVID-19 pandemic adversely affects social life, economic and financial markets worldwide. Appropriate treatment protocols are of great importance but taking drug-drug interactions into account in treatment practices prevents unwanted results in patient treatment.Copyright © 2021 University of Ankara. All rights reserved.
ABSTRACT
There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.
ABSTRACT
Anti-inflammatory treatment of infections is challenging due to the heterogeneity of etiologic agents and complex immune interactions. Nevertheless, anti-inflammatory medications are commonly used in infections to reduce unpleasant symptoms and to modify host response. They may play a fundamental role in managing infection with over-inflammation by decreasing inflammatory organ damage, e.g., COVID-19. However, by its inherent inhibition of immune functions, they might also contribute to the development of serious bacterial infections. Moreover, reducing a patient's symptoms and signs may provide a false sense of security and delay diagnosing threatening infections. © 2022 Elsevier Inc. All rights reserved.
ABSTRACT
BACKGROUND: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models. METHODS AND RESULTS: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all nâ¯=â¯1). CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831. LAY SUMMARY: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.
ABSTRACT
AIMS: Nadroparin is administered to COVID-19 intensive care unit (ICU) patients as thromboprophylaxis. Despite existing population pharmacokinetic (PK) models for nadroparin in literature, the population PK of nadroparin in COVID-19 ICU patients is unknown. Moreover, optimal dosing regimens achieving anti-Xa target levels (0.3-0.7 IU/mL) are unknown. Therefore, a population PK analysis was conducted to investigate different dosing regimens of nadroparin in COVID-19 ICU patients. METHODS: Anti-Xa levels (n = 280) from COVID-19 ICU patients (n = 65) receiving twice daily (BID) 5700 IU of subcutaneous nadroparin were collected to perform a population PK analysis with NONMEM v7.4.1. Using Monte Carlo simulations (n = 1000), predefined dosing regimens were evaluated. RESULTS: A 1-compartment model with an absorption compartment adequately described the measured anti-Xa levels with interindividual variability estimated for clearance (CL). Inflammation parameters C-reactive protein, D-dimer and estimated glomerular filtration rate based on the Chronic Kidney Disease Epidemiology Collaboration equation allowed to explain the interindividual variability of CL. Moreover, CL was decreased in patients receiving corticosteroids (22.5%) and vasopressors (25.1%). Monte Carlo simulations demonstrated that 5700 IU BID was the most optimal dosing regimen of the simulated regimens for achieving prespecified steady-state t = 4 h anti-Xa levels with 56.7% on target (0.3-0.7 IU/mL). CONCLUSION: In our study, clearance of nadroparin is associated with an increase in inflammation parameters, use of corticosteroids, vasopression and renal clearance in critically ill patients. Furthermore, of the simulated regimens, targeted anti-Xa levels were most adequately achieved with a dosing regimen of 5700 IU BID. Future studies are needed to elucidate the underlying mechanisms of found covariate relationships.
Subject(s)
COVID-19 , Venous Thromboembolism , Humans , Nadroparin/pharmacokinetics , Anticoagulants , Venous Thromboembolism/prevention & control , Intensive Care Units , Inflammation , Critical Illness , Anti-Bacterial AgentsABSTRACT
INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.
Subject(s)
COVID-19 , Neoplasms , Humans , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Drug Repositioning , Neoplasms/drug therapyABSTRACT
The COVID-19 epidemic demonstrated the importance of technology in the healthcare sector. A lack of ventilators and essential drugs results in a high mortality rate. The most important lesson from the pandemic is that we must use all available resources to alleviate the situation during the pandemic. In this paper, we combine pharmacovigilance and machine learning to predict the effect of an adverse reaction on a patient. We take VAERS data and preprocess it before feeding it to various machine learning algorithms. We assess our model using various parameters. © 2023, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
ABSTRACT
In this regular feature, aesthetic nurse Claudia McGloin presents a brief synopsis of a range of recently published articles on medical aesthetics. Research roundup aims to provide an overview, rather than a detailed summary and critique, of the papers selected. Should you wish to look at any of the papers in more detail, a full reference is provided at the end of each study summary
ABSTRACT
The mass casualties caused by the delta variant and the wave of the newer "Omicron" variant of SARS-COV-2 in India have brought about great concern among healthcare officials. The government and healthcare agencies are seeking effective strategies to counter the pandemic. The application of nanotechnology and repurposing of drugs are reported as promising approaches in the management of COVID-19 disease. It has also immensely boomed the search for productive, re-liable, cost-effective, and bio-assimilable alternative solutions. Since ancient times, the traditional-ly employed Ayurvedic bhasmas have been used for diverse infectious diseases, which are now employed as nanomedicine that could be applied for managing COVID-19-related health anomalies. Like currently engineered metal nanoparticles (NPs), the bhasma nanoparticles (BNPs) are also packed with unique physicochemical properties, including multi-elemental nanocrystalline compo-sition, size, shape, dissolution, surface charge, hydrophobicity, and multi-pathway regulatory as well as modulatory effects. Because of these conformational and configurational-based physico-chemical advantages, Bhasma NPs may have promising potential to manage the COVID-19 pandemic and reduce the incidence of pneumonia-like common lung infections in children as well as age-related inflammatory diseases via immunomodulatory, anti-inflammatory, antiviral, and adju-vant-related properties.Copyright © 2023 Bentham Science Publishers.
ABSTRACT
Objective: The COVID-19 pandemic, which started in Wuhan, China and affected the whole world, still represents a unique global challenge with its contagiousness and lethality. The symptoms of COVID-19 patients may differ depending on the severity of the disease. According to the report published by the Ministry of Health Coronavirus Research Advisory Board on the diagnosis, treatment and control of COVID-19, drug combination therapy (hydroxychloroquine, lopinavir / ritonavir and favipiravir) is recommended by health authorities. Drug-drug interaction is a possible situation as a result of simultaneous use of these drugs, which are metabolized by cytochrome P 450 enzymes (CYP), which are mostly found in the liver, with some other drugs. In this review, we aimed to show the pharmacokinetic drug-drug interactions of the drugs used in the treatment of COVID-19, especially by indicating the metabolism pathways. Result and Discussion: The COVID-19 pandemic adversely affects social life, economic and financial markets worldwide. Appropriate treatment protocols are of great importance but taking drug-drug interactions into account in treatment practices prevents unwanted results in patient treatment.Copyright © 2021 University of Ankara. All rights reserved.
ABSTRACT
Objective: The COVID-19 pandemic, which started in Wuhan, China and affected the whole world, still represents a unique global challenge with its contagiousness and lethality. The symptoms of COVID-19 patients may differ depending on the severity of the disease. According to the report published by the Ministry of Health Coronavirus Research Advisory Board on the diagnosis, treatment and control of COVID-19, drug combination therapy (hydroxychloroquine, lopinavir / ritonavir and favipiravir) is recommended by health authorities. Drug-drug interaction is a possible situation as a result of simultaneous use of these drugs, which are metabolized by cytochrome P 450 enzymes (CYP), which are mostly found in the liver, with some other drugs. In this review, we aimed to show the pharmacokinetic drug-drug interactions of the drugs used in the treatment of COVID-19, especially by indicating the metabolism pathways. Result and Discussion: The COVID-19 pandemic adversely affects social life, economic and financial markets worldwide. Appropriate treatment protocols are of great importance but taking drug-drug interactions into account in treatment practices prevents unwanted results in patient treatment.Copyright © 2021 University of Ankara. All rights reserved.
ABSTRACT
Introduction: In the randomised double-blind placebo-controlled CounterCovid study, imatinib reduced mortality in COVID-19 patients. High levels of alpha-1 acid glycoprotein (AAG) were associated with increased total imatinib concentrations in COVID-19 patients. Aim(s): We aimed to explore possible relationships between pharmacokinetic(PK) profiles of oral imatinib in COVID19 patients and pharmacodynamic (PD) outcomes. We hypothesize that high total imatinib concentrations may be associated with improved clinical outcomes in COVID-19 patients, when adjusted for AAG. Method(s): PK profiles were expressed as trough concentration at steady state(Css). PD responses were the ratio between partial oxygen pressure and fraction of inspired oxygen(P/F), WHO ordinal scale for clinical improvement(WHO-score) and oxygen supplementation liberation(O2lib). Linear regression, linear mixed effects models and time-to-event analysis were performed and adjusted for possible confounders. Result(s): Individual Css could be determined from 168 patients. Css did associate significantly with P/F (beta=-199,42;p-value=0.013) and O2lib (HR 0.75;p-value= 0.021), adjusted for sex, age, neutrophil-lymphocyte ratio, dexamethasone usage, AAG and baseline P/F-and WHO-score. Css did not significantly associate with WHO-score. Concusion: Higher total exposure following oral imatinib in COVID-19 patients did not associate with improved clinical outcomes. Total Css showed an inverse association with PD-outcomes. This association may be biased by disease-course and variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite at Css may better explain exposure-response associations.
ABSTRACT
The coronavirus (COVID-19) is a global public health pandemic disease emerged from the novel strain of the coronavirus 2 (SARS-CoV-2) that caused severe acute respiratory syndrome. It is the most significant respiratory illness that has affected the world since World War II. Currently, there is no globally approved drug for the treatment of pandemic COVID-19 except for some recently approved vaccines. Instead, various non-specific treatment options are being utilized by different countries. While some of these are effective, there is a lack of well-documented studies on the impact of traditional medicines on the management of SARS-CoV-2 in vitro and in silico. For thousands of years, traditional healers have been using various herbs and spices products and dietary plants to treat various diseases. This review aims to provide information on the use of traditional spices & herbs in COVID-19 protection and treatment and present the main characteristics of these products and their potential antiviral actions. Various databases were searched for articles related to the use of various herbs for the treatment of viral infections. Many of these studies show that various plant compounds can be utilized for the treatment of viral infections. This study aims to summarize the common used of herbal products and dietary supplements with potent bioactive compounds in treatment or prevent of COVID-19.
ABSTRACT
For the third year COVID-19 pandemic is still a global health challenge, despite the availability of vaccines and protection methods, treatment protocols still being updated continuously to observe the optimum management for patients. Cyclooxegynase (COX) enzymes are involved in inflammation and thrombosis related to COVID-19. COX-Thromboxane2 pathway is one of the important pathways that results in thrombus formation. In this study the COX activity level changes were measured by ELISA technique in COVID-19 plasma samples that treated with SIRT1 activators resveratrol and linear BAS SIRT1 aptamer, a significant lowering in COX activity was observed with promising potential atrithrombotic action in COVID-19 to be further investigated in future.
ABSTRACT
Antiviral drugs such as Remdesivir (Veklury), Nirmatrelvir with Ritonavir (Paxlovid), Azvudine, and Molnupiravir (Lagevrio) can reduce the risk for severe and fatal Coronavirus Disease (COVID)-19. Although chronic kidney disease is a highly prevalent risk factor for severe and fatal COVID-19, most clinical trials with these drugs excluded patients with impaired kidney function. Advanced CKD is associated with a state of secondary immunodeficiency (SIDKD), which increases the susceptibility to severe COVID-19, COVID-19 complications, and the risk of hospitalization and mortality among COVID-19 patients. The risk to develop COVID-19 related acute kidney injury is higher in patients with precedent CKD. Selecting appropriate therapies for COVID-19 patients with impaired kidney function is a challenge for healthcare professionals. Here, we discuss the pharmacokinetics and pharmacodynamics of COVID-19-related antiviral drugs with a focus on their potential use and dosing in COVID-19 patients with different stages of CKD. Additionally, we describe the adverse effects and precautions to be taken into account when using these antivirals in COVID-19 patients with CKD. Lastly, we also discuss about the use of monoclonal antibodies in COVID-19 patients with kidney disease and related complications.
ABSTRACT
Gyrolab® is an open immunoassay platform that automates the complete immunoassay protocol in a microfluidic disc. The column profiles generated with Gyrolab immunoassays are used to gain more information about biomolecular interactions that can be useful in assay development or quantify analytes in samples. Gyrolab immunoassays can be used to cover a broad concentration range and diversity of matrices in applications ranging from biomarker monitoring, pharmacodynamics and pharmacokinetics studies, to bioprocess development in many areas, including therapeutic antibodies, vaccines, and cell and gene therapy.This chapter is an overview of Gyrolab technology, including system components and the assay development workflow, including the process of selecting affinity reagents, Gyrolab Bioaffy CDs, and assay conditions to optimize immunoassays. Two case studies are included. The first involves an assay for the humanized antibody pembrolizumab used in cancer immunotherapy that can generate data for pharmacokinetics studies. The second case study involves quantification of the biomarker and biotherapeutic interleukin-2 (IL-2) in human serum and buffer. IL-2 has been implicated in the cytokine storm associated with COVID-19, and cytokine release syndrome (CRS), which can occur during chimeric antigen receptor T cell (CART) therapy used in treating cancer. These molecules also have therapeutic relevance in combination.