scholarly journals Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

2021 ◽  
Vol 22 (23) ◽  
pp. 12858
Author(s):  
Friedrich Hahn ◽  
Stuart T. Hamilton ◽  
Christina Wangen ◽  
Markus Wild ◽  
Jintawee Kicuntod ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Clinical Symptoms ◽  
Adenovirus Type ◽  
Drug Induced ◽  
Varicella Zoster ◽  
Bifunctional Molecules ◽  
Medical Needs ◽  
Drug Classes ◽  
Spectrum Activity ◽  
Target Binding

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.

Drug-induced Myopathies

2021 ◽  
Author(s):  
Jürgen Steinmeyer ◽  
Johannes Flechtenmacher
Keyword(s):  
Kidney Failure ◽  
Clinical Symptoms ◽  
Serum Levels ◽  
Drug Dosage ◽  
Lipid Lowering ◽  
Drug Induced ◽  
Drug Classes ◽  
Alternative Drug ◽  
High Doses ◽  
Toxic Myopathy

AbstractDifferential diagnosis of muscle pain and weakness is extensive, including neurological, vertebral, arthrogenic, vascular, traumatic, immunological, endocrine, genetic and infectious aetiologies, as well as medication or toxin-related causes. Muscles are highly sensitive to a large number of drugs, especially with high doses. Although many drug classes can cause toxic myopathy, a significant number of cases are caused by lipid-lowering drugs, long-term use of corticosteroids, and, most often, alcohol misuse. Some drug interactions, e.g. those that are metabolised via the enzyme CYP3A4, can increase the serum levels of the drugs and drug-induced toxicity. A careful history of patientʼs drug and alcohol consumption is therefore vital. Clinical symptoms depend on the drug, dosage and patientʼs sensitivity. They can vary from asymptomatic increase in serum levels of creatine kinase, mild myalgia and cramps to muscle weakness, rhabdomyolysis, kidney failure and even death. The pathogenesis is often only partially known and multifactorial. Toxic myopathy is often reversible once the drug is discontinued, alternative drug therapy is started or a different dosage regimen is chosen. Complications such as acute kidney failure must be avoided, and analgesic therapy may be indicated.

scholarly journals Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6290
Author(s):  
Hye-Won Lee
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Imaging Techniques ◽  
Predictive Biomarkers ◽  
Effective Control ◽  
Extrinsic Factors ◽  
Medical Needs

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

scholarly journals Drug-Induced Photosensitivity—From Light and Chemistry to Biological Reactions and Clinical Symptoms

2021 ◽  
Vol 14 (8) ◽  
pp. 723
Author(s):  
Justyna Kowalska ◽  
Jakub Rok ◽  
Zuzanna Rzepka ◽  
Dorota Wrześniok
Keyword(s):  
Defense Mechanisms ◽  
Clinical Symptoms ◽  
Chemical Properties ◽  
Additional Treatment ◽  
Cosmetic Products ◽  
Aesthetic Value ◽  
Drug Usage ◽  
Drug Induced ◽  
Biochemical Level ◽  
The Aesthetic

Photosensitivity is one of the most common cutaneous adverse drug reactions. There are two types of drug-induced photosensitivity: photoallergy and phototoxicity. Currently, the number of photosensitization cases is constantly increasing due to excessive exposure to sunlight, the aesthetic value of a tan, and the increasing number of photosensitizing substances in food, dietary supplements, and pharmaceutical and cosmetic products. The risk of photosensitivity reactions relates to several hundred externally and systemically administered drugs, including nonsteroidal anti-inflammatory, cardiovascular, psychotropic, antimicrobial, antihyperlipidemic, and antineoplastic drugs. Photosensitivity reactions often lead to hospitalization, additional treatment, medical management, decrease in patient’s comfort, and the limitations of drug usage. Mechanisms of drug-induced photosensitivity are complex and are observed at a cellular, molecular, and biochemical level. Photoexcitation and photoconversion of drugs trigger multidirectional biological reactions, including oxidative stress, inflammation, and changes in melanin synthesis. These effects contribute to the appearance of the following symptoms: erythema, swelling, blisters, exudation, peeling, burning, itching, and hyperpigmentation of the skin. This article reviews in detail the chemical and biological basis of drug-induced photosensitivity. The following factors are considered: the chemical properties, the influence of individual ranges of sunlight, the presence of melanin biopolymers, and the defense mechanisms of particular types of tested cells.

A case of statin-induced liver injury with positive rechallenge with a second statin. Is there a class effect?

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Giovanna Onfiani ◽  
Fabio Nascimbeni ◽  
Francesca Carubbi
Keyword(s):  
Liver Injury ◽  
Clinical Symptoms ◽  
High Risk Population ◽  
Drug Induced ◽  
Case Presentation ◽  
Drug Induced Liver Injury ◽  
Aged Woman ◽  
Cardiovascular Morbidity And Mortality ◽  
Middle Aged Woman

Abstract Objectives Statins have proved to reduce cardiovascular morbidity and mortality in high-risk population and are generally well tolerated, although adverse events can occur. Up to 3% of patients develop aminotransferases elevation, which usually normalizes with continued treatment and hardly is associated with clinical symptoms. Serious statin-related liver injury is exceedingly rare. Furthermore, literature regarding rechallenge with a second statin is extremely poor. Some authors caution that re-exposure to these drugs is associated with a more serious liver injury but safe switching to a second statin after drug-induced liver injury (DILI) is also reported. Case presentation We describe a case of a middle-aged woman who developed hepatocellular liver injury after simvastatin dose escalation; a rechallenge with low dose rosuvastatin caused rapid recurrence of DILI. Conclusions In our opinion, clinicians should be very cautious upon rechallenge and closely follow-up patients who experienced statin-induced liver injury when trying re-exposure to another statin.

scholarly journals Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review

2021 ◽  
pp. 120347542110045
Author(s):  
Sara Mirali ◽  
Abrahim Abduelmula ◽  
Asfandyar Mufti ◽  
Muskaan Sachdeva ◽  
Jensen Yeung
Keyword(s):  
Systematic Review ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Complete Resolution ◽  
Kinase Inhibitors ◽  
Healthcare Providers ◽  
Latency Period ◽  
Braf Inhibitors ◽  
Palmoplantar Keratoderma ◽  
Drug Induced

Background Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK. Methods EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword “palmoplantar keratoderma.” 40 studies met the inclusion criteria. Results A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( n = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, n = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, n = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, n = 8/247), or chemotherapy (2.4%, n = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( n = 12/24) achieving complete resolution and 50% ( n = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( n = 10) and topical corticosteroids ( n = 4). Conclusions PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.

Drug-Induced Restless Legs Syndrome

2018 ◽  
Vol 52 (7) ◽  
pp. 662-672 ◽  
Author(s):  
Edna Patatanian ◽  
Melanie K. Claborn
Keyword(s):  
Restless Legs Syndrome ◽  
English Language ◽  
Case Reports ◽  
Data Extraction ◽  
Case Series ◽  
Predisposing Factors ◽  
Drug Induced ◽  
Restless Legs ◽  
Drug Classes ◽  
Study Selection

Objective: To review the literature on drug-induced restless legs syndrome (DI-RLS). Data Sources: The review included a search for English-language literature from 1966 to December 2017 in the MEDLINE, PubMed, and Ovid databases using the following search terms: restless legs syndrome (RLS), periodic limb movement, adverse effects, and drug-induced. In addition, background articles on the pathophysiology, etiology, and epidemiology of RLS were retrieved. Bibliographies of relevant articles were reviewed for additional citations. Study Selection and Data Extraction: All case reports, case series, and review articles of DI-RLS were identified and analyzed. There were only a small number of controlled clinical trials, and most data were from case reports and case series. Results: Several drugs and drug classes have been implicated in DI-RLS, with antidepressants, antipsychotics, and antiepileptics having the most evidence. In addition, RLS may be linked with a number of disorders or underlying predisposing factors as well. Conclusions: The prevalence of RLS is variable and ranges from 3% to 19% in the general population. There are many predisposing factors to RLS, but an emerging body of evidence suggests that there is an association between numerous drugs and RLS.

scholarly journals Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation

2021 ◽  
Author(s):  
Mark Borris D. Aldonza ◽  
Junghwa Cha ◽  
Insung Yong ◽  
Jayoung Ku ◽  
Dabin Lee ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Tumor Regression ◽  
Therapy Resistance ◽  
Critical Component ◽  
Label Free ◽  
Drug Induced ◽  
Pan Cancer ◽  
Core Fucosylation

AbstractCancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post-translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy-induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

scholarly journals Posterior Reversible Encephalopathy Syndrome (PRES) and Drug-Induced Hypersensitivity Syndrome (DIHS) following Immunotherapy and BRAF/MEK Inhibition with Continued Response in Metastatic Melanoma

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
J. M. Sabile ◽  
D. J. Grider ◽  
K. A. Prickett ◽  
L. Hu ◽  
P. V. Mallidi
Keyword(s):  
Drug Reaction ◽  
Metastatic Melanoma ◽  
Posterior Reversible Encephalopathy Syndrome ◽  
Kinase Inhibitors ◽  
Hypersensitivity Syndrome ◽  
Checkpoint Inhibition ◽  
Drug Induced ◽  
Posterior Reversible Encephalopathy ◽  
Mek Kinase ◽  
Reversible Encephalopathy

Background. The role of immunotherapy continues to evolve across both solid and hematologic malignancies. However, while use of immunotherapy has increased via the advent of checkpoint inhibition, chimeric antigen receptors, and vaccines against malignant cells, there remains uncertainty regarding the recognition and management of delayed immune-related reactions and post treatment immune-related sensitivity to subsequent medications, such as BRAF/MEK kinase inhibitors. Furthermore, it is unclear how immunotherapy may alter the adverse effect profile and efficacy of subsequent lines of treatment. Case Presentation. Discussed is a patient with stage IV metastatic melanoma who failed first-line treatment with a combination of nivolumab and ipilimumab. He was then treated with BRAF/MEK kinase inhibition via Encorafenib and Binimetinib. Shortly thereafter, the patient developed posterior reversible encephalopathy syndrome (PRES) and a generalized pruritic rash that was biopsied with consideration toward drug reaction versus drug-induced hypersensitivity syndrome (DIHS), formerly called drug reaction with eosinophilia and systemic symptoms (DRESS). The BRAF/MEK combination was held and steroid taper initiated with continued response even beyond conclusion of the steroid taper. Discussion and Conclusions. This case highlights the diagnostic challenge presented by PRES and DIHS in the setting of immunotherapy and BRAF/MEK kinase inhibition for malignant melanoma. The clinical rationale for reinitiating therapy following severe immune reactions subsequent to immunotherapy in the setting of relapsed/refractory metastatic melanoma is discussed. Additionally, the durable response our patient experienced throughout the drug hold period and steroid taper and its clinical potential etiologies and applications are reviewed. As checkpoint inhibition and tyrosine-kinase inhibitors have become cornerstones of cancer therapy, larger studies and long-term observations are needed to investigate the risks and benefits across different sequences of therapy.

scholarly journals Complex treatment of diseases of the nasal cavity and paranasal sinuses at the present time

2021 ◽  
pp. 134-139
Author(s):  
V. M. Svistushkin ◽  
K. V. Eremeeva
Keyword(s):  
Nasal Cavity ◽  
Paranasal Sinuses ◽  
Clinical Symptoms ◽  
Local Treatment ◽  
Silver Ions ◽  
Upper Respiratory Tract ◽  
Drug Induced ◽  
High Incidence ◽  
Upper Respiratory ◽  
Pain Symptoms

The search for rational treatment of diseases of the nasal cavity and paranasal sinuses is due to the high incidence among the world's population. Despite the absolutely clear recommendations that would seem to greatly facilitate the choice and scope of therapy, it is extremely important to have a differentiated approach to each patient, depending on age, concomitant pathology, the nature of the course of the disease, the severity of clinical, primarily pain symptoms, and the presence of rhinogenic complications. Differential diagnosis of viral and bacterial acute rhinosinusitis (ARS) allows to avoid unreasonable prescription of antibiotics in the former case and choose therapy in such a way as to help relieve clinical symptoms, timely cure the disease and prevent complications. A systematic review of the literature was conducted with the analysis of scientific research data on the evaluation of the effectiveness of protargol or silver proteinate in the local treatment of upper respiratory tract diseases. A review of studies shows that silver proteinate has astringent, antiseptic and anti-inflammatory effects. The spectrum of antimicrobial action of silver is much wider than many antibiotics and sulfonamides. At the same time, pathogenic microflora is more sensitive to silver ions than non-pathogenic microflora. The analysis of the works also demonstrates the absence of adverse reactions when using this drug. The obtained data allow us to recommend preparations based on silver proteinate as a complex therapy for acute and chronic diseases of the nasal cavity and nasopharynx. The vasoconstrictive effect of protargol allows it to be used as an alternative to decongestants in order to avoid the development of drug-induced rhinitis and tachyphylaxis. Sialor® is a new, convenient, affordable, longer-shelf-life form of silver proteinate.

scholarly journals Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

2021 ◽  
Vol 11 ◽  
Author(s):  
Tong Zhu
Keyword(s):  
Drug Development ◽  
Drug Exposure ◽  
Phase 1 ◽  
Drug Candidate ◽  
Phase 2 ◽  
Medical Needs ◽  
Clinical Drug Development ◽  
Human Pharmacology ◽  
Exposure Target ◽  
Target Binding

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

Sign in / Sign up

Export Citation Format

Share Document