Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Synthesis Strategy of Tetrapyrrolic Photosensitizers for Their Practical Application in Photodynamic Therapy

This review presents a wide range of tetrapyrrole photosensitizers used for photodynamic therapy (PDT), antimicrobial photodynamic therapy, photoinactivation of pathogens. Methods of synthesis and design of new photosensitizers with greater selectivity of accumulation in tumor tissue and increased photoinduced antitumor activity are considered. The issues of studying the properties of new photosensitizers, their photoactivity, the ability to generate singlet oxygen, and the possibility of using targeted photodynamic therapy in clinical practice are discussed. The review examines the work on PDT by national and foreign researchers.

Safety and Pharmacokinetics of a Novel Double Prodrug Asc10 in Healthy Subjects

Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.

IDWeek 2022

IDWeek is the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS) and the Society of Infectious Diseases Pharmacists (SIDP). For the first time since the COVID-19 public health emergency began, IDWeek 2022 returned to in-person attendance. It was held in Washington, D.C., and the meeting comprised 5 days of live sessions and on-demand content that included posters and oral presentations.Copyright © 2023 Clarivate.

RETHINKING REMDESIVIR: ENHANCING ANTI-SARS-CoV-2 ACTIVITY OF ORAL LIPID RVn PRODRUGS

Background: SARS-CoV-2 evolution has contributed to successive waves of infections and severely compromised the efficacy of available SARS-CoV-2 monoclonal antibodies. Decaying vaccine-induced immunity, vaccine hesitancy, and limited vaccine protection in older and immunocompromised populations further compromises vaccine efficacy at the population level. Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease due to COVID-19. An orally bioavailable RDV analog could facilitate earlier widespread administration to non-hospitalized COVID-19 patients. Method(s): We synthesized monoalkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. We evaluated the in vivo efficacy of our lead compound, 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (V2043), in an oral treatment model of murine SARS-CoV-2 infection. We then synthesized numerous phospholipid analogs of RVn and determined which modifications enhanced in vitro antiviral activity and selectivity. The most effective compounds against SARS-CoV-2 were then evaluated for antiviral activity against other RNA viruses. Result(s): Oral treatment of SARS-CoV-2 infected BALB/c mice with V2043 (60 mg/kg once daily for 5 days, starting 12 hrs after infection) reduced lung viral load by more than 100-fold versus vehicle at day 2 and to below the LOD at day 5. V2043 inhibited previous and contemporary SARS-CoV-2 Variants of concern to a similar degree, as measured by the half maximal effective concentration (EC50) in a human lung epithelial cell line (Calu-3). Evaluation of multiple RVn analogs with hydrophobic esters at the sn-2 of glycerol revealed that in vitro antiviral activity was improved by the introduction of a 3-fluoro-4-methoxysubstituted benzyl or a 3-or 4-cyano-substituted benzyl. These compounds showed a 2-to 6-fold improvement in antiviral activity compared to analogs having an unsubstituted benzyl, such as V2043, and were more active than RDV. These compounds also showed enhanced antiviral activity against multiple contemporary and emerging RNA viruses. Conclusion(s): Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections and as preparation for future outbreaks of pandemic RNA viruses.

Drug Design Strategies for the Treatment of Coronavirus Infection

The increasing size and density of the human population is leading to an increasing risk of infectious diseases that threaten to spread yet another pandemics. The widespread use of vaccination has reduced morbidity and mortality associated with viral infections and in some cases eradicated the virus from the population entirely. Regrettably, some virus species retain the ability to mutate rapidly and thus evade the vaccine-induced immune response. New antiviral drugs are therefore needed for the treatment and prevention of viral diseases. Modern research into the structures and properties of viral proteases, which are of key importance in the life cycle of viruses, makes it possible, in our opinion, to turn these enzymes into promising targets for the development of effective viral disease control methods.

Multifunctional pH-responsive nanogel for malaria and cancer treatment: Hitting two targets with one arrow

Malaria and cancer have been considered deadly diseases around the world. Cancer and malaria both have high incidence rates despite numerous research efforts to develop effective strategies for mitigating the burden of these two distinct ailments. Herein, pH-responsive nanogel based on methacrylic acid-functionalized with bovine serum albumin (PMAA-BSA) with an average diameter of similar to 75 nm was fabricated for smart delivery of chloro-quine (CQ). These nanoplatforms exhibited high drug loading efficacy (26.42%). Also it displayed a higher CQ release rate (92.03%) under simulated acidic microenvironment of the digestive vacuole (DV) and tumor tissue whereas 40.01% CQ was released under a neutral physiological environment. More importantly, this unique pH -responsive nanogel lowered the IC50 of CQ by approximately 2.8-fold and 1.9-fold in MCF-7 cells at 24 and 48 h, respectively. Interestingly, blank PMAA-BSA nanogels displayed anti-plasmodial activity and no one to the best of our knowledge has developed a drug vehicle with inherent antimalarial features. PMAA-BSA-CQ through its synergistic effects exhibited great anti-plasmodial activity under both in vitro and in vivo conditions. Furthermore, PMAA-BSA-CQ fully eradicate the parasites in Plasmodium berghei infected mice and prolonged their survival rate. In conclusion, such pH-responsive nanogel with targeting ability and non-toxicity could be used as a very promising nanoplatform for intracellular and tumor trigger release of antimalarial/anti-cancer drugs.

Use of physiological based pharmacokinetic modeling for cross-species prediction of pharmacokinetic and tissue distribution profiles of a novel niclosamide prodrug.

Introduction: Niclosamide (Nc) is an FDA-approved anthelmintic drug that was recently identified in a drug repurposing screening to possess antiviral activity against SARS-CoV-2. However, due to the low solubility and permeability of Nc, its in vivo efficacy was limited by its poor oral absorption. Method: The current study evaluated a novel prodrug of Nc (PDN; NCATS-SM4705) in improving in vivo exposure of Nc and predicted pharmacokinetic profiles of PDN and Nc across different species. ADME properties of the prodrug were determined in humans, hamsters, and mice, while the pharmacokinetics (PK) of PDN were obtained in mice and hamsters. Concentrations of PDN and Nc in plasma and tissue homogenates were measured by UPLC-MS/MS. A physiologically based pharmacokinetic (PBPK) model was developed based on physicochemical properties, pharmacokinetic and tissue distribution data in mice, validated by the PK profiles in hamsters and applied to predict pharmacokinetic profiles in humans. Results: Following intravenous and oral administration of PDN in mice, the total plasma clearance (CLp) and volume of distribution at steady-state (Vdss) were 0.061-0.063 L/h and 0.28-0.31 L, respectively. PDN was converted to Nc in both liver and blood, improving the systemic exposure of Nc in mice and hamsters after oral administration. The PBPK model developed for PDN and in vivo formed Nc could adequately simulate plasma and tissue concentration-time profiles in mice and plasma profiles in hamsters. The predicted human CLp/F and Vdss/F after an oral dose were 2.1 L/h/kg and 15 L/kg for the prodrug respectively. The predicted Nc concentrations in human plasma and lung suggest that a TID dose of 300 mg PDN would provide Nc lung concentrations at 8- to 60-fold higher than in vitro IC50 against SARS-CoV-2 reported in cell assays. Conclusion: In conclusion, the novel prodrug PDN can be efficiently converted to Nc in vivo and improves the systemic exposure of Nc in mice after oral administration. The developed PBPK model adequately depicts the mouse and hamster pharmacokinetic and tissue distribution profiles and highlights its potential application in the prediction of human pharmacokinetic profiles.

Modified Synthesis and Isolation of an Advanced Intermediate of Remdesivir

Synthesis and isolation of an advanced intermediate (S)-2-Ethylbutyl 2-(((S)-(4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate (1b), which is being used for the manufacture of the prodrug diastereoisomer 1d called Remdesivir have been carried out in high yield with efficient stereoselectivity. The isolated advanced intermediate 1b was a dia-stereoselective nucleoside phosphoramidate prodrug used as an antiviral agent having a mix-ture of two (SS) and (SR) diastereomers with stereocenter at phosphorus, which was purified by converting into a more stable diastereoselective isomer (SS) by simple physical fractional crystallization process, resulting in an improved yield of ~45%. The recrystallization has been afforded diastereomerically in 99% pure (SS)-isomer 1b. The 1H NMR characterization data confirm the (SS)-isomer (1b). The developed process holds significant potential for large-scale reactions relatively with commercially available low-cost solvents and co-solvents, resulting in an alternative cheaper process. © 2022 Bentham Science Publishers.

Remdesivir (GS-5734) for COVID-19 Treatment: Past and Recent Updates

Background: SARS-CoV-2 is a pandemic now, and several measures have been taken by countries to prevent, control, and treat the disease. WHO has been working meticulously and has been providing up to date information and statistics on incidences and death. Several broad--spectrum anti-viral drugs are available and have been used in the past to fight against the viral out-break. Recently remdesivir, an experimental prodrug from Gilead Sciences, has been found to be a potential drug to be used as a therapy to treat COVID-19. Objective(s): Here, we have reviewed several previous findings from the literature and present an up to date information on remdesivir. Result(s): Remdesivir was initially invented for use against Ebola virus treatment and has proved ef-fective against different strains of Ebola, Nipah, and other strains of coronaviruses. Clinical trials with remdesivir for COVID-19 patients have begun, and several off label use of remdesivir have been reported recently. Currently, the drug seems to have an effect against the SARS-CoV-2 virus, with side effects among a few patients. Although the results are not conclusive, they are partly promising. This review provides past and recent updates on the use of remdesivir. Conclusion(s): From the review, we conclude that the drug remdesivir is known to exhibit its mechanism of action by terminating the RNA synthesis, and it is a potential drug against the novel coron-avirus.Copyright © 2021 Bentham Science Publishers.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately. © 2023 American Chemical Society.

Potential Anti-SARS-CoV-2 Prodrugs Activated by Phosphorylation and Their Role in the Aged Population.

The COVID-19 pandemic has flared across every part of the globe and affected populations from different age groups differently. People aged from 40 to 80 years or older are at an increased risk of morbidity and mortality due to COVID-19. Therefore, there is an urgent requirement to develop therapeutics to decrease the risk of the disease in the aged population. Over the last few years, several prodrugs have demonstrated significant anti-SARS-CoV-2 effects in in vitro assays, animal models, and medical practice. Prodrugs are used to enhance drug delivery by improving pharmacokinetic parameters, decreasing toxicity, and attaining site specificity. This article discusses recently explored prodrugs such as remdesivir, molnupiravir, favipiravir, and 2-deoxy-D-glucose (2-DG) and their implications in the aged population, as well as investigating recent clinical trials.

Enhanced Remdesivir Analogues to Target SARS-CoV-2.

We report the short synthesis of novel C-nucleoside Remdesivir analogues, their cytotoxicity and an in vitro evaluation against SARS-CoV-2 (CoV2). The described compounds are nucleoside analogues bearing a nitrogen heterocycle as purine analogues. The hybrid structures described herein are designed to enhance the anti-CoV2 activity of Remdesivir. The compounds were evaluated for their cytotoxicity and their anti-CoV2 effect. We discuss the impact of combining both sugar and base modifications on the biological activities of these compounds, their lack of cytotoxicity and their antiviral efficacy.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers. © 2022 The Authors

DRUG DESIGN STRATEGIES FOR THE TREATMENT OF CORONAVIRUS INFECTION

The increasing size and density of the human population is leading to an increasing risk of infectious diseases that threaten to spread yet another pandemics. The widespread use of vaccination has reduced morbidity and mortality associated with viral infections and in some cases eradicated the virus from the population entirely. Regrettably, some virus species retain the ability to mutate rapidly and thus evade the vaccine-induced immune response. New antiviral drugs are therefore needed for the treatment and prevention of viral diseases. Modern research into the structures and properties of viral proteases, which are of key importance in the life cycle of viruses, makes it possible, in our opinion, to turn these enzymes into promising targets for the development of effective viral disease control methods.

AMICOUMACIN-BASED PRODRUG DEVELOPMENT APPROACH

Coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, is highly contagious and has a severe morbidity. Providing care to patients with COVID-19 requires the development of new types of antiviral drugs. The aim of this work is to develop a prodrug for the treatment of coronavirus disease using the antibiotic Amicoumacin A (Ami), the mechanism of action of which is based on translation inhibition. Enzymatic hydrolysis of an inactivated prodrug by the SARS-CoV-2 main protease can lead to the release of the active Ami molecule and, as a consequence, the suppression of protein biosynthesis in infected cells. To test the proposed hypothesis, a five-stage synthesis of an inactivated analogue of Amicoumacin A was carried out. Its in vitro testing with the SARS-CoV-2 recombinant protease MPro showed a low percentage of hydrolysis. Further optimization of the peptide fragment of the inactivated analog recognized by the SARS-CoV-2 MPro protease may lead to an increase in proteolysis and the release of Amicoumacin A.

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants.

The nucleoside analog ß-D-N4-hydroxycytidine is the active metabolite of the prodrug molnupiravir and is accepted as an efficient drug against COVID-19. Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) enzyme, which is responsible for replicating the viral genome during the replication process of certain types of viruses. It works by disrupting the normal function of the RdRp enzyme, causing it to make mistakes during the replication of the viral genome. These mistakes can prevent the viral RNA from being transcribed, converted into a complementary DNA template, translated, or converted into a functional protein. By disrupting these crucial steps in the viral replication process, molnupiravir can effectively inhibit the replication of the virus and reduce its ability to cause disease. This review article sheds light on the impact of molnupiravir and its metabolite on SARS-CoV-2 variants of concern, such as delta, omicron, and hybrid/recombinant variants. The detailed mechanism and molecular interactions using molecular docking and dynamics have also been covered. The safety and tolerability of molnupiravir in patients with comorbidities have also been emphasized.

Improving properties of the nucleobase analogs T-705/T-1105 as potential antiviral.

In this minireview we describe our work on the improvement of the nucleobase analogs Favipiravir (T-705) und its non-fluorinated derivative T-1105 as influenza and SARS-CoV-2 active compounds. Both nucleobases were converted into nucleotides and then included in our nucleotide prodrugs technologies cycloSal-monophosphates, DiPPro-nucleoside diphosphates and TriPPPro-nucleoside triphosphates. Particularly the DiPPro-derivatives of T-1105-RDP proved to be very active against influenza viruses. T-1105-derivatives in general were found to be more antivirally active as compared to their T-705 counterpart. This may be due to the low chemical stability of all ribosylated derivatives of T-705. The ribosyltriphosphate derivative of T-1105 was studied for the potential to act as a inhibitor of the SARS-CoV-2 RdRp and was found to be an extremely potent compound causing lethal mutagenesis. The pronucleotide technologies, the chemical synthesis, the biophysical properties and the biological effects of the compounds will be addressed as well.

ONE MORE FEATHER IN THE CAP (DECITABINE): YET ANOTHER CASE OF CHEMOTHERAPY-INDUCED LUNG INJURY

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Lung toxicity due to antineoplastic therapy is reported with both cytotoxic and molecularly targeted agents [1]. We present one such case of lung injury induced by capecitabine. CASE PRESENTATION: A 79-year-old female with history of triple negative infiltrating duct carcinoma of the right breast (status post mastectomy and adjuvant chemotherapy with docetaxel and cyclophosphamide 3 years prior) presented to the hospital with dyspnea on exertion following her fourth cycle of capecitabine therapy for breast cancer recurrence. Patient developed nausea, vomiting, and malaise with cycles 1, 2, and 3 of capecitabine therapy with onset of severe dyspnea on exertion, cough, and hypoxia following cycle 4. Computed tomography (CT) scan of the chest on admission showed consolidative opacities in the right upper, right middle, and anterior right lower lobe along with smaller opacities in the left lung apex and small subcentimeter nodules;no pulmonary embolism. Antibiotics were given for a short duration for suspected pneumonia without improvement. Capecitabine was held on discharge. She presented again to the emergency room with worsening shortness of breath, diarrhea, fatigue, and dizziness. COVID test was negative. Chest x-ray redemonstrated patchy airspace disease involving the right apical, lateral, mid lower lung field. Oral steroids were recommended for suspected organizing pneumonia, but the patient refused due to concerns about side effects. Her hospital course was complicated by Clostridium difficile infection (treated with oral vancomycin) and left lower extremity deep venous thrombosis (treated with anticoagulation). Subsequently she followed up with pulmonology outpatient. Repeat imaging showed evolving infiltrates in the same areas with elevated aspergillus IgG level (18.0 mcg/ml) and IgE (178 kU/L) but negative galactomannan and sputum bacterial/fungal/acid fast cultures. Oral steroids were initiated with clinical and symptomatic improvement. DISCUSSION: Capecitabine is a prodrug of fluorouracil (antimetabolite). It is used as a chemotherapy agent in multiple types of cancer including breast cancer. Respiratory side effects include cough (<7%) and bronchitis (<5%). Lung injury/pneumonitis is a rare complication with only a few cases reported to date [2,3]. The timing of symptoms with chemotherapy administration and the negative infectious work-up supports capecitabine as the inciting etiology of lung injury. Withholding chemotherapy and starting systemic steroids were effective treatments in this case of chemotherapy induced lung toxicity. CONCLUSIONS: Capecitabine induced lung injury is a rare but important entity and should always be kept in mind while evaluating dyspnea in cancer patients. Reference #1: Capri G, Chang J, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol. 2010;21(3):474. Epub 2009 Oct 8. DOI: 10.1093/annonc/mdp373 Reference #2: C. J. Benthin, G. Allada. Capecitabine-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine 2016;193:A1653. Reference #3: Andrew K Chan, Bok A Choo, John Glaholm. Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature. Onkologie. 2011;34(8-9):443-6. doi: 10.1159/000331133. Epub 2011 Aug 19. DISCLOSURES: No relevant relationships by William Karkowsky No relevant relationships by Chahat Puri No relevant relationships by Sahib Singh

Genotoxicity Assessment of Potentially Mutagenic Nucleoside Analogues Using ToxTracker

Since the late 1950s researchers have developed nucleoside analogues to target viral replication and infections. Following the HIV/AIDS outbreak several early nucleoside analogues were employed. These compounds can interfere with viral transcription and translation events targeting DNA and RNA polymerases. The downside is that this is not necessarily restricted to the viral polymerases but can also target the host polymerases and have detrimental effects causing for instance mutations and carcinogenicity. In a retrospective study, we applied the ToxTracker® genotoxicity reporter assay to assess the potential of a selection of representative nucleoside analogues to cause genotoxicity. Among the early nucleoside analogues, several triggered a genotoxic response, in line with historical data. Generally, later generation nucleoside analogues did not trigger the genotoxicity reporters in ToxTracker but in some cases the reporters for oxidative stress and protein damage were activated. Remdesivir and Molnupiravir, two nucleoside analogues that are currently being repurposed for Covid-19 treatment, were designed as pro-drugs and will after metabolization release their respective active metabolites. Neither pro-drug nor their metabolites triggered any genotoxicity biomarkers but the metabolite of Molnupiravir (EIDD-1931) did trigger oxidative stress, p53 and protein damage at concentrations relevant for human treatment. Overall, the ToxTracker data were in line with the in vivo micronucleus assay while the AMES test for the nucleoside analogues had problems to assess their mutagenic potential. Nucleoside analogues continue to be attractive treatment options for viral infections. ToxTracker readily distinguished between the genotoxic analogues and those with different profiles and provides a basis for clustering and potency ranking, offering a comprehensive tool to assess the toxicity of nucleoside analogues.