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The Journal of Urology Nov 2022Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue...
PURPOSE
Intravesical gemcitabine-docetaxel has emerged as an efficacious and well-tolerated salvage therapy for non-muscle-invasive bladder cancer. However, further rescue therapies are needed for subsequent recurrences or intolerance, particularly when cystectomy is refused or precluded. Valrubicin is a U.S. Food and Drug Administration-approved agent for bacillus Calmette-Guérin unresponsive disease, yet as monotherapy has demonstrated poor efficacy. We report our experience with sequential intravesical valrubicin and docetaxel as a rescue therapy for non-muscle-invasive bladder cancer.
MATERIALS AND METHODS
We retrospectively identified all patients with recurrent non-muscle-invasive bladder cancer treated with valrubicin and docetaxel between April 2013 and June 2021. Patients received weekly sequential intravesical instillations of 800 mg valrubicin and 37.5 mg docetaxel for 6 weeks. If disease-free at first follow-up, monthly maintenance of 2 years was initiated. The primary outcome was recurrence-free survival, assessed using the Kaplan-Meier method.
RESULTS
The analysis included 75 patients with median follow-up of 21 months (IQR: 13-37). Twelve patients with low-grade disease had a 73% recurrence-free survival at 2 years. Sixty-three patients with recurrent high-grade disease had a 38% 2-year high-grade recurrence-free survival. Forty-two (56%) patients had carcinoma in situ present; recurrence-free survival was similar for those with and without carcinoma in situ ( = .63). Two patients died of metastatic bladder cancer while 10 underwent cystectomy. Among patients with high-grade disease, overall, cancer-specific, and cystectomy-free survivals were 87%, 96%, and 84% at 2 years, respectively. Adverse events included bladder spasms (n = 18), urinary frequency (n = 10), and dysuria (n = 8). Two patients could not tolerate valrubicin and docetaxel induction.
CONCLUSIONS
In a heavily pretreated population, our results suggest valrubicin and docetaxel is an effective rescue treatment for patients with recurrent non-muscle-invasive bladder cancer. Further prospective evaluation is needed.
Topics: Adjuvants, Immunologic; Administration, Intravesical; BCG Vaccine; Carcinoma in Situ; Docetaxel; Doxorubicin; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Retrospective Studies; Salvage Therapy; Urinary Bladder Neoplasms
PubMed: 35830552
DOI: 10.1097/JU.0000000000002848 -
Journal of Inorganic Biochemistry Apr 2022Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2...
Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.
Topics: Anthracyclines; Arachidonic Acid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Humans; Molecular Dynamics Simulation; Myocytes, Cardiac; Protein Binding; Static Electricity
PubMed: 35078036
DOI: 10.1016/j.jinorgbio.2022.111722 -
Briefings in Bioinformatics Mar 2022Drug repositioning is an efficient and promising strategy for traditional drug discovery and development. Many research efforts are focused on utilizing deep-learning...
Drug repositioning is an efficient and promising strategy for traditional drug discovery and development. Many research efforts are focused on utilizing deep-learning approaches based on a heterogeneous network for modeling complex drug-disease associations. Similar to traditional latent factor models, which directly factorize drug-disease associations, they assume the neighbors are independent of each other in the network and thus tend to be ineffective to capture localized information. In this study, we propose a novel neighborhood and neighborhood interaction-based neural collaborative filtering approach (called DRWBNCF) to infer novel potential drugs for diseases. Specifically, we first construct three networks, including the known drug-disease association network, the drug-drug similarity and disease-disease similarity networks (using the nearest neighbors). To take the advantage of localized information in the three networks, we then design an integration component by proposing a new weighted bilinear graph convolution operation to integrate the information of the known drug-disease association, the drug's and disease's neighborhood and neighborhood interactions into a unified representation. Lastly, we introduce a prediction component, which utilizes the multi-layer perceptron optimized by the α-balanced focal loss function and graph regularization to model the complex drug-disease associations. Benchmarking comparisons on three datasets verified the effectiveness of DRWBNCF for drug repositioning. Importantly, the unknown drug-disease associations predicted by DRWBNCF were validated against clinical trials and three authoritative databases and we listed several new DRWBNCF-predicted potential drugs for breast cancer (e.g. valrubicin and teniposide) and small cell lung cancer (e.g. valrubicin and cytarabine).
Topics: Algorithms; Computational Biology; Databases, Factual; Drug Discovery; Drug Repositioning; Neural Networks, Computer
PubMed: 35039838
DOI: 10.1093/bib/bbab581 -
Archivos Espanoles de Urologia Sep 2021Most patients at first diagnosis of bladder cancer (BC) present with non muscle invasive disease (NMIBC). BCG intravesical therapy after transurethral resection of the... (Review)
Review
Most patients at first diagnosis of bladder cancer (BC) present with non muscle invasive disease (NMIBC). BCG intravesical therapy after transurethral resection of the bladder tumor is the gold standard in intermediate and high risk NMIBC patients. However, it is estimated that approximately 50% of these patients will present with BCG failure which increases their risk for progression to muscle invasive disease. Currently, the best option for these patients is radical cystectomy. Thus, it is of great interest to pursue new, therapeutic options for BCG failure patients to avoid the necessity of radical cystectomy. We hereby review novel treatment modalities for BCG failure patients. METHODS: This is a narrative review. Keywords for the search were BCG failure, BCG unresponsive, BCG refractory, BCG relapsing and BCG intolerance. Evidence was identified through a search for publications with a ''BCG unresponsive'' tag through 2020. Studies were selected if they contained clinical data on BCG unresponsive therapeutics with near-term availability. Clinical trial landscape evaluation for emerging therapies was performed by searching ClinicalTrials.gov for recruiting/ open interventional trials in 2020. RESULTS: Novel treatment modalities for BCG failure include intravesical chemotherapy, BCG re-challenge or combination of BCG with IFN-α2β, valrubicin, radiotherapy, electromotive drug administration, vicinium, chemohyperthermia, photodynamic therapy, gene therapy, vaccine therapy and immunotherapy. For patients in whom BCG has once failed a repeat course of BCG or BCG plus interferon appears to be a reasonable practice. Likewise, single agent gemcitabine may be considered a treatment modality. However, after 2 or more BCG failures, especially in patients with earlier relapses or cancer persistence, single agent intravesical chemotherapy with valrubicin, gemcitabine or docetaxel appears to be less active than doublet/triplet intravesical chemotherapy or mitomycin chemothermotherapy. Gene therapy or conjugated antibodies may play a role upon further relapse. Single agent pembrolizumab is unlikely to be used as first line, but may be useful, along with multiple new immunotherapeutics, as part of a multimodal approach towards BCG unresponsive disease. CONCLUSIONS: Results from ongoing trials will provide us useful information about many of the existing regimens and probably new drugs will soon be available for this group of patients.
Topics: Adjuvants, Immunologic; Administration, Intravesical; BCG Vaccine; Cystectomy; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 34472437
DOI: No ID Found -
Future Virology Jun 2021The newly emerged human coronavirus, SARS-CoV-2, had begun to spread last year and sparked worldwide. In this study, molecular docking is utilized to test some...
The newly emerged human coronavirus, SARS-CoV-2, had begun to spread last year and sparked worldwide. In this study, molecular docking is utilized to test some previously approved drugs against the SARS-CoV-2 nonstructural protein 15 (Nsp15). We screened 23 drugs, from which three (saquinavir, valrubicin and aprepitant) show a paramount predicted binding affinity (-9.1, -9.6 and -9.2 kcal/mol, respectively) against SARS-CoV-2 Nsp15. Moreover, saquinavir and aprepitant make nonbonded interactions with Leu201 in the active site cavity of Nsp15, while the drug valrubicin interacts with Arg199 and Leu201. This binding pattern may be effective against the targeted protein, leading to Nsp15 blockage and virus abolition. Additionally, the pharmacological properties of the screened drugs are known since they have been approved against different viruses.
PubMed: 34290822
DOI: 10.2217/fvl-2020-0233 -
Antioxidants (Basel, Switzerland) Jun 2021More than a year ago, the first case of infection by a new coronavirus was identified, which subsequently produced a pandemic causing human deaths throughout the world....
More than a year ago, the first case of infection by a new coronavirus was identified, which subsequently produced a pandemic causing human deaths throughout the world. Much research has been published on this virus, and discoveries indicate that oxidative stress contributes to the possibility of getting sick from the new SARS-CoV-2. It follows that free radical scavengers may be useful for the treatment of coronavirus 19 disease (COVID-19). This report investigates the antioxidant properties of nine antivirals, two anticancer molecules, one antibiotic, one antioxidant found in orange juice (Hesperidin), one anthelmintic and one antiparasitic (Ivermectin). A molecule that is apt for scavenging free radicals can be either an electron donor or electron acceptor. The results I present here show Valrubicin as the best electron acceptor (an anticancer drug with three F atoms in its structure) and elbasvir as the best electron donor (antiviral for chronic hepatitis C). Most antiviral drugs are good electron donors, meaning that they are molecules capable of reduzing other molecules. Ivermectin and Molnupiravir are two powerful COVID-19 drugs that are not good electron acceptors, and the fact that they are not as effective oxidants as other molecules may be an advantage. Electron acceptor molecules oxidize other molecules and affect the conditions necessary for viral infection, such as the replication and spread of the virus, but they may also oxidize molecules that are essential for life. This means that the used to defend us from COVID-19 may also harm us. This study posits the idea that oxide reduction balance may help explain the toxicity or efficacy of these drugs. These results represent a further advance on the road towards understanding the action mechanisms of drugs used as possible treatments for COVID-19. Looking ahead, clinical studies are needed to define the importance of antioxidants in treating COVID-19.
PubMed: 34207391
DOI: 10.3390/antiox10060979 -
Hematology/oncology Clinics of North... Jun 2021Transurethral resection of bladder tumor remains the cornerstone of non-muscle invasive bladder cancer management, proper risk stratification, and appropriate selection... (Review)
Review
Transurethral resection of bladder tumor remains the cornerstone of non-muscle invasive bladder cancer management, proper risk stratification, and appropriate selection of adjuvant therapy. A single, postoperative dose of intravesical chemotherapy is used for low-risk patients; patients with high-grade, high-risk disease should receive intravesical bacillus Calmette-Guérin (BCG) induction and maintenance therapy. For patients who develop BCG-unresponsive disease, cystectomy remains the standard of care. Pembrolizumab and valrubicin are approved in the BCG failure setting and as alternative treatments to cystectomy. Nadofaragene firadenovec, vicinium, hyperthermic chemotherapy, and various combination therapies are under investigation as treatment options for patients in the salvage setting.
Topics: Administration, Intravesical; BCG Vaccine; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Salvage Therapy; Urinary Bladder Neoplasms
PubMed: 33958148
DOI: 10.1016/j.hoc.2021.02.003 -
SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study.European Journal of Pharmacology Apr 2021The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for...
The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Doxorubicin; Drug Repositioning; Enzyme Inhibitors; Humans; Lopinavir; Molecular Docking Simulation; Molecular Dynamics Simulation; SARS-CoV-2; Serine Endopeptidases; Topoisomerase II Inhibitors; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33539819
DOI: 10.1016/j.ejphar.2021.173922 -
Biochemical Pharmacology Jan 2021The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause... (Review)
Review
The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antioxidants; Antiviral Agents; Drug Repositioning; Humans; SARS-CoV-2; Treatment Outcome; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33191206
DOI: 10.1016/j.bcp.2020.114296 -
Medicinal Chemistry (Shariqah (United... 2021Several quinones are on the pharmaceutical market as drugs for the treatment of several diseases. (Review)
Review
BACKGROUND
Several quinones are on the pharmaceutical market as drugs for the treatment of several diseases.
OBJECTIVE
The aim of this review was to provide an overview of the quinones that have become drugs for several therapeutic applications.
METHODS
We have comprehensively and critically discussed all the information available in the literature about quinone-based drugs.
RESULTS
In this review, the various aspects of the chemistry and biochemistry of these drugs are highlighted, including their repositioning, drug combination and their new uses.
CONCLUSION
A number of studies related to quinone drugs for different pharmaceutical uses show that the interest in new applications is still increasing in recent years.
Topics: Benzoquinones; Chemistry, Pharmaceutical; Pharmaceutical Preparations; Quinones
PubMed: 33155925
DOI: 10.2174/1573406416666201106104756