Wide Therapeutic Window Research Articles

Lessons Learned from Managing Antithrombotic Therapy in Children Supported with Pediatric Ventricular Assist Devices.

Stroke, thromboembolism, and bleeding are the most recognized complications associated with pediatric ventricular assist devices (VADs) and the leading cause of death and disability on VAD support. Recently, newer antithrombotic strategies like bivalirudin have emerged that appear to be associated with a reduction in the neurologic event rates, especially for smaller pediatric-specific VADs like the Berlin Heart and PediMag/CentriMag systems where the risk of stroke is the highest. While contemporary antithrombotic therapies have likely contributed to lowering adverse event rates, we speculate that clotting and bleeding adverse events may have dropped because of a variety of other seemingly small changes to antithrombotic management that are independent of the antithrombotic agents used. This view is supported by recent reports documenting low stroke rates with anticoagulants other than bivalirudin, a drug that may have a wider therapeutic window but is not available in all locations throughout the world. The primary purpose of this report is 1) to summarize contemporary antithrombotic regimens used for smaller pediatric VADs today associated with low event rates in the United States and abroad and () to review 10 practical lessons learned and pitfalls to avoid that we believe to be important to reducing bleeding and clotting events based on our collective experience managing pediatric VADs over the past 20 years irrespective of the antithrombotic agents used.

Structural basis for the selectivity of 3rd generation EGFR inhibitors: a molecular dynamics study

Activating mutations in the EGFR kinase domain are known to be a common cause of Non-Small Cell Lung Cancer (NSCLC) and are thus targeted for treatment. First generation Tyrosine Kinase Inhibitors (TKIs) were used to treat NSCLC patients with the known activating mutations L858R and exon 19 deletion but were resisted by a second mutation T790M in the active site of the kinase domain. Second generation members of TKIs have an electrophilic moiety that can form a covalent bond with Cys797 and are effective against T790M EGFR but are toxic because they inhibit WT EGFR as well. Third generation TKIs, like Osimertinib, can bind to and irreversibly inhibit T790M mutants selectively, while sparing the wild-type enzyme. Thus, they possess a better safety profile and a wider therapeutic window. However, the reason behind their selectivity is still not well understood. In this study, computational MD simulations were carried out on Osimertinib in complex with both WT and L858R/T790M Double Mutant (DM) EGFR to provide an insight into the selectivity of Osimertinib and its molecular interactions within the active site. A high-resolution trajectory analysis showed that the key selectivity residues are Val726, met793, and Cys797. Interaction of Osimertinib with these residues is improved due to the T790M mutation which optimizes the ligand orientation for binding, as evident from the RMSD and the distances monitored. These results can provide guidance for the development of more selective 3rd generation EGFR TKIs. Communicated by Ramaswamy H. Sarma

Abstract 1399: Discovery and development of PARP inhibitor senaparib

Abstract Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair. PARP inhibitors have been shown to be effective against cancers with DNA repair defects, such as with BRCA1 or BRCA2 mutations. Several PARP inhibitors, including olaparib, rucaparib, niraparib, talazoparib, fluzoparib and pamiparib have been approved for the treatment of several types of cancer. In this presentation, we will report our discovery and development of senaparib (IMP4297) as a potent PARP inhibitor. We will present studies led to the identification of senaparib as a clinical candidate, as well as IND enabling in vitro and in vivo characterization of senaparib. Preclinical data indicated that senaparib had a wide therapeutic window (single agent effective dose of 2.5-21 mg/kg QD, in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model), which was confirmed in clinical studies (effective dose of 20-120 mg QD, and no DLT was found up to 150 mg QD). Senaparib is currently in several phase I/II, phase II and phase III clinical studies for the treatment of multiple tumor types either as single agent or in combination with temozolomide (TMZ). The most advanced study of senaparib is a phase III study as maintenance therapy in platinum-sensitive advanced ovarian cancer patients following first-line chemotherapy (ClinicalTrials.gov Identifier: NCT04169997). Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Mingchuan Guo, Chih-Yi Hsieh, Ye Edward Tian. Discovery and development of PARP inhibitor senaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1399.

Selection of Payloads for Antibody-Drug Conjugates Targeting Ubiquitously Expressed Tumor-Associated Antigens: a Case Study.

The main objective of this work was to demonstrate which kind of payload is the suitable choice for antibody-drug conjugates directed to widely expressed tumor-associated antigen. Trop-2 is overexpressed in various solid tumors, but it is also present on the epithelium of several normal tissues. A well-designed anti-Trop-2 ADC demands a good balance of efficacy and toxicity. In this research, MMAE, SN-38, and DXd were selected as candidates for payloads of the anti-Trop-2 mAb SY02. The antitumor activities and safety profiles of these ADCs were investigated to compare the therapeutic windows. Robust in vitro cytotoxicity was observed on human pancreatic cancer cell CFPAC-1 and breast cancer cell MDA-MB-468 with IC50 generally in the subnanomolar range. Consistent with in vitro assay, SY02-DXd and SY02-SN-38 demonstrated superior efficacy in CFPAC-1 xenograft models with TGI rates of 98.2% and 87.3%, respectively. However, SY02-MMAE could hardly inhibit the tumor growth. Subsequently, antitumor activities of these ADCs were further compared in MDA-MB-468 xenograft model. Complete tumor regression was observed in SY02-DXd and SY02-MMAE groups, indicating their potent antitumor activities. In an exploratory safety and pharmacokinetic study, SY02-DXd demonstrated the best safety profile with minimal adverse events in cynomolgus monkeys, while SY02-MMAE exhibited severe on-target skin toxicity which caused death. In conclusion, SY02-DXd demonstrated superior efficacy and safety with the widest therapeutic window. Based on the efficacy and safety results, moderate cytotoxic payloads would be ideal choices for ADCs targeting ubiquitously expressed antigens.

Cell-Free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer.

Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new class of cancer therapeutics, targeting multiple pathways and providing a durable clinical response, wide therapeutic window and high level of safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report, for the first time, a methodology that uses circulating plasma cell-free RNA (cfRNA) as a sensitive indicator of patient response upon drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four healthy controls receiving three doses of 100 or 200 mg APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. We performed comparative analyses of the circulating transcriptome and were able to detect significant perturbation following APG-157 treatment. Transcripts associated with inflammatory response, leukocyte activation and cytokine were upregulated upon treatment with APG-157 in cancer patients, but not in healthy or placebo-treated patients. A platelet-related transcriptional signature could be detected in cancer patients but not in healthy individuals, indicating a platelet-centric pathway involved in the development of HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive circulating biomarkers for monitoring the efficacy of APG-157 in HNC.

Characterization of Novel, Agmatine‐Based NMDA Receptor Antagonists in Multiple Pain States

The worsening opioid epidemic has highlighted the need for the development of new, safe, and effective analgesic therapeutics. Opioid therapy currently is associated with the risk of conversion to addiction, diversion from patients for whom use is intended, and the development of analgesic tolerance, or the loss of efficacy with continued treatment. To this end, we have developed a line of non‐opioid, agmatine‐based compounds and assessed them for their efficacy in reversing behavioral expressions of pain in animal models, as well as evaluated their safety following chronic exposure. We have previously shown that agmatine, decarboxylated L‐arginine, is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that preferentially antagonizes receptors that express NR2B subunits. This preferential antagonism is desirable for NMDA‐based therapeutics as it can lead to a widening of the therapeutic window and avoidance of the side effects commonly associated with NMDA antagonism including motor ataxia and psychoactive effects. However, agmatine has shown limited penetration through the blood brain barrier (BBB) and a short systemic half‐life, limiting its clinical utility. We have designed strategically‐substituted agmatine (SSA) compounds with the goal of improving its penetration through the BBB by increasing the lipophilicity of agmatine, potentially improving distribution across the BBB and increasing its half‐life following systemic delivery. To this end, we have evaluated this series of SSAs for safety and efficacy in multiple animal models of pain.Mice (21‐30 g, M/F) were assessed for their baseline mechanical sensitivity, and then one of several models of pain was induced: inflammatory pain (Complete Freund’s Adjuvant, (CFA) injected into a hindpaw), neuropathic pain (spared nerve injury surgery), or post‐surgical pain (hindpaw muscle incision). Mechanical sensitivity was again assessed, then an SSA compound, agmatine (the parent compound), or vehicle control was administered, and mechanical sensitivity was recorded for up to three hours following administration. The SSA compounds effectively reversed pain behaviors in mice following administration in the various pain models. Additionally, side effects characteristic of NMDA receptor antagonists were assessed and not found at the range of doses that produced analgesia, indicating a wide therapeutic window.These data indicate that the strategically‐substituted agmatines are anti‐hyperalgesic compounds with a wide therapeutic window, avoiding the motor impairment typical of drugs of this class.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Progress in Assays of HMGB1 Levels in Human Plasma-The Potential Prognostic Value in COVID-19.

Extracellular HMGB1 protein is known to induce inflammatory responses leading to an inflammatory storm. The outbreak of the Severe Acute Respiratory Syndrome COVID-19 due to the SARS-CoV-2 virus has resulted in a huge health concern worldwide. Recent data revealed that plasma/serum HMGB1 levels of patients suffering from inflammation-mediated disorders—such as COVID-19, cancer, and autoimmune disorders—correlate positively with disease severity and vice versa. A late release of HMGB1 in sepsis suggests the existence of a wide therapeutic window for treating sepsis. Rapid and accurate methods for the detection of HMGB1 levels in plasma/serum are, therefore, of great importance for monitoring the occurrence, treatment success, and survival prediction of patients with inflammation-mediated diseases. In this review, we briefly explain the role of HMGB1 in the cell, and particularly the involvement of extracellular HMGB1 (released from the cells) in inflammation-mediated diseases, with an emphasis on COVID-19. The current assays to measure HMGB1 levels in human plasma—Western blotting, ELISA, EMSA, and a new approach based on electrochemical immunosensors, including some of our preliminary results—are presented and thoroughly discussed.

Immunosuppressant Drug Level Monitoring in Pediatric Heart Transplant Recipients: A Report from the TEAMMATE Trial

<h3>Purpose</h3> The TEAMMATE Trial is studying everolimus (EVL) with low-dose tacrolimus (LDTAC) vs. standard tacrolimus (TAC) with mycophenolate (MMF) in a randomized trial in children enrolled at 6 months post-heart transplant. Since therapeutic levels are correlated with lower rejection rates, we sought to describe the immunosuppressant drug level monitoring experience in the trial to date. <h3>Methods</h3> All children in the TEAMMATE Trial remaining on assigned therapy as of August 2021 were included. Drug levels were obtained at 0, 3, 6, 9, 12, 18, 24, & 30 months post-randomization. Formulation, time to therapeutic level, and number of dose adjustments were tracked at each study visit. Stability was assessed by the coefficient of variation (CoV) (SD/mean). Adherence was assessed by the % of levels within range; and the SD of levels divided by therapeutic window (lower values indicating better adherence). Independence of all levels was assumed in analysis. <h3>Results</h3> A total of 211 children were randomized to either EVL/LDTAC (n=107) or usual care TAC/MMF (n=104). After randomization, a therapeutic level was achieved in 94% (EVL) & 91% (MMF). Liquid formulation was used in 37% of EVL subjects. Median time to a therapeutic level for EVL was 10 (tablet) & 11 (liquid) days. The CoV was lower for TAC (36%), EVL (47%), & LDTAC (52%), compared to MMF (103%). Drug levels were in target range 80% (EVL), 20% (MMF), 55% (LDTAC), & 54% (TAC) of the time (<b>Figure</b>). The SD of levels divided by therapeutic window was lowest for EVL (44%), compared to TAC (94%), LDTAC (112%), & MMF (158%). In response to these levels, dose changes were made in 13% (EVL) & 18% (LDTAC) in the EVL/LDTAC group (16% combined) and in 27% (TAC) and 11% (MMF) in the control group (22% combined). <h3>Conclusion</h3> EVL achieves stable target levels more frequently than MMF, LDTAC or TAC, likely due to decreased trough level variability and its wider therapeutic window. Fewer dose adjustments have been required for the EVL/LDTAC regimen compared to TAC/MMF.

HOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers

BackgroundThe tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition.MethodsHere we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed.ResultshOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys.ConclusionshOA-DN30 unique ability to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.

In vivo imaging with two-photon microscopy to assess the tumor-selective binding of an anti-CD137 switch antibody

STA551, a novel anti-CD137 switch antibody, binds to CD137 in an extracellular ATP concentration-dependent manner. Although STA551 is assumed to show higher target binding in tumor tissues than in normal tissues, quantitative detection of the target binding of the switch antibody in vivo is technically challenging. In this study, we investigated the target binding of STA551 in vivo using intravital imaging with two-photon microscopy. Tumor-bearing human CD137 knock-in mice were intravenously administered fluorescently labeled antibodies. Flow cytometry analysis of antibody-binding cells and intravital imaging using two-photon microscopy were conducted. Higher CD137 expression in tumor than in spleen tissues was detected by flow cytometry analysis, and T cells and NK cells were the major CD137-expressing cells. In the intravital imaging experiment, conventional and switch anti-CD137 antibodies showed binding in tumors. However, in the spleen, the fluorescence of the switch antibody was much weaker than that of the conventional anti-CD137 antibody and comparable with that of the isotype control. In conclusion, we were able to assess switch antibody biodistribution in vivo through intravital imaging with two-photon microscopy. These results suggest that the tumor-selective binding of STA551 leads to a wide therapeutic window and potent antitumor efficacy without systemic immune activation.

Review of Some Herbal Agents Having Antiviral Activity

Antiviral is such as an agent, defined as used to treat the targeted virus, or vaccine to produce an antibody against the virus. It gives a proactive therapeutic effect. On the other hand, there is a long traditional use of herbal medicine in the medical platform. The herbal medicine is ornamented with a wide therapeutic window and its side effect is less. The synthetic drug sometimes invites some adverse effects, which is more important that is it occurs more frequently. This gives the opportunity to the researchers to get the noble drug based on the herbal formulation. This review reveals the many herbal plants with their use against the specific virus with the experimental method, based on the knowledge of the Indian traditional system of medicine. The recent database shows the growing research with the herbal medicine, with their therapeutics, especially this time of the society, suffering from the covid -19 (Coronavirus disease), because the doctors have no other options except steroid. So traditional plants open a new chapter in the research of the new antiviral drug.

Synthesis of zinc oxide based etoricoxib and montelukast nanoformulations and their evaluation through analgesic, anti-inflammatory, anti-pyretic and acute toxicity activities

The current study described the synthesis of novel low dose PVA capped Etoricoxib (ET) and montelukast (MT) conjugated Zinc Oxide (ZnO) nanomaterials (NMs) as potential anti-inflammatory, analgesic and antipyretic agents. A facile coprecipitation protocol was used for synthesis of NMs by combination of ET, MT and ZnO NP. The efficient synthesis of ET and MT conjugated ZnO NMs were confirmed through UV–visible, XRD, FTIR and DLS analysis. Data of in vivo anti-inflammatory activity indicated that potency of ZnO NMs was found to be greater than drugs (ET and MT). Analgesic potency of NMs was much higher than that of drugs (ET and MT). The in vivo antipyretic activity indicates that the results of NMs and drugs (ET and MT) are of similar effect but that of NMs are more potent based on per weight basis. A wide therapeutic window was shown by the acute toxicity study carried out via LD50 method. It is concluded that the novel low dose PVA capped ET and MT conjugated ZnO NMs were potential analgesic, antipyretic and anti-inflammatory agents.

Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson's Disease, and Huntington's Disease.

Stem cells, specifically embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (IPSCs), and neural progenitor stem cells (NSCs), are a possible treatment for stroke, Parkinson’s disease (PD), and Huntington’s disease (HD). Current preclinical data suggest stem cell transplantation is a potential treatment for these chronic conditions that lack effective long-term treatment options. Finding treatments with a wider therapeutic window and harnessing a disease-modifying approach will likely improve clinical outcomes. The overarching concept of stem cell therapy entails the use of immature cells, while key in recapitulating brain development and presents the challenge of young grafted cells forming neural circuitry with the mature host brain cells. To this end, exploring strategies designed to nurture graft-host integration will likely enhance the reconstruction of the elusive neural circuitry. Enriched environment (EE) and exercise facilitate stem cell graft-host reconstruction of neural circuitry. It may involve at least a two-pronged mechanism whereby EE and exercise create a conducive microenvironment in the host brain, allowing the newly transplanted cells to survive, proliferate, and differentiate into neural cells; vice versa, EE and exercise may also train the transplanted immature cells to learn the neurochemical, physiological, and anatomical signals in the brain towards better functional graft-host connectivity.

Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits

BackgroundMilvexian (BMS‐986177/JNJ‐70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials. ObjectivesTo evaluate in vitro properties and in vivo characteristics of milvexian. MethodsIn vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic‐induced carotid arterial thrombosis and cuticle bleeding time (BT). ResultsMilvexian is an active‐site, reversible inhibitor of human and rabbit FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial thromboplastin time (APTT) without changing prothrombin time and potently prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for in vivo prevention and treatment of thrombosis. For prevention, milvexian 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of control. Seventy‐five minutes after milvexian administration, CBF averaged 1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and milvexian 0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; n = 6/group). The combination of milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy. ConclusionsMilvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.

Identification, purification, and pharmacological activity analysis of Desmodus rotundus salivary plasminogen activator alpha1 (DSPAα1) expressed in transgenic rabbit mammary glands.

Desmodus rotundus plasminogen activator alpha 1(DSPAα1) is a thrombolytic protein with advantages, such as a long half-life, high accuracy and specificity for thrombolysis, wide therapeutic window, and no neurotoxicity. To date, DSPAα1 has only been expressed in the Chinese hamster ovary, insect cells, transgenic tobacco plants, and Pichia pastoris. To the best of our knowledge, we are the first to report the expression of DSPAα1 in transgenic rabbit mammary glands, extract the product, and analyze its pharmacology activity. An efficient mammary gland-specific expression vector pCL25/DSPAα1 was transferred to prokaryotic zygotes in rabbits by microinjection to generate six DSPAα1 transgenic rabbits. The recombinant DSPAα1 (rDSPAα1) expression in transgenic rabbit milk was 1.19 ± 0.26mg/mL. The rDSPAα1 purification protocol included pretreatment, ammonium sulfate precipitation, benzamidine affinity chromatography, cation exchange chromatography, and Cibacron blue affinity chromatography; approximately 98% purity was achieved using gel electrophoresis. According to sequencing results, the primary structure of rDSPAα1 was consistent with the theoretical design sequence, and its molecular weight was consistent with that of the natural protein. N-terminal sequencing results indicated rDSPAα1 to be a mature protein, as the goat signal peptide sequence of the expression vector was no longer detected. The fibrinolytic activity of rDSPAα1 was estimated to be 773,333IU/mg. Fibrin-agarose plate assay and in vitro rat blood clot degradation assay showed that rDSPAα1 had strong thrombolytic activity. In conclusion, we report recombinant DSPAα1 with high thrombolytic activity expressed in transgenic rabbit mammary glands.

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis.

BackgroundThe clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP).MethodsA combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP.FindingsEBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin.InterpretationThis study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Development of Next-Generation Poly(ADP-Ribose) Polymerase 1-Selective Inhibitors.

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use of PARP inhibitors for certain rational combination strategies, such as chemotherapy and targeted therapy regimens. Currently approved PARP inhibitors are essentially equipotent against PARP1 and PARP2 enzymes. In this review, we describe the development of next-generation PARP1-selective inhibitors that have entered phase I clinical trials. These inhibitors have demonstrated increased PARP1 inhibitory potency and exquisitely high PARP1 selectivity in preclinical studies-features that may lead to improved clinical efficacy and a wider therapeutic window. First-in-human clinical trials seeking to establish the safety, tolerability, and recommended phase II dose, as well as antitumor activity of these novel agents, have commenced. If successful, this next-generation of PARP1-selective agents promises to build on the succeses of current PARP inhibitor treatment paradigms in cancer medicine.

Therapeutic time windows of compounds against NMDA receptors signaling pathways for ischemic stroke.

Much evidence has proved that excitotoxicity induced by excessive release of glutamate contributes largely to damage caused by ischemia. In view of the key role played by NMDA receptors in mediating excitotoxicity, compounds against NMDA receptors signaling pathways have become the most promising type of anti-stroke candidate compounds. However, the limited therapeutic time window for neuroprotection is a key factor preventing NMDA receptor-related compounds from showing efficacy in all clinical trials for ischemic stroke. In this perspective, the determination of therapeutic time windows of these kinds of compounds is useful in ensuring a therapeutic effect and accelerating clinical application. This mini-review discussed the therapeutic time windows of compounds against NMDA receptors signaling pathways, described related influence factors and the status of clinical studies. The purpose of this review is to look for compounds with wide therapeutic time windows and better clinical application prospect.

Synthesis and cytotoxic activity of 1,2,3-triazoles derived from 2,3-seco-dihydrobetulin via a click chemistry approach

In search of new cytotoxic derivatives based on the lupane scaffold, the seco-lupane azides were coupled with a number of alkynes under the 1,3-dipolar cycloaddition (CuAAC) conditions to afford 1,2,3-triazoles. Phenylalkynes having different substituents at the para position were used as starting materials. Similarly, coupling of the seco-lupane thiocyanate with sodium azide gave 5-thiotetrazole. The cytotoxicity of thirteen derivatives were investigated, as well as the effect of substituents in the phenyl ring on the activity of 1,2,3-triazoles. Limited activity was observed for some of these products. Most of the studied compounds were inactive in cancer cell lines and healthy fibroblasts. Triazole 46 exhibited cytotoxic activity against CEM and MCF-7 cancer cell lines, however, it was also toxic to normal human BJ fibroblasts. Two other derivatives – triazole 45 and tetrazole 49 – exhibited low cytotoxicity. Compound 49 showed good selectivity towards tumor cell lines compared to normal fibroblasts. This compound did not affect the growth of normal human fibroblasts and therefore has a wide therapeutic window.