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Background: During the ongoing outbreak of clade II monkeypox virus (MPXV), many U.S. patients were prescribed tecovirimat, an antiviral drug that was made available under an expanded access Investigational New Drug (EA-IND) program. We evaluated EA-IND data to summarize characteristics of treated patients, outcomes, and serious adverse events (SAEs)., Methods: We evaluated data from patients prescribed tecovirimat from May 29, 2022, through July 10, 2023. Baseline patient characteristics, clinical courses, and outcomes were evaluated via intake forms, outcome forms, and patient diaries. Data were summarized in aggregate by human immunodeficiency virus (HIV) status and by comorbidities of special interest. Reported SAEs were also compiled., Results: Tecovirimat was prescribed for over 7100 patients in the United States, most often for lesions in sensitive anatomical areas, such as certain anogenital lesions (83.5%; 5135 out of 6148 patients), and pain (52.5%; 3227 out of 6148 patients). The demographic and clinical characteristics mirrored those of patients worldwide. Among the 7181 patients with returned intake forms, 1626 also had returned outcome forms (22.6%). Many patients with severe immunocompromise (e.g., HIV with CD4 counts <200 cells/μl) received multiple courses of tecovirimat (43.1%; 22 out of 51 patients), including intravenously, and often experienced poor outcomes (35.3%; 18 out of 51 patients). Overall, 223 SAEs and 40 deaths were reported. Most SAEs were among patients who were severely immunocompromised, one of whom experienced hallucinations after tecovirimat was administered at twice the standard dose., Conclusions: Tecovirimat was used extensively. The returned EA-IND data suggest that life-threatening or protracted infections occurred in persons who were severely immunocompromised. SAEs were not commonly reported. The EA-IND data are not definitive; controlled clinical trial data are essential to elucidating if and how tecovirimat should be used.

Monkeypox (Mpox) is a virus that originally infected only animals. Caused by the monkeypox virus, this infection presents with symptoms similar to smallpox. Although two years have passed since the 2022 outbreak, new cases continue to emerge monthly. Initially, human cases of mpox were confined to outbreaks in central and western Africa. However, the virus has recently spread globally, possibly due to a decline in vaccination rates. In this context, evidence for effective therapies, such as antivirals, is urgently needed. Three antivirals-tecovirimat, brincidofovir, and cidofovir-are known to have activity against the mpox virus. Their use is currently limited to expanded access for treating non-variola orthopoxvirus infections, with ongoing phase 3 trials. This review will discuss the mechanisms of action, clinical use, and efficacy of these antivirals.

Burning mouth syndrome (BMS) is characterized by burning sensations in the oral region without corresponding abnormalities and is often accompanied by uncomfortable sensations. Herein, we present cases of BMS in which the remaining uncomfortable sensations improved with perospirone augmentation with clonazepam. Case 1: A 61-year-old man complained of a burning pain in his tongue, a sensation of dryness and discomfort as if his tongue was sticking to a palatal plate. With the diagnosis of BMS, psychopharmacotherapy was initiated with amitriptyline. At the dose of amitriptyline 50 mg, the pain lessened but uncomfortable sensations persisted. Further attempts to alleviate symptoms by combining aripiprazole with amitriptyline, aripiprazole with mirtazapine, or aripiprazole with clonazepam were limited; however, nearly all symptoms were relieved by a combination of perospirone 8.0 mg with clonazepam 1.5 mg. Case 2: A 51-year-old woman complained of a burning sensation along with oral dryness and crumb-like feeling on her tongue. She was diagnosed with BMS and began treatment with amitriptyline. Her burning sensation improved at the dose of 25 mg, but uncomfortable sensations persisted. Augmentation of amitriptyline with aripiprazole, aripiprazole either with valproate, mirtazapine, or clonazepam failed to produce a significant improvement. However, a regimen of perospirone 6.0 mg and clonazepam 1.5 mg relieved the crumb-like sensation and pain and culminated in a stabilized condition. The reported cases suggested that multiple approaches targeting the dopaminergic circuit in basal ganglia involving the serotoninergic and GABA systems, through the administration of perospirone with clonazepam is an effective adjunctive treatment for the remaining uncomfortable sensations in patients with BMS., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Monkeypox is a viral zoonotic disease commonly reported in humans in parts of Central and West Africa. This protocol is for an Expanded Access Programme (EAP) to be implemented in the Central African Republic, where Clade I monkeypox virus diseases is primarily responsible for most monkeypox infections. The objective of the programme is to provide patients with confirmed monkeypox with access to tecovirimat, a novel antiviral targeting orthopoxviruses, and collect data on clinical and virological outcomes of patients to inform future research., Methods: The study will be conducted at participating hospitals in the Central African Republic. All patients who provide informed consent to enrol in the programme will receive tecovirimat. Patients will remain in hospital for the duration of treatment. Data on clinical signs and symptoms will be collected every day while the patient is hospitalised. Blood, throat and lesion samples will be collected at baseline and then on days 4, 8, 14 and 28. Patient outcomes will be assessed on Day 14 -end of treatment-and at Day 28. Adverse event and serious adverse event data will be collected from the point of consent until Day 28., Discussion: This EAP is the first protocolised treatment programme in Clade I MPXV. The data generated under this protocol aims to describe the use of tecovirimat for Clade I disease in a monkeypox endemic region of Central Africa. It is hoped that this data can inform the definition of outcome measures used in future research and contribute to the academic literature around the use of tecovirimat for the treatment of monkeypox. The EAP also aims to bolster research capacity in the region in order for robust randomised controlled trials to take place for monkeypox and other diseases., Trial Registration: {2a & 2b}: ISRCTN43307947., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bourner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: The virus known as monkeypox is the source of the zoonotic disease monkeypox, which was historically widespread in Central Africa and West Africa. The cases of monkeypox in humans are uncommon outside of West and Central Africa, but copious nonendemic nations outside of Africa have recently confirmed cases. People when interact with diseased animals, then, they may inadvertently contact monkeypox. There are two drugs in the market: brincidofovir and tecovirimat and both of these drugs are permitted for the cure of monkeypox by the US Food and Drug Administration. The present review summarizes the various parameters of monkeypox in context with transmission, signs and symptoms, histopathological and etiological changes, and possible treatment. Monkeypox is clinically similar to that of smallpox infection but epidemiologically, these two are different, the present study also signifies the main differences and similarities of monkeypox to that of other infectious diseases. As it is an emerging disease, it is important to know about the various factors related to monkeypox so as to control it on a very early stage of transmission., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)

The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development., (© 2023 by The American Society of Hematology.)

Objectives: Human monkeypox virus (MPXV) infection is a recently declared public health emergency of international concern by the World Health Organization. Besides, there is scant literature available on the use of antivirals in MPXV infection. This systematic review compiles all evidence of various antivirals used on their efficacy and safety and summarizes their mechanisms of action., Methods: A review was done of all original studies mentioning individual patient data on the use of antivirals in patients with MPXV infection., Results: Of the total 487 non-duplicate studies, 18 studies with 71 individuals were included. Tecovirimat was used in 61 individuals, followed by cidofovir in seven and brincidofovir (BCV) in three individuals. Topical trifluridine was used in four ophthalmic cases in addition to tecovirimat. Of the total, 59 (83.1%) were reported to have complete resolution of symptoms; one was experiencing waxing and waning of symptoms, only one (1.8%) had died, and the others were having a resolution of symptoms. The death was thought unrelated to tecovirimat. Elevated hepatic panels were reported among all individuals treated with BCV (leading to treatment discontinuation) and five treated with tecovirimat., Conclusion: Tecovirimat is the most used and has proven beneficial in several aggravating cases. No major safety concerns were detected upon its use. Topical trifluridine was used as an adjuvant treatment option along with tecovirimat. BCV and cidofovir were seldom used, with the latter often being used due to the unavailability of tecovirimat. BCV was associated with treatment discontinuation due to adverse events., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

As of September 11, 2022, 57 669 reports of monkeypox infection raised global concern. Previous vaccinia virus vaccination can protect from monkeypox. However, after smallpox eradication, immunization against that was stopped. Indeed, therapeutic options following the disease onset are of great value. This study aimed to review the available evidence on virology and treatment approaches for monkeypox and provide guidance for patient care and future studies. Since no randomized clinical trials were ever performed, we reviewed monkeypox animal model studies and clinical trials on the safety and pharmacokinetics of available medications. Brincidofovir and tecovirimat were the most studied medications that got approval for smallpox treatment according to the Animal Rule. Due to the conserved virology among Orthopoxviruses, available medications might also be effective against monkeypox. However, tecovirimat has the strongest evidence to be effective and safe for monkeypox treatment, and if there is a choice between the two drugs, tecovirimat has shown more promise so far. The risk of resistance should be considered in patients who failed to respond to tecovirimat. Hence, the target-based design of novel antivirals will enhance the availability and spectrum of effective anti-Orthopoxvirus agents., (© 2022 Wiley Periodicals LLC.)

Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against the family of orthopoxviruses, including vaccinia and the human monkeypox virus (HMPXV). Efficacy studies have thus far been limited to animal models, with human safety trials showing no serious adverse events. Currently approved by the FDA only for the treatment of smallpox, tecovirimat shows promise for the treatment of HMPXV. Tecovirimat has been prescribed via an expanded access for an investigational new drug protocol during the 2022 outbreak. This review will examine the literature surrounding tecovirimat's mechanism of action, pharmacokinetics, safety, efficacy, and potential for resistance.

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. We isolated and sequenced a virus from the first clinical MPXV case diagnosed in France (May 2022). We report that tecovirimat (ST-246), a US Food and Drug Administration approved drug, is efficacious against this isolate in vitro at nanomolar concentrations, whereas cidofovir is only effective at micromolar concentrations. Our results support the use of tecovirimat in ongoing human clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The recent emergence of the monkeypox virus (MPXV) in non-endemic countries has been designated a Public Health Emergency of International Concern by the World Health Organization. There are currently no approved treatments for MPXV infection in the United States or Canada. The antiviral drug tecovirimat (commonly called TPOXX), previously approved for smallpox treatment, is currently being deployed for treatment of MPXV infections where available based on previously accrued data. We tested the efficacy of TPOXX both in vitro and in vivo against a clade 2 Canadian 2022 isolate of MPXV isolated during the current outbreak. TPOXX prevented MPXV replication in vitro with an effective concentration in the nanomolar range. To evaluate TPOXX efficacy in vivo, we first characterized the CAST/EiJ mouse model with the same 2022 Canadian isolate. Unlike previous descriptions of this model, the Canadian isolate was not lethal in CAST/EiJ mice, although it replicated efficiently in the respiratory tract after intranasal infection. Subsequent experiments demonstrated that daily oral TPOXX treatment markedly reduced viral titers in the tissues 1 and 2 weeks after infection. Our data indicate that TPOXX is highly effective against currently circulating MPXV strains and could be an important contributor to curbing the ongoing outbreak.

Although photodynamic therapy (PDT) has attracted great interest, the photosensitizers in clinical had weak inhibition on metastasis and invasion of cancers. Additionally the immune response induced by PDT was insufficient to eradicate cancer. Herein, indoximod, an inhibitor of indoleamine 2,3-dioxygenase (IDO), is introduced to concatenate with zinc phthalocyanines (ZnPc) for effectively overcoming above inadequacy. Due to indoximod moiety, photosensitizer 1-MT-Pc can obtain enhanced intracellular uptake and high reactive oxygen species (ROS) generation. More impressively, 1-MT-Pc can achieve remarkable photocytotoxicity towards TNBC cells and negligible damage to normal cells. Meanwhile, 1-MT-Pc effectively inhibits metastasis and invasion of TNBC cells. Importantly, 1-MT-Pc exhibit elevated inhibitory effect on 4T1 tumor by enhanced PDT and immunotherapy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Poor tumor selectivity, low stability and quenched fluorescence are the main challenges to be overcome for nanomedicine, and are mainly caused by the dissociation of the nanostructure and aggregation of chromophores in the biological environment. Herein, covalently connected nanoparticles RGD-graphene-phthalocyanine (RGD-GO-SiPc) were constructed based on RGD peptide, silicon phthalocyanine (SiPc) and graphene oxide (GO) via a conjugation reaction for fluorescence imaging-guided cancer-targeted combinatorial phototherapy. The prepared RGD-GO-SiPc exhibited supreme biological stability, high-contrast fluorescence imaging, significantly enhanced NIR absorption, high photothermal conversion efficiency (25.6%), greatly improved cancer-targeting capability, and synergistic photodynamic (PDT) and photothermal therapy (PTT) efficacy along with low toxicity. Both in vitro and in vivo biological studies showed that RGD-GO-SiPc is a kind of promising multifunctional nanomedicine for fluorescence imaging-guided combined photothermal and photodynamic therapy with dual active/passive tumor-targeting properties.

Polycyclodextrin (denoted PCD) composed of cyclodextrin monomer units and 1,3-diethoxypropan-2-ol containing many hydroxyl groups with lone pairs of electrons, easily coordinated with transition metals with empty orbitals. The CD unit can also provide host-guest binding sites for functional molecules. This article utilizes this feature of PCD for the first time as a "linker" to combine transition metal nanomaterials with synergistic functional molecules. We synthesized PCD with 50% CD monomer by epichlorohydrin cross-linking method. Utilizing the coordination effect of the hydroxyl group in PCD and the iron ion in photothermal nanoparticles (PB-Yb), the PCD is coated on its surface; simultaneously, CD in PCD can form a host-guest complex with adamantane-modified zinc phthalocyanine (Pc) photosensitizer. Using PCD as a "linker", PB-Yb and Pc (denoted PYPP) were combined to improve the solubility of PB-Yb, reduce the aggregation degree of Pc to increase their activity, and achieve photothermal and photodynamic synergistic tumor therapy., (Copyright © 2021. Published by Elsevier Ltd.)

The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 μM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC 50 of 0.07-0.38 μM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC 50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 μM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection., (Copyright © 2021. Published by Elsevier Inc.)

The risk of contamination and dissemination by SARS-CoV-2 has a strong link with nasal, oral and pharyngeal cavities. Recently, our research group observed the promising performance of an anionic phthalocyanine derivative (APD) used in a mouthwash protocol without photoexcitation; this protocol improved the general clinical condition of patients infected with SARS-CoV-2. The present two-arm study evaluated in vitro the antiviral activity and cytotoxicity of APD. Additionally, a triple-blind randomized controlled trial was conducted with 41 hospitalized patients who tested positive for COVID-19. All the included patients received World Health Organization standard care hospital treatment (non-intensive care) plus active mouthwash (experimental group AM/n = 20) or nonactive mouthwash (control group NAM/n = 21). The adjunct mouthwash intervention protocol used in both groups consisted one-minute gargling/rinsing / 5 times/day until hospital discharge. Groups were compared considering age, number of comorbidities, duration of symptoms prior admission and length of hospital stay (LOS). The associations between group and sex, age range, presence of comorbidities, admission to Intensive care unit (ICU) and death were also evaluated. The in vitro evaluation demonstrated that APD compound was highly effective for reduction of SARS-CoV-2 viral load in the 1.0 mg/mL (99.96%) to 0.125 mg/mL (92.65%) range without causing cytotoxicity. Regarding the clinical trial, the median LOS of the AM group was significantly shortened (4 days) compared with that of the NAM group (7 days) (p = 0.0314). Additionally, gargling/rinsing with APD was very helpful in reducing the severity of symptoms (no ICU care was needed) compared to not gargling/rinsing with APD (28.6% of the patients in the NAM group needed ICU care, and 50% of this ICU subgroup passed way, p = 0.0207). This study indicated that the mechanical action of the protocol involving mouthwash containing a compound with antiviral effects against SARS-CoV-2 may reduce the symptoms of the patients and the spread of infection. The use of APD in a mouthwash as an adjuvant the hospital COVID-19 treatment presented no contraindication and reduced the hospital stay period.Trial registration: The clinical study was registered at REBEC-Brazilian Clinical Trial Register (RBR-58ftdj)., (© 2021. The Author(s).)

Ischemic white matter damage (WMD) is increasingly being considered as one of the major causes of neurological disorders in older adults and preterm infants. The functional consequences of WMD triggers a progressive cognitive decline and dementia particularly in patients with ischemic cerebrovascular diseases. Despite the major stride made in the pathogenesis mechanisms of ischemic WMD in the last century, effective medications are still not available. So, there is an urgent need to explore a promising approach to slow the progression or modify its pathological course. In this review, we discussed the animal models, the pathological mechanisms and the potential therapeutic agents for ischemic WMD. The development in the studies of anti-oxidants, free radical scavengers, anti-inflammatory or anti-apoptotic agents and neurotrophic factors in ischemic WMD were summarized. The agents which either alleviate oligodendrocyte damage or promote its proliferation or differentiation may have potential value for the treatment of ischemic WMD. Moreover, drugs with multifaceted protective activities or a wide therapeutic window may be optimal for clinical translation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2 . Extensive structure-activity relationship (SAR) studies resulted in AZD0284 ( 20 ), which combined potent inhibition of IL-17A secretion from primary human T H 17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.

The inhibition mechanism of the main protease (M pro ) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of M pro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se-S covalent bond mediated by EBS and EBS-OH on M pro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of M pro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies.

Noise overexposure leads to hair cell loss, synaptic ribbon reduction, and auditory nerve deterioration, resulting in transient or permanent hearing loss depending on the exposure severity. Oxidative stress, inflammation, calcium overload, glutamate excitotoxicity, and energy metabolism disturbance are the main contributors to noise-induced hearing loss (NIHL) up to now. Gene variations are also identified as NIHL related. Glucocorticoid is the only approved medication for NIHL treatment. New pharmaceuticals targeting oxidative stress, inflammation, or noise-induced neuropathy are emerging, highlighted by the nanoparticle-based drug delivery system. Given the complexity of the pathogenesis behind NIHL, deeper and more comprehensive studies still need to be fulfilled., Competing Interests: The authors claim that there are no conflicts of interest., (Copyright © 2021 Huanyu Mao and Yan Chen.)

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982)., (© 2021 by The American Society of Hematology.)

Importance: There is an unmet need for psychometrically sound instruments to measure pruritus associated with prurigo nodularis (PN)., Objective: To evaluate the psychometric properties of the itch numeric rating scale (itch NRS), both the Worst Itch Numeric Rating Scale (WI-NRS) and the Average Itch Numeric Rating Scale (AI-NRS)., Design, Setting, and Participants: This secondary analysis is based on a secondary end point of a phase 2 randomized clinical trial of serlopitant for treatment of pruritus associated with PN. This randomized, double-blind, placebo-controlled study was conducted at 15 sites in Germany. Eligible patients were aged 18 to 80 years and had generalized PN for more than 6 weeks that was refractory to previous antipruritic therapies. Patients were required to have a visual analog scale itch score of 7 or higher at screening. Data were collected from July 2014 to June 2016 and analyzed from June 2016 to January 2017., Main Outcomes and Measures: The itch NRS (AI-NRS and WI-NRS) was correlated together with the following measures: the electronic verbal rating scale (eVRS) for itch self-categorization, average itch visual analog scale (AI-VAS), worst itch visual analog scale (WI-VAS), the pruritus-specific quality-of-life rating instrument ItchyQoL, Dermatology Life Quality Index (DLQI), and Prurigo Activity and Severity Score (items 7b and 7a: percentage healed prurigo lesions and percentage of prurigo lesions with excoriations)., Results: There were 123 participants in this study; the mean (SD) age of participants was 57.3 (11.58) years, and 58 (47.2%) were male. Strong associations (r ≥ 0.5) were observed between itch NRS items (WI-NRS and AI-NRS) and AI-VAS (24 hours) at weeks 2, 4, and 8 (r = 0.72-0.90; P < .001). Similar strong associations were also observed between itch NRS items and WI-VAS (24 hours) and eVRS for itch severity across weeks 2, 4, and 8 (r = 0.65-0.92; all P < .001). Strong correlations were seen between change scores for WI-NRS and WI-VAS and AI-VAS (r = 0.76 and 0.70, respectively; both P < .001). Similar findings were seen for AI-NRS, where correlations between change scores for WI-VAS and AI-VAS were 0.71 and 0.72, respectively (both P < .001). Analyses for the itch NRS items also showed that test-retest reliability was acceptable and provided evidence of acceptable convergent validity based on the eVRS and visit verbal rating score for itch self-categorization, ItchyQoL, and DLQI., Conclusions and Relevance: Results from this secondary analysis show that the itch NRS items WI-NRS and AI-NRS have good psychometric properties for pruritus associated with PN and should be considered acceptable tools for assessing pruritus in future clinical trials of PN., Trial Registration: ClinicalTrials.gov Identifier: NCT02196324.

This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition., (© 2020 Wiley Periodicals LLC.)

Introduction: As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients., Methods: This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100 mg/100 mg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated., Results: The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital., Conclusion: Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.

In late December 2019, coronavirus disease 2019 (COVID-19) first broke out in Wuhan, China, and has now become a global pandemic. However, there is no specific antiviral treatment for COVID-19. This study enrolled 33 COVID-19 patients in the nineth hospital of Nanchang from 27th January to 24th February 2020. Clinical indexes of patients upon admission/discharge were examined. Patients were divided into two groups according to different treatment plans (danoprevir and lopinavir/ritonavir). The days to achieve negative nucleic acid testing and the days of hospital stays were counted and statistically analyzed. COVID-19 patients treated with danoprevir or lopinavir/ritonavir were all improved and discharged. Indexes like blood routine, inflammation and immune-related indexes were significantly recovered after treatment. Additionally, under the circumstance that there was no significant difference in patients' general information between the two groups, we found that the mean time to achieve both negative nucleic acid testing and hospital stays of patients treated with danoprevir were significantly shorter than those of patients with lopinavir/ritonavir. Collectively, applying danoprevir is a good treatment plan for COVID-19 patients., (© 2020 Wiley Periodicals LLC.)

Background: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone., Methods: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated., Results: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint., Conclusions: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia., Competing Interests: Declaration of Competing Interest Dr. Miller received travel expenses to present the work under consideration at the 2017 American College of Neuropsychopharmacology annual meeting. In the past 12 months, Dr. Miller received research support from the Augusta University; the Stanley Medical Research Institute; NARSAD; and the National Institute of Mental Health; and Honoraria from Psychiatric Times. Dr. Siu reports consulting fees from the Chinese University of Hong Kong, and Sunovion. In the last 3 years, Dr. Harvey has received consulting fees or travel reimbursements from Teva, Takeda Pharma, Sunovion Pharma, Sanofi Pharma, Otsuka America (Otsuka Digital Health), Minerva Pharma, Lundbeck Pharma, Jazz Pharma, Intra-Cellular Therapies, Genentech (Roche Pharma), Forum Pharma, Boehringer Ingelheim. Biogen, Allergan, Akili, and Alkermes. He receives royalties from the MATRICS Consensus Battery and the Brief Assessment of Cognition in Schizophrenia. He is the chief scientific officer of i-Function, Inc. He has research grants from the Stanley Medical Research Foundation and Takeda. In the last 3 years Dr. Newcomer has received grant support from Otsuka America Pharmaceutical Co. Ltd., the Substance Abuse and Mental Health Services Administration, and the National Institutes of Health; served as a consultant to Alkermes, Auris, Indivior, Otsuka, and Sunovion; serves on a Data Safety Monitoring Board for Amgen; and has been involved in patent litigation on behalf of Sunovion. and. Drs. Loebel, Pikalov, Tsai, and Tocco are employees of Sunovion Pharmaceuticals Inc., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch., Objective: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639)., Methods: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening., Results: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients., Limitations: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded., Conclusion: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population., (Copyright © 2020. Published by Elsevier Inc.)

Clostridium difficile infection (CDI) is an enteric bacterial disease that is increasing in prevalence worldwide. C. difficile capitalizes on gut inflammation and microbiome dysbiosis to establish infection, with symptoms ranging from watery diarrhea to toxic megacolon. We reported that the safe-in-human clinical drug ebselen (ClinicalTrials.gov: NCT03013400, NCT01452607, NCT00762671, and NCT02603081) has biochemical, cell-based, and in vivo efficacy against the toxins of C. difficile . Here, we show that ebselen treatment reduces recurrence rates and decreases colitis in a hamster model of relapsing CDI. Furthermore, ebselen treatment does not alter microbiome diversity and promotes recovery back to that of healthy controls after antibiotic-induced dysbiosis in healthy and C. difficile -infected mice. This increased microbiome recovery upon ebselen treatment correlates with a decrease in host-derived inflammatory markers, suggesting that the anti-inflammatory properties of ebselen, combined with its anti-toxin function, help to mitigate the major clinical challenges of CDI, including recurrence, microbial dysbiosis, and colitis., Competing Interests: DECLARATION OF INTERESTS M.B. is a co-founder, chair of the Scientific Advisory Board and shareholder of Facile Therapeutics, which is a company working to develop ebselen for treatment of CDI. The authors declare a patent application WO2015/200358Al that covers the use of ebselen for treatment of C. difficile infections.

Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of ~15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (~160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4 + IFNγ + T and CD8 + IFNγ + T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANC02) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers. STATEMENT OF SIGNIFICANCE: In order to effectively accumulate and penetrate the PDA that is poorly vascularized and enriched with dense fibrotic stroma, the size of nanomedicine has to be well controlled. Here, we reported an immunochemotherapy regimen based on co-delivery of GEM, PTX and IDO1 inhibitor NLG919 through an ultra-small sized GEM-based nanocarrier (PGEM). We demonstrated that the PGEM carrier was effective in accumulating and penetrating into PDA tumors. Besides, PGEM co-loaded with PTX and NLG9 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth as well as in prolonging the survival rate in PANC02 xenograft model. Our work represents a potential strategy for enhancing PDA tumor penetration and immunochemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC 50  = 4.3 nM) and HSP90a inhibition (IC 50  = 46.8 nM) along with substantial cell growth inhibitory effects with GI 50  = 0.76 μM (lung A549) and GI 50  = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI 50  = 0.37 μM) and lung H1975 cell lines (GI 50  = 0.13 μM) mediated through selective HDAC6 inhibition (IC 50  = 33.3 nM) and HSP90 inhibition (IC 50  = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Masson SAS.)

Purpose: In this review, we summarize the importance of AR variants with a particular focus on clinically relevant members of this family., Methods: A non-systematic literature review was performed based on Medline and PubMed., Results: Endocrine therapy represents the central paradigm for the management of prostate cancer. Eventually, in response to androgen ablation therapy, several resistance mechanisms against the endocrine therapy might develop that can circumvent the therapy approaches. One specific resistance mechanism that has gained increasing attention is the generation of alternatively spliced variants of the androgen receptor, with AR-V7 being the most prominent. More broadly, AR-V7 is one member of a group of alternatively spliced AR variants that share a common feature, the missing ligand-binding domain. These ΔLBD androgen receptor variants have shown the capability to induce androgen receptor-mediated gene transcription even under conditions of androgen deprivation and to drive cancer progression., Conclusion: The methods used for detecting AR-Vs, at least on the mRNA level, are well-advanced and harbor the potential to be introduced into clinical diagnostics. It is important to note, that the testing, especially of AR-V7 has its limitations in predicting treatment response. More promising is the great number of active clinical trials aimed at reducing the AR-Vs, and using this to re-sensitize CRPC towards endocrine treatment might provide additional treatment options for CRPC patients in the future.

Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0-6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia., Objective: We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes., Methods: We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system., Results: The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase., Conclusion: Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac 2 O or Ac 2 O/AcCl in the presence of a catalytic amount of H 2 SO 4 in order to yield new isoindole derivatives 8a-d and 9a-d. The anticancer activity of these compounds was evaluated against the HeLa cell lines. The synthesized compounds showed inhibitory effects on the viability of HeLa cells and the degree of cytotoxicity was increased with the level of bigger branched isoindole derivatives. To better understand the acting mechanism of these molecules, western blot analysis was performed with using mTOR and its downstream substrates. In addition, human mTOR and ribozomal S6 kinase β1 (RS6Kβ1) have been investigated with molecular modelling studies as possible targets for compound series 8 and 9., (Copyright © 2019 Elsevier Inc. All rights reserved.)

177Lu‑DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)‑positive neuroendocrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90‑inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with 177Lu‑DOTATATE. The NET cell lines BON, NCI‑H727 and NCI‑H460, were first characterized with regards to 177Lu‑DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three‑dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. 177Lu‑DOTATATE uptake was observed in the BON and NCI‑H727 cells, while the NCI‑H460 cells exhibited no detectable uptake. Accordingly, 177Lu‑DOTATATE reduced the growth of BON and NCI‑H727 spheroids, while no effect was observed in the NCI‑H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and 177Lu‑DOTATATE exerted synergistic therapeutic effects on the BON and NCI‑H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of γ H2A histone family member X (γH2AX) following combined treatment with onalespib and 177Lu‑DOTATATE. Moreover, flow cytometric analyses revealed a two‑fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate 177Lu‑DOTATATE treatment in a SSTR‑specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and 177Lu‑DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

NLG919 is an effective small molecule inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO-1) in anti-tumour immunotherapy, but the poor aqueous solubility limits its application for effective intravenous dosing. In this study a cyclodextrin (CD) complexation strategy has been systematically evaluated to achieve a simple and feasible method to prepare an NLG919 injectable formulation. From a series of CDs, HP-β-CD proved to be the most conducive for NLG919 solubilization (approx 800-fold increase). Characterization studies using DSC, 1 H NMR, XRPD and molecular simulation demonstrated that the NLG919/HP-β-CD loading mechanism involved an increasing pH-dependent binding affinity. Importantly cell-based studies in vitro and anti-tumour activity in vivo demonstrated that the pharmacological activity of NLG919 as an IDO-1 inhibitor was not influenced by HP-β-CD complexation. Furthermore, the combination of NLG919/HP-β-CD with paclitaxel (PTX) significantly improved anti-tumour chemotherapy compared to PTX alone. In summary, NLG919/HP-β-CD is shown to highly enhance the aqueous solubility of NLG919 with activity unaffected, greatly facilitating the intravenous use of this small molecule immunotherapeutic to improve the efficacy of PTX., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The classification of smallpox by the U.S. Centers for Disease Control and Prevention (CDC) as a Category A Bioterrorism threat agent has resulted in the U.S. Government investing significant funds to develop and stockpile a suite of medical countermeasures to ameliorate the consequences of a smallpox epidemic. This stockpile includes both vaccines for prophylaxis and antivirals to treat symptomatic patients. In this manuscript, we describe the path to approval for the first therapeutic against smallpox, identified during its development as ST-246, now known as tecovirimat and TPOXX ® , a small-molecule antiviral compound sponsored by SIGA Technologies to treat symptomatic smallpox. Because the disease is no longer endemic, the development and approval of TPOXX ® was only possible under the U.S. Food and Drug and Administration Animal Rule (FDA 2002). In this article, we describe the combination of animal model studies and clinical trials that were used to satisfy the FDA requirements for the approval of TPOXX ® under the Animal Rule., (Published by Elsevier B.V.)

Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8 + T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Vascular depression can respond poorly to antidepressants. This study aimed to explore the efficacy and safety of tandospirone plus escitalopram for treating vascular depression with anxiety. This pilot randomized controlled trial included consecutive inpatients/outpatients with vascular depression/anxiety at the Department of Neurology, Fujian Medical University Union Hospital, China (January 2014 to December 2016). Among 157 patients screened, 100 were randomly divided into the tandospirone + escitalopram (combination therapy) and escitalopram (monotherapy) groups equally, and then followed for 8 weeks. Efficacy was evaluated using the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA), Clinical Global Impression (CGI) and Mini-Mental State examination (MMSE) scales. Adverse events (AEs) were assessed with the Treatment Emergent Symptom Scale (TESS). HAMD and HAMA scores decreased progressively, showing reductions versus baseline at 1, 2, 4 and 8 weeks in both groups (P < 0.001). HAMD and HAMA scores were lower in the tandospirone + escitalopram group than those in the escitalopram group at 1 and 2 weeks (P < 0.001), but not at 4 and 8 weeks. Improvements in CGI scores (severity, improvement and efficacy indexes) were greater in the tandospirone + escitalopram group than that in the escitalopram group at 1 and 2 weeks (P < 0.01), but not at 4 and 8 weeks. The tandospirone + escitalopram group had higher MMSE scores than that in the escitalopram group at 4 and 8 weeks (P < 0.01). All AEs were mild, and the rates were comparable between groups. Augmentation of escitalopram with tandospirone accelerates the onset of anti-depressive and anxiolytic effects and improves cognitive function in patients with vascular depression and anxiety., (Copyright © 2019. Published by Elsevier Ltd.)