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1.
J Med Entomol ; 59(1): 301-307, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1784366

ABSTRACT

The efficacy of three groups of insect growth regulators, namely juvenile hormone mimics (methoprene and pyriproxyfen), chitin synthesis inhibitors (diflubenzuron and novaluron), and molting disruptor (cyromazine) was evaluated for the first time, against Aedes albopictus Skuse (Diptera: Culicidae) larvae from 14 districts in Sabah, Malaysia. The results showed that all field populations of Ae. albopictus were susceptible towards methoprene, pyriproxyfen, diflubenzuron, novaluron, and cyromazine, with resistance ratio values ranging from 0.50-0.90, 0.60-1.00, 0.67-1.17, 0.71-1.29, and 0.74-1.07, respectively. Overall, the efficacy assessment of insect growth regulators in this study showed promising outcomes and they could be further explored as an alternative to conventional insecticides.


Subject(s)
Aedes , Juvenile Hormones/pharmacology , Mosquito Control/methods , Aedes/drug effects , Aedes/growth & development , Animals , Diflubenzuron/pharmacology , Insect Vectors/drug effects , Insect Vectors/growth & development , Insecticides/pharmacology , Larva/drug effects , Larva/growth & development , Malaysia , Methoprene/pharmacology , Phenylurea Compounds/pharmacology , Pyridines/pharmacology
2.
Lancet Psychiatry ; 9(3): 199-210, 2022 03.
Article in English | MEDLINE | ID: covidwho-1747370

ABSTRACT

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.


Subject(s)
Antidiuretic Hormone Receptor Antagonists/administration & dosage , Autism Spectrum Disorder/drug therapy , Benzodiazepines/administration & dosage , Communication Disorders/drug therapy , Pyridines/administration & dosage , Triazoles/administration & dosage , Adult , Antidiuretic Hormone Receptor Antagonists/adverse effects , Autism Spectrum Disorder/complications , Benzodiazepines/adverse effects , Communication Disorders/etiology , Double-Blind Method , Female , Humans , Male , Pyridines/adverse effects , Treatment Outcome , Triazoles/adverse effects
3.
Expert Opin Pharmacother ; 23(5): 543-549, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1662063

ABSTRACT

INTRODUCTION: Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug-drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. AREAS COVERED: The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. EXPERT OPINION: Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.


Subject(s)
Aspergillosis , COVID-19 , Antifungal Agents/adverse effects , Aspergillosis/chemically induced , Aspergillosis/drug therapy , COVID-19/drug therapy , Delayed Diagnosis , Humans , Nitriles/adverse effects , Pyridines , Triazoles/adverse effects
4.
J Proteomics ; 255: 104501, 2022 03 20.
Article in English | MEDLINE | ID: covidwho-1654819

ABSTRACT

Phosphorylation of viral proteins serves as a regulatory mechanism during the intracellular life cycle of infected viruses. There is therefore a pressing need to develop a method to efficiently purify and enrich phosphopeptides derived from viral particles in biological samples. In this study, we utilized Phos-tag technology to analyze the functional phosphorylation of the nucleocapsid protein (N protein; NP) of severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Viral particles were collected from culture supernatants of SARS-CoV-2-infected VeroE6/TMPRSS2 cells by ultracentrifugation, and phosphopeptides were purified by Phos-tag magnetic beads for LC-MS/MS analysis. Analysis revealed that NP was reproducibly phosphorylated at serine 79 (Ser79). Multiple sequence alignment and phylogenetic analysis showed that the Ser79 was a distinct phospho-acceptor site in SARS-CoV-2 but not in other beta-coronaviruses. We also found that the prolyl-isomerase Pin1 bound to the phosphorylated Ser79 in NP and positively regulated the production of viral particles. These results suggest that SARS-CoV-2 may have acquired the potent virus-host interaction during its evolution mediated by viral protein phosphorylation. Moreover, Phos-tag technology can provide a useful means for analyzing the functional phosphorylation of viral proteins. SIGNIFICANCE: In this study, we aimed to investigate the functional phosphorylation of SARS-CoV-2 NP. For this purpose, we used Phos-tag technology to purify and enrich virus-derived phosphopeptides with high selectivity and reproducibility. This method can be particularly useful in analyzing viral phosphopeptides from cell culture supernatants that often contain high concentrations of fetal bovine serum and supplements. We newly identified an NP phosphorylation site at Ser79, which is important for Pin1 binding. Furthermore, we showed that the interaction between Pin1 and phosphorylated NP could enhance viral replication in a cell culture model.


Subject(s)
Nucleocapsid Proteins , Phosphopeptides , Chromatography, Liquid , Coronavirus Nucleocapsid Proteins , Humans , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , Nucleocapsid Proteins/chemistry , Phosphopeptides/chemistry , Phosphoproteins , Phosphorylation , Phylogeny , Pyridines , Reproducibility of Results , SARS-CoV-2 , Tandem Mass Spectrometry
5.
Eur Rev Med Pharmacol Sci ; 26(1): 54-58, 2022 01.
Article in English | MEDLINE | ID: covidwho-1636663

ABSTRACT

OBJECTIVE: Direct-acting oral anticoagulants (DOACs) have established indications, according to recent guidelines for the treatment and prevention of venous thromboembolism (VTE), including pulmonary embolism (PE), with a safer profile compared to vitamin K antagonist (VKA) in terms of a lower risk for major bleeding and no need of blood coagulation tests. However, DOACs are not indicated in the treatment of patients with triple-positive antiphospholipid syndrome (APS). This limitation is often extended in clinical practice to patients with isolated positivity. The COVID-19 pandemic has sometimes made it difficult to maintain a safe VKA treatment, due to the practical difficulties of performing INR. PATIENTS AND METHODS: We evaluated 39 patients with a previous unprovoked VTE/PE, who were no longer eligible for VKA treatment due to the difficulty of performing INR during the COVID-19 pandemic lockdown, in Italy. All patients had a positive LAC and refused a long-term anticoagulation with low molecular weight heparin. They were shifted to edoxaban. RESULTS: Any recurrence of VTE/PE occurred during the observation period (up to eight months of treatment), while only one minor bleeding event was recorded (Hazard ratio=0.06, 95% confidence interval 0.03-0.11, p=0.094). No arterial events occurred during the observation period. Hemoglobin, platelets, and creatinine were unchanged during the observation period. CONCLUSIONS: Edoxaban treatment may be safe and effective in preventing the recurrence of VTE/PE in patients with isolated LAC positivity, without the occurrence of arterial events.


Subject(s)
COVID-19/epidemiology , Factor Xa Inhibitors/therapeutic use , Lupus Coagulation Inhibitor/drug effects , Pandemics , Pulmonary Embolism/drug therapy , Pyridines/therapeutic use , Thiazoles/therapeutic use , Venous Thromboembolism/drug therapy , Adult , COVID-19/prevention & control , Factor Xa Inhibitors/adverse effects , Female , Humans , Italy , Male , Middle Aged , Pyridines/adverse effects , Quarantine , Thiazoles/adverse effects
7.
J Immunotoxicol ; 18(1): 23-29, 2021 12.
Article in English | MEDLINE | ID: covidwho-1593522

ABSTRACT

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.


Subject(s)
Benzylidene Compounds/pharmacology , COVID-19/drug therapy , Cholinergic Agents/pharmacology , Inflammation/drug therapy , Nicotine/metabolism , Pyridines/pharmacology , SARS-CoV-2/physiology , Tobacco Use Disorder/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cigarette Smoking/adverse effects , Dexamethasone/therapeutic use , HMGB1 Protein/blood , Humans , Pandemics , alpha7 Nicotinic Acetylcholine Receptor/agonists
8.
Chest ; 161(1): e5-e11, 2022 01.
Article in English | MEDLINE | ID: covidwho-1595933

ABSTRACT

CASE PRESENTATION: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.


Subject(s)
Acute Kidney Injury/virology , Antifungal Agents/therapeutic use , COVID-19/complications , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Aged , Amphotericin B/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Atrial Fibrillation/complications , Bronchoscopy , Dexamethasone/therapeutic use , Diabetes Mellitus, Type 2/complications , Fatal Outcome , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Nitriles/therapeutic use , Obesity/complications , Oxygen Inhalation Therapy , Pyridines/therapeutic use , Respiration, Artificial , SARS-CoV-2 , Smoking/adverse effects , Tomography, X-Ray Computed , Triazoles/therapeutic use , Voriconazole/therapeutic use
9.
Trials ; 22(1): 831, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1529943

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Subject(s)
Anti-HIV Agents , Lamivudine , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Atazanavir Sulfate , Healthy Volunteers , Humans , Oligopeptides , Pyridines , Ritonavir , Tenofovir , Uganda
10.
Chem Commun (Camb) ; 57(83): 10911-10914, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1488037

ABSTRACT

We present Zn2+-dependent dimethyl-dipyridophenazine PNA conjugates as efficient RNA cleaving artificial enzymes. These PNAzymes display site-specific RNA cleavage with 10 minute half-lives and cleave clinically relevant RNA models.


Subject(s)
Peptide Nucleic Acids/chemistry , Phenazines/chemistry , Pyridines/chemistry , RNA/chemistry , Catalysis , Hydrogen-Ion Concentration , Hydrolysis , Ribonucleases/chemistry , Zinc/chemistry
11.
Med Sci Monit ; 26: e922281, 2020 Mar 31.
Article in English | MEDLINE | ID: covidwho-1453382

ABSTRACT

BACKGROUND Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. MATERIAL AND METHODS Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-alpha, IL-1ß, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. RESULTS Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. CONCLUSIONS IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Inflammation/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridines/pharmacology , Respiratory Distress Syndrome, Newborn/drug therapy , Animals , Animals, Newborn , Apoptosis/drug effects , Apoptosis/immunology , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Humans , Inflammation/diagnosis , Inflammation/immunology , Inflammation/pathology , Injections, Intraperitoneal , Lipopolysaccharides/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Phosphodiesterase 4 Inhibitors/therapeutic use , Pyridines/therapeutic use , Respiratory Distress Syndrome, Newborn/diagnosis , Respiratory Distress Syndrome, Newborn/immunology , Respiratory Distress Syndrome, Newborn/pathology , Signal Transduction/drug effects , Signal Transduction/immunology
12.
Molecules ; 26(19)2021 Sep 24.
Article in English | MEDLINE | ID: covidwho-1438673

ABSTRACT

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Esters/chemistry , Esters/pharmacology , Halogenation , Humans , Ibuprofen/analogs & derivatives , Ibuprofen/pharmacology , Indomethacin/analogs & derivatives , Indomethacin/pharmacology , Molecular Docking Simulation , Pyridines/chemistry , Pyridines/pharmacology , SARS-CoV-2/metabolism , Salicylic Acid/chemistry , Salicylic Acid/pharmacology , Vero Cells
13.
Int J Pharm ; 608: 121122, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1433361

ABSTRACT

Herein, we demonstrated the development and characterization of a dry powder inhaler (DPI) formulation of edoxaban (EDX); and investigated the in-vitro anticoagulation effect for the management of pulmonary or cerebral coagulopathy associated with COVID-19 infection. The formulations were prepared by mixing the inhalable micronized drug with a large carrier lactose and dispersibility enhancers, leucine, and magnesium stearate. The drug-excipient interaction was studied using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) methods. The drug and excipients showed no physical inter particulate interaction. The in-vitro drug aerosolization from the developed formulation was determined by a Twin Stage Impinger (TSI) at a flow rate of 60 ± 5 L /min. The amount of drug deposition was quantified by an established HPLC-UV method. The fine particle fraction (FPF) of EDX API from drug alone formulation was 7%, whereas the formulations with excipients increased dramatically to almost 7-folds up to 47%. The developed DPI formulation of EDX showed a promising in-vitro anticoagulation effect at a very low concentration. This novel DPI formulation of EDX could be a potential and effective inhalation therapy for managing pulmonary venous thromboembolism (VTE) associated with COVID-19 infection. Further studies are warranted to investigate the toxicity and clinical application of the inhaled EDX DPI formulation.


Subject(s)
Blood Coagulation Disorders/drug therapy , COVID-19 , Dry Powder Inhalers , Pyridines/administration & dosage , Thiazoles/administration & dosage , Administration, Inhalation , Aerosols , Blood Coagulation Disorders/virology , COVID-19/complications , Humans , Particle Size , Powders
14.
Endocr Pract ; 27(9): 956-965, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1414178

ABSTRACT

OBJECTIVE: Cushing disease (CD) is characterized by chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Surgery remains the first-line treatment option; however, medical therapy is essential if surgery is contraindicated or fails to achieve remission or when recurrence occurs after surgical remission. Osilodrostat (Isturisa), a novel steroidogenic inhibitor, is now approved for the treatment of CD in the United States and Cushing syndrome in Europe. Herein, we review pharmacology and data on the efficacy, safety, and clinical use of osilodrostat and provide guidance on its use in treating patients with CD. METHODS: We reviewed the literature and published clinical trial data of osilodrostat use in patients with Cushing syndrome. Detailed information related to the clinical assessment of osilodrostat use, potential drug-to-drug interactions, drug initiation, dose titration, and the monitoring of drug tolerability were discussed. RESULTS: Clinical trial data demonstrated that osilodrostat, by virtue of inhibiting 11-ß hydroxylase, potently and rapidly decreased the 24-hour urinary free cortisol levels and sustained these reductions, with improved glycemia, blood pressure, body weight, and quality of life as well as lessened depression. Osilodrostat may interact with certain drugs, resulting in QT prolongation, which requires careful assessment of concomitant medications and periodic monitoring using electrocardiogram, respectively. The common adverse effects include adrenal insufficiency, hypokalemia, edema, and hyperandrogenic symptoms, which can be minimized using a slower up-titration dosing regimen. CONCLUSION: Osilodrostat is an effective, new treatment option for CD, with positive effects on cardiovascular and quality of life parameters as well as tolerable adverse effects. This article provides a review of the pharmacology of osilodrostat and offers practical recommendations on the use of osilodrostat to treat CD.


Subject(s)
Pituitary ACTH Hypersecretion , Humans , Imidazoles , Pituitary ACTH Hypersecretion/drug therapy , Pyridines , Quality of Life
15.
J Med Chem ; 64(19): 14702-14714, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1412442

ABSTRACT

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an antiviral EC50 value of 2.8 µM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC50 value of 1.2 µM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Pyridines/chemistry , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero Cells
16.
J Thromb Thrombolysis ; 53(2): 273-281, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1401065

ABSTRACT

SARS-CoV-2 represents the causative agent of the current pandemic (COVID-19). The drug repurposing technique is used to search for possible drugs that can bind to SARS-CoV-2 proteins and inhibit viral replication. In this study, the FDA-approved antiplatelets are tested against the main protease and spike proteins of SARS-CoV-2 using in silico methods. Molecular docking and molecular dynamics simulation are used in the current study. The results suggest the effectiveness of vorapaxar, ticagrelor, cilostazol, cangrelor, and prasugrel in binding the main protease (Mpro) of SARS-CoV-2. At the same time, vorapaxar, ticagrelor, and cilostazol are the best binders of the spike protein. Therefore, these compounds could be successful candidates against COVID-19 that need to be tested experimentally.


Subject(s)
Antiviral Agents , Platelet Aggregation Inhibitors , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cilostazol , Coronavirus 3C Proteases/antagonists & inhibitors , Humans , Lactones , Molecular Docking Simulation , Molecular Dynamics Simulation , Platelet Aggregation Inhibitors/pharmacology , Pyridines , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Ticagrelor
17.
Eur Rev Med Pharmacol Sci ; 25(16): 5310-5317, 2021 08.
Article in English | MEDLINE | ID: covidwho-1395678

ABSTRACT

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.


Subject(s)
Antiemetics/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Palonosetron/therapeutic use , Pyridines/therapeutic use , Aged , Antiemetics/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , COVID-19 , Female , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Humans , Irinotecan/administration & dosage , Irinotecan/therapeutic use , Leucovorin/administration & dosage , Leucovorin/therapeutic use , Male , Middle Aged , Nausea/prevention & control , Oxaliplatin/administration & dosage , Oxaliplatin/therapeutic use , Palonosetron/administration & dosage , Pandemics , Prospective Studies , Pyridines/administration & dosage , Vomiting/prevention & control
18.
J Mol Model ; 27(10): 276, 2021 Sep 04.
Article in English | MEDLINE | ID: covidwho-1391881

ABSTRACT

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores - 9.2988, - 8.3629, and - 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π-π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.


Subject(s)
Molecular Dynamics Simulation , Piperidines/chemistry , Protons , Pyridines/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , SARS-CoV-2/metabolism , Viral Proteins/metabolism
19.
Nat Commun ; 12(1): 668, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1387328

ABSTRACT

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 µM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.


Subject(s)
COVID-19/drug therapy , Coronavirus Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Viral Proteases/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Humans , Indoles/pharmacology , Pyridines/pharmacology , Vero Cells , Viral Proteases/metabolism
20.
N Engl J Med ; 385(9): 815-825, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1373470

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).


Subject(s)
Aminophenols/therapeutic use , Benzodioxoles/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Indoles/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinolines/therapeutic use , Adolescent , Adult , Aminophenols/adverse effects , Benzodioxoles/adverse effects , Child , Chloride Channel Agonists/adverse effects , Chlorides/analysis , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Double-Blind Method , Drug Combinations , Female , Genotype , Humans , Indoles/adverse effects , Male , Pyrazoles/adverse effects , Pyridines/adverse effects , Quinolines/adverse effects , Sweat/chemistry
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