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  1. Article ; Online: Advanced therapeutic inhalation aerosols of a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor for targeted pulmonary drug delivery in pulmonary hypertension: design, characterization, aerosolization,

    Acosta, Maria F / Muralidharan, Priya / Grijalva, Carissa L / Abrahamson, Michael D / Hayes, Don / Fineman, Jeffrey R / Black, Stephen M / Mansour, Heidi M

    Therapeutic advances in respiratory disease

    2021  Volume 15, Page(s) 1753466621998245

    Abstract: Inhalable nanostructured microparticles of simvastatin, a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor, were rationally designed for targeted pulmonary delivery as dry powder inhalers (DPIs) for the treatment of pulmonary hypertension (PH). ... ...

    Abstract Inhalable nanostructured microparticles of simvastatin, a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor, were rationally designed for targeted pulmonary delivery as dry powder inhalers (DPIs) for the treatment of pulmonary hypertension (PH). Advanced particle engineering design technology was employed to develop inhalable dry powders using different dilute feed concentrations and spray drying pump rates. Several analytical techniques were used comprehensively to characterize the physicochemical properties of the resulting powders. Scanning electron microscopy (SEM) was used to visualize particle morphology (shape), surface structure, size, and size distribution. Karl Fischer titration (KFT) was employed to quantify the residual water content in the powders. X-ray powder diffraction (XRPD) was used to determine crystallinity. Hot-stage microscopy (HSM) under cross-polarizing lens was used to observe the presence or absence of birefringence characteristic of crystallinity. Differential scanning calorimetry (DSC) was employed to quantify thermotropic phase behavior. Attenuated total reflectance (ATR)-Fourier-transform infrared (FTIR) spectroscopy and Raman spectroscopy were used to determine the molecular fingerprint of simvastatin powders before and after particle engineering design.
    MeSH term(s) Administration, Inhalation ; Aerosols ; Animals ; Cell Culture Techniques ; Crystallization ; Disease Models, Animal ; Drug Delivery Systems ; Dry Powder Inhalers ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/physiopathology ; Lung/metabolism ; Lung/physiopathology ; Male ; NF-E2-Related Factor 2/drug effects ; NF-E2-Related Factor 2/metabolism ; Nanostructures ; Particle Size ; Powders ; Rats ; Rats, Sprague-Dawley ; Sheep ; Simvastatin/administration & dosage ; Simvastatin/chemistry ; Simvastatin/pharmacology ; Vascular Resistance/drug effects ; rho-Associated Kinases/antagonists & inhibitors
    Chemical Substances Aerosols ; NF-E2-Related Factor 2 ; Powders ; Simvastatin (AGG2FN16EV) ; rho-Associated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-03-15
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2476459-0
    ISSN 1753-4666 ; 1753-4658
    ISSN (online) 1753-4666
    ISSN 1753-4658
    DOI 10.1177/1753466621998245
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6753: Show issues Location:
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  2. Article ; Online: Inhalable Nanoparticles/Microparticles of an AMPK and Nrf2 Activator for Targeted Pulmonary Drug Delivery as Dry Powder Inhalers.

    Acosta, Maria F / Abrahamson, Michael D / Encinas-Basurto, David / Fineman, Jeffrey R / Black, Stephen M / Mansour, Heidi M

    The AAPS journal

    2020  Volume 23, Issue 1, Page(s) 2

    Abstract: Metformin is an activator of the AMPK and Nrf2 pathways which are important in the pathology of several complex pulmonary diseases with unmet medical needs. Organic solution advanced spray drying in the absence of water in closed-mode was used to design ... ...

    Abstract Metformin is an activator of the AMPK and Nrf2 pathways which are important in the pathology of several complex pulmonary diseases with unmet medical needs. Organic solution advanced spray drying in the absence of water in closed-mode was used to design and develop respirable dry powders. Following comprehensive characterization, the influence of physicochemical properties was correlated with performance as aerosols using inertial impaction and three different human dry powder inhaler (DPI) devices varying in device properties. In vitro cell assays were conducted to test safety in 2D human pulmonary cell lines and in 3D small airway epithelia comprising primary cells at the air-liquid interface (ALI). In addition, in vitro transepithelial electrical resistance (TEER) was carried out. Metformin remained crystalline following advanced spray drying under these conditions. All SD powders consisted of nanoparticles/microparticles in the solid state. In vitro aerosol dispersion performance showed high aerosolization for all SD metformin powders with all DPI devices tested. High emitted dose for all powders with all three DPI devices was measured. Differences in other aerosol performance parameters and the interplay between the properties of different formulations produced at specific pump rates and the three different DPI devices were correlated with spray drying pump rate and device properties. Safety over a wide metformin dose range was also demonstrated in vitro. Aerosol delivery of metformin nanoparticles/microparticles has the potential to be a new "first-in-class" therapeutic for the treatment of a number of pulmonary diseases including pulmonary vascular diseases such as pulmonary hypertension.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Administration, Inhalation ; Aerosols ; Cell Line ; Drug Compounding/methods ; Dry Powder Inhalers ; Humans ; Hypertension, Pulmonary/drug therapy ; Metformin/administration & dosage ; NF-E2-Related Factor 2/agonists ; Nanoparticles/administration & dosage ; Particle Size ; Powders ; Primary Cell Culture ; Spray Drying
    Chemical Substances Aerosols ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Powders ; Metformin (9100L32L2N) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
    Language English
    Publishing date 2020-11-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1550-7416
    ISSN (online) 1550-7416
    DOI 10.1208/s12248-020-00531-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Comparison of l-Carnitine and l-Carnitine HCL salt for targeted lung treatment of pulmonary hypertension (PH) as inhalation aerosols: Design, comprehensive characterization, in vitro 2D/3D cell cultures, and in vivo MCT-Rat model of PH.

    Acosta, Maria F / Muralidhran, Priya / Abrahamson, Michael D / Grijalva, Carissa L / Carver, Megan / Tang, Haiyang / Klinger, Christina / Fineman, Jeffrey R / Black, Stephen M / Mansour, Heidi M

    Pulmonary pharmacology & therapeutics

    2021  Volume 65, Page(s) 101998

    Abstract: Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors' knowledge, there are no reports using L- ... ...

    Abstract Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors' knowledge, there are no reports using L-Car or L-Car HCl as an inhaled aerosol through the respiratory route in a targeted manner either from dry powder inhaler (DPI) or liquid delivery system. The purpose of the comprehensive and systematic comparative study between L-Car and L-Car HCl salt was to design and develop dry powder inhalers (DPIs) of each. This was followed by comprehensive physicochemical characterization, in vitro cell viability as a function of dose on 2D human pulmonary cell lines from different lung regions and in vitro cell viability on 3D small airway epithelia human primary cells at the air-liquid interface (ALI). In addition in vitro transepithelial electrical resistance (TEER) in air-interface culture (AIC) conditions on 2D human pulmonary cell line and 3D small airway epithelia human primary cells was carried out. In vitro aerosol dispersion performance using three FDA-approved human DPI devices with different device properties was also examined. Following advanced spray drying under various conditions, two spray drying pump rates (low and medium) were found to successfully produce spray-dried L-Car powders while four spray drying pump rates (low, medium, medium-high, and high) all resulted in the production of spray-dried L-Car HCl powders. Raw L-Car and L-Car HCl were found to be crystalline. All SD powders retained crystallinity following spray drying and polymorphic interconversion in the solid-state was identified as the mechanism for retaining crystallinity after the advanced spray drying process. All SD powders aerosolized readily with all three human DPI devices. However, the in vitro dispersion parameters for the SD powders was not conducive for in vivo administration to rats in DPIs due to hygroscopicity and nanoaggreation. In vivo rat studies were successfully accomplished using inhaled liquid aerosols. Safety was successfully demonstrated in vivo in healthy Sprague Dawley rats. Furthermore, therapeutic efficacy was successfully demonstrated in vivo in the monocrotaline (MCT)-rat model of PH after two weeks of daily L-Car inhalation aerosol treatment.
    MeSH term(s) Administration, Inhalation ; Aerosols ; Animals ; Carnitine ; Cell Culture Techniques ; Dry Powder Inhalers ; Hypertension, Pulmonary/drug therapy ; Lung ; Monocrotaline ; Particle Size ; Powders ; Rats ; Rats, Sprague-Dawley
    Chemical Substances Aerosols ; Powders ; Monocrotaline (73077K8HYV) ; Carnitine (S7UI8SM58A)
    Language English
    Publishing date 2021-02-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1399707-5
    ISSN 1522-9629 ; 1094-5539
    ISSN (online) 1522-9629
    ISSN 1094-5539
    DOI 10.1016/j.pupt.2021.101998
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2389: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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