A Quantitative Study of US FDA Inspection Data for Drug Manufacturing Sites

Pazhayattil, Ajay Babu; Ingram, Marzena; Sayeed, Naheed

doi:10.1007/s43441-019-00015-3

Cited by 2 publications

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“…Macher et al (2006) investigated how different factors, such as days between inspection, compliance history, and the quality of training of the inspectors, impact the classification a facility receives. Similarly, Pazhayattil et al (2020) explored how violations of different sections of the CGMP were correlated with the inspection classifications. Hein et al (2019) compared various data-driven methods to predict the classification facilities would receive.…”

Section: Literature Reviewmentioning

confidence: 99%

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA

2022

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Background PAH is a devastating and incurable disease characterized by abnormal pulmonary vascular phenotypes and progressive right ventricular failure, but the underlying mechanisms are incompletely understood. There is an urgent need of new therapeutic approaches, and a better understanding of disease pathogenesis is essential in identifying novel pathways that can be therapeutically targeted. Stress granules (SGs) are small intracellular structures that form in response to stress and contain mRNA molecules and mRNA‐binding proteins. These granules allow cells to temporarily halt translation by “parking” or sequestering certain mRNAs in a protected zone (the stress granule) and this allows the cells to survive in conditions of stress. The role of SGs in abnormal vascular and cardiac homeostasis in PAH is not known. Hypotheses We hypothesized that increased SG formation may contribute to both abnormal vascular cellular phenotypes and cardiac failure in human and experimental PAH. Further, we examined whether treatment with the carbonic anhydrase Acetazolamide (ACTZ) which is known to ameliorate experimental PAH, would alter SG tissue abundance in the lungs and heart. Methods We used the adult rat (Sprague Dawley) sugen/hypoxia (Su/Hx) model of severe pulmonary hypertension and studied tissue sections from lungs, heart and skeletal muscle as well as isolated primary pulmonary artery smooth muscle cells (PASMCs). We also used PASMCs from patients with PAH. We applied a combination of immunofluorescence and protein expression studies as well as drug (ACTZ) treatment and in vitro induction of oxidative stress (arsenite) to assess SG formation and SG related markers in experimental PAH and the effect of ACTZ. Results We have discovered that PASMCs from patients with PAH have a higher number of stress granules in response to oxidative stress than cells from normal individuals. We also found that PASMCs from a preclinical model of PAH (Sugen/Hypoxia) have more stress granules and increased SG components in response to oxidative stress compared to normal animals. Further, we found that treatment of PASMCs with ACTZ resulted in lower number of stress granules after cell stress. In addition, we found increased G3BP1 (key component of SG assembly) puncta in alveoli and bronchi and sarcoplasmic G3BP1 puncta in cardiac and soleus muscles from the rat sugen/hypoxia (Su/Hx) model compared to controls and with ACTZ treatment. Conclusions We conclude that there is increased SG formation in PASMCs and tissues in experimental PAH and acetazolamide inhibits stress granule assembly in response to oxidative stress. Further studies are needed to define the role of SG in disease pathogenesis, and evaluate whether targeting stress granules may be effective in restoring normal cellular function and improving PAH.

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Section: Literature Reviewmentioning

confidence: 99%

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA

2022

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“…donijeti odluku o ukidanju proizvodne dozvole, ukidanju ili suspendiranju rješenja za stavljanje lijeka u promet, narediti povlačenje lijeka/djelatne tvari/ pomoćne tvari iz prometa ili obustavu njihova isporučivanja na teritoriju Republike Hrvatske, odnosno propisati druge regulatorne mjere). [19][20][21][22][23] Na temelju provedene inspekcije, izvješća i dostavljenog očitovanja o nedostatcima, inspektor izrađuje završni izvještaj i mišljenje o ispunjavanju uvjeta dobre proizvođačke prakse, temeljem kojeg se izdaje rješenje o davanju/ uskraćivanju/ izmjeni/ ukidanju proizvodne dozvole, rješenje o davanju ili uskraćivanju upisa/izmjene upisa u očevidnik ili rješenje o brisanju iz očevidnika proizvođača, uvoznika i veleprodaja djelatnih i/ili pomoćnih tvari, ili davanju potvrde o provođenju dobre proizvođačke prakse (GMP potvrda), odnosno u slučaju neispunjavanja uvjeta izdaje se Rješenje i Izjava o neispunjavanju uvjeta dobre proizvođačke prakse (engl. Non-Compliance).…”

Section: Provođenje Gmp Nadzoraunclassified

Pandemija COVID-19 mijenja uobičajen pristup u nadzoru nad dobrom proizvođačkom praksom

2021

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Dobra proizvođačka praksa (GMP) je skup različitih smjernica, pravila i normi koje jamče učinkovitost, kvalitetu, sigurnost i dosljednost u proizvodnji i kontroli lijekova. Nadzor nad dobrom proizvođačkom praksom u Hrvatskoj provodi Agencija za lijekove i medicinske proizvode (HALMED). U svrhu održavanja konzistentnih inspekcijskih standarda, HALMED ima razvijen Poslovnik kakvoće izrađen u skladu s europskim smjernicama. Inspektori Agencije imaju odgovarajuća znanja i iskustvo te se trajno usavršavaju. Po obavljenoj inspekciji, HALMED izdaje proizvodnu dozvolu i potvrdu o provođenje dobre proizvođačke prakse (GMP potvrdu) za proizvođače u Republici Hrvatskoj te GMP potvrdu za proizvođače iz trećih zemalja. S obzirom na nemogućnost izlaska inspektora na teren uslijed pandemijske situacije, sve se češće pribjegava ocjeni na daljinu.

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A Quantitative Study of US FDA Inspection Data for Drug Manufacturing Sites

Cited by 2 publications

References 0 publications

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA

Pandemija COVID-19 mijenja uobičajen pristup u nadzoru nad dobrom proizvođačkom praksom

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A Quantitative Study of US FDA Inspection Data for Drug Manufacturing Sites

Cited by 2 publications

References 0 publications

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas 1,2, Fotios Spyropoulos1,2,Helen Christou 1,21Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA 2Harvard Medical School, Boston, MA 02215, USA

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas 1,2, Fotios Spyropoulos1,2,Helen Christou 1,21Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA 2Harvard Medical School, Boston, MA 02215, USA

Pandemija COVID-19 mijenja uobičajen pristup u nadzoru nad dobrom proizvođačkom praksom

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Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA

Role of Stress Granules in the Pathogenesis of Pulmonary Hypertension Kosmas Kosmas ^1,2, Fotios Spyropoulos^1,2,Helen Christou ^1,2¹Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA ²Harvard Medical School, Boston, MA 02215, USA