Safety and Efficacy: The Role of Chemistry, Manufacturing, and Controls in Pharmaceutical Drug Development

Excimer laser coronary atherectomy (ELCA) is a long-established adjunctive therapy that can be applied during percutaneous coronary intervention (PCI). Technical aspects have evolved and there is an established safety and efficacy record across a number of clinical indications in contemporary interventional practice where complex lesions are routinely encountered. The role of ELCA during PCI for thrombus, non-crossable or non-expandable lesions, chronic occlusions and stent under-expansion are discussed in this review. The key advantage of ELCA over alternative atherectomy interventions is delivery on a standard 0.014-inch guidewire. Additionally, the technique can be mastered by any operator after a short period of training. The major limitation is presence of heavy calcification although when rotational atherectomy (RA) is required but cannot be applied due to inability to deliver the dedicated RotaWire™ (Boston Scientific), ELCA can create an upstream channel to permit RotaWire passage and complete the case with RA – the RASER technique.

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943-P: Role of Model-Informed Drug Development in Confirming Additional Clinical Benefits of Dulaglutide

Diabetes ◽

10.2337/db20-943-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 943-P

Author(s):

LAI-SAN THAM ◽

JEANNE GEISER ◽

CHENG CAI TANG ◽

KAREN SCHNECK ◽

DAVID COX ◽

...

Keyword(s):

Drug Development ◽

Clinical Benefits

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Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00558-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Miao-Miao Zhao ◽

Wei-Li Yang ◽

Fang-Yuan Yang ◽

Li Zhang ◽

Wei-Jin Huang ◽

...

Keyword(s):

Drug Development ◽

Cathepsin L ◽

Human Cells ◽

New Drugs ◽

Disease Course ◽

Promising Target ◽

First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

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The Role of Network Science in Glioblastoma

Cancers ◽

10.3390/cancers13051045 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1045

Author(s):

Marta B. Lopes ◽

Eduarda P. Martins ◽

Susana Vinga ◽

Bruno M. Costa

Keyword(s):

Personalized Medicine ◽

Drug Development ◽

Information Flow ◽

Clinical Studies ◽

Network Science ◽

Cancer Genomics ◽

High Dimensional ◽

Network Discovery ◽

Software Implementations

Network science has long been recognized as a well-established discipline across many biological domains. In the particular case of cancer genomics, network discovery is challenged by the multitude of available high-dimensional heterogeneous views of data. Glioblastoma (GBM) is an example of such a complex and heterogeneous disease that can be tackled by network science. Identifying the architecture of molecular GBM networks is essential to understanding the information flow and better informing drug development and pre-clinical studies. Here, we review network-based strategies that have been used in the study of GBM, along with the available software implementations for reproducibility and further testing on newly coming datasets. Promising results have been obtained from both bulk and single-cell GBM data, placing network discovery at the forefront of developing a molecularly-informed-based personalized medicine.

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Safety and Efficacy of Single-Dose Ketorolac for Postoperative Pain Management After Primary Palatoplasty: A Prospective Cohort Study With Historical Controls

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211012864 ◽

2021 ◽

pp. 105566562110128

Author(s):

Jason R. Stein ◽

Esperanza Mantilla-Rivas ◽

Marudeen Aivaz ◽

Md Sohel Rana ◽

Ishwarya Shradha Mamidi ◽

...

Keyword(s):

Single Dose ◽

Postoperative Pain Management ◽

Postoperative Hemorrhage ◽

Bleeding Complications ◽

Control Group ◽

Study Group ◽

Safety And Efficacy ◽

Opioid Dose ◽

Historical Controls

Objective: To analyze safety and efficacy of single-dose ketorolac after primary palatoplasty (PP). Design: Consecutive cohort of patients undergoing PP, comparing to historical controls. Setting: A large academic children’s hospital. Patients, Participants: A consecutive cohort of 111 patients undergoing PP (study n = 47) compared to historical controls (n = 64). Interventions: All patients received intraoperative acetaminophen, dexmedetomidine, and opioids while the study group received an additional single dose of ketorolac (0.5 mg/kg) at the conclusion of PP. Main Outcome Measures: Safety of ketorolac was measured by significant bleeding complications and need for supplementary oxygen. Efficacy was assessed through bleeding, Face Legs Activity Cry Consolability (FLACC) scale, and opioid dose. Results: Length of stay was similar for both groups (control group 38.5 hours [95% CI: 3.6-43.3] versus study group 37.6 hours [95% CI: 31.3-44.0], P = .84). There were no significant differences in all postoperative FLACC scales. The mean dose of opioid rescue medication measured as morphine milligram equivalents did not differ between groups ( P = .56). Significant postoperative hemorrhage was not observed. Conclusions: This is the first prospective study to evaluate the safety and efficacy of single-dose ketorolac after PP. Although lack of standardization between study and historical control groups may have precluded observation of an analgesic benefit, analysis demonstrated a single dose of ketorolac after PP is safe. Further investigations with more patients and different postoperative regimens may clarify the role of ketorolac in improving pain after PP.

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Drug-induced cardiac toxicity: emphasizing the role of electrocardiography in clinical research and drug development

Journal of Electrocardiology ◽

10.1016/j.jelectrocard.2003.11.003 ◽

2004 ◽

Vol 37 (1) ◽

pp. 19-24 ◽

Cited By ~ 28

Author(s):

Ihor Gussak ◽

Jeffrey Litwin ◽

Robert Kleiman ◽

Scott Grisanti ◽

Joel Morganroth

Keyword(s):

Drug Development ◽

Clinical Research ◽

Cardiac Toxicity ◽

Drug Induced

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Challenges in CNS drug development and the role of imaging

Psychopharmacology ◽

10.1007/s00213-021-05838-3 ◽

2021 ◽

Author(s):

Oliver D. Howes ◽

Mitul A. Mehta

Keyword(s):

Drug Development

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From Lock-In to Transformation: A Path-Centric Theory of Emerging Technology an Organizing

Organization Science ◽

10.1287/orsc.2021.1543 ◽

2021 ◽

Author(s):

Brian T. Pentland ◽

Youngjin Yoo ◽

Jan Recker ◽

Inkyu Kim

Keyword(s):

Drug Discovery ◽

Dynamic Simulation ◽

Emerging Technologies ◽

Emerging Technology ◽

Basic Question ◽

Transformative Change ◽

Pharmaceutical Drug ◽

Wide Range ◽

Lock In

We offer a path-centric theory of emerging technology and organizing that addresses a basic question. When does emerging technology lead to transformative change? A path-centric perspective on technology focuses on the patterns of actions afforded by technology in use. We identify performing and patterning as self-reinforcing mechanisms that shape patterns of action in the domain of emerging technology and organizing. We use a dynamic simulation to show that performing and patterning can lead to a wide range of trajectories, from lock-in to transformation, depending on how emerging technology in use influences the pattern of action. When emerging technologies afford new actions that can be flexibly recombined to generate new paths, decisive transformative effects are more likely. By themselves, new affordances are not likely to generate transformation. We illustrate this theory with examples from the practice of pharmaceutical drug discovery. The path-centric perspective offers a new way to think about generativity and the role of affordances in organizing.

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