scholarly journals Cannabinoquinones: Synthesis and Biological Profile

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 991
Author(s):  
Diego Caprioglio ◽  
Daiana Mattoteia ◽  
Orazio Taglialatela-Scafati ◽  
Eduardo Muñoz ◽  
Giovanni Appendino
Keyword(s):  
Oxidative Degradation ◽  
Alkyl Substituent ◽  
Systematic Investigation ◽  
Clinical Development ◽  
Drug Status ◽  
Phase 2 ◽  
Biological Profile ◽  
Oxidative Dearomatization ◽  
Sufficient Stability ◽  
Clinical Potential

Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance on the alkyl substituent, have provided sufficient stability for a systematic investigation of their bioactivity and for further clinical development. These studies culminated in the discovery of the aminocannabinoquinone VCE-004.8 (5), a compound under phase 2 clinical development with orphan drug status by EMA and FDA for the management of scleroderma. The synthesis and rich chemistry of these compounds will be described, summarizing their biological profile and clinical potential.

scholarly journals Targeting B cells to modify MS, NMOSD, and MOGAD

2020 ◽  
Vol 8 (1) ◽  
pp. e919
Author(s):  
Jonas Graf ◽  
Jan Mares ◽  
Michael Barnett ◽  
Orhan Aktas ◽  
Philipp Albrecht ◽  
...  
Keyword(s):  
B Cell ◽  
Case Series ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Clinical Development ◽  
B Cell Depletion ◽  
Phase 2 ◽  
Proven Efficacy ◽  
Advanced Stages ◽  
Related Proteins

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell–related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell–depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G–associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell–depleting agents will be discussed.

scholarly journals Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies

2021 ◽  
Vol 5 (8) ◽  
pp. 2264-2271
Author(s):  
Anand A. Patel ◽  
Kirk Cahill ◽  
Caner Saygin ◽  
Olatoyosi Odenike
Keyword(s):  
Myelodysplastic Syndromes ◽  
Dna Methyltransferase ◽  
Cytidine Deaminase ◽  
Oral Formulation ◽  
Clinical Development ◽  
Phase 2 ◽  
Myeloid Malignancies ◽  
Dna Methyltransferase Inhibitors ◽  
Pharmacodynamic Profile ◽  
Early Phase Clinical Trials

Abstract Since the US Food and Drug Administration (FDA) approvals of parenteral decitabine and azacitidine, DNA methyltransferase inhibitors, otherwise referred to as DNA hypomethylating agents (HMAs), have been a mainstay in the treatment of higher-risk myelodysplastic syndromes. The development of oral HMAs has been an area of active interest; however, oral bioavailability has been quite poor due to rapid metabolism by cytidine deaminase (CDA). This led to the development of the novel CDA inhibitor cedazuridine, which was combined with an oral formulation of decitabine. Preclinical work demonstrated a pharmacokinetic and pharmacodynamic profile approximate to parenteral decitabine, leading to early-phase clinical trials of oral cedazuridine-decitabine (C-DEC) in myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). A combination of oral decitabine 35 mg with oral cedazuridine 100 mg was established as the recommended phase 2 dose. Phase 2 data confirmed bioequivalence of C-DEC when compared with parenteral decitabine, and a larger phase 3 trial has demonstrated similar results, leading to the FDA approval of C-DEC for use in intermediate/high-risk myelodysplastic syndrome (MDS) and CMML. This review will focus upon the current role of HMA therapy in MDS/CMML, preclinical and clinical development of C-DEC, and potential roles of oral HMA therapy in myeloid malignancies moving forward.

scholarly journals Dalbavancin safety in the phase 2/3 clinical development program

Critical Care ◽  
2008 ◽  
Vol 12 (Suppl 2) ◽  
pp. P27
Author(s):  
E Seltzer ◽  
L Goldberg ◽  
D Krause ◽  
D Simoneau ◽  
E Boudry
Keyword(s):  
Development Program ◽  
Clinical Development ◽  
Phase 2 ◽  
Clinical Development Program

scholarly journals Use of Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Phase 2 and 3 Dosing Strategies for Doripenem

2005 ◽  
Vol 49 (9) ◽  
pp. 3944-3947 ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Brenda B. Cirincione ◽  
Matthew A. Wikler ◽  
Paul G. Ambrose
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Clinical Development ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Bacterial Strains ◽  
Target Attainment ◽  
Dosing Strategies ◽  
Simulation Results ◽  
Support Phase

ABSTRACT A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 μg/ml and that less susceptible strains could be treated with prolonged infusions.

HST5040: An investigational oral small molecule therapy entering phase 2 clinical development for methylmalonic (MMA) and propionic (PA) acidemias

2021 ◽  
Vol 132 ◽  
pp. S162
Author(s):  
Gerald Cox ◽  
Allison Armstrong ◽  
Mavis Waller ◽  
Mark Hayes ◽  
Maria Sol Collado ◽  
...  
Keyword(s):  
Small Molecule ◽  
Clinical Development ◽  
Phase 2

Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2—3 liraglutide clinical development studies

2011 ◽  
Vol 8 (3) ◽  
pp. 237-240 ◽  
Author(s):  
Steven P Marso ◽  
Jason B Lindsey ◽  
Joshua M Stolker ◽  
John A House ◽  
Gabriela Martinez Ravn ◽  
...  
Keyword(s):  
Pooled Analysis ◽  
Clinical Development ◽  
Development Studies ◽  
Cardiovascular Safety ◽  
Phase 2 ◽  
Patient Level

Antibacterial properties and clinical potential of pleuromutilins

2019 ◽  
Vol 36 (1) ◽  
pp. 220-247 ◽  
Author(s):  
Olivia Goethe ◽  
Abigail Heuer ◽  
Xiaoshen Ma ◽  
Zhixun Wang ◽  
Seth B. Herzon
Keyword(s):  
Critical Review ◽  
Antibacterial Properties ◽  
Clinical Development ◽  
Clinical Potential

A critical review of the chemistry, biology, and clinical development of pleuromutilin-based antibiotics is presented.

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