scholarly journals Synthesis and analysis of 4-(3-fluoropropyl)-glutamic acid stereoisomers to determine the stereochemical purity of (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) for clinical use

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243831
Author(s):  
Kai-Ting Shih ◽  
Ya-Yao Huang ◽  
Chia-Ying Yang ◽  
Mei-Fang Cheng ◽  
Yu-Wen Tien ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Glutamic Acid ◽  
Scale Up ◽  
Enantiomeric Excess ◽  
Optical Purity ◽  
Daily Basis ◽  
Brain Diseases ◽  
Ductal Adenocarcinoma ◽  
Chiral Hplc ◽  
Clinical Use

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC− transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials.

scholarly journals Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3919
Author(s):  
Stuart Ruddell ◽  
Elena Sugrue ◽  
Sarah Memarzadeh ◽  
Lorna Mae Hellam ◽  
Sam J. Wilson ◽  
...  
Keyword(s):  
Biological Activities ◽  
Enantiomeric Excess ◽  
Optical Purity ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Chiral Hplc ◽  
Enantiomeric Resolution ◽  
Hiv Replication ◽  
Computational Docking ◽  
Lack Of Information

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2618
Author(s):  
Tatyana A. Kuznetsova ◽  
Boris G. Andryukov ◽  
Ilona D. Makarenkova ◽  
Tatyana S. Zaporozhets ◽  
Natalya N. Besednova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Clinical Manifestations ◽  
Optimal Dose ◽  
Monosaccharide Composition ◽  
Structural Features ◽  
Sulfated Polysaccharides ◽  
Clinical Use ◽  
Hemostasis System

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.

scholarly journals NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice

BMC Cancer ◽  
2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Ferdinando De Vita ◽  
Jole Ventriglia ◽  
Antonio Febbraro ◽  
Maria Maddalena Laterza ◽  
Alessio Fabozzi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives

2021 ◽  
Author(s):  
Mikael Christiansen ◽  
Erik Lerkevang Grove ◽  
Anne-Mette Hvas
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Trials ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Clinical Use ◽  
Action Current ◽  
Potential Clinical Benefit ◽  
Treatment Indications ◽  
Prevention Of Cardiovascular Disease

AbstractThe ability of aspirin to inhibit platelet aggregation has positioned this agent within the most frequently used drugs worldwide. The aim of this article is to review the contemporary clinical use of aspirin and also to discuss unresolved issues not yet translated into clinical practice. Results from several clinical trials have led to strong guideline recommendations for aspirin use in the acute management and secondary prevention of cardiovascular disease. On the contrary, guidelines regarding aspirin use as primary prevention of cardiovascular disease are almost conservative, supported by recent trials reporting that the bleeding risk outweighs the potential benefits in most patients. In pregnancy, aspirin has proved efficient in preventing preeclampsia and small-for-gestational-age births in women at high risk, and is hence widely recommended in clinical guidelines. Despite the vast amount of clinical data on aspirin, several unresolved questions remain. Randomized trials have reported that aspirin reduces the risk of recurrent venous thromboembolism, but the clinical relevance remains limited, because direct oral anticoagulants are more effective. Laboratory studies suggest that a twice-daily dosing regimen or evening intake may lead to more efficient platelet inhibition, and the potential clinical benefit of such strategies is currently being explored in ongoing clinical trials. Enteric-coated formulations of aspirin are frequently used, but it remains unclear if they are safer and as efficient as plain aspirin. In the future, aspirin use after percutaneous coronary interventions might not be mandatory in patients who also need anticoagulant therapy, as several trials support shorter aspirin duration strategies. On the other hand, new treatment indications for aspirin will likely arise, as there is growing evidence that aspirin may reduce the risk of colorectal cancer and other types of cancer.

Selective VEGFR Inhibitors for Anticancer Therapeutics in Clinical Use and Clinical Trials

2012 ◽  
Vol 18 (20) ◽  
pp. 2921-2935 ◽  
Author(s):  
Cunlong Zhang ◽  
Chunyan Tan ◽  
Huaiwei Ding ◽  
Tian Xin ◽  
Yuyang Jiang
Keyword(s):  
Clinical Trials ◽  
Clinical Use ◽  
Anticancer Therapeutics

scholarly journals Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials

2018 ◽  
Vol 16 (1) ◽  
Author(s):  
Andrew Gdowski ◽  
Kaitlyn Johnson ◽  
Sunil Shah ◽  
Ignacy Gryczynski ◽  
Jamboor Vishwanatha ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Scale Up ◽  
Production Method

scholarly journals Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Jiali Du ◽  
Jichun Gu ◽  
Ji Li
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Solid Tumours ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Iii Trials ◽  
Exploitation And Exploration ◽  
Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

scholarly journals Quick and effective method of bone marrow mesenchymal stem cell extraction

Open Medicine ◽  
2015 ◽  
Vol 10 (1) ◽  
Author(s):  
Zivile Gudleviciene ◽  
Gabrielis Kundrotas ◽  
Regina Liudkeviciene ◽  
Jelena Rascon ◽  
Marcin Jurga
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Density Gradient ◽  
Tissue Regeneration ◽  
Immune Regulation ◽  
Small Volume ◽  
Extraction Methods ◽  
Common Source ◽  
Human Mscs ◽  
Clinical Use

AbstractBackground. Mesenchymal stem cells (MSCs) are currently exploited in numerous clinical trials to investigate their potential in immune regulation, hematopoesis or tissue regeneration. The most common source of MSCs for clinical use is human bone marrow. To generate sufficient numbers of cells relevant to clinical use in most cases the high volumes (20-50 ml) of bone marrow aspirates are taken. Methods. In this pilot study, 8 healthy bone marrow donors were included. Two different MSC extraction methods were evaluated: MSCs extraction from 60 ml of bone marrow using density gradient and MSCs extraction from 6 ml using red blood cell (RBC) lysis. Results. Our results showed that after RBC lysis the efficient amount of human MSCs can be isolated from 10 times less bone marrow volume (6 ml). Moreover, using small volume of bone marrow the adequate therapeutical dose of MSCs could be achieved during similar period of time (3-4 weeks). In conclusion, we have shown that MSCs isolation using RBC lysis is an effective and more advantageous method in comparison to standard MSCs isolation using density-gradient. Using RBC lysis from small volume of bone marrow the same amount of MSCs were obtained as usually using large volume and density-gradient.

Sign in / Sign up

Export Citation Format

Share Document