Chemical modification of ovatodiolide revealed a promising amino-prodrug with improved pharmacokinetic profile

2020 ◽  
Vol 56 (75) ◽  
pp. 11018-11021
Author(s):  
Junhong Xiang ◽  
Xuemei Zhang ◽  
Dehong Wang ◽  
Jiaxin Li ◽  
Qiuying Li ◽  
...  
Keyword(s):  
Chemical Modification ◽  
Pharmacokinetic Profile ◽  
Promising Candidate ◽  
Further Development

Stepwise modification of ovatodiolide revealed a prodrug NMP-diepoxyovatodiolide, which is a very promising candidate for further development of liver-related drugs.

scholarly journals Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness

2020 ◽  
Vol 10 (4) ◽  
pp. 242
Author(s):  
Giulia Di Prima ◽  
Giuseppina Campisi ◽  
Viviana De Caro
Keyword(s):  
Buccal Mucosa ◽  
Therapeutic Strategy ◽  
Therapeutic Response ◽  
Ex Vivo ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Promising Candidate ◽  
Steady State Condition ◽  
Drug Pharmacokinetic ◽  
Drug Flux

Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient’s needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h−1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient’s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials.

scholarly journals Preclinical Pharmacokinetics of C118P, a Novel Prodrug of Microtubules Inhibitor and Its Metabolite C118 in Mice, Rats, and Dogs

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2883 ◽  
Author(s):  
Cang Zhang ◽  
Xiaolan Zhang ◽  
Guangji Wang ◽  
Ying Peng ◽  
Xueyuan Zhang ◽  
...  
Keyword(s):  
Clinical Development ◽  
High Dose ◽  
Protein Inhibitor ◽  
Promising Candidate ◽  
Preclinical Pharmacokinetics ◽  
Tumor Bearing ◽  
Microtubule Protein ◽  
Further Development

C118P, a phosphate prodrug of C118, which is a novel microtubule protein inhibitor, is currently under Phase I clinical development in China for treating ovarian cancer and lung cancer. The preclinical pharmacokinetics of prodrug C118P and its metabolite C118 were extensively characterized in vivo in mice, rats, and dogs and in vitro to support the further development of C118P. The preclinical tissue distribution and excretion were investigated in rats. Plasma protein binding in mice, rat, and human, and hepatic microsomal metabolic stability in mice, rat, dog, monkey, and human, were also evaluated. The (AUC0-inf) and C30s of C118P at 50 mg/kg in rats and 6 mg/kg in dogs, and the C2min of C118 at 6 mg/kg in dogs increased less than the dosage increase, suggested nonlinear pharmacokinetic occurred at high dose. As a prodrug, C118P can be quickly hydrolyzed into C118 after an intravenous administration. The unbound C118 in plasma is slightly higher than C118P. C118P can hardly penetrate the tissue, while C118 can distribute widely into tissues. In tumor-bearing nude mice, the concentration of C118 is high in lung, ovary, and tumor, with an extended half-life in tumor. C118P is a promising candidate prodrug for further clinical development.

scholarly journals Synthesis and Antitumor Activity of a Series of Novel 1-Oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione Derivatives

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 936
Author(s):  
Ze Yang ◽  
Qiu Zhong ◽  
Shilong Zheng ◽  
Guangdi Wang ◽  
Ling He
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Oxidative Cyclization ◽  
Human Lung Cancer ◽  
Reaction Conditions ◽  
Promising Candidate ◽  
Metal Catalyzed ◽  
Further Development

A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (10a and 10b), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 11b and 11h were the most potent against A549 cell line with 0.18 and 0.19 µM of IC50, respectively; compounds 11d, 11h, and 11k showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC50, respectively, while the activities of 11h, 11k, and 12c against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC50, respectively. Compound 11h is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines.

Preparation and characterization of hydroxybutyl chitosan

e-Polymers ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Bin Zhu ◽  
Changzheng Wei ◽  
Chunlin Hou ◽  
Qisheng Gu ◽  
Dajun Chen
Keyword(s):  
Chemical Modification ◽  
Sol Gel ◽  
Chitosan Solution ◽  
Water Soluble ◽  
Full Potential ◽  
Thermosensitive Polymer ◽  
New Type ◽  
Gel Phase ◽  
Further Development

AbstractThe insolubility in neutral condition is a major problem that confronts the further development of processing and uses of chitosan. Special emphasis has been put on the chemical modification of chitosan to explore its full potential. Studies on these methods are also encouraging and many kinds of water-soluble and alcohol-soluble derivatives have appeared. In this article, hydroxybutyl chitosan, a new type of thermosensitive polymer, was prepared through the chemical modification of 1,2-epoxybutane. Hydroxybutyl chitosan solution underwent sol/gel phase transition at a certain temperature lower than 20 °C, however, at high temperature, hydroxybutyl chitosan can form hydrogel with a certain mechanical strength. Hydroxybutyl chitosan could be an ideal themosensitive material applied in drug delivery system, tissue engineering and other biomedical fields.

scholarly journals SARS-CoV-2 Epitope Mapping on Microarrays Highlights Strong Immune-Response to N Protein Region

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 35
Author(s):  
Angelo Musicò ◽  
Roberto Frigerio ◽  
Alessandro Mussida ◽  
Luisa Barzon ◽  
Alessandro Sinigaglia ◽  
...  
Keyword(s):  
Cross Reactivity ◽  
Serum Samples ◽  
Promising Candidate ◽  
Strong Immune Response ◽  
Serological Tests ◽  
Discrimination Ability ◽  
N Protein ◽  
Peptide Microarrays ◽  
Epitope Discovery ◽  
Further Development

A workflow for rapid SARS-CoV-2 epitope discovery on peptide microarrays is herein reported. The process started with a proteome-wide screening of immunoreactivity based on the use of a high-density microarray followed by a refinement and validation phase on a restricted panel of probes using microarrays with tailored peptide immobilization through a click-based strategy. Progressively larger, independent cohorts of Covid-19 positive sera were tested in the refinement processes, leading to the identification of immunodominant regions on SARS-CoV-2 spike (S), nucleocapsid (N) protein and Orf1ab polyprotein. A summary study testing 50 serum samples highlighted an epitope of the N protein (region 155–71) providing good diagnostic performance in discriminating Covid-19 positive vs. healthy individuals. Using this epitope, 92% sensitivity and 100% specificity were reached for IgG detection in Covid-19 samples, and no cross-reactivity with common cold coronaviruses was detected. Likewise, IgM immunoreactivity in samples collected within the first month after symptoms onset showed discrimination ability. Overall, epitope 155–171 from N protein represents a promising candidate for further development and rapid implementation in serological tests.

scholarly journals Synthesis and Cytotoxicities of Novel Podophyllotoxin Xyloside Derivatives

2019 ◽  
Vol 14 (7) ◽  
pp. 1934578X1986066
Author(s):  
Cheng-Ting Zi ◽  
Liu Yang ◽  
Bang-Lei Zhang ◽  
Yan Li ◽  
Zhong-Tao Ding ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Promising Candidate ◽  
Human Cancer Cell Lines ◽  
Diphenyltetrazolium Bromide ◽  
Further Development ◽  
Mcf 7

Novel podophyllotoxin xyloside derivatives 8 to 11 were synthesized and evaluated for their cytotoxicities against a panel of 5 human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using [3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. These derivatives showed good to moderate activities, with compound 9 having an IC50 value of 4.42 μM against the A-549 cell line. Overall, compound 9 might be a promising candidate for further development.

scholarly journals ENERGY SAVING OF WOOD DUE TO ITS MODIFICATION

2021 ◽  
Author(s):  
Tamara Storodubtseva ◽  
A. Buryakova ◽  
A. Rabotkin
Keyword(s):  
Corrosion Resistance ◽  
Chemical Modification ◽  
Thermomechanical Processing ◽  
Radiation Chemical ◽  
Mineral Oils ◽  
High Heating ◽  
Natural Wood ◽  
Thermochemical Modification ◽  
Further Development ◽  
Modified Wood

Modified wood is wood that is improved with special modifiers in order to increase its strength, durability and water-, bio-, fire- and corrosion resistance, which, unlike natural wood, makes it more resistant to various environmental factors. This wood is good to use in construction, and it will be effective for further development, as the buildings will be used longer, and less likely to be subject to repair and reconstruction, which will reduce deforestation. The most popular methods of modification are thermomechanical modification with preliminary steaming of wood, its heating, or with preliminary impregnation with mineral oils; thermochemical modification; chemical modification; radiation-chemical modification. Each type of the above modifications differs in its properties, and also have their own impact on a particular type of wood. The most common and most effective method of modification is achieved by thermomechanical processing. Since it is when the wood is heated, after the introduction of the necessary modifiers into it, the polymers begin to heat up, due to which the vessels of the wood harden, which affects its density. To avoid the destruction of wood, it is very important to monitor the temperature and prevent it from reaching high heating levels.

scholarly journals Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

2007 ◽  
Vol 51 (7) ◽  
pp. 2424-2429 ◽  
Author(s):  
Ghazia Asif ◽  
Selwyn J. Hurwitz ◽  
Aleksandr Obikhod ◽  
David Delinsky ◽  
Janarthanan Narayanasamy ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Pharmacokinetic Profile ◽  
Preclinical Development ◽  
Immunodeficiency Virus ◽  
Oral Pharmacokinetics ◽  
Average Serum ◽  
Median Effective Concentration ◽  
Further Development

ABSTRACT β-d-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h−1; fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

Oral Transmucosal Etomidate in Volunteers 

1998 ◽  
Vol 88 (1) ◽  
pp. 89-95 ◽  
Author(s):  
James B. Streisand ◽  
Ruurd L. Jaarsma ◽  
Mason A. Gay ◽  
Mary Jane Badger ◽  
Lynn Maland ◽  
...  
Keyword(s):  
Side Effects ◽  
Dosage Form ◽  
Time Course ◽  
Venous Blood ◽  
Pharmacokinetic Profile ◽  
Clinically Significant ◽  
Transmucosal Administration ◽  
Further Development ◽  
Adult Volunteers ◽  
Transmucosal Delivery

Background The oral transmucosal route of delivery is now used for many drugs, including fentanyl and midazolam. Etomidate's pharmacokinetic profile and physiochemical properties suggest it may be suitable for transmucosal delivery. Transmucosal delivery might extend etomidate's use to sedation and anxiolysis. This is the first study in humans to examine the oral transmucosal administration of a novel etomidate dosage form. Methods Ten healthy adult volunteers consumed 12.5-mg, 25-mg, 50-mg, and 100-mg doses of oral transmucosal etomidate (OTET) on four different study days. Serum etomidate concentrations, sedation, respiratory and cardiovascular variables, taste, and side effects were determined. Results Five minutes after OTET administration, etomidate was detected in the venous blood. Mean peak concentrations occurred 20-30 min later and ranged from 61-174 ng/ml, related to the dose administered. Drowsiness and light sleep occurred in a dose-related manner 10-20 min after administration and lasted for 30-60 min. No episodes of SpO2 <90%, hypotension, or emesis occurred at any dose throughout the study. Nausea was rare. Two volunteers exhibited a brief episode of involuntary tremor after the 100-mg dose. The bitter taste of OTET was judged increasingly unpleasant with escalating doses. Conclusions Oral transmucosal etomidate produces dose-related increases in sedation and clinically significant serum concentrations with minimal side effects. The time course of these effects suggests that OTET might be useful when brief mild to moderate sedation with rapid recovery is desirable. Further development of this novel dosage form is warranted.

scholarly journals A potential microbial control for fireweed (Epilobium angustifolium)

2005 ◽  
Vol 75 (1) ◽  
pp. 19-33 ◽  
Author(s):  
R.S. Winder ◽  
A.K. Watson
Keyword(s):  
Microbial Control ◽  
Pathogenic Fungi ◽  
Field Trials ◽  
Control Agent ◽  
Malt Extract ◽  
Promising Candidate ◽  
Test Species ◽  
Epilobium Angustifolium ◽  
Screening Assays ◽  
Further Development

Diseased fireweed (Epilobium angustifolium) plants were collected in Quebec and organisms isolated from these plants were evaluated as potential biocontrol agents. Thirteen pathogenic fungi were isolated and three of these (Colletotrichum dematium, Seimatosporium kriegerianum, and Alternaria alternata) were virulent in initial screening assays. C. dematium was selected for further study because it was the most virulent pathogen, causing large necrotic lesions on leaves and stems of infected plants. Inoculum production was optimized on modified malt extract agar and the virulence enhanced by suppression of the conidial matrix with tannic acid and the addition of extracts of Aloe saponaria. The fungus was pathogenic to fireweed and E. lanceolatum, while other test species were very resistant or immune. Measurements of conidial and appressorial dimensions and its restricted host range support the hypothesis that the isolate may be an unreported form-species. Application of formulated conidia consistently provided 100% mortality of 7-wk-old inoculated fireweed rosettes within 48 h using 109 conidia m-2, from 10- to 15-d-old inoculum, and a 18- to 24-h dew period. Virulence was diminished in older plants. In field trials, growth of inoculated rosettes was reduced by 33%. These results suggest that C. dematium is a promising candidate for further development as a control agent for seedling fireweed in silviculture.

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