Design and Optimization of Novel Taste-Masked Medicated Chocolates of Dextromethorphan with In vitro and In vivo Taste Evaluation

Osteoarthritis (OA) is an evolving disease and a major cause of pain and impaired mobility. A deeper understanding of cartilage metabolism in response to loading is critical to achieve greater insight into OA mechanisms. While physiological joint loading helps maintain cartilage integrity, reduced or excessive loading have catabolic effects. The main scope of this study is to present an original methodology potentially capable to elucidate the effect of cyclic joint loading on cartilage metabolism, to identify mechanisms involved in preventing or slowing down OA progression, and to provide preliminary data on its application. In the proposed protocol, the combination of biomechanical data and medical imaging are integrated with molecular information about chondrocyte mechanotransduction and tissue homeostasis. The protocol appears to be flexible and suitable to analyze human OA knee cartilage explants, with different degrees of degeneration, undergoing ex vivo realistic cyclic joint loading estimated via gait analysis in patients simulating mild activities of daily living. The modulation of molecules involved in cartilage homeostasis, mechanotransduction, inflammation, pain and wound healing can be analyzed in chondrocytes and culture supernatants. A thorough analysis performed with the proposed methodology, combining in vivo functional biomechanical evaluations with ex vivo molecular assessments is expected to provide new insights on the beneficial effects of physiological loading and contribute to the design and optimization of non-pharmacological treatments limiting OA progression.

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Design of BET Inhibitor Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities

10.26434/chemrxiv.13241966 ◽

2020 ◽

Author(s):

Farrukh Vohidov ◽

Jannik N. Andersen ◽

Kyriakos D. Economides ◽

Michail V. Shipitsin ◽

Olga Burenkova ◽

...

Keyword(s):

Clinical Stage ◽

Therapeutic Index ◽

Design And Optimization ◽

Bet Inhibitor ◽

Normal Tissues ◽

Pharmaceutical Ingredients ◽

Tumor Pharmacokinetics ◽

Predictive Design

<div><p>Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic index of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive design and optimization. Here, using BET bromodomain inhibitors (BETi)—a class of epigenetic regulators with proven anti-cancer activity but clinical development hindered by systemic adverse effects–– we introduce a platform that overcomes these challenges. Through tuning of traceless linkers appended to a “brush prodrug” scaffold, we demonstrate that it is possible to correlate <i>in vitro </i>prodrug activation kinetics with <i>in vivo </i>tumor pharmacokinetics, leading to novel BETi prodrugs with enhanced anti-tumor efficacy and devoid of dose-limiting toxicities. This work has immediate clinical implications, introducing principles for the predictive design of prodrugs and potentially overcoming hurdles in drug development. </p></div>

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Design and optimization of gastro-floating sustained-release tablet of pregabalin: In vitro and in vivo evaluation

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2018.04.011 ◽

2018 ◽

Vol 545 (1-2) ◽

pp. 37-44 ◽

Cited By ~ 14

Author(s):

Chao Qin ◽

Mengmeng Wu ◽

Siyuan Xu ◽

Xiaowei Wang ◽

Wenxing Shi ◽

...

Keyword(s):

Sustained Release ◽

In Vivo Evaluation ◽

Design And Optimization ◽

Sustained Release Tablet ◽

Release Tablet

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Design and Optimization of Curcumin–HPβCD Bioadhesive Vaginal Tablets by 23 Factorial Design: In Vitro and In Vivo Evaluation

Journal of Pharmaceutical Innovation ◽

10.1007/s12247-014-9203-4 ◽

2014 ◽

Vol 10 (1) ◽

pp. 21-35 ◽

Cited By ~ 3

Author(s):

Umme Hani ◽

H. G. Shivakumar ◽

Atul Srivastava ◽

Nawaz Mahammed ◽

Shailesh Thirumaleshwar ◽

...

Keyword(s):

Factorial Design ◽

In Vivo Evaluation ◽

Design And Optimization ◽

23 Factorial Design

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Design and optimization of nano invasomal gel of Glibenclamide and Atenolol combination: in vitro and in vivo evaluation

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00240-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

P. Anitha ◽

S. V. Satyanarayana

Keyword(s):

Disease Risk ◽

Skin Permeation ◽

Skin Irritation ◽

Entrapment Efficiency ◽

Noncommunicable Disease ◽

In Vivo Evaluation ◽

Design And Optimization ◽

In Vitro Skin Permeation

Abstract Background There are many circumstances where chronic disease is associated with other disorders, especially in diseases such as diabetes with noncommunicable disease risk factors, such as hypertension. The current therapies for treating such chronic comorbid diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic treatment regimen. The present study is aimed to develop and optimize the combinational nano invasomal gel of Glibenclamide (GLB) and Atenolol (ATN) as a novel combination therapy for comorbid treatment of diabetic hypertensive patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities. Results OCNIG showed that the % entrapment efficiency of GLB is 96.67 ± 0.65% and % entrapment efficiency of ATN is 93.76 ± 0.89%, flux of GLB (240.43 ± 1.76 μg/cm2/h), and flux of ATN (475.2 ± 1.54 μg/cm2/h) which was found to conform to the expected value. The results indicated desired release and permeation profiles. Optimized formulation showed significant pharmacokinetic properties, which shows improvement in bioavailability by 134.30% and 180.32% respectively for two drugs, when compared to marketed oral preparation. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats, compared to oral and drug-loaded nano invasomes formulations. Conclusion Overall, the results showed that nano invasomal gel was found to be a useful and promising transdermal delivery system for the treatment of concurrent diseases.

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Amine Containing Analogs of Sulindac for Cancer Prevention

The Open Medicinal Chemistry Journal ◽

10.2174/1874104501812010001 ◽

2018 ◽

Vol 12 (1) ◽

pp. 1-12

Author(s):

Bini Mathew ◽

Judith V. Hobrath ◽

Michele C. Connelly ◽

R. Kiplin Guy ◽

Robert C. Reynolds

Keyword(s):

Cancer Cell ◽

Cancer Cell Line ◽

Colorectal Polyps ◽

Anticancer Activities ◽

Design And Optimization ◽

Sulindac Sulfide ◽

Inflammatory Drugs ◽

Nanomolar Range

Background:Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activityin vitroand demonstratingin vivoxenograft activity.Objective:Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.Method:A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted sulindac amine sub-libraries. All analogs were screened against three cancer cell lines (prostate, colon and breast).Results:Several active compounds were identifiedviain vitrocancer cell line screening with the most potent compound (26) in the nanomolar range.Conclusion:Compound26and analogs showing the most potent inhibitory activity may be considered for further design and optimization efforts as anticancer hit scaffolds.

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