scholarly journals Enhancing Natural Product Clinical Trials (P13-037-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Sorkin ◽  
Adam Kuszak ◽  
Guido Pauli ◽  
Gregory Bloss ◽  
Bruce Barrett ◽  
...  
Keyword(s):  
Public Health ◽  
Clinical Trials ◽  
Natural Product ◽  
Null Hypothesis ◽  
Protein Denaturation ◽  
Model Systems ◽  
Vitro Assay ◽  
Good Practices ◽  
Product Identity

Abstract Objectives To discuss good practices and criteria for optimal design and interpretation of pre-clinical and clinical natural product (NP) research in order to increase benefit from our investment in NP clinical trials (CT). Background: Large, randomized, controlled CT often fail to reject the null hypothesis or show rigorous evidence of benefit. This includes recent large, NIH-supported CT of nutrients such as vitamin D and selenium, and of botanical dietary supplements. Negative and positive outcomes may be equally important for public health, but because large CT cost at least $20 M each, plus opportunity costs, it is important that CT designs maximize the yield of actionable information regardless of outcome. Methods Experts and stakeholders from academia, government and the private sector collaboratively developed a broadly attended workshop in which good practices to enhance rigor, reproducibility and translational relevance were discussed. Results N/A. Conclusions Critical issues in CT design include product identity, reproducibility and pharmacology (where feasible), power to test a primary outcome significant to consumers, and placebo controls. When basing a CT on traditional use or prior in vitro or in vivo studies, similarity of product (e.g., source identity, methods of preparation, form and intake), health outcome and population (e.g., age, sex, genetics, diet and environment), require careful consideration. Appropriate controls for known types of in vitro assay interference (e.g., aggregation, membrane disruption, protein denaturation) are imperative. Compounds with limited bioavailability, or activity only at concentrations above those achievable by ingestion, are likely poor candidates for dietary CT. Translational validity of model systems should be carefully assessed. Appropriate analyses (e.g., p-curve and meta-regression methods) should be used to obtain bias-corrected effect size estimates, and to identify research areas where the evidence base may be weaker than published findings suggest. Finally, CT prioritization should consider expected impact on public health, and whether known NP causal mechanisms of action are such that useful information, e.g., on product bioavailability or biological activity, are generated even if the completed CT fails to reject the null hypothesis. Funding Sources NIH, FDA, USDA.

Curcumin: Natural Antimicrobial and Anti Inflammatory Agent

2021 ◽  
pp. 1-8
Author(s):  
Pehlivanović Belma ◽  
Čaklovica Kenan ◽  
Lagumdžija Dina ◽  
Omerović Naida ◽  
Žiga Smajić Nermina ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Protein Denaturation ◽  
Dose Range ◽  
In Vitro Assays ◽  
Natural Antimicrobial ◽  
In Vivo Models ◽  
Vitro Assay ◽  
Inflammatory Agent ◽  
Anti Inflammatory

The pursuance of novel antimicrobial and anti-inflammatory agents has been expanding due to a significant need for more efficient pharmacotherapy of various infections and chronic diseases. During the last decade, pharmacokinetics, pharmacodynamics and pharmacological properties of curcumin have been extensively studied. The aim of the present study was to evaluate the antibacterial activity of curcumin against both Gram-positive and Gram-negative bacteria as well as its antifungal activity by using in vitro agar well diffusion assay. Moreover, the anti-inflammatory activity of curcumin was determined with in vitro assay of inhibition of protein denaturation. Results demonstrated wide antimicrobial activity of curcumin upon all of the test bacteria and fungi. The strongest activity of curcumin was observed at a concentration of 0.50 mg/ml against S. aureus, L. monocytogenes, E. coli, P. aeruginosa and C. albicans, resulting in a maximum zone of inhibition of 14.7 mm, 14.3 mm, 13.7 mm, 10.7 mm and 10.7 mm, respectively. Findings suggested that the antimicrobial activity of curcuminis dependent upon the concentrations. Furthermore, results demonstrated high effectiveness of curcumin compared to standard acetylsalicylic acid in inhibiting heat-induced protein denaturation, which activity is also depended upon the concentrations. The present study emphasises the potential application of curcumin as a natural antimicrobial and anti-inflammatory agent. However, findings of this study are restricted to in vitro assays and consideration should be given to conducting a study involving wider dose range test substances as well as including further research on in vivo models.

Combining galiximab with the chemotherapeutic agents fludarabine or doxorubicin improves efficacy in animal models of lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3040-3040 ◽  
Author(s):  
H. K. Hariharan ◽  
T. Murphy ◽  
D. Clanton ◽  
L. Berquist ◽  
P. Chu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Clinical Benefit ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Model Systems ◽  
Anti Cd20

3040 Background: Galiximab, a primatized monoclonal antibody that binds with high affinity to CD80 and mediates antibody- dependent, cell-mediated cytotoxicity in vitro, is currently under investigation for the treatment of follicular non-Hodgkin’s lymphoma (NHL). In a phase I/II monotherapy study, galiximab produced an overall response rate of 11%, and tumor reductions were observed in 46% of patients. Initial clinical trials also demonstrate that galiximab is well tolerated and suggest that combining galiximab with rituximab (anti-CD20) provides clinical benefit. These results are consistent with preclinical studies in murine lymphoma xenograft model systems, which demonstrate the superiority of combination therapy. Methods: To further define the therapeutic potential of galiximab, the Raji subcutaneous and the SKW disseminated lymphoma murine xenograft models were used to define the in vivo efficacy of galiximab alone or in combination with fludarabine or doxorubicin. Similar studies were performed with rituximab. Results: In the Raji model, both galiximab and rituximab exhibited maximal inhibition of the growth of preestablished (150-mg) tumors at a dose of 3 mg/kg/wk. Interestingly, higher doses of galiximab (but not rituximab) showed reduced inhibition. Galiximab (3 mg/kg/wk) inhibited tumor growth alone (P<0.0001 vs. control) and showed significantly enhanced activity when combined with fludarabine (50 or 100 mg/kg daily for 5 days; P<0.0002 vs. galiximab alone and P<0.003 vs. fludarabine alone). Similar results were observed with rituximab. In the SKW model, treatment with galiximab (5 mg/kg/wk for 6 doses) significantly enhanced survival compared with a control (P<0.0001) or doxorubicin (2.5 mg/kg/day for 3 doses; P<0.0001). Studies combining fludarabine or doxorubicin with both galiximab and rituximab are ongoing. Conclusions: Studies in animal models of lymphoma indicate that galiximab may provide clinical benefit when used in combination with chemotherapeutic agents such as fludarabine and doxorubicin, and provide a rationale for the investigation of these novel chemoimmunotherapy combinations in clinical trials. No significant financial relationships to disclose.

scholarly journals The C-terminal region of α-crystallin: involvement in protection against heat-induced denaturation

1993 ◽  
Vol 294 (2) ◽  
pp. 435-438 ◽  
Author(s):  
L Takemoto ◽  
T Emmons ◽  
J Horwitz
Keyword(s):  
Protein Denaturation ◽  
In Vitro Assay ◽  
Terminal Region ◽  
Tryptic Digestion ◽  
Vitro Assay ◽  
Induced Aggregation

Recent studies have demonstrated that the alpha-crystallins can protect other proteins against heat-induced denaturation and aggregation. To determine the possible involvement of the C-terminal region in this activity, the alpha-crystallins were subjected to limited tryptic digestion, and the amount of cleavage from the N-terminal and C-terminal regions of the alpha-A and alpha-B crystallin chains was assessed using antisera specific for these regions. Limited tryptic digestion resulted in cleavage only from the C-terminal region of alpha-A crystallin. This trypsin-treated alpha-A crystallin preparation showed a decreased ability to protect proteins from heat-induced aggregation using an in vitro assay. Together, these results demonstrate that the C-terminal region of alpha-A crystallin is important for its ability to protect against heat-induced aggregation, which is consistent with the hypothesis that post-translational changes that are known to occur at the C-terminal region may have significant effects on the ability of alpha-A crystallin to protect against protein denaturation in vivo.

scholarly journals Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

2021 ◽  
Vol 15 (10) ◽  
pp. e0009870
Author(s):  
Nina Svensen ◽  
Susan Wyllie ◽  
David W. Gray ◽  
Manu De Rycker
Keyword(s):  
Clinical Trials ◽  
Chagas Disease ◽  
Time Resolution ◽  
Standard Of Care ◽  
Live Imaging ◽  
Model Systems ◽  
High Time Resolution ◽  
Laboratory Findings

Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.

scholarly journals Therapeutic Application of Chloroquine and Hydroxychloroquine in Clinical Trials for COVID-19: A systematic review

2020 ◽  
Author(s):  
Divya RSJB Rana ◽  
Santosh Dulal
Keyword(s):  
Public Health ◽  
Systematic Review ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Virus Disease ◽  
Global Public Health ◽  
Therapeutic Application ◽  
Clinical Trial Registries ◽  
Corona Virus

AbstractThe corona virus disease -2019 (COVID-19) pandemic has caused a massive global public health havoc. Recent published clinical trials show conflicting data for use of chloroquine/hydroxychloroquine for COVID-19. This study meticulously evaluated the various dosages of chloroquine and hydroxychloroquine utilized in clinical trials registered in Chinese and US clinical trial registries for the treatment of pneumonia caused by SARS-CoV-2. Moreover, the results of published clinical trials and in vitro studies using chloroquine and hydroxychloroquine relevant to the disease are discussed.

Gender-Based Differences in the Toxicity of Pharmaceuticals—The Food and Drug Administration's Perspective

2001 ◽  
Vol 20 (3) ◽  
pp. 149-152 ◽  
Author(s):  
Margaret Ann Miller
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Sex Difference ◽  
Qt Interval ◽  
Drug Effects ◽  
Drug Efficacy ◽  
Model Systems ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Induced

Women experience more adverse reactions to treatment with therapeutic drugs than men. Theories proposed to explain this include overdosing, different pharmacokinetics and pharmacodynamics, women are more likely to report adverse events than men, or women take more medications than men. Food and Drug Administration (FDA) Office of Women's Health (OWH) funds research to promote including women in clinical trials and understanding the biology of sex-related differences in the safety of FDA-regulated products. Including women in clinical trials advances the understanding of drug efficacy and safety in women by providing information on drug dosing, pharmacokinetics, and pharmacodynamics. A Baysian statistical analysis of sex differences in adverse events showed that although about the same number of adverse events were reported for men and women, those reported for women were more serious. One example of a sex difference in the toxicity of pharmaceuticals is the drug-induced cardiac arrhythmia, torsades de point. OWH funded studies in animals and humans to investigate the mechanism behind this sex difference. These studies demonstrated that shortening the QT interval increases the risk of developing torsades and that androgens protect against torsades by slowing cardiac repolarization and prolonging the QT interval. Understanding the mechanisms behind other reported sex-related differences in adverse drug effects requires additional research. The preliminary studies conducted to date suggest that this sex-related difference is likely to be a multifactorial problem requiring information from several fields of study. Ideally, individuals at risk for developing an adverse event should be identified prior to therapeutic intervention. The OWH plans to fund more studies to investigate the role of hormonal variations on drug metabolism and drug-drug interactions. Animal and in vitro model systems are needed to fully understand the mechanism of how gender influences drug toxicity.

scholarly journals In vitro anti-inflammatory activity of aqueous extract of Albizia lebbeck leaf (L.)

2020 ◽  
Vol 9 (5) ◽  
pp. 356-360
Author(s):  
Kamala Lakshmi B ◽  
◽  
S Valarmathi ◽  
Keyword(s):  
Aqueous Extract ◽  
Protein Denaturation ◽  
Research Work ◽  
Moderate Activity ◽  
Phytochemical Screening ◽  
Albizia Lebbeck ◽  
Vitro Assay ◽  
Maximum Inhibition ◽  
Anti Inflammatory

Albizia lebbeck (L.) Benth is an important traditional tree found throughout India. All part of this tree is considered as folk medicine and used for treatment of various disease. Current research work was carried out to identify the bioactive compound by phytochemical screening and to evaluate anti-inflammatory potential of aqueous leaf extract of A. lebbeck. The phytochemical screening of the leaf of A. lebbeck shows the presence of alkaloid, flavonoid, tannin, phenol, saponin, glycoside and free amino acid. The maximum inhibition of protein denaturation was found to be 78.06±0.5% at 500 µg/mL concentration and its IC₅₀ was 330 µg/mL concentration. The maximum inhibition in membrane stabilization was found to be 74.09±0.33% at 500 µg/mL concentration and its IC₅₀ was 440 µg/mL concentration. The maximum protection in hypotonicity induced haemolysis shows about 69.34±0.38% at 500 µg/mL concentration and its IC₅₀ was 400 µg/mL concentration. In vitro assay shows the moderate activity of anti-inflammatory in aqueous extract of A. lebbeck, when compared with the standard.

scholarly journals Improving Natural Product Research Translation: from Source to Clinical Trial

2019 ◽  
Author(s):  
Barbara C Sorkin ◽  
Adam J Kuszak ◽  
Naomi K Fukagawa ◽  
Freddie Ann Hoffman ◽  
Mahtab Jafari ◽  
...  
Keyword(s):  
Public Health ◽  
Clinical Trial ◽  
Natural Product ◽  
Phase Iii ◽  
Research Translation ◽  
Natural Product Research ◽  
Research Questions ◽  
The Continuum

While great interest in health effects of natural product (NP) foods and dietary supplements persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs,especially Phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for: NPcharacterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. NPCTsprioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

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