scholarly journals Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy

2021 ◽  
Author(s):  
Swastika Maity ◽  
Manas Kinra ◽  
Madhavan Nampoothiri ◽  
Devinder Arora ◽  
K. Sreedhara Ranganath Pai ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Caffeic Acid ◽  
Drug Research ◽  
Shikimate Pathway ◽  
Experimental Models ◽  
Promising Candidate ◽  
Effective Combination ◽  
Overwhelming Evidence ◽  
Combination Regimens ◽  
Active Natural

AbstractIncreased effectiveness and decreasing toxicity are prime objectives in drug research. Overwhelming evidence suggests the use of appropriate combination therapy for the better efficacy of drugs owing to their synergistic profile. Dietary active constituents play a major role in health outcomes. Therefore, it is possible to increase the effectiveness of the drug by combining contemporary medication with active natural/semi-synthetic constituents. One such dietary constituent, caffeic acid (CA), is a by-product of the shikimate pathway in plants and is a polyphenol of hydroxycinnamic acid class. Extensive research on CA has proposed its efficacy against inflammatory, neurodegenerative, oncologic, and metabolic disorders. The synergistic/additive effects of CA in combination with drugs like caffeine, metformin, pioglitazone, and quercetin have been reported in several experimental models and thus the present review is an attempt to consolidate outcomes of this research. Multi-target-based mechanistic studies will facilitate the development of effective combination regimens of CA.

ACE2 as therapeutic agent

2020 ◽  
Vol 134 (19) ◽  
pp. 2581-2595
Author(s):  
Qiuhong Li ◽  
Maria B. Grant ◽  
Elaine M. Richards ◽  
Mohan K. Raizada
Keyword(s):  
Therapeutic Agent ◽  
Renin Angiotensin System ◽  
Peptide Hormone ◽  
Experimental Models ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Beneficial Effects ◽  
Overwhelming Evidence ◽  
Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

scholarly journals Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines

2021 ◽  
Vol 9 (2) ◽  
pp. 307
Author(s):  
Evelyn J. Franco ◽  
Xun Tao ◽  
Kaley C. Hanrahan ◽  
Jieqiang Zhou ◽  
Jürgen B. Bulitta ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Cell Lines ◽  
Interferon Alpha ◽  
Chikungunya Virus ◽  
Plaque Assay ◽  
Human Infection ◽  
Viral Burden ◽  
Combination Regimens

Chikungunya virus (CHIKV) is an alphavirus associated with a broad tissue tropism for which no antivirals or vaccines are approved. This study evaluated the antiviral potential of favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) against CHIKV as mono- and combination-therapy in cell lines that are clinically relevant to human infection. Cells derived from human connective tissue (HT-1080), neurons (SK-N-MC), and skin (HFF-1) were infected with CHIKV and treated with different concentrations of FAV, IFN, or RBV. Viral supernatant was sampled daily and the burden was quantified by plaque assay on Vero cells. FAV and IFN were the most effective against CHIKV on various cell lines, suppressing the viral burden at clinically achievable concentrations; although the degree of antiviral activity was heavily influenced by cell type. RBV was not effective and demonstrated substantial toxicity, indicating that it is not a feasible candidate for CHIKV. The combination of FAV and IFN was then assessed on all cell lines. Combination therapy enhanced antiviral activity in HT-1080 and SK-N-MC cells, but not in HFF-1 cells. We developed a pharmacokinetic/pharmacodynamic model that described the viral burden and inhibitory antiviral effect. Simulations from this model predicted clinically relevant concentrations of FAV plus IFN completely suppressed CHIKV replication in HT-1080 cells, and considerably slowed down the rate of viral replication in SK-N-MC cells. The model predicted substantial inhibition of viral replication by clinical IFN regimens in HFF-1 cells. Our results highlight the antiviral potential of FAV and IFN combination regimens against CHIKV in clinically relevant cell types.

Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16567-e16567
Author(s):  
Anish B. Parikh ◽  
Sarah P. Psutka ◽  
Yuanquan Yang ◽  
Katharine Collier ◽  
Abdul Miah ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Kaplan Meier ◽  
Grade 3 ◽  
Combination Regimens

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]

scholarly journals The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens

2021 ◽  
Author(s):  
Agata Blasiak ◽  
Anh TL Truong ◽  
Alexandria Remus ◽  
Lissa Hooi ◽  
Shirley Gek Kheng Seah ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Drug Efficacy ◽  
Drug Combinations ◽  
Multiple Drug ◽  
Original Strain ◽  
Live Virus ◽  
Drug Synergy ◽  
Positive Treatment ◽  
Strong Candidate ◽  
Combination Regimens

Objectives: We aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19. Methods: A pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain and B.1.351 variant) and Vero E6 assay with a quadratic optimization workflow. Results: Within 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived. Conclusions: IDentif.AI 2.0 rapidly revealed promising drug combinations for a clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence.

scholarly journals Currently Available Strategies for Target Identification of Bioactive Natural Products

2021 ◽  
Vol 9 ◽  
Author(s):  
Gen Li ◽  
Xuling Peng ◽  
Yajing Guo ◽  
Shaoxuan Gong ◽  
Shijie Cao ◽  
...  
Keyword(s):  
Natural Products ◽  
Pharmaceutical Industry ◽  
Drug Research ◽  
Target Identification ◽  
Biologically Active ◽  
Bioactive Natural Products ◽  
Target Sites ◽  
Wide Availability ◽  
Research Findings ◽  
Active Natural

In recent years, biologically active natural products have gradually become important agents in the field of drug research and development because of their wide availability and variety. However, the target sites of many natural products are yet to be identified, which is a setback in the pharmaceutical industry and has seriously hindered the translation of research findings of these natural products as viable candidates for new drug exploitation. This review systematically describes the commonly used strategies for target identification via the application of probe and non-probe approaches. The merits and demerits of each method were summarized using recent examples, with the goal of comparing currently available methods and selecting the optimum techniques for identifying the targets of bioactive natural products.

Effective combination therapy with high concentration of Minoxidil and Carboxygas in resistant Androgenetic alopecia: Report of nine cases

2020 ◽  
Vol 19 (11) ◽  
pp. 2953-2957 ◽  
Author(s):  
Mohammad Ali Nilforooshzadeh ◽  
Elaheh Lotfi ◽  
Maryam Heidari‐Kharaji ◽  
Sara Zolghadr ◽  
Parvin Mansouri
Keyword(s):  
Combination Therapy ◽  
Androgenetic Alopecia ◽  
High Concentration ◽  
Effective Combination

scholarly journals Nitric oxide as a mediator of gastrointestinal mucosal injury?—Say it ain't so

1995 ◽  
Vol 4 (6) ◽  
pp. 397-405 ◽  
Author(s):  
Paul Kubes ◽  
John L. Wallace
Keyword(s):  
Nitric Oxide ◽  
Gastrointestinal Tract ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Mucosal Blood Flow ◽  
Mucosal Injury ◽  
Experimental Models ◽  
Radical Species ◽  
Overwhelming Evidence ◽  
Mucosal Defence

Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down-regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury.

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