Journal Description
Drugs and Drug Candidates
Drugs and Drug Candidates
is an international, peer-reviewed, open access journal on drug discovery, development, and knowledge. It is published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- Rapid Publication: first decisions in 16 days; acceptance to publication in 5.8 days (median values for MDPI journals in the second half of 2022).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
- Drugs and Drug Candidates is a companion journal of Pharmaceuticals.
Latest Articles
How Far Have We Developed Antibody–Drug Conjugate for the Treatment of Cancer?
Drugs Drug Candidates 2023, 2(2), 377-421; https://doi.org/10.3390/ddc2020020 - 23 May 2023
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Cancer, also known as malignant tumour or neoplasm, is a leading cause of death worldwide. One distinct feature from normal cells is that cancerous cells often overexpress protein on the cell membrane—for instance, the overexpression of human epidermal growth factor receptor 2. The
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Cancer, also known as malignant tumour or neoplasm, is a leading cause of death worldwide. One distinct feature from normal cells is that cancerous cells often overexpress protein on the cell membrane—for instance, the overexpression of human epidermal growth factor receptor 2. The expression of a specific protein on the cancerous cell surface acts as a marker that differentiates the normal cell and facilitates the recognition of cancerous cells. An emerging anticancer treatment, Antibody–Drug Conjugates (ADCs), utilises this unique feature to kill cancerous cells. ADCs consist of an antibody linked with a cytotoxic payload, mainly targeting the antigen found on cancerous cells. This design can increase the specificity in delivering the cytotoxin to the drug target, thus increasing the drug efficacy and reducing the side effect of cancer treatment due to off-target toxicities. There are tremendous quantities of clinical trials conducted to evaluate the safety and effectiveness of this magic drug in treating different types of cancers. However, only 12 ADCs have been approved by the FDA until now. This review provides the principles of ADCs and highlights the ADCs that FDA has approved. In addition, some of the ADCs that undergo clinical trials are discussed in this review. The application of computational techniques in addressing ADCs’ challenges and neoantigen-targeted cancer vaccines is also highlighted. Although ADCs have been seen as promising magic drugs in cancer treatment, the problems such as toxicity, the stability of the linker, the specificity of an antibody with antigen, and so on, remain a challenge in developing ADCs.
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Open AccessFeature PaperArticle
Reduction of Cancer Stem Cells and Invasiveness of Human Melanoma and Breast Cancer by Cucurbitacin B from Lagenaria siceraria
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, , , , and
Drugs Drug Candidates 2023, 2(2), 358-376; https://doi.org/10.3390/ddc2020019 - 22 May 2023
Abstract
Cucurbitacins are secondary metabolites that are commonly found in the Cucurbitacae family. Many biological properties have been reported for cucurbitacins, including anti-inflammatory, antioxidant, antiviral, anti-malaria, and anticancer properties. While studies for the anticancer property of cucurbitacins focus mostly on the cell-cycle progression and
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Cucurbitacins are secondary metabolites that are commonly found in the Cucurbitacae family. Many biological properties have been reported for cucurbitacins, including anti-inflammatory, antioxidant, antiviral, anti-malaria, and anticancer properties. While studies for the anticancer property of cucurbitacins focus mostly on the cell-cycle progression and apoptosis, no study has considered the effect of cucurbitacin on other cancer behaviors. Here, we report cell-proliferation-based drug testing on random herbal extracts leading to the identification of cucurbitacin B as an anticancer compound. Interestingly, cucurbitacin B had no effect on the proliferation of rat embryonic myoblast cells. We also found that cucurbitacin B significantly reduced the invasiveness of at least two highly metastatic breast cancer and melanoma cells. Using known cancer stem-cell markers, we observed a significant reduction of the melanoma stem cells. Molecularly, cucurbitacin B caused reduction of the metastasis-promoting gene Snail in melanoma and one of the cancer stem cell markers, ALDH1A1 (aldehyde dehydrogenase 1 A1), in breast cancer. Finally, we report the potential toxicity of cucurbitacin B in developing skin tissue and the olfactory organ using zebrafish embryo. In summary, our study suggests the potential use of cucurbitacin B for cancer metastasis and relapse treatment.
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(This article belongs to the Collection Drug Candidates from Natural Sources)
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Open AccessReview
The Readiness to Harness the Floristic Uniqueness of Mauritius in Biomedicine
Drugs Drug Candidates 2023, 2(2), 335-357; https://doi.org/10.3390/ddc2020018 - 10 May 2023
Abstract
Resistance to the existing arsenal of therapeutic agents significantly impedes successful drug therapy. One approach to combat this burgeoning global crisis is to provide novel and more effective clinical agents. Terrestrial plants have long been exploited as a source of novel drug candidates.
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Resistance to the existing arsenal of therapeutic agents significantly impedes successful drug therapy. One approach to combat this burgeoning global crisis is to provide novel and more effective clinical agents. Terrestrial plants have long been exploited as a source of novel drug candidates. In this line, the endemic floral diversity of the Republic of Mauritius cannot be ignored. However, developing drugs from these plants is a multi-stepped, lengthy process that requires multistakeholder involvement from scientists, policymakers, and conservationists as well as the local community. This review aims at summarising the reported bioactivities of the endemic plants. The electronic databases were searched using relevant keywords. A total of 33 original research articles were considered. A repertoire of 17 families comprising 53 Mauritian-endemic plant species has been reported for their anticancer activity (n = 20), antimicrobial activity (n = 36), antidiabetic activity (n = 3), and clinical enzyme inhibitory activity (n = 25). Five plant extracts, namely Acalypha integrifolia, Labourdonaisia glauca, Eugenia tinifolia, Syzygium coriaceum, and Terminalia bentzoë, have been earmarked as worthy to be further investigated for their anticancer potential. Moreover, two Psiadia species, namely P. arguta and P. terebinthina, have shown promising antimicrobial activity. This review highlights the extracts’ potent anticancer and antimicrobial activities, focussing on their proposed mechanism of action. Moreover, the need for metabolite profiling for identifying bioactive ingredient(s) is emphasised.
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(This article belongs to the Collection Drug Candidates from Natural Sources)
Open AccessReview
Virtual Screening Algorithms in Drug Discovery: A Review Focused on Machine and Deep Learning Methods
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, , , and
Drugs Drug Candidates 2023, 2(2), 311-334; https://doi.org/10.3390/ddc2020017 - 05 May 2023
Abstract
Drug discovery and repositioning are important processes for the pharmaceutical industry. These processes demand a high investment in resources and are time-consuming. Several strategies have been used to address this problem, including computer-aided drug design (CADD). Among CADD approaches, it is essential to
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Drug discovery and repositioning are important processes for the pharmaceutical industry. These processes demand a high investment in resources and are time-consuming. Several strategies have been used to address this problem, including computer-aided drug design (CADD). Among CADD approaches, it is essential to highlight virtual screening (VS), an in silico approach based on computer simulation that can select organic molecules toward the therapeutic targets of interest. The techniques applied by VS are based on the structure of ligands (LBVS), receptors (SBVS), or fragments (FBVS). Regardless of the type of VS to be applied, they can be divided into categories depending on the used algorithms: similarity-based, quantitative, machine learning, meta-heuristics, and other algorithms. Each category has its objectives, advantages, and disadvantages. This review presents an overview of the algorithms used in VS, describing them and showing their use in drug design and their contribution to the drug development process.
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(This article belongs to the Collection Artificial Intelligence Applied to Medicinal Chemistry)
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Open AccessArticle
Synergistic Interaction of Glycyrrhizin with Norfloxacin Displays ROS-Induced Bactericidal Activity against Multidrug-Resistant Staphylococcus aureus
Drugs Drug Candidates 2023, 2(2), 295-310; https://doi.org/10.3390/ddc2020016 - 26 Apr 2023
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Acquired bacterial resistance against several antibiotics has severely impaired the drug treatment regime. Multidrug-resistant Staphylococcus aureus (MDRSA) causes several life-threatening human pathologies. The introduction of novel antibiotics is a tedious process. Therefore, we have introduced glycyrrhizin (Gly) as a bioenhancer of norfloxacin (Nor),
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Acquired bacterial resistance against several antibiotics has severely impaired the drug treatment regime. Multidrug-resistant Staphylococcus aureus (MDRSA) causes several life-threatening human pathologies. The introduction of novel antibiotics is a tedious process. Therefore, we have introduced glycyrrhizin (Gly) as a bioenhancer of norfloxacin (Nor), which showed synergistic interactions and a robust drug response. The drug resistance reversal potential of Gly against MDRSA was monitored. Gly and GlyNor (glycyrrhizin + norfloxacin) were used for spectrofluorometer and flow cytometry analysis for the measurement of free radicals and its effect upon cell membranes and macromolecules. Morphological analysis was carried out with the help of SEM. qRT-PCR analysis was conducted for gene regulation. Gly was observed to lower the MIC (minimum inhibitory concentration) of different groups of antibiotics up to 64-fold against MDRSA. GlyNor exerted oxidative stress, as evidenced by the measurement of reactive oxygen species (ROS) and their effect upon cell components. Gly and GlyNor showed membrane damage potential. The expression analysis of oxidative-related and MDR genes showed the up- and downregulation of these genes, respectively. GlyNor significantly lengthened post-antibiotic effects (PAE) and showed reduced mutation frequency rate (MFR). The synergistic bioenhancer properties of Gly with Nor and their enhanced ROS generation against MDRSA are reported for the first time in this study. Severe oxidative stress caused membrane damage, DNA fragmentation, transcriptional changes, and bacterial cell death. We strongly believe this could be a potential measure against rapidly evolving MDRSA.
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Open AccessArticle
Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents
Drugs Drug Candidates 2023, 2(2), 279-294; https://doi.org/10.3390/ddc2020015 - 21 Apr 2023
Abstract
Pseudomonas aeruginosa, a life-threatening bacteria listed as a priority pathogen by World Health Organization WHO, is known to cause severe nosocomial infections and fatality in immunocompromised individuals through its quorum sensing (QS) mediated biofilm formation. P. aeruginosa’s antibiotic-resistant biofilms are highly challenging
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Pseudomonas aeruginosa, a life-threatening bacteria listed as a priority pathogen by World Health Organization WHO, is known to cause severe nosocomial infections and fatality in immunocompromised individuals through its quorum sensing (QS) mediated biofilm formation. P. aeruginosa’s antibiotic-resistant biofilms are highly challenging to the existing antibiotic treatment options. There is an urgent clinical need to develop novel alternative therapeutic molecules such as antibiofilm and antiquorum sensing agents to counter the emergence of an unprecedented pace of antibiotic resistance of pathogens. In this context, a library of seventy 3-amidocoumarin derivatives was designed, and docking studies were performed against the P. aeruginosa LasR receptor using AutoDock 4.0. Based on docking results, a final series of sixteen 3-amidocoumarin derivatives (4a–p) were synthesized and evaluated for antibiofilm activity in vitro. Eight compounds significantly inhibited the formation of P. aeruginosa PAO1 biofilm. Compounds 4f, 4l and 4o showed maximum % inhibition in antibiotic-resistant P. aeruginosa PAO1 biofilm formation in the range of 80% to 86%. Further, the structure–activity relationship (SAR) studies revealed that the presence of electron-donating and bromo substituents at benzamido and coumarin moieties, respectively, effectively enhances the antibiofilm activity. In addition, the binding interactions between the synthesized compounds and active sites of the LasR QS receptor (Protein Data Bank Code: 2uv0) in P. aeruginosa were also investigated by molecular docking. The high binding affinities indicate that these compounds might be suitable for development into potent inhibitors of QS and biofilm disruptors.
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(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessReview
Therapeutic Perspectives of Metal Nanoformulations
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, , , , , , , , , , , , and
Drugs Drug Candidates 2023, 2(2), 232-278; https://doi.org/10.3390/ddc2020014 - 13 Apr 2023
Abstract
In recent decades, acceptance of nanoparticles (NPs) in therapeutic applications has increased because of their outstanding physicochemical features. By overcoming the drawbacks of conventional therapy, the utilization of metal NPs, metal-oxide, or metal supported nanomaterials have shown to have significant therapeutic applications in
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In recent decades, acceptance of nanoparticles (NPs) in therapeutic applications has increased because of their outstanding physicochemical features. By overcoming the drawbacks of conventional therapy, the utilization of metal NPs, metal-oxide, or metal supported nanomaterials have shown to have significant therapeutic applications in medicine. This is proved by a lot of clinical and laboratory investigations that show improved treatment outcomes, site-specific drug delivery, and fewer side effects compared to traditional medicine. The metal NPs interaction with living cells (animal and plant) showed many ways to develop therapeutic models with the NPs. Despite all of the advancements that science has achieved, there is still a need to find out their performance for long-term use to solve modern challenges. In this regard, the present documentation reviews some potential metals, including silver (Ag), gold (Au), zinc (Zn), copper (Cu), iron (Fe), and nickel (Ni) NPs, as therapeutic agents in various areas such as anticancer, antimicrobial, antidiabetic, and applicable for the treatment of many other diseases. Depending on the outstanding ongoing research and practical trials, metal-based NPs can be considered the hope of prospective modern therapeutic areas.
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(This article belongs to the Collection Bioinorganic Chemistry in Drug Discovery)
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Open AccessSystematic Review
A Systematic Review of Molecular Pathway Analysis of Drugs for Potential Use in Liver Cancer Treatment
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, , , , , , , and
Drugs Drug Candidates 2023, 2(2), 210-231; https://doi.org/10.3390/ddc2020013 - 03 Apr 2023
Abstract
Liver cancer is a high mortality cancer, and its increasing prevalence is a concern worldwide. Current treatment modalities for liver cancer include chemotherapy and immunotherapy. These therapies provide symptomatic relief and help prolong the lives of patients but are not an absolute cure.
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Liver cancer is a high mortality cancer, and its increasing prevalence is a concern worldwide. Current treatment modalities for liver cancer include chemotherapy and immunotherapy. These therapies provide symptomatic relief and help prolong the lives of patients but are not an absolute cure. In this paper we have explored an alternative approach, drug repurposing, to identify drugs for treating liver cancer. Databases like PubMed, ScienceDirect, and JSTOR were used for literature mining, and the PRISMA 2020 systemic review guidelines were followed to identify drugs that have been trialed for repurposing in liver cancer. The protein receptors and target protein classes of all the drugs were identified using the Swiss Target Prediction tool. Further, the biological interactions and pathways followed by the drugs were studied via protein interaction networks using Cytoscape. Molecular pathways such as Bile acid receptor activity, Inosine-5′-monophosphate (IMP) dehydrogenase activity, JUN kinase activity, Nitric-oxide synthase activity, and Mitogen-activated protein (MAP) kinase activity were observed to be influenced by these drugs. The fact that the genes targeted by these repurposed drugs are common with the differentially expressed genes in liver cancer is an excellent starting point to verify the current hypothesis.
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(This article belongs to the Section Marketed Drugs)
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Open AccessArticle
Optimizing Protein Production in Therapeutic Phages against a Bacterial Pathogen, Mycobacterium abscessus
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Drugs Drug Candidates 2023, 2(1), 189-209; https://doi.org/10.3390/ddc2010012 - 21 Mar 2023
Abstract
Therapeutic phages against pathogenic bacteria should kill the bacteria efficiently before the latter evolve resistance against the phages. While many factors contribute to phage efficiency in killing bacteria, such as phage attachment to host, delivery of phage genome into the host, phage mechanisms
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Therapeutic phages against pathogenic bacteria should kill the bacteria efficiently before the latter evolve resistance against the phages. While many factors contribute to phage efficiency in killing bacteria, such as phage attachment to host, delivery of phage genome into the host, phage mechanisms against host defense, phage biosynthesis rate, and phage life cycle, this paper focuses only on the optimization of phage mRNA for efficient translation. Phage mRNA may not be adapted to its host translation machinery for three reasons: (1) mutation disrupting adaptation, (2) a recent host switch leaving no time for adaptation, and (3) multiple hosts with different translation machineries so that adaptation to one host implies suboptimal adaptation to another host. It is therefore important to optimize phage mRNAs in therapeutic phages. Theoretical and practical principles based on many experiments were developed and applied to phages engineered against a drug-resistant Mycobacterium abscessus that infected a young cystic fibrosis patient. I provide a detailed genomic evaluation of the three therapeutic phages with respect to translation initiation, elongation, and termination, by making use of both experimental results and highly expressed genes in the host. For optimizing phage genes against M. abscessus, the start codon should be AUG. The DtoStart distance from base-pairing between the Shine-Dalgarno (SD) sequence and the anti-SD sequence should be 14–16. The stop codon should be UAA. If UAG or UGA is used as a stop codon, they should be followed by nucleotide U. Start codon, SD, or stop codon should not be embedded in a secondary structure that may obscure the signals and interfere with their decoding. The optimization framework should be generally applicable to developing therapeutic phages against bacterial pathogens.
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(This article belongs to the Section In Silico Approaches in Drug Discovery)
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Open AccessFeature PaperReview
A Review of the Patentability of Rosemary-Derived Drugs and Bioactive Compounds
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and
Drugs Drug Candidates 2023, 2(1), 172-188; https://doi.org/10.3390/ddc2010011 - 16 Mar 2023
Abstract
We reviewed the patentability of rosemary-derived drugs and bioactive compounds over the last 20 years and analyzed patent documents related to the rosemary (Rosmarinus officinalis Linné) plant using patent analysis techniques. A total of 12,320 patent documents (patent applications and granted patents)
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We reviewed the patentability of rosemary-derived drugs and bioactive compounds over the last 20 years and analyzed patent documents related to the rosemary (Rosmarinus officinalis Linné) plant using patent analysis techniques. A total of 12,320 patent documents (patent applications and granted patents) were identified, with China having the highest number of patent documents at 4384. The year 2017 had the most patent documents (1122). Patent classification codes indicate that most inventions are for medicinal preparations and cosmetics characterized by their composition. Further, expert driving forces and knowledge clusters showed that research and development has focused on methods to bring pharmaceutical products into specific physical or administering forms, which are described in the majority of patents. To demonstrate the innovation trends in rosemary-derived drugs and bioactive compounds, a selection of relevant patent documents, with publication dates between 2002 and 2022, is described at the end of the study. This selection contains a total of 13 patent documents, including six patent applications and seven granted patents, and deals with pharmaceutical and biomedical applications, processes for extracting rosemary-derived biomolecules (e.g., rosmarinic acid, carnosic acid, and carnosol), and cosmetic and food applications.
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(This article belongs to the Section Intellectual Property, Regulatory Affairs, and Market Analysis)
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Open AccessReview
Recent Developments in Electrospun Nanofibers as Delivery of Phytoconstituents for Wound Healing
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, , , , , , and
Drugs Drug Candidates 2023, 2(1), 148-171; https://doi.org/10.3390/ddc2010010 - 15 Mar 2023
Abstract
Wound healing is an unresolved therapeutic challenge for the medical community, as wound assessment and management is a complex procedure involving numerous factors that play a significant role in the healing process. Several factors, including bacterial infections, underlying conditions, malnutrition, obesity, aging, and
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Wound healing is an unresolved therapeutic challenge for the medical community, as wound assessment and management is a complex procedure involving numerous factors that play a significant role in the healing process. Several factors, including bacterial infections, underlying conditions, malnutrition, obesity, aging, and smoking are the most frequent causes of a delayed wound-healing process. The shortcomings related to the currently used wound dressings include poor antimicrobial properties, weak mechanical features, poor biodegradability, biocompatibility, etc. Modern medicine has expanded the use of phytoconstituents based on nanotechnology to regenerate and repair soft and hard tissues. Electrospun nanofiber platforms are the most recent and promising among many types of conventional wound dressings due to their distinct characteristics. Many plant extracts and their phytoconstituents are well-known as adequate substitutes for wound healing agents because of their wide range of active ingredients, accessibility, and limited side effects. Incorporating these phytoconstituents into electrospun nanofibers combines the structural properties of the nanofibers with the antibacterial and therapeutic properties of the plants, making the nanofibers ideal for use as wound dressings. This review focuses on the antibacterial and therapeutic applications of nanofiber wound dressings containing phytoconstituents and their potential to revolutionize wound healing.
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(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Pharmacological Blockade of TGF-Beta Reduces Renal Interstitial Fibrosis in a Chronic Ischemia–Reperfusion Animal Model
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, , , , , , , , , , , and
Drugs Drug Candidates 2023, 2(1), 137-147; https://doi.org/10.3390/ddc2010009 - 13 Mar 2023
Abstract
The targeting of transforming growth factor β (TGF-β) has been shown to reduce complications related to ischemia-reperfusion injury (IRI) post-surgically. Pirfenidone (PFD) specifically inhibits TGF-β expression and has been demonstrated to provide protection from IRI in short-term allograft models, though not yet in
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The targeting of transforming growth factor β (TGF-β) has been shown to reduce complications related to ischemia-reperfusion injury (IRI) post-surgically. Pirfenidone (PFD) specifically inhibits TGF-β expression and has been demonstrated to provide protection from IRI in short-term allograft models, though not yet in long-term models. A chronic unilateral IRI model was established using male Wistar rats. The animals were divided into two groups: one with IRI and a pre-treatment of PFD (0.5 mg/kg) followed by 0.5 mg/kg/day of orally administered PFD for 30 days, and a control group without PFD treatment. A sham group was also included. Kidneys and blood samples were collected after 30 days, and the renal function was evaluated by measuring the serum creatinine and KIM-1 levels. RT-PCR was used to analyze fibrosis-related genes, and Luminex to quantify the pro-inflammatory serum IL-18 cytokine. Renal section staining and histological analysis were used to detect collagen deposits. Comparison within the groups showed an increase in serum creatinine and KIM-1 expression after IRI in the control group, while PFD reduced COLL1A1 and TGF-β expression and demonstrated a reduction in fibrosis through histological stains. The treatment group also showed a reduction in IL-18. Our results suggest that PFD exerts protective effects on chronic renal IRI, reducing fibrosis development and inflammation. This study provides new insights into the treatment and management of chronic renal function loss after IRI.
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(This article belongs to the Section Preclinical Research)
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Open AccessReview
Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery
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and
Drugs Drug Candidates 2023, 2(1), 121-136; https://doi.org/10.3390/ddc2010008 - 07 Mar 2023
Abstract
Recurrence of cancer after primary tumour resection is a leading cause of cancer-related mortality. Preclinical research indicates that surgery induces a stress response that inhibits cell-mediated immunity as a possible basis for risk of recurrence. Other preclinical evidence suggests that, conversely, propofol and
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Recurrence of cancer after primary tumour resection is a leading cause of cancer-related mortality. Preclinical research indicates that surgery induces a stress response that inhibits cell-mediated immunity as a possible basis for risk of recurrence. Other preclinical evidence suggests that, conversely, propofol and local anaesthetics diminish the effects of the surgical stress response and so could directly inhibit cancer progression, and this is supported by several retrospective cohort studies and meta-analyses. However, the first large-scale randomised clinical trial (RCT), comparing recurrence after mastectomy in patients anaesthetised with either propofol/local anaesthetic or sevoflurane/opioids, concluded that recurrence was not significantly improved in the propofol/local anaesthetic group (p = 0.84). Other cancers may prove more responsive and results from a number of ongoing RCTs, encompassing several cancer types, are currently awaited. These trials should establish whether choice of anaesthetic technique is an important determinant of cancer recurrence risk.
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(This article belongs to the Section Marketed Drugs)
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Open AccessArticle
An Investigation on the Relationships between Mass Spectrometric Collisional Data and Biological Activity/Stability of Some N-Acylethanolamine Acid Amidase (NAAA) β-Lactone Inhibitors
Drugs Drug Candidates 2023, 2(1), 109-120; https://doi.org/10.3390/ddc2010007 - 02 Mar 2023
Abstract
The rationale of the present study is that relationships between in vitro biological activity and mass spectrometric (MS) collisional data of molecular species have been already reported in the literature. Herein, the same approach has been employed to investigate possible correlations between MS
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The rationale of the present study is that relationships between in vitro biological activity and mass spectrometric (MS) collisional data of molecular species have been already reported in the literature. Herein, the same approach has been employed to investigate possible correlations between MS stability and biological activity/stability data of a series of β-lactone amides and carbamates N-acylethanolamine acid amidase (NAAA) inhibitors. Electrospray ionization MS experiments were performed using an LCQ Deca ion trap and samples were introduced by direct infusion. Mass spectra of positive and negative ions have been obtained, and collisional experiments were performed on selected ionic species. Collisional-induced fragmentation pathways of molecular species related to β-lactone amide inhibitors are different in comparison to those of carbamates, being the former species more stable than the latter, due to β-lactone reactivity. Correlations were found between the characteristic collision energy (CE50) obtained by the breakdown curves and in vitro NAAA inhibitory potency of the β-lactone amides and carbamates analyzed. In the case of carbamates, a relationship between CE50 values and bovine serum albumin (BSA) stability data was also found, while any correlation was not found for amides due to their instability to BSA. β-Lactone NAAA inhibitors’ activity can be qualitatively associated with their lability, as measured by CE50 values. The results obtained could suggest that MS may be used as a preliminary experimental tool to identify carbamate NAAA inhibitors endowed with good biological stability.
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(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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Open AccessReview
Stearylamine Liposome as an Anti-Parasitic Agent
Drugs Drug Candidates 2023, 2(1), 95-108; https://doi.org/10.3390/ddc2010006 - 27 Feb 2023
Abstract
The uncontrolled increasing clinical resistance to the current anti-parasitic drugs towards important protozoan parasites (Plasmodium, Leishmania, Trypanosoma and Toxoplasma) has stimulated the search for novel and safe therapeutic agents at affordable prices for countries in which these parasites are
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The uncontrolled increasing clinical resistance to the current anti-parasitic drugs towards important protozoan parasites (Plasmodium, Leishmania, Trypanosoma and Toxoplasma) has stimulated the search for novel and safe therapeutic agents at affordable prices for countries in which these parasites are endemic. For the past few decades, the criticality of the cationic lipid stearylamine (SA) in liposomes has been explored in these human parasites. Previously, SA was incorporated in the liposomal formulation to impart a net positive charge for enhanced cellular uptake. However, the discovery of SA in liposomes alone elicits a strong anti-parasitic activity with immunomodulatory potential. Additionally, the SA liposome possesses a significant inhibitory potential on multiple life stages of the parasite cycle and delivers an equal effect on both drug-sensitive and resistant parasites. Moreover, the delivery of standard anti-parasitic drugs using SA liposome vesicles has enhanced the efficacy of drugs due to the synergistic impacts without causing any apparent toxicity on the host cells. In addition, the delivery of antigens as vaccine candidates using SA liposomes elicits a pronounced immune response in clearing the infection compared to other cationic lipids and SA-free liposomes. Nonetheless, SA liposome mediates its anti-parasitic activity by targeting the negatively charged phosphatidylserine-exposed infected host cell surface or by interaction with negatively charged sialic acid of free-living parasites. Overall, SA liposome confers its protection by acting as a chemotherapeutic agent with immunomodulatory activity. Therefore, a broadly acting anti-parasitic agent (SA liposome) is promising in tackling the deadly parasitic infections in endemic regions and warrants further clinical investigations.
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(This article belongs to the Section Preclinical Research)
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Open AccessFeature PaperReview
Testolactone: The Rise and Fall of a Drug
Drugs Drug Candidates 2023, 2(1), 69-94; https://doi.org/10.3390/ddc2010005 - 04 Feb 2023
Abstract
Testolactone is structurally related to testosterone and belongs to the first generation of aromatase inhibitors. It is a non-selective irreversible aromatase enzyme inhibitor that was one of the first steroids used in the clinical treatment of breast cancer. The use of testolactone in
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Testolactone is structurally related to testosterone and belongs to the first generation of aromatase inhibitors. It is a non-selective irreversible aromatase enzyme inhibitor that was one of the first steroids used in the clinical treatment of breast cancer. The use of testolactone in the treatment of breast cancer started in 1970, although its ability to inhibit aromatase was not discovered until 1975. Its use was primarily based on the inhibition of estrogen synthesis, which was applied in the treatment of estrogen-dependent breast cancers, in the treatment of disorders of sex steroid excess, familial male-limited precocious puberty, or in the treatment of patients with McCune–Albright syndrome, etc. The weak inhibitory activity of testolactone, and the moderate clinical response, prevented its widespread use, which ultimately resulted in withdrawal from the drug market in 2008. This review paper is dedicated to testolactone, its rise in the second half of the 20th century, and its fall in the first decade of the 21st century. Regardless of withdrawal from the market, for many years testolactone was a drug that improved the quality of life of patients facing one of the most serious diseases today, and for this reason, this paper describes medicinal application, synthesis, and modifications of testolactone.
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(This article belongs to the Section Marketed Drugs)
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Open AccessArticle
Betulinic Acid: Triterpenoid Derivative Induced NADPH-d Expression in the Urinary System with a Possible Renal Protective Role of Nitric Oxide
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, , , , and
Drugs Drug Candidates 2023, 2(1), 52-68; https://doi.org/10.3390/ddc2010004 - 02 Feb 2023
Abstract
The birch tree-derived pentacyclic lupine type-triterpenoid Betulinic acid has demonstrated a variety of biological activities BetA is known for its harmlessness on normal healthy cells. However, recent investigations have indicated that BetA can cause cellular changes in mouse normal embryonic fibroblasts even with
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The birch tree-derived pentacyclic lupine type-triterpenoid Betulinic acid has demonstrated a variety of biological activities BetA is known for its harmlessness on normal healthy cells. However, recent investigations have indicated that BetA can cause cellular changes in mouse normal embryonic fibroblasts even with a minimal concentration. This report cautioned the use of BetA at the clinical level, which encouraged us to examine whether BetA could produce any key effect on normal healthy cells of any organs in mice. The present study extended its investigation to evaluate whether BetA could induce any changes in the renal system and the expression pattern of NADPH-diaphorase an indirect marker of the enzyme nitric oxide synthase in mice. Our results indicated that BetA exposure induced NADPH-d expression in both organs without causing any significant morphological changes. Moreover, NADPH-d activity patterns in the organs of BetA-treated animals tremendously increased (from day 4 until day 12) when compared to controls. The expression of NADPH-d in both the kidney and bladder implies that NADPH-d-mediated nitric oxide signaling could be a mechanism involved in BetA-induced nephroprotection. These outcomes are of direct clinical importance and could pay the way for the improvement of BetA as an important pharmaceutical product.
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(This article belongs to the Section Preclinical Research)
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Open AccessArticle
Isolation and Characterization of Prophylactic Antimalarial Agents from Ochna kibbiensis Leaves
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, , , , and
Drugs Drug Candidates 2023, 2(1), 37-51; https://doi.org/10.3390/ddc2010003 - 24 Jan 2023
Abstract
Ochna kibbiensis (Family: Ochnaceae) has been employed in ethnomedicine for the treatment of malaria and inflammation, among others. The aim of this study was to isolate and characterize prophylactic antimalarial agents from the leaves of O. kibbiensis against Plasmodium berghei, in vivo
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Ochna kibbiensis (Family: Ochnaceae) has been employed in ethnomedicine for the treatment of malaria and inflammation, among others. The aim of this study was to isolate and characterize prophylactic antimalarial agents from the leaves of O. kibbiensis against Plasmodium berghei, in vivo and in silico. The median lethal dose (LD50) of the methanol extract and its fractions (hexane, dichloromethane, ethylacetate and butanol) was determined according to Lorke’s method while the antimalarial effect of the extract and its fractions was investigated according to the method described by Peters prophylactic test using Chloroquine-sensitive Plasmodium berghei (NK65). All the extract/fractions exhibited LD50 values ≥ 5000 mg/kg with the exception of the n-butanol fraction (1702.94 mg/kg), which indicate that the plant is non-toxic. Dichloromethane fraction exhibited a significant (p < 0.05) and dose-dependent prophylactic effect with 47.62, 85.12, and 100.0% prophylaxis (at 500, 250, and 125 mg/kg), while the least effect was observed by the butanol fraction with a percentage prophylaxis of 64.29 and 76.19, respectively; the standard drug, pyrimethamine, had 95.24% prophylaxis. Based on the results obtained, dichloromethane fraction of O. kibbiensis was subjected to chromatographic purification, which led to the isolation of a mixture of two compounds identified as stigmasterol and β-sitosterol by analysis of the NMR spectral data and comparison with existing literature; the compounds exhibited good binding affinities (−5.129 and −4.889 kcal/mol) against pfLDH and a favorable ADMET profile. In conclusion, the leaves of O. kibbiensis have demonstrated a significant prophylactic antimalarial activity and the two known steroids (stigmasterol and β-sitosterol) were isolated from the dichloromethane fraction for the first time.
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Indonesian Vegetables: Searching for Antioxidant and Antidiabetic Therapeutic Agents
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, , , , , , and
Drugs Drug Candidates 2023, 2(1), 14-36; https://doi.org/10.3390/ddc2010002 - 20 Jan 2023
Abstract
Diabetes mellitus prevalence in Indonesia reached 19.5 million cases, which has affected the productive age population. The indigenous people of Indonesia are blessed with the second largest biodiversity in the world, including vegetables, which are also prepared as medicaments. Vegetables are well-known as
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Diabetes mellitus prevalence in Indonesia reached 19.5 million cases, which has affected the productive age population. The indigenous people of Indonesia are blessed with the second largest biodiversity in the world, including vegetables, which are also prepared as medicaments. Vegetables are well-known as natural antioxidants which evolved in metabolic disease prevention, including diabetes mellitus. One of the Government of Indonesia’s strategic plans in health is to develop new antidiabetic from nature. In this study, nineteen vegetable species were collected and evaluated for their antioxidant activity followed by computational-based bioprospecting. The study indicated Ipomoea aquatica, Paederia foetida, Plumbago zeylanica, Nauclea pallida, Sauropus androgynus, Wrightia pubescens, and Psophocarpus tetragonolobus to contain high antioxidant components. Computational experiments on chemical constituents previously reported from the same species showed potent compounds with high affinity against α-glucosidase (3a4a). 7-O-β-D-glucopyranosyl-dihydroquercetin-3-O-α-D-glucopyranoside 1, stigmasterol 7, and chitanone 12 are the most potent compounds from Ipomoea aquatica, Paederia foetida, and Plumbago zeylanica, respectively, which are superior to a standard drug, acarbose. The four vegetable species are feasible for conventional drug sources or developed as botanical dosage according to the Indonesian government’s strategic plan. Further studies are necessary to ensure adequate preclinical and clinical data to meet the requirement of safe and potent medicine. Nevertheless, Nauclea pallida and Psophocarpus tetragonolobus are valuable species with potent yet understudied antioxidant sources.
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Open AccessReview
Angiogenesis under Opioids Preconditioning in Renal Ischemia Reperfusion
by
, , , , and
Drugs Drug Candidates 2023, 2(1), 1-13; https://doi.org/10.3390/ddc2010001 - 07 Jan 2023
Abstract
Renal ischemia reperfusion (IR) presents a common challenge for organ graft and function after transplantation. In the kidney, although there are several mechanisms involved in the IR injury, some studies have pointed to angiogenesis as an important process in the pathophysiology of IR
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Renal ischemia reperfusion (IR) presents a common challenge for organ graft and function after transplantation. In the kidney, although there are several mechanisms involved in the IR injury, some studies have pointed to angiogenesis as an important process in the pathophysiology of IR and, therefore, as a possible target mechanism to reduce IR damage. Angiogenesis can be modulated by different molecules and recent evidence has shown that opioids are among these molecules. Angiogenesis preconditioning with opioids is a useful and non-invasive strategy to increase the transplant success rate. Although some results have suggested an interaction between the opioid system and VEGF-mediated angiogenesis, more studies are required to fully elucidate the specific mechanisms involved in these actions. The present review summarizes the recent findings on kidney IR-related mechanisms, with as special emphasis on vascular changes. Finally, the evidence about the modulation of angiogenesis by opioids in a preconditioning scheme will be addressed.
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(This article belongs to the Section Clinical Research)
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