Pharmaceuticals

Open AccessArticle

Glycoconjugates of Mucochloric Acid—Synthesis and Biological Activity

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Pharmaceuticals 2023, 16(4), 525; https://doi.org/10.3390/ph16040525 (registering DOI) - 31 Mar 2023

Abstract

The pharmacological effects of the presence of a sugar moiety, 1,2,3-triazole ring and silyl groups in the structure of biologically active compounds have been extensively studied in drug design and medicinal chemistry. These components can be useful tools to tailoring the bioavailability of [...] Read more.

The pharmacological effects of the presence of a sugar moiety, 1,2,3-triazole ring and silyl groups in the structure of biologically active compounds have been extensively studied in drug design and medicinal chemistry. These components can be useful tools to tailoring the bioavailability of target molecules. Herein we present the study on the impact of the sugar substituent structure and triisopropylsilyl group presence on the anticancer activity of mucochloric acid (MCA) derivatives containing the furan-2(5H)-one or 2H-pyrrol-2-one core. The obtained results clearly indicated that tested compounds caused a significant decrease in cell viability of HCT116 and MCF-7 cell lines. MCF-7 cells indicate serious resistance toward investigated compounds in comparison with HCT116 cell line, it suggests that estrogen-dependent breast cancer cells are significantly less sensitive to the tested derivatives. Depending on the structure of the sugar, the type and site of connection with the furanone or 2H-pyrrol-2-one derivative and the presence of the silyl group, the selectivity of the compound towards cancer cells can be controlled. The obtained results may have an impact on the design of new furanone-based anticancer compounds. Full article

Open AccessCommunication

Evaluation of [¹⁸F]Favipiravir in Rodents and Nonhuman Primates (NHP) with Positron Emission Tomography

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Pharmaceuticals 2023, 16(4), 524; https://doi.org/10.3390/ph16040524 - 31 Mar 2023

Abstract

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this [...] Read more.

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [¹⁸F]Favipiravir in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [¹⁸F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [¹⁸F]Favipiravir in vivo. The [¹⁸F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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Open AccessReview

Modulatory Effect of Medicinal Plants and Their Active Constituents on ATP-Sensitive Potassium Channels (K_ATP) in Diabetes

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Lina T. Al Kury

Pharmaceuticals 2023, 16(4), 523; https://doi.org/10.3390/ph16040523 - 31 Mar 2023

Abstract

Hyperglycemia, which is a chronic metabolic condition caused by either a defect in insulin secretion or insulin resistance, is a hallmark of diabetes mellitus (DM). Sustained hyperglycemia leads to the onset and development of many health complications. Despite the number of available antidiabetic [...] Read more.

Hyperglycemia, which is a chronic metabolic condition caused by either a defect in insulin secretion or insulin resistance, is a hallmark of diabetes mellitus (DM). Sustained hyperglycemia leads to the onset and development of many health complications. Despite the number of available antidiabetic medications on the market, there is still a need for novel treatment agents with increased efficacy and fewer adverse effects. Many medicinal plants offer a rich supply of bioactive compounds that have remarkable pharmacological effects with less toxicity and side effects. According to published evidence, natural antidiabetic substances influence pancreatic β-cell development and proliferation, inhibit pancreatic β-cell death, and directly increase insulin output. Pancreatic ATP-sensitive potassium channels play an essential role in coupling glucose metabolism to the secretion of insulin. Although much of the literature is available on the antidiabetic effects of medicinal plants, very limited studies discuss their direct action on pancreatic K_ATP. The aim of this review is to focus on the modulatory effects of antidiabetic medicinal plants and their active constituents on pancreatic K_ATP. The K_ATP channel should be regarded as a key therapeutic milestone in the treatment of diabetes. Therefore, continuous research into the interaction of medicinal plants with the K_ATP channel is crucial. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus)

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Open AccessArticle

HMG-CoA Reductase Inhibitors Suppress Monosodium Urate-Induced NLRP3 Inflammasome Activation through Peroxisome Proliferator-Activated Receptor-γ Activation in THP-1 Cells

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Pharmaceuticals 2023, 16(4), 522; https://doi.org/10.3390/ph16040522 - 31 Mar 2023

Abstract

Peroxisome proliferator-activated receptor γ (PPAR-γ) is thought to negatively regulate NLRP3 inflammasome activation. The aim of this study was to identify the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation through the regulation [...] Read more.

Peroxisome proliferator-activated receptor γ (PPAR-γ) is thought to negatively regulate NLRP3 inflammasome activation. The aim of this study was to identify the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation through the regulation of PPAR-γ in THP-1 cells. The expression of PPAR-γ, NLRP3, caspase-1, and interleukin-1β (IL-1β) in human monocytic THP-1 cells transfected with PPAR-γ siRNA or not and stimulated with MSU crystals was assessed using quantitative a real time-polymerase chain reaction and Western blotting. The expression of those markers in THP-1 cells pretreated with statins (atorvastatin, simvastatin, and mevastatin) was also evaluated. Intracellular reactive oxygen species (ROS) were measured using H₂DCF-DA and flow cytometry analyses. THP-1 cells treated with MSU crystals (0.3 mg/mL) inhibited PARR-γ and increased NLRP3, caspase-1, and IL-1β mRNA and protein expression, and all those changes were significantly reversed by treatment with atorvastatin, simvastatin, or mevastatin. PPAR-γ activity revealed that MSU crystals suppressed PPAR-γ activity, which was markedly augmented by atorvastatin, simvastatin, and mevastatin. Transfecting cells with PPAR-γ siRNA attenuated the inhibitory effect of statins on MSU crystal-mediated NLRP3 inflammasome activation. Statins also significantly reduced the intracellular ROS generation caused by stimulation with MSU crystals. The inhibitory effects of atorvastatin and simvastatin on intracellular ROS generation were reduced in THP-1 cells transfected with PPAR-γ siRNA. This study demonstrates that PPAR-γ is responsible for suppressing MSU-mediated NLRP3 inflammasome activation. The inhibitory effect of statins on MSU-induced NLRP3 inflammasome activation depends on PPAR-γ activity and production and the inhibition of ROS generation. Full article

(This article belongs to the Section Pharmacology)

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Open AccessArticle

Head-to-Head Comparison between [⁶⁸Ga]Ga-DOTA.SA.FAPi and [¹⁸F]F-FDG PET/CT Imaging in Patients with Breast Cancer

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Pharmaceuticals 2023, 16(4), 521; https://doi.org/10.3390/ph16040521 - 31 Mar 2023

Abstract

This study aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-DOTA.SA.FAPi with that of [¹⁸F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [¹⁸F]F-FDG and [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT scans of histologically proven breast cancer patients [...] Read more.

This study aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-DOTA.SA.FAPi with that of [¹⁸F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [¹⁸F]F-FDG and [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT scans of histologically proven breast cancer patients were compared according to patient-based and lesion-based analysis. Forty-seven patients with a mean age of 44.8 ± 9.9 years (range: 31–66 years) were evaluated. A total of 85% of patients had invasive ductal carcinoma, and 15% had invasive lobular carcinoma. The tracer uptake [SULpeak, SULavg, and the median tumor-to-background ratio (TBR)] was significantly higher in [⁶⁸Ga]Ga-DOTA.SA.FAPi than with [¹⁸F]F-FDG PET/CT for lymph nodes, pleural metastases, and liver lesions (p < 0.05). However, for brain metastasis, only the median TBR was significantly higher (p < 0.05) compared to [¹⁸F]F-FDG. In patient-based analysis the sensitivity of [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT was higher, but not significant than that of [¹⁸F]F-FDG PET/CT in the detection of both primary tumors and metastatic lesions. According to lesion-based analysis, on diagnostic CT, 47 patients had 44 primary tumors, 248 lymph nodes, 15 pleural, 88 liver, and 42 brain metastases. [⁶⁸Ga]Ga-DOTA.SA.FAPi scan identified more abnormal lesions than [¹⁸F]F-FDG in all the primary and metastatic sites with a maximum marked difference in the primary site [88.6% vs. 81.8%; p-0.001], lymph nodes [89.1% vs. 83.8%; p-0.0001], pleural metastases [93.3% vs. 73%; p-0.096] and brain metastasis [100% vs. 59.5%; p-0.0001]. [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT was superior to [¹⁸F]F-FDG PET/CT in the imaging of breast cancers. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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Open AccessReview

Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain

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Pharmaceuticals 2023, 16(4), 520; https://doi.org/10.3390/ph16040520 - 31 Mar 2023

Abstract

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, [...] Read more.

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed. Full article

(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)

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Open AccessOpinion

Targeting Protein-Protein Interactions to Inhibit Cyclin-Dependent Kinases

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Mark Klein

Pharmaceuticals 2023, 16(4), 519; https://doi.org/10.3390/ph16040519 - 31 Mar 2023

Abstract

Cyclin-dependent kinases (CDKs) play diverse and critical roles in normal cells and may be exploited as targets in cancer therapeutic strategies. CDK4 inhibitors are currently approved for treatment in advanced breast cancer. This success has led to continued pursuit of targeting other CDKs. [...] Read more.

Cyclin-dependent kinases (CDKs) play diverse and critical roles in normal cells and may be exploited as targets in cancer therapeutic strategies. CDK4 inhibitors are currently approved for treatment in advanced breast cancer. This success has led to continued pursuit of targeting other CDKs. One challenge has been in the development of inhibitors that are highly selective for individual CDKs as the ATP-binding site is highly conserved across this family of proteins. Protein-protein interactions (PPI) tend to have less conservation amongst different proteins, even within protein families, making targeting PPI an attractive approach to improving drug selectivity. However, PPI can be challenging to target due to structural and physicochemical features of these interactions. A review of the literature specific to studies focused on targeting PPI involving CDKs 2, 4, 5, and 9 was conducted and is presented here. Promising lead molecules to target select CDKs have been discovered. None of the lead molecules discovered have led to FDA approval; however, the studies covered in this review lay the foundation for further discovery and develop of PPI inhibitors for CDKs. Full article

(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions (PPIs): Current Strategies for the Development of New Drugs)

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Open AccessArticle

Oral Cancer Pain Includes Thermal Allodynia That May Be Attenuated by Chronic Alcohol Consumption

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Cara B. Gonzales

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Jorge J. De La Chapa

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Amol M. Patwardhan

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Kenneth M. Hargreaves

Pharmaceuticals 2023, 16(4), 518; https://doi.org/10.3390/ph16040518 - 31 Mar 2023

Abstract

Background: Oral cancer is one of the most painful cancer types, and is often refractory to existing analgesics. Oral cancer patients frequently develop a tolerance to opioids, the mainstay of current cancer pain therapy, leaving them with limited therapeutic options. Thus, there is [...] Read more.

Background: Oral cancer is one of the most painful cancer types, and is often refractory to existing analgesics. Oral cancer patients frequently develop a tolerance to opioids, the mainstay of current cancer pain therapy, leaving them with limited therapeutic options. Thus, there is a great need to identify molecular mechanisms driving oral cancer pain in an effort to develop new analgesics. Previous reports demonstrate that oral cancer patients experience intense mechanical pain and pain in function. To date, no studies have examined thermal pain in oral cancer patients or the role that alcohol consumption plays in oral cancer pain. This study aims to evaluate patient-reported pain levels and thermal allodynia, potential molecular mechanisms mediating thermal allodynia, and the effects of alcohol consumption on patient-perceived pain. Methods: This study evaluated human oral squamous cell carcinoma (OSCC) cell lines for their ability to activate thermosensitive channels in vitro and validated these findings in a rat model of orofacial pain. Patient-reported pain in a south Texas OSCC cohort (n = 27) was examined using a visual analog scale (VAS). Covariant analysis examined variables such as tobacco and alcohol consumption, ethnicity, gender, and cancer stage. Results: We determined that OSCC secretes factors that stimulate both the Transient Receptor Potential Ankyrin type 1 channel (TRPA1; noxious cold sensor) and the Transient Receptor Potential Vanilloid type 1 channel (TRPV1; noxious heat sensor) in vitro and that OSCC-secreted factors sensitize TRPV1 nociceptors in vivo. These findings were validated in this cohort, in which allodynia to cold and heat were reported. Notably, subjects that reported regular alcohol consumption also reported lower pain scores for every type of pain tested, with significantly reduced cold-induced pain, aching pain, and burning pain. Conclusion: Oral cancer patients experience multiple types of cancer pain, including thermal allodynia. Alcohol consumption correlates with reduced OSCC pain and reduced thermal allodynia, which may be mediated by TRPA1 and TRPV1. Hence, reduced pain in these patients may contribute to a delay in seeking care, and thus a delay in early detection and treatment. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Oral Cancer and Oral Cancer Pain)

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Open AccessArticle

Synthesis, Anticancer, Antimicrobial and Antioxidant Potential of Novel 4-(Substituted phenyl-1,3,4-oxadiazol/thiadiazol-2-yl)-4-(4-substituted phenyl) Azetidin-2-One Derivatives

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Abdulrahman Alshammari

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Metab Alharbi

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Abdul Hayee

Pharmaceuticals 2023, 16(4), 517; https://doi.org/10.3390/ph16040517 - 30 Mar 2023

Abstract

By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium [...] Read more.

By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium acetate with water and stirring well, followed by adding aldehydes in methanol at room temperature. Acetate (glacial) was used as the catalyst to produce Schiff’s bases (intermediates) by treating substituted aldehydes with 2-amino 1,3,4 oxadiazole/thiadiazole(s). Using the mixture of triethylamine (dropwise) and chloroacetylchloride with vigorous stirring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. The newly synthesized conjugates were evaluated for their anticancer potential using MCF-7 cell lines. Amoxicillin and fluconazole were used as reference drugs to determine their antimicrobial activity. Synthesized derivatives were evaluated for their antioxidant properties using 2-diphenyl-1-picrylhydrazyl (DPPH). In vitro cytotoxicity screening (MTTS assay) revealed that derivatives AZ-5, 9, 10, 14 and 19 demonstrated high efficacy with the percentage of inhibition at different concentration ranges (0.1 μM, 0.5 μM, 1 μM, 2 μM) of 89% to 94% μM as compared to doxorubicin as standard drug. The antimicrobial study indicated that compounds AZ-10, 19, and AZ-20 were found to have significant antimicrobial potential with MIC ranges of 3.34 µM to 3.71 µM in comparison to reference drugs having 4.29 µM to 5.10 µM. Based on antioxidant screening, most of the synthetic derivatives showed greater stability and effectiveness than the standard drug. According to the antioxidant screening, compounds AZ-5 and AZ-15 (IC₅₀ = 45.02 μg/mL and 42.88 μg/mL, respectively) showed the greatest potency, as compared to ascorbic acid (IC₅₀ = 78.63 μg/mL). Structure-activity relationship (SAR) studies of synthesized novel derivatives revealed that para-substituted halogen and nitro derivatives have remarkable potential against MCF-7 cancer cell lines and different microbial strains. Current evidence indicates that the synthesized derivatives may be promising candidates for use in the prevention and treatment of these infections. These synthesized compounds require further mechanism-based research to understand how they interact with the cells. Full article

(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)

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Open AccessArticle

Antibacterial Properties and Computational Insights of Potent Novel Linezolid-Based Oxazolidinones

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M. Shaheer Malik

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Shaikh Faazil

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Meshari A. Alsharif

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Qazi Mohammad Sajid Jamal

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Pharmaceuticals 2023, 16(4), 516; https://doi.org/10.3390/ph16040516 - 30 Mar 2023

Abstract

The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial [...] Read more.

The mounting evidence of bacterial resistance against commonly prescribed antibiotics warrants the development of new antibacterial drugs on an urgent basis. Linezolid, an oxazolidinone antibiotic, is a lead molecule in designing new oxazolidinones as antibacterial agents. In this study, we report the antibacterial potential of the novel oxazolidinone-sulphonamide/amide conjugates that were recently reported by our research group. The antibacterial assays showed that, from the series, oxazolidinones 2 and 3a exhibited excellent potency (MIC of 1.17 μg/mL) against B. subtilis and P. aeruginosa strains, along with good antibiofilm activity. Docking studies revealed higher binding affinities of oxazolidinones 2 and 3a compared to linezolid, which were further validated by molecular dynamics simulations. In addition to this, other computational studies, one-descriptor (log P) analysis, ADME-T and drug likeness studies demonstrated the potential of these novel linezolid-based oxazolidinones to be taken forward for further studies. Full article

(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry)

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Open AccessReview

Role of Fenugreek, Cinnamon, Curcuma longa, Berberine and Momordica charantia in Type 2 Diabetes Mellitus Treatment: A Review

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Marisol Cortez-Navarrete

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Karina G. Pérez-Rubio

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Miriam de J. Escobedo-Gutiérrez

Pharmaceuticals 2023, 16(4), 515; https://doi.org/10.3390/ph16040515 - 30 Mar 2023

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disease that has become a major global health concern. Given the efficacy of antidiabetic drugs, pharmacological therapy is considered the first-line treatment of T2DM; however, due to their potential side effects and high costs, new [...] Read more.

Type 2 diabetes mellitus (T2DM) is a complex disease that has become a major global health concern. Given the efficacy of antidiabetic drugs, pharmacological therapy is considered the first-line treatment of T2DM; however, due to their potential side effects and high costs, new and cost-effective treatments with minimal side effects are needed. Medicinal plants have been used for centuries as part of traditional medicine to treat T2DM. Among these, fenugreek, cinnamon, Curcuma longa, berberine, and Momordica charantia have demonstrated different degrees of hypoglycemic activity in clinical studies and animal models. Therefore, the aim of this review is to synthesize the mechanisms of action of five medicinal plants, as well as the experimental and clinical evidence of their hypoglycemic activity from the published literature. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus)

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Open AccessArticle

Horsetail (Equisetum hyemale) Extract Accelerates Wound Healing in Diabetic Rats by Modulating IL-10 and MCP-1 Release and Collagen Synthesis

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Hilda Aguayo-Morales

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Crystel A. Sierra-Rivera

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Jesús A. Claudio-Rizo

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Luis E. Cobos-Puc

Pharmaceuticals 2023, 16(4), 514; https://doi.org/10.3390/ph16040514 - 30 Mar 2023

Abstract

Traditionally, Equisetum hyemale has been used for wound healing. However, its mechanism of action remains to be elucidated. For this purpose, a 40% ethanolic extract of E. hyemale was prepared. Phytochemical screening revealed the presence of minerals, sterols, phenolic acids, flavonols, a lignan, [...] Read more.

Traditionally, Equisetum hyemale has been used for wound healing. However, its mechanism of action remains to be elucidated. For this purpose, a 40% ethanolic extract of E. hyemale was prepared. Phytochemical screening revealed the presence of minerals, sterols, phenolic acids, flavonols, a lignan, and a phenylpropenoid. The extract reduced the viability of RAW 264.7 cells and skin fibroblasts at all times evaluated. On the third day of treatment, this reduction was 30–40% and 15–40%, respectively. In contrast, the extract increased the proliferation of skin fibroblasts only after 48 h. In addition, the extract increased IL-10 release and inhibited MCP-1 release. However, the extract did not affect both TGF-β1 and TNF-α released by RAW 264.7 cells. The higher release of IL-10 could be related to the up-/downregulation of inflammatory pathways mediated by the extract components associated with their bioactivity. The extract inhibited the growth of Staphylococcus aureus and Escherichia coli. Topical application of the extract accelerated wound healing in diabetic rats by increasing fibroblast collagen synthesis. These results suggest that E. hyemale extract has great potential for use in the treatment of wounds thanks to its phytochemical composition that modulates cytokine secretion, collagen synthesis, and bacterial growth. Full article

(This article belongs to the Special Issue Ethnopharmacology in Latin America)

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Graphical abstract

Open AccessEditorial

Development of Medicines for Rare Pediatric Diseases

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Danilo Marimpietri

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Guendalina Zuccari

Pharmaceuticals 2023, 16(4), 513; https://doi.org/10.3390/ph16040513 - 30 Mar 2023

Abstract

To date, approximately 7000 rare diseases exist, affecting between 6% and 8% of the global population and >30 million people in the European Union [...] Full article

(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)

Open AccessArticle

Umbilical Cord Mesenchymal Stromal Cells for Steroid-Refractory Acute Graft-versus-Host Disease

Pharmaceuticals 2023, 16(4), 512; https://doi.org/10.3390/ph16040512 - 30 Mar 2023

Abstract

Background: Steroid-refractory acute graft-vs.-host disease (SR-aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation with a dismal prognosis and for which there is no consensus-based second-line therapy. Ruxolitinib is not easily accessible in many countries. A possible therapy is the administration of [...] Read more.

Background: Steroid-refractory acute graft-vs.-host disease (SR-aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation with a dismal prognosis and for which there is no consensus-based second-line therapy. Ruxolitinib is not easily accessible in many countries. A possible therapy is the administration of mesenchymal stromal cells (MSCs). Methods: In this retrospective study, 52 patients with severe SR-aGVHD were treated with MSCs from umbilical cord (UC-MSCs) in nine institutions. Results: The median (range) age was 12.5 (0.3–65) years and the mean ± SD dose (×10⁶/kg) was 4.73 ± 1.3 per infusion (median of four infusions). Overall (OR) and complete response (CR) rates on day 28 were 63.5% and 36.6%, respectively. Children (n = 35) had better OR (71.5% vs. 47.1%, p = 0.12), CR (48.6% vs. 11.8%, p = 0.03), overall survival (p = 0.0006), and relapse-free survival (p = 0.0014) than adults (n = 17). Acute adverse events (all of them mild or moderate) were detected in 32.7% of patients, with no significant difference in children and adult groups (p = 1.0). Conclusions: UC-MSCs are a feasible alternative therapy for SR-aGVHD, especially in children. The safety profile is favorable. Full article

(This article belongs to the Special Issue New Advances in Mesenchymal Stromal Cells as Therapeutic Tools)

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Open AccessReview

Natural Coumarin Derivatives Activating Nrf2 Signaling Pathway as Lead Compounds for the Design and Synthesis of Intestinal Anti-Inflammatory Drugs

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Luiz C. Di Stasi

Pharmaceuticals 2023, 16(4), 511; https://doi.org/10.3390/ph16040511 - 30 Mar 2023

Abstract

Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor related to stress response and cellular homeostasis that plays a key role in maintaining the redox system. The imbalance of the redox system is a triggering factor for the initiation and progression [...] Read more.

Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor related to stress response and cellular homeostasis that plays a key role in maintaining the redox system. The imbalance of the redox system is a triggering factor for the initiation and progression of non-communicable diseases (NCDs), including Inflammatory Bowel Disease (IBD). Nrf2 and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) are the main regulators of oxidative stress and their activation has been recognized as a promising strategy for the treatment or prevention of several acute and chronic diseases. Moreover, activation of Nrf2/keap signaling pathway promotes inhibition of NF-κB, a transcriptional factor related to pro-inflammatory cytokines expression, synchronically promoting an anti-inflammatory response. Several natural coumarins have been reported as potent antioxidant and intestinal anti-inflammatory compounds, acting by different mechanisms, mainly as a modulator of Nrf2/keap signaling pathway. Based on in vivo and in vitro studies, this review focuses on the natural coumarins obtained from both plant products and fermentative processes of food plants by gut microbiota, which activate Nrf2/keap signaling pathway and produce intestinal anti-inflammatory activity. Although gut metabolites urolithin A and urolithin B as well as other plant-derived coumarins display intestinal anti-inflammatory activity modulating Nrf2 signaling pathway, in vitro and in vivo studies are necessary for better pharmacological characterization and evaluation of their potential as lead compounds. Esculetin, 4-methylesculetin, daphnetin, osthole, and imperatorin are the most promising coumarin derivatives as lead compounds for the design and synthesis of Nrf2 activators with intestinal anti-inflammatory activity. However, further structure–activity relationships studies with coumarin derivatives in experimental models of intestinal inflammation and subsequent clinical trials in health and disease volunteers are essential to determine the efficacy and safety in IBD patients. Full article

(This article belongs to the Special Issue Natural Coumarins as Lead Compounds and Their Synthetic Analogues with Biological Activities)

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Open AccessSystematic Review

Redefining the Incidence and Profile of Fluoropyrimidine-Associated Cardiotoxicity in Cancer Patients: A Systematic Review and Meta-Analysis

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Pharmaceuticals 2023, 16(4), 510; https://doi.org/10.3390/ph16040510 - 30 Mar 2023

Abstract

Aim: The cardiac toxicity that occurs during administration of anti-tumor agents has attracted increasing concern. Fluoropyrimidines have been used for more than half a century, but their cardiotoxicity has not been well clarified. In this study, we aimed to assess the incidence and [...] Read more.

Aim: The cardiac toxicity that occurs during administration of anti-tumor agents has attracted increasing concern. Fluoropyrimidines have been used for more than half a century, but their cardiotoxicity has not been well clarified. In this study, we aimed to assess the incidence and profile of fluoropyrimidine-associated cardiotoxicity (FAC) comprehensively based on literature data. Methods: A systematic literature search was performed using PubMed, Embase, Medline, Web of Science, and Cochrane library databases and clinical trials on studies investigating FAC. The main outcome was a pooled incidence of FAC, and the secondary outcome was specific treatment-related cardiac AEs. Random or fixed effects modeling was used for pooled meta-analyses according to the heterogeneity assessment. PROSPERO registration number: (CRD42021282155). Results: A total of 211 studies involving 63,186 patients were included, covering 31 countries or regions in the world. The pooled incidence of FAC, by meta-analytic, was 5.04% for all grades and 1.5% for grade 3 or higher. A total of 0.29% of patients died due to severe cardiotoxicities. More than 38 cardiac AEs were identified, with cardiac ischemia (2.24%) and arrhythmia (1.85%) being the most frequent. We further performed the subgroup analyses and meta-regression to explore the source of heterogeneity, and compare the cardiotoxicity among different study-level characteristics, finding that the incidence of FAC varied significantly among different publication decades, country/regions, and genders. Patients with esophagus cancer had the highest risk of FAC (10.53%), while breast cancer patients had the lowest (3.66%). The treatment attribute, regimen, and dosage were significantly related to FAC. When compared with chemotherapeutic drugs or targeted agents, such a risk was remarkably increased (χ² = 10.15, p < 0.01; χ² = 10.77, p < 0.01). The continuous 5-FU infusion for 3–5 consecutive days with a high dosage produced the highest FAC incidence (7.3%) compared with other low-dose administration patterns. Conclusions: Our study provides comprehensive global data on the incidence and profile of FAC. Different cancer types and treatment appear to have varying cardiotoxicities. Combination therapy, high cumulative dose, addition of anthracyclines, and pre-existing heart disease potentially increase the risk of FAC. Full article

(This article belongs to the Section Pharmacology)

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Open AccessArticle

Hylin-a1: A Host Defense Peptide with Antibacterial Potential against Staphylococcus aureus Multi-Resistant Strains

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Massimiliano Galdiero

Pharmaceuticals 2023, 16(4), 509; https://doi.org/10.3390/ph16040509 - 29 Mar 2023

Abstract

In recent years, the resistance of pathogenic microorganisms to common antimicrobial agents has raised to a severe public health problem. The moderate and wise use of antimicrobials and the prevention of infections are the most effective strategies for decreasing the spread and development [...] Read more.

In recent years, the resistance of pathogenic microorganisms to common antimicrobial agents has raised to a severe public health problem. The moderate and wise use of antimicrobials and the prevention of infections are the most effective strategies for decreasing the spread and development of resistance. Therefore, the World Health Organization (WHO) has intensified the search for new drugs to fight emerging pathogens. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), play a crucial role in innate immunity, representing one of the first line of defense against microbial attacks. In this study, we evaluated the antibacterial activity of the AMP named Hylin-a1 (derived from the skin of the frog Heleioporus albopunctatus) against Staphylococcus aureus strains. S. aureus represents a commensal bacterium but also the principal causative agent of several human infections, including bacteremia, endocarditis, skin and device-related infections. Hylin-a1 toxicity was evaluated on human keratinocytes; once the non-cytotoxic concentration range was determined, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were analyzed, and time-killing assays were performed to verify the bacteriostatic and/or bactericidal activity of the peptide. We found that Hylin-a1 exerted a bacteriostatic action against most of the tested strains, with 90% inhibition at the concentration of 6.25 μM. Noteworthy, the peptide at a very low concentration (~3 μM) significantly blocked the growth of β-lactam- and methicillin-resistant S. aureus. The levels of interleukin (IL)-1β, IL-6 and IL-8 were quantified through a molecular assay, indicating that the peptide was able also to regulate the inflammatory response following bacterial infection. The effect of Hylin-a1 on S. aureus cell morphology was also evaluated. Altogether, these results indicate the high therapeutic potential of Hylin-a1 against a wide variety of clinical manifestations caused by S. aureus. Full article

(This article belongs to the Special Issue Antimicrobial Peptides and Proteins: A Potential Approach to Treat and Combat Antimicrobial Resistance)

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Open AccessArticle

Trends in the Use of Driving-Impairing Medicines According to the DRUID Category: A Population-Based Registry Study with Reference to Driving in a Region of Spain between 2015 and 2019

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Eduardo Gutiérrez-Abejón

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Paloma Criado-Espegel

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M. Aránzazu Pedrosa-Naudín

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Diego Fernández-Lázaro

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Francisco Herrera-Gómez

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F. Javier Álvarez

Pharmaceuticals 2023, 16(4), 508; https://doi.org/10.3390/ph16040508 - 29 Mar 2023

Abstract

The European DRUID (Drive Under the Influence of drugs, alcohol, and medicines) program classifies medications into three categories according to their effect on one’s fitness to drive. The trend in the use of driving-impairing medicines (DIMs) in a region of Spain between 2015 [...] Read more.

The European DRUID (Drive Under the Influence of drugs, alcohol, and medicines) program classifies medications into three categories according to their effect on one’s fitness to drive. The trend in the use of driving-impairing medicines (DIMs) in a region of Spain between 2015 and 2019 was analyzed through a population-based registry study. Pharmacy dispensing records for DIMs are provided. The use of DIMs on drivers was weighted according to the national driver’s license census. The analysis was performed considering the population distribution by age and sex, treatment length, and the three DRUID categories. DIMs were used by 36.46% of the population and 27.91% of drivers, mainly chronically, with considerable daily use (8.04% and 5.34%, respectively). Use was more common in females than in males (42.28% vs. 30.44%) and increased with age. Among drivers, consumption decreases after 60 years of age for females and after 75 years of age for males. There was a 34% increase in the use of DIMs between 2015 and 2019, with a focus on daily use (>60%). The general population took 2.27 ± 1.76 DIMs, fundamentally category II (moderate influence on fitness to drive) (20.3%) and category III (severe influence on fitness to drive) (19.08%). The use of DIMs by the general population and drivers is significant and has increased in recent years. The integration of the DRUID classification into electronic prescription tools would assist physicians and pharmacists in providing adequate information to the patient about the effects of prescribed medications on their fitness to drive. Full article

(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World)

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Open AccessArticle

Effects of Statin Dose, Class, and Use Intensity on All-Cause Mortality in Patients with Type 2 Diabetes Mellitus

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Pharmaceuticals 2023, 16(4), 507; https://doi.org/10.3390/ph16040507 - 29 Mar 2023

Abstract

Purpose: to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes. Methods: The research sample consisted of individuals aged [...] Read more.

Purpose: to examine the impact of statins on reducing all-cause mortality among individuals diagnosed with type 2 diabetes. This investigation explored the potential correlations between dosage, drug classification, and usage intensity with the observed outcomes. Methods: The research sample consisted of individuals aged 40 years or older diagnosed with type 2 diabetes. Statin usage was determined as a frequent usage over a minimum of one month subsequent to type 2 diabetes diagnosis, where the average statin dose was ≥28 cumulative defined daily doses per year (cDDD-year). The analysis employed an inverse probability of treatment-weighted Cox hazard model, utilizing statin usage status as a time-varying variable, to evaluate the impact of statin use on all-cause mortality. Results: The incidence of mortality was comparatively lower among the cohort of statin users (n = 50,804 (12.03%)), in contrast to nonusers (n = 118,765 (27.79%)). After adjustments, the hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality was estimated to be 0.32 (0.31–0.33). Compared with nonusers, pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.06 (0.04–0.09), 0.28 (0.27–0.29), 0.29 (0.28–0.31), 0.31 (0.30–0.32), 0.31 (0.30–0.32), 0.36 (0.35–0.38), and 0.48 (0.47–0.50), respectively). In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in all-cause mortality (aHRs (95% CIs) = 0.51 (0.5–0.52), 0.36 (0.35–0.37), 0.24 (0.23–0.25), and 0.13 (0.13–0.14), respectively; p for trend <0.0001). Because it had the lowest aHR (0.32), 0.86 DDD of statin was considered optimal. Conclusions: In patients diagnosed with type 2 diabetes, consistent utilization of statins (≥28 cumulative defined daily doses per year) was shown to have a beneficial effect on all-cause mortality. Moreover, the risk of all-cause mortality decreased as the cumulative defined daily dose per year of statin increased. Full article

(This article belongs to the Special Issue Drug Candidates for the Prevention and Treatment of Cardiovascular Diseases in Patients with Diabetes Mellitus)

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