Pharmaceuticals

12 pages, 2489 KiB

Open AccessArticle

Concurrent Imaging and Clinical Study of the Efficacy of Hyaluronic Acid Injection for Knee Osteoarthritis: A Synovial Membrane Investigation with Ultrasound Imaging

by Chien-Chih Wang, Tsung-Ming Hu, Chien-Lung Chen, Chung-Chih Hong, Yu-Hui Chang and Chung-Lan Kao

Pharmaceuticals 2023, 16(8), 1186; https://doi.org/10.3390/ph16081186 - 21 Aug 2023

Viewed by 1733

Abstract

We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 [...] Read more.

We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 mL) in the subpatellar bursa, at a 2-week interval. Knee ultrasound imaging evaluations were performed before injection (baseline) and at 1 and 6 months after the second injection and included the measurements of synovial vascularity by using color Doppler ultrasound, synovial fluid depth over the suprapatellar bursa (SF), and synovial hypertrophy (SH). Initial clinical assessments included a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). VAS scores decreased significantly at both 1-month and 6-month evaluations (p < 0.001). WOMAC scores also significantly decreased at 1 month (p < 0.001), but not at 6 months (p = 0.23). The ultrasound parameters did not significantly change, except color Doppler grading, which tended to decrease at the 6-month evaluation (p = 0.059). Our findings revealed that two ultrasound-guided HA injections following fluid drainage improved pain and knee function but did not considerably influence imaging-detected synovitis in patients with knee OA. Full article

(This article belongs to the Special Issue Pharmacotherapy of Bone Diseases)

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Study workflow. Two hyaluronic acid (HA) injections were administered with a 2-week interval, and post-treatment evaluations were performed at 1 and 6 months after the second injection. WOMAC, the Western Ontario and McMaster Universities Arthritis Index; VAS, visual analogue scale. Full article ">Figure 2
Ultrasound evaluation of the knee in a patient with stage II knee osteoarthritis and synovitis. (a) The patient lay supine with 30° knee flexion. (b) The ultrasound probe was placed over the knee just superior to the patella to examine the suprapatellar bursa. (c) Knee ultrasound longitudinal view indicating the position of the suprapatellar bursa between the patella and femur. PFFP, prefemoral fat pad; SPFP, suprapatellar fat pad; QT, trilaminar quadriceps tendon; Hypoechoic space (asterisk) reflects joint effusion. Full article ">Figure 3
Ultrasound evaluation of synovitis and ultrasound-guided administration of hyaluronic acid (HA) in a patient with stage II knee osteoarthritis and synovitis. (a) The ultrasound revealed synovial hypertrophy (asterisk) and a synovial fluid depth of 1.34 cm in diameter (hypoechoic space between arrows). (b) Color flow imaging revealed grade 2 vascularity. (c) Ultrasound-guided procedure with a needle (arrow) for fluid (asterisk) aspiration. (d) The amount of fluid decreased and HA was injected with the needle (arrow). Full article ">Figure 4
Knee X-ray (a,d) and ultrasound (b,c,e,f) in an individual with a healthy knee (a–c) and a patient with stage IV knee osteoarthritis (d–f). (a) Normal joint space without narrowing. (b) Normal hyaline cartilage (arrow). (c) Minimal joint effusion over SF (asterisk). (d) Large osteophytes, marked joint space narrowing, severe sclerosis, and definite bony deformity (asterisk). (e) Irregular hyaline cartilage (arrow). (f) Moderate effusion over SF (asterisk). Full article ">

16 pages, 7136 KiB

Open AccessArticle

ED Formula, a Complex of Ecklonia cava and Chrysanthemum indicum, Ameliorates Airway Inflammation in Lipopolysaccharide-Stimulated RAW Macrophages and Ovalbumin-Induced Asthma Mouse Model

by Hyun Kang, Chan-Hwi Park, Sang-Oh Kwon and Sung-Gyu Lee

Pharmaceuticals 2023, 16(8), 1185; https://doi.org/10.3390/ph16081185 - 21 Aug 2023

Cited by 3 | Viewed by 1361

Abstract

Ecklonia cava (E. cava) and Chrysanthemum indicum Linne (C. indicum) are natural raw materials known to have beneficial effects on inflammatory-related diseases, as evidenced by various sources in the literature. This study aimed to investigate the airway-protective effects of [...] Read more.

Ecklonia cava (E. cava) and Chrysanthemum indicum Linne (C. indicum) are natural raw materials known to have beneficial effects on inflammatory-related diseases, as evidenced by various sources in the literature. This study aimed to investigate the airway-protective effects of a formulation called ED, comprising E. cava and C. indicum, by evaluating its potential anti-inflammatory properties. Methods: The major components of ED were analyzed using high-performance liquid chromatography (HPLC) and its anti-inflammatory activity was assessed in RAW 264.7 cells through measurements of nitric oxide’s (NO) inhibitory effect, cyclooxygenase (COX)-2 protein expression, and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, the anti-inflammatory effect of ED was evaluated in an ovalbumin-induced asthma model by measuring cytokine levels in serum, bronchoalveolar lavage fluid (BALF), and lung tissue. Through HPLC analysis, the major components of ED, dieckol and luteolin, were identified. ED demonstrated no cytotoxicity and effectively reduced NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Moreover, ED downregulated COX-2 expression through the MAPK signaling pathway in LPS-induced RAW 264.7 cells. In the ovalbumin-induced asthma model, the ED-treated group exhibited reduced levels of inflammatory cytokines in lung tissue. Furthermore, the ED-treated group showed a decrease in the number of inflammatory cells in BALF and lower serum interleukin (IL)-6 levels compared to the ovalbumin-treated group. These results suggest that ED has the potential to be a novel therapeutic agent for improving inflammatory respiratory diseases. Full article

(This article belongs to the Section Natural Products)

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(A,B) HPLC spectrum of ED. (C) Dieckol and luteolin content in ED (unit: mg/g ED). Full article ">Figure 2
Effects of ED and its active compounds on the viability and inflammation of RAW 264.7 cells. (A) The bars the cell viability, in percent, of cells treated with ED and its active compounds with the various concentrations for 24 h, then subjected to MTT assay. (B) Cells were incubated with LPS (100 ng/mL) with or without ED and its active compounds for 24 h. Secretions of NO were determined using a Griess reagent. (C–E) Western blot analysis for the inhibitory effects of ED and its active compounds on the protein expression level of COX-2. β-actin was detected and used as an internal control. The average value of three independent experiments is shown. All data are expressed as the mean ± SD of the experiment. ### p < 0.001 compared to the control group; * p < 0.05, ** p < 0.01, and *** p < 0.001 compared to the LPS control group. n.s.: not statistically significant. See also <a href="#app1-pharmaceuticals-16-01185" class="html-app">Figure S1</a>. Full article ">Figure 3
Effects of ED on the phosphorylation of (A,B) NF-κB and MAPK, (C) JNK, (D) ERK, and (E) p38 in RAW 264.7 cells. Lamin B1 and β-actin were detected and used as internal controls. The relative protein levels of p-JNK, p-ERK, and p-p38 were quantified using the Image J program and normalized to total JNK, ERK, and p38, respectively. The average value of three independent experiments is shown. All data are expressed as the mean ± SD of the experiment. ### p < 0.001 compared to the control group; ** p < 0.01 and *** p < 0.001 compared to the LPS control group. See also <a href="#app1-pharmaceuticals-16-01185" class="html-app">Figure S2</a>. Full article ">Figure 4
Effects of ED treatment on total cell count in OVA-induced asthmatic mice. (A) Diff-Quick staining (magnification ×200) of cells in BALF. (B) BALF was centrifuged and the pellet was assessed for total cell count using the Trypan blue dye exclusion test and differential count on cytospin slides using Diff-Quick staining. All results are shown as the mean ± SD (n = 5 per group). # p < 0.05 compared to the normal group. ** p < 0.01, compared to the OVA group. Full article ">Figure 5
Effects of ED on histology of lung tissue in OVA-induced asthma mice. The lungs were stained using H&E (×200) and PAS (×200). *: Inflammatory cell infiltration, ↑: mucus secretion. Full article ">Figure 6
The effects of ED on serum level of IL-6 in OVA-induced asthmatic mice. All results are shown as the mean ± SD (n = 5 per group). ## p < 0.01 compared to the normal group. ** p < 0.01, compared to the OVA group. Full article ">Figure 7
Effect of ED on the mRNA levels of cytokines in the lungs of OVA-induced asthmatic mice. RT-PCR analyses analysis using GAPDH as the loading control was performed for measurement of iNOS, TNF-α, IL-1β, and COX-2 mRNA expression in lung tissues. The relative mRNA levels of iNOS, TNF-α, IL-1β, and COX-2 were quantified using the Image J program. All results are shown as the mean ± SD (n = 5 per group). ## p < 0.01 compared to the normal group. * p < 0.05 and ** p < 0.01, compared to the OVA group. Full article ">Figure 8
Experimental protocol. BALB/c mice were sensitized to OVA intraperitoneally on days 1 and 14 and challenged with aerosolized OVA on days 21–26. ED and Bronpass Tables were administered orally, starting from day 15, once daily for 12 days. Full article ">

17 pages, 28574 KiB

Open AccessArticle

Antioxidant Activity of Quercetin-Containing Liposomes-in-Gel and Its Effect on Prevention and Treatment of Cutaneous Eczema

by Chang Liu, Xiaoman Cheng, Yifang Wu, Weifang Xu, Hongmei Xia, Ruoyang Jia, Yinyin Liu, Si Shen, Yinxiang Xu and Zhiqing Cheng

Pharmaceuticals 2023, 16(8), 1184; https://doi.org/10.3390/ph16081184 - 21 Aug 2023

Cited by 4 | Viewed by 3157

Abstract

Cutaneous eczema is a kind of skin disease is characterized by inflammation. The main manifestations are various types of dermatitis, eczema, and urticaria. There are usually complications such as erythema, blisters, and epidermal peeling. The quercetin might have a therapeutic effect on cutaneous [...] Read more.

Cutaneous eczema is a kind of skin disease is characterized by inflammation. The main manifestations are various types of dermatitis, eczema, and urticaria. There are usually complications such as erythema, blisters, and epidermal peeling. The quercetin might have a therapeutic effect on cutaneous eczema due to its favorable antioxidant activity and anti-inflammatory effects. Currently, there are few studies on transdermal administration of antioxidant drugs for the treatment of cutaneous eczema. The aim of this study was to prepare quercetin-containing liposomes-in-gel (QU-LG), its antioxidant properties were evaluated, and it was used in the skin of mice suffering from dermal eczema to see if it had preventive and therapeutic effects in an attempt to make it a new option for the treatment of cutaneous eczema. QU-LG was prepared by the injection method to form the quercetin-containing liposomes (QU-L) and evenly dispersed in the natural dissolution of carboxymethylcellulose sodium (1%, CMC-Na). The release of QU-LG across the dialysis membranes was up to 30% and clearance of 1,1-diphenyl-2-picrylhydrazyl (DPPH) was 65.16 ± 3.513%. In anti-oxidation assay QU-LG inhibited malondialdehyde (MDA) production in liver better than the commercially available drug dexamethasone acetate cream. Compared with untreated mice, mice treated with QU-LG showed a statistically significant reduction in dermatopathologic symptoms. The results suggested that QU-LG had good antioxidant activity in vivo and in vitro and could be used for the prevention and treatment of cutaneous eczema. Full article

(This article belongs to the Section Natural Products)

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13 pages, 2784 KiB

Open AccessArticle

Synthesis, In Silico Logp Study, and In Vivo Analgesic Activity of Analogs of Tetrapeptide FELL

by Boryana Borisova, Hristina Nocheva, Stéphane Gérard, Marie Laronze-Cochard, Stefan Dobrev, Silvia Angelova, Stoyko Petrin and Dancho Danalev

Pharmaceuticals 2023, 16(8), 1183; https://doi.org/10.3390/ph16081183 - 21 Aug 2023

Cited by 2 | Viewed by 1213

Abstract

Background: The inflammatory process represents a specific response of the organism’s immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, [...] Read more.

Background: The inflammatory process represents a specific response of the organism’s immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, medical doctors prescribe various analgesics for pain treatment, but unfortunately, many of them have adverse effects or are not strong enough to suppress the pain. Thus, the search for new pain-relieving medical drugs continues. Methods: New tetrapeptide analogs of FELL with a generaanalgesic-Glu-X³-X⁴-Z, where X = Nle, Ile, or Val and Z = NH₂ or COOH, containing different hydrophobic amino acids at positions 3 and 4, were synthesized by means of standard solid-phase peptide synthesis using the Fmoc/OtBu strategy in order to study the influence of structure and hydrophobicity on the analgesic activity. The purity of all compounds was monitored by HPLC, and their structures were proven by ESI-MS. Logp values (partition coefficient in octanol/water) for FELL analogs were calculated. Analgesic activity was examined by the Paw-pressure test (Randall-Selitto test). Results: The obtained results reveal that Leu is the best choice as a hydrophobic amino acid in the FELL structure. Conclusions: The best analgesic activity is found in the parent compound FELL and its C-terminal amide analog. Full article

(This article belongs to the Special Issue New Endogenous Opioid Peptides and Peptidomimetics with Potential Biological Importance)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
General structure of newly synthesized tetrapeptides. Full article ">Figure 2
PPT of newly synthesized peptide analogs. Measurements have been performed every 10 min, starting from the 10th minute after peptide administration until the 50th minute. The results are presented in arbitrary units (AU) as mean values ± S.E.M. *** p < 0.001, ** p < 0.01 vs. controls; +++ p < 0.001, ++ p < 0.01, + p < 0.05 vs. BB11. Full article ">Figure 3
PPT of newly synthesized peptide analogs after Naloxone (Nal) or AM251 pre-treatment. Measurements have been performed every 10 min starting from the 10th minute after peptide administration until the 50th minute. The results are presented in arbitrary units (AU) as mean values ± S.E.M. *** p < 0.001, ** p < 0.01, * p < 0.05 vs. controls; Nal+BB11 and AM251+BB11 have been compared to BB11 +++ p < 0.001; Nal+BB1 and AM251+BB1 have been compared to BB1 +++ p < 0.001, ++ p < 0.01. Full article ">Figure 4
Structures of the natural BB11 peptide and its analogs. Differences with the parent structure (BB11) are circled. Full article ">Figure 5
Schematic representation of the general procedure for targeted peptide synthesis. Full article ">Figure 6
Schematic representation of the general SPPS cycle. Full article ">

14 pages, 4844 KiB

Open AccessArticle

Quercetin Alleviated Inflammasome-Mediated Pyroptosis and Modulated the mTOR/P70S6/P6/eIF4E/4EBP1 Pathway in Ischemic Stroke

by Abdullah Alattar, Reem Alshaman, Yusuf S. Althobaiti, Ghareb M. Soliman, Howaida S. Ali, Waleed Salman Khubrni, Phil Ok Koh, Najeeb Ur Rehman and Fawad Ali Shah

Pharmaceuticals 2023, 16(8), 1182; https://doi.org/10.3390/ph16081182 - 21 Aug 2023

Cited by 4 | Viewed by 1891

Abstract

Stroke ranks as the world’s second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent [...] Read more.

Stroke ranks as the world’s second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent downstream pathways. Male Sprague Dawley rats were subjected to 72 h of transient middle cerebral artery ischemia, followed by the administration of 10 mg/kg of quercetin. Our findings demonstrated that MCAO induced elevated ROS which were coupled to inflammasome-mediated pyroptosis and altered mTOR-related signaling proteins. We performed ELISA, immunohistochemistry, and Western blotting to unveil the underlying role of the Nrf2/HO-1 and PDK/AKT/mTOR pathways in the ischemic cortex and striatum. Our results showed that quercetin post-treatment activated the Nrf2/HO-1 cascade, reversed pyroptosis, and modulated the autophagy-related pathway PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1. Further, quercetin enhances the sequestering effect of 14-3-3 and reversed the decrease in interaction between p-Bad and 14-3-3 and p-FKHR and 14-3-3. Our findings showed that quercetin exerts its protective benefits and rescues neuronal damage by several mechanisms, and it might be a viable neuroprotective drug for ischemic stroke therapy. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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18 pages, 5964 KiB

Open AccessArticle

Ancistrocladinium A Induces Apoptosis in Proteasome Inhibitor-Resistant Multiple Myeloma Cells: A Promising Therapeutic Agent Candidate

by Daniela Brünnert, Raina Seupel, Pankaj Goyal, Matthias Bach, Heike Schraud, Stefanie Kirner, Eva Köster, Doris Feineis, Ralf C. Bargou, Andreas Schlosser, Gerhard Bringmann and Manik Chatterjee

Pharmaceuticals 2023, 16(8), 1181; https://doi.org/10.3390/ph16081181 - 18 Aug 2023

Cited by 2 | Viewed by 2053

Abstract

The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma [...] Read more.

The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)

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Chemical structures of (A) dioncophylline A, (B) ancistrocladinium A, (C,D) biotinylated ancistrocladinium A as (C) the general derivative and the schematic labeling with biotin and its interaction with streptavidin, and (D) the specific, here prepared and used biotin-labeled analog of ancistrocladinium A. Full article ">Figure 2
Ancistrocladinium A induces apoptosis in MM cells. Results of viability analyses upon treatment of MM cells and non-malignant PBMCs with ancistrocladinium A are shown either as dose-response curves (A,B) or as a dot blot (C). Human MM cell lines, including PI-resistant sub-cell lines (A), PBMCs of three healthy donors (B), or primary CD138+ MM cells from four patients (C), were treated for 3 d with different concentrations of ancistrocladinium A prior to viability analysis by flow cytometry-based annexin V/propidium iodide staining. The respective EC50 values of all analyzed cell lines are summarized in the table (D). Three to five independent experiments were performed for MM cell line experiments. Full article ">Figure 3
Identification of ancistrocladinium A-interacting proteins in INA-6 cell lysates. (A) Significantly enriched proteins are represented by gray-filled circles. Protein ratios and intensities are median values derived from three different replicates. The size of the circles correlates with the number of identified razors and unique peptides. Identified proteins are grouped according to their function, and each group is marked by a different color. Carboxylases have biotin as a prosthetic group and were, therefore, enriched specifically by the streptavidin beads, which were used as a control. Statistical significance was calculated using the Benjamini–Hochberg method (adjusted limma p-value < 0.02). (B) Pie chart showing the distribution of the different functional groups of significantly enriched proteins. Full article ">Figure 4
Ancistrocladinium A induces ATF4 protein expression in INA-6 cells. (A) Splicing effect on ATF4-RNA 4 h after treatment of INA-6 cells with ancistrocladinium A (B) INA-6, MM1.S, AMO1 cells and (C) two primary CD138+ MM cell samples were treated for 4 h with 3 µM ancistrocladinium A followed by protein lysis and Western blot analysis of ATF4 or GAPDH, which served as a loading control. Full article ">Figure 5
Ancistrocladinium A induces H2A.X phosphorylation. (A,C) INA-6, MM1.S, AMO1 cells, and (B) two primary MM cell samples were treated for 4 h with 3 µM ancistrocladinium A followed by protein lysis and Western blot analysis of H2X.A expression and phosphorylation, and of PARP cleavage. (C) INA-6, MM1.S, and AMO1 cells were analyzed for DNA damage response proteins ATM, ATR, and its phosphorylation sites, p53 and phosphorylation of CHK1. Expression analysis of GAPDH served as a loading control. Full article ">Figure 6
Combination with ancistrocladinium A enhances the apoptotic effects of panobinostat or carfilzomib on primary MM cells. The cell lines INA-6, JJN3, MM1.S, and MM1.SR180Ixa were treated for 3 d with EC25 concentrations of (A) ancistrocladinium A, panobinostat or a combination of both, (B) ancistrocladinium A, carfilzomib or a combination of both for 3 d followed by flow-cytometry-based viability analysis using an annexin V/propidium iodide staining assay. (C,D) Eighteen primary CD138+ MM cell samples, co-cultured on BM stromal cells, were treated with 4 µM ancistrocladinium A, 5 nM panobinostat, or 1.5 nM carfilzomib alone, or with a combination approach either with of ancistrocladinium A and panobinostat or ancistrocladinium A and carfilzomib for 3 d followed by viability analysis. DMSO treatment served as a solvent control, and results were normalized to the respective DMSO control. To statistically interpret the significance of the data, a 2-way ANOVA test followed by a Tukey’s multiple comparisons test was performed (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001). Full article ">

15 pages, 3618 KiB

Open AccessArticle

Protective Role of Betulinic Acid against Cisplatin-Induced Nephrotoxicity and Its Antibacterial Potential toward Uropathogenic Bacteria

by Fatemah A. Alherz, Engy Elekhnawy, Hend Mostafa Selim, Thanaa A. El-Masry, Aya H. El-Kadem, Ismail A. Hussein and Walaa A. Negm

Pharmaceuticals 2023, 16(8), 1180; https://doi.org/10.3390/ph16081180 - 18 Aug 2023

Viewed by 1408

Abstract

Acute kidney injury (AKI) is one of the major side effects of cisplatin, a remarkable anticancer agent. Therefore, there is a growing need to find an agent that could mitigate cisplatin-induced nephrotoxicity. Betulinic acid (BA) is a natural compound isolated from Silene succulenta [...] Read more.

Acute kidney injury (AKI) is one of the major side effects of cisplatin, a remarkable anticancer agent. Therefore, there is a growing need to find an agent that could mitigate cisplatin-induced nephrotoxicity. Betulinic acid (BA) is a natural compound isolated from Silene succulenta Forssk for the first time, with miraculous biological activities and no reports of its effect on the nephrotoxicity induced by cisplatin. Mice received BA orally with doses of 30 and 50 mg/kg before the intraperitoneal injection of cisplatin. Betulinic acid was found to decrease serum levels of creatinine and tissue levels of NGAL and kidney injury molecule (KIM-1) and improve the histological changes in the kidney. In addition, BA decreased the oxidative stress marker malondialdehyde (MDA), increased superoxide dismutase (SOD) antioxidative activity and suppressed the intensity of IL-1B and NFкB immuno-staining. Interestingly, betulinic acid enhanced autophagy by increasing beclin 1, ATG5, and LC3II and decreasing p62 expressions. Thus, our findings suggest betulinic acid as a potential agent that may protect from acute kidney injury by targeting inflammation, oxidative stress, and autophagy processes. Novel drugs are needed to combat the spreading of multidrug resistance between pathogenic bacteria, especially uropathogenic isolates. So, we elucidated the antibacterial properties of BA on Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Betulinic acid had minimum inhibitory concentration values (128 to 512 µg/mL). In addition, it adversely affected the membrane integrity of the tested isolates. Accordingly, betulinic acid should be clinically investigated in the future for urinary tract diseases. Full article

(This article belongs to the Special Issue Pharmacotherapy of Kidney Diseases)

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Chemical structure of the BA. Full article ">Figure 2
Impact of betulinic acid on the integrity of membranes (at 0.5 MIC values): (A) P. aeruginosa, (B) E. coli, (C) P. mirabilis, and (D) K. pneumoniae isolates. There was a significant decrease in the membrane integrity, as revealed by the significant increase (p < 0.05) in the 260 nm absorbing materials. Full article ">Figure 3
Effect of Betulinic acid pretreatment on (A) serum KIM-1 level, (B) serum NGAL level, and (C) serum creatinine. Cisplatin (25 mg/kg, i.p) was used for nephrotoxicity induction. Betulinic acid (30 mg/kg and 50 mg/kg orally) was given for 10 days. Data expressed as mean ± SD (n = 6/group), a means significant vs. control, b means significant vs. cisplatin group. p ˂ 0.05. Full article ">Figure 4
Effect of Betulinic acid pretreatment on (A) Beclin 1 gene expression, (B) ATG5 gene expression, (C) LC3II gene expression, (D) P62 gene expression. Cisplatin (25 mg/kg, i.p) was used for nephrotoxicity induction. Betulinic acid (30 mg/kg and 50 mg/kg, orally) was given for 10 days. Data expressed as mean ± SD (n = 3/group), a means significant vs. control, b means significant vs. cisplatin group. p ˂ 0.05. Full article ">Figure 5
The protein expression level for Beclin 1, ATG5, LCII3 and P62 against B actin (A). Individual protein expression levels for (B) Beclin 1, (C) ATG5, (D) LC3II, (E) P62. Cisplatin (25 mg/kg, i.p) was used for nephrotoxicity induction. Betulinic acid (30 mg/kg and 50 mg/kg orally) was given for 10 days. Data expressed as mean ± SD (n = 3/group), a means significant vs. control, b means significant vs. cisplatin group. p ˂ 0.05. Full article ">Figure 6
Histopathological findings of the kidney sections [H&E × 100]. (A) Cortex of the control group revealed average sized glomeruli (red arrows) with average sized tubules lined surrounding it (blue arrows). (B) The medulla section of the control group exhibited columnar cells lining average sized tubules (red arrows). (C) Cortex section of the positive control showed destructed glomeruli with one atrophic glomerulus (black arrow) surrounded by high inflammatory cells infiltrate (blue arrows) and some tubules revealing hyaline degeneration (red arrows). (D) Medulla section of the positive control exhibited many tubules filled with hyaline casts (red arrows) and inflammatory cells (blue arrow). (E) Cortex section of 30 mg/kg Betulinic acid pre-treated group revealed atrophic glomeruli (green arrows), moderate inflammatory cells (red arrows) and some hyalinized tubules (black arrow) and average sized glomeruli (blue arrows). (F) Medulla of the 30 mg/kg Betulinic acid pre-treated group revealed tubules filled with hyaline casts (red arrows) and inflammatory cells (blue arrow). (G) Cortex of the 50 mg/kg Betulinic acid pre-treated group exhibited few atrophic glomeruli (red arrow), few inflammatory cells (black arrows) and average sized glomeruli (blue arrows). (H) Medulla of kidney with 50 mg/kg Betulinic acid pre-treated group revealed average sized tubules lined with columnar cells (red arrows). (I) Cortex of Betulinic acid-only pretreated kidney showed average sized tubules lined with columnar cells (blue arrows) surrounding average sized glomeruli (red arrows). (J) Medulla of Betulinic acid-only pre-treated kidney revealed average sized tubules lined with columnar cells (red arrows). Full article ">Figure 7
IL-1β (A) and NFҡB (B) Immunohistochemical findings of the kidney sections. (A,1) Section in the kidney of control group showed positive IL-1β expression in less than 5% of cells (score 0) [×100]. (A,2) Section in Cisplatin group showed strong IL-1β expression in more than 50% of cells (score 3) [×100]. (A,3) Section in 30 mg/kg Betulinic acid pre-treated kidney showed moderate IL-1β expression (score 2) [×100]. (A,4) Section in 50 mg/kg Betulinic acid pre-treated showed weak IL-1β expression (score 1) [×100]. (A,5) Section in Betulinic acid only treated kidney positive IL-1β expression in less than 5% of cells (score 0) [×100]. (B,1) Section in the kidney of control group showed positive NFкB expression in less than 5% of cells (score 0) [×100]. (B,2) Section in the Cisplatin group showed strong NFкB expression in more than 50% of cells (score 3) [×100]. (B,3) Section in 30 mg/kg Betulinic acid pre-treated kidney showed moderate NFкB expression (score 2) [×100]. (B,4) Section 50 mg/kg Betulinic acid pre-treated showed weak NFкB expression (score 1) [×100]. (B,5) Section in Betulinic acid only treated kidney positive NFкB expression in less than 5% of cells (score 0) [×100]. Full article ">

23 pages, 4824 KiB

Open AccessArticle

Taste-Masked Flucloxacillin Powder Part 2: Formulation Optimisation Using the Mixture Design Approach and Storage Stability

by Okhee Yoo, Sam Salman, Britta S. von Ungern-Sternberg and Lee Yong Lim

Pharmaceuticals 2023, 16(8), 1179; https://doi.org/10.3390/ph16081179 - 18 Aug 2023

Viewed by 1208

Abstract

Flucloxacillin is prescribed to treat skin infections but its highly bitter taste is poorly tolerated in children. This work describes the application of the D-optimal mixture experimental design to identify the optimal component ratio of flucloxacillin, Eudragit EPO and palmitic acid to prepare [...] Read more.

Flucloxacillin is prescribed to treat skin infections but its highly bitter taste is poorly tolerated in children. This work describes the application of the D-optimal mixture experimental design to identify the optimal component ratio of flucloxacillin, Eudragit EPO and palmitic acid to prepare flucloxacillin taste-masked microparticles that would be stable to storage and would inhibit flucloxacillin release in the oral cavity while facilitating the total release of the flucloxacillin load in the lower gastrointestinal tract (GIT). The model predicted ratio was found to be very close to the stoichiometric equimolar component ratio, which supported our hypothesis that the ionic interactions among flucloxacillin, Eudragit EPO and palmitic acid underscore the polyelectrolyte complex formation in the flucloxacillin taste-masked microparticles. The excipient–drug interactions showed protective effects on the microparticle storage stability and minimised flucloxacillin release at 2 min in dissolution medium. These interactions had less influence on flucloxacillin release in the dissolution medium at 60 min. Storage temperature and relative humidity significantly affected the chemical stability of the microparticles. At the preferred storage conditions of ambient temperature under reduced RH of 23%, over 90% of the baseline drug load was retained in the microparticles at 12 months of storage. Full article

(This article belongs to the Section Pharmaceutical Technology)

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18 pages, 375 KiB

Open AccessReview

Pain Management in Children Admitted to the Emergency Room: A Narrative Review

by Daniela Cunico, Arianna Rossi, Matteo Verdesca, Nicola Principi and Susanna Esposito

Pharmaceuticals 2023, 16(8), 1178; https://doi.org/10.3390/ph16081178 - 18 Aug 2023

Cited by 2 | Viewed by 3595

Abstract

Pain is a biopsychosocial experience characterized by sensory, physiological, cognitive, affective, and behavioral components. Both acute and chronic pain can have short and long-term negative effects. Unfortunately, pain treatment is often inadequate. Guidelines and recommendations for a rational approach to pediatric pain frequently [...] Read more.

Pain is a biopsychosocial experience characterized by sensory, physiological, cognitive, affective, and behavioral components. Both acute and chronic pain can have short and long-term negative effects. Unfortunately, pain treatment is often inadequate. Guidelines and recommendations for a rational approach to pediatric pain frequently differ, and this may be one of the most important reasons for the poor attention frequently paid to pain treatment in children. This narrative review discusses the present knowledge in this regard. A literature review conducted on papers produced over the last 8 years showed that although in recent years, compared to the past, much progress has been made in the treatment of pain in the context of the pediatric emergency room, there is still a lot to do. There is a need to create guidelines that outline standardized and easy-to-follow pathways for pain recognition and management, which are also flexible enough to take into account differences in different contexts both in terms of drug availability and education of staff as well as of the different complexities of patients. It is essential to guarantee an approach to pain that is as uniform as possible among the pediatric population that limits, as much as possible, the inequalities related to ethnicity and language barriers. Full article

(This article belongs to the Special Issue Pharmacology of Pediatric Medicines)

4 pages, 216 KiB

Open AccessEditorial

An Update on Psychoactive Substances: Pharmacology and Toxicology Issues

by Stefania Chiappini and Fabrizio Schifano

Pharmaceuticals 2023, 16(8), 1177; https://doi.org/10.3390/ph16081177 - 18 Aug 2023

Viewed by 1149

Abstract

This Special Issue, titled “Psychoactive Substances: Pharmacology and Toxicology”, aims to provide an up-to-date overview of the pharmacology, clinical information, and toxicology of psychotropics, as well as the effects associated with their intake [...] Full article

(This article belongs to the Special Issue Psychoactive Substances: Pharmacology and Toxicology)

24 pages, 11517 KiB

Open AccessSystematic Review

Neuroendocrine Biomarkers of Herbal Medicine for Major Depressive Disorder: A Systematic Review and Meta-Analysis

by Hye-Bin Seung, Hui-Ju Kwon, Chan-Young Kwon and Sang-Ho Kim

Pharmaceuticals 2023, 16(8), 1176; https://doi.org/10.3390/ph16081176 - 18 Aug 2023

Viewed by 1438

Abstract

Major depressive disorder (MDD) is a medical condition involving persistent sadness and loss of interest; however, conventional treatments with antidepressants and cognitive behavioral therapy have limitations. Based on the pathogenesis of MDD, treatments using herbal medicines (HM) have been identified in animal studies. [...] Read more.

Major depressive disorder (MDD) is a medical condition involving persistent sadness and loss of interest; however, conventional treatments with antidepressants and cognitive behavioral therapy have limitations. Based on the pathogenesis of MDD, treatments using herbal medicines (HM) have been identified in animal studies. We conducted a systematic review of clinical studies to identify neurobiological outcomes and evaluate the effectiveness of HM in treating MDD. A meta-analysis was performed by searching nine databases from their inception until 12 September 2022, including 31 randomized controlled trials with 3133 participants, to examine the effects of HM on MDD using neurobiological biomarkers and a depression questionnaire scale. Quality assessment was performed using a risk of bias tool. Compared to antidepressants alone, HM combined with an antidepressant significantly increased concentrations of serotonin (SMD = 1.96, 95% CI: 1.24–2.68, p < 0.00001, I² = 97%), brain-derived neurotrophic factor (SMD = 1.38, 95% CI: 0.92–1.83, p < 0.00001, I² = 91%), and nerve growth factors (SMD = 2.38, 95% CI: 0.67–4.10, p = 0.006, I² = 96%), and decreased cortisol concentrations (SMD = −3.78, 95% CI: −4.71 to −2.86, p < 0.00001, I² = 87%). Although HM or HM with an antidepressant benefits MDD treatment through improving neuroendocrine factors, these findings should be interpreted with caution because of the low methodological quality and clinical heterogeneity of the included studies. Full article

(This article belongs to the Special Issue Neuropharmacology of Plant Extracts and Their Active Compounds)

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20 pages, 3697 KiB

Open AccessArticle

Neuropharmacological Effects of the Dichloromethane Extract from the Stems of Argemone ochroleuca Sweet (Papaveraceae) and Its Active Compound Dihydrosanguinarine

by Eunice Yáñez-Barrientos, Juan Carlos Barragan-Galvez, Sergio Hidalgo-Figueroa, Alfonso Reyes-Luna, Maria L. Gonzalez-Rivera, David Cruz Cruz, Mario Alberto Isiordia-Espinoza, Martha Alicia Deveze-Álvarez, Clarisa Villegas Gómez and Angel Josabad Alonso-Castro

Pharmaceuticals 2023, 16(8), 1175; https://doi.org/10.3390/ph16081175 - 18 Aug 2023

Cited by 1 | Viewed by 1622

Abstract

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography–mass spectrometry (GC–MS), [...] Read more.

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography–mass spectrometry (GC–MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1–50 mg/kg p.o.) and DHS (0.1–10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED₅₀) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED₅₀ = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED₅₀ = 3 mg/kg) and the tail suspension test (ED₅₀ = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED₅₀ = 2 mg/kg) in the hole board test. The AOE (1–50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABA_A receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS. Full article

(This article belongs to the Special Issue Neuropharmacology of Plant Extracts and Their Active Compounds)

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39 pages, 11167 KiB

Open AccessReview

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

by Galina I. Buravchenko and Andrey E. Shchekotikhin

Pharmaceuticals 2023, 16(8), 1174; https://doi.org/10.3390/ph16081174 - 17 Aug 2023

Cited by 4 | Viewed by 2388

Abstract

N-Oxides of heterocyclic compounds are the focus of medical chemistry due to their diverse biological properties. The high reactivity and tendency to undergo various rearrangements have piqued the interest of synthetic chemists in heterocycles with N-oxide fragments. Quinoxaline 1,4-dioxides are an [...] Read more.

N-Oxides of heterocyclic compounds are the focus of medical chemistry due to their diverse biological properties. The high reactivity and tendency to undergo various rearrangements have piqued the interest of synthetic chemists in heterocycles with N-oxide fragments. Quinoxaline 1,4-dioxides are an example of an important class of heterocyclic N-oxides, whose wide range of biological activity determines the prospects of their practical use in the development of drugs of various pharmaceutical groups. Derivatives from this series have found application in the clinic as antibacterial drugs and are used in agriculture. Quinoxaline 1,4-dioxides present a promising class for the development of new drugs targeting bacterial infections, oncological diseases, malaria, trypanosomiasis, leishmaniasis, and amoebiasis. The review considers the most important methods for the synthesis and key directions in the chemical modification of quinoxaline 1,4-dioxide derivatives, analyzes their biological properties, and evaluates the prospects for the practical application of the most interesting compounds. Full article

(This article belongs to the Special Issue Novel Heterocyclic Compounds for Drug Discovery)

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16 pages, 1857 KiB

Open AccessArticle

Extraction Methods, Chemical Characterization, and In Vitro Biological Activities of Plinia cauliflora (Mart.) Kausel Peels

by Mariana Moraes Pinc, Mariana Dalmagro, Elton da Cruz Alves Pereira, Guilherme Donadel, Renan Tedeski Thomaz, Camila da Silva, Paula Derksen Macruz, Ezilda Jacomassi, Arquimedes Gasparotto Junior, Jaqueline Hoscheid, Emerson Luiz Botelho Lourenço and Odair Alberton

Pharmaceuticals 2023, 16(8), 1173; https://doi.org/10.3390/ph16081173 - 17 Aug 2023

Cited by 5 | Viewed by 1408

Abstract

Plinia cauliflora (Mart.) Kausel, popularly known as jabuticaba, possesses bioactive compounds such as flavonoids, tannins, and phenolic acids, known for their antioxidant, antibacterial, wound healing, and cardioprotective effects. Therefore, this study aimed to standardize the P. cauliflora fruit peel extraction method, maximize phenolic [...] Read more.

Plinia cauliflora (Mart.) Kausel, popularly known as jabuticaba, possesses bioactive compounds such as flavonoids, tannins, and phenolic acids, known for their antioxidant, antibacterial, wound healing, and cardioprotective effects. Therefore, this study aimed to standardize the P. cauliflora fruit peel extraction method, maximize phenolic constituents, and evaluate their antioxidative and antimicrobial effects. Various extraction methods, including vortex extraction with and without precipitation at 25, 40, and 80 °C, and infusion extraction with and without precipitation, were performed using a completely randomized design. Extraction without precipitation (E − P) showed the highest yield (57.9%). However, the precipitated extraction (E + P) method displayed a yield of 45.9%, higher levels of phenolic derivatives, and enhanced antioxidant capacity. Major compounds, such as D-psicose, D-glucose, and citric acid, were identified through gas chromatography–mass spectrometry (GC-MS) analysis. Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) analysis identified citric acid, hexose, flavonoids, tannins, and quercetin as the major compounds in the extracts. Furthermore, the extracts exhibited inhibitory effects against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli bacteria. In conclusion, the E + P method efficiently obtained extracts with high content of bioactive compounds showing antioxidant and antimicrobial capacities with potential application as a dietary supplement. Full article

(This article belongs to the Section Natural Products)

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29 pages, 474 KiB

Open AccessReview

Pharmaceutical Approaches to Normal Tension Glaucoma

by Maria Letizia Salvetat, Francesco Pellegrini, Leopoldo Spadea, Carlo Salati and Marco Zeppieri

Pharmaceuticals 2023, 16(8), 1172; https://doi.org/10.3390/ph16081172 - 17 Aug 2023

Cited by 5 | Viewed by 3323

Abstract

Normal tension glaucoma (NTG) is defined as a subtype of primary open-angle glaucoma (POAG) in which the intraocular pressure (IOP) values are constantly within the statistically normal range without treatment and represents approximately the 30–40% of all glaucomatous cases. The pathophysiology of this [...] Read more.

Normal tension glaucoma (NTG) is defined as a subtype of primary open-angle glaucoma (POAG) in which the intraocular pressure (IOP) values are constantly within the statistically normal range without treatment and represents approximately the 30–40% of all glaucomatous cases. The pathophysiology of this condition is multifactorial and is still not completely well known. Several theories have been proposed to explain the onset and progression of this disease, which can be divided into IOP-dependent and IOP-independent factors, suggesting different therapeutic strategies. The current literature strongly supports the fundamental role of IOP in NTG. The gold standard treatment for NTG tends to be based on the lowering IOP even if “statistically normal”. Numerous studies have shown, however, that the IOP reduction alone is not enough to slow down or stop the disease progression in all cases, suggesting that other IOP-independent risk factors may contribute to the NTG pathogenesis. In addition to IOP-lowering strategies, several different therapeutic approaches for NTG have been proposed, based on vaso-active, antioxidant, anti-inflammatory and/or neuroprotective substances. To date, unfortunately, there are no standardized or proven treatment alternatives for NTG when compared to traditional IOP reduction treatment regimes. The efficacy of the IOP-independent strategies in decreasing the risk or treating NTG still remains inconclusive. The aim of this review is to highlight strategies reported in the current literature to treat NTG. The paper also describes the challenges in finding appropriate and pertinent treatments for this potentially vision-threatening disease. Further comprehension of NTG pathophysiology can help clinicians determine when to use IOP-lowering treatments alone and when to consider additional or alternatively individualized therapies focused on particular risk factors, on a case-by-case basis. Full article

(This article belongs to the Special Issue Pharmacology of Glaucoma)

23 pages, 5299 KiB

Open AccessArticle

Taste-Masked Flucloxacillin Powder Part 1: Optimisation of Fabrication Process Using a Mixture Design Approach

by Okhee Yoo, Sam Salman, Britta S. von Ungern-Sternberg and Lee Yong Lim

Pharmaceuticals 2023, 16(8), 1171; https://doi.org/10.3390/ph16081171 - 17 Aug 2023

Cited by 2 | Viewed by 1266

Abstract

It is extremely challenging to formulate age-appropriate flucloxacillin medicines for young children, because flucloxacillin sodium (FS) has a lingering, highly bitter taste, dissolves quickly in saliva, and requires multiple daily dosing at relatively large doses for treating skin infections. In this paper, we [...] Read more.

It is extremely challenging to formulate age-appropriate flucloxacillin medicines for young children, because flucloxacillin sodium (FS) has a lingering, highly bitter taste, dissolves quickly in saliva, and requires multiple daily dosing at relatively large doses for treating skin infections. In this paper, we describe a promising taste-masked flucloxacillin ternary microparticle (FTM) formulation comprising FS, Eudragit EPO (EE), and palmitic acid (PA). To preserve the stability of the thermolabile and readily hydrolysed flucloxacillin, the fabrication process employed a non-aqueous solvent evaporation method at ambient temperature. Optimisation of the fabrication method using a mixture design approach resulted in a robust technique that generated stable and reproducible FTM products. The optimised method utilised only a single solvent evaporation step and minimal amounts of ICH class III solvents. It involved mixing two solution phases—FS dissolved in ethanol:acetone (1:4 v/v), and a combination of EE and PA dissolved in 100% ethanol—to give a ternary FS:EE:PA system in ethanol: acetone (3:1 v/v). Solvent evaporation yielded the FTMs containing an equimolar ratio of FS:EE:PA (1:0.8:0.6 w/w). The fabrication process, after optimisation, demonstrated robustness, reproducibility, and potential scalability. Full article

(This article belongs to the Section Pharmaceutical Technology)

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22 pages, 8290 KiB

Open AccessArticle

Design of Tetra-Peptide Ligands of Antibody Fc Regions Using In Silico Combinatorial Library Screening

by Marko Jukič, Sebastjan Kralj, Anja Kolarič and Urban Bren

Pharmaceuticals 2023, 16(8), 1170; https://doi.org/10.3390/ph16081170 - 17 Aug 2023

Cited by 1 | Viewed by 1801

Abstract

Peptides, or short chains of amino-acid residues, are becoming increasingly important as active ingredients of drugs and as crucial probes and/or tools in medical, biotechnological, and pharmaceutical research. Situated at the interface between small molecules and larger macromolecular systems, they pose a difficult [...] Read more.

Peptides, or short chains of amino-acid residues, are becoming increasingly important as active ingredients of drugs and as crucial probes and/or tools in medical, biotechnological, and pharmaceutical research. Situated at the interface between small molecules and larger macromolecular systems, they pose a difficult challenge for computational methods. We report an in silico peptide library generation and prioritization workflow using CmDock for identifying tetrapeptide ligands that bind to Fc regions of antibodies that is analogous to known in vitro recombinant peptide libraries’ display and expression systems. The results of our in silico study are in accordance with existing scientific literature on in vitro peptides that bind to antibody Fc regions. In addition, we postulate an evolving in silico library design workflow that will help circumvent the combinatorial problem of in vitro comprehensive peptide libraries by focusing on peptide subunits that exhibit favorable interaction profiles in initial in silico peptide generation and testing. Full article

(This article belongs to the Special Issue The Role of Molecular Docking in the Design of Targeted Therapeutic Entities and Nanomaterials)

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14 pages, 2599 KiB

Open AccessArticle

Formulation and Evaluation of Plumbagin-Loaded Niosomes for an Antidiabetic Study: Optimization and In Vitro Evaluation

by Rama Tyagi, Ayesha Waheed, Neeraj Kumar, Abdul Ahad, Yousef A. Bin Jardan, Mohd. Mujeeb, Ashok Kumar, Tanveer Naved and Swati Madan

Pharmaceuticals 2023, 16(8), 1169; https://doi.org/10.3390/ph16081169 - 17 Aug 2023

Cited by 3 | Viewed by 1526

Abstract

Diabetes treatment requires focused administration with quality systemic circulation to determine the optimal therapeutic window. Intestinal distribution through oral administration with nanoformulation provides several benefits. Therefore, the purpose of this study is to create plumbagin enclosed within niosomes using the quality by design [...] Read more.

Diabetes treatment requires focused administration with quality systemic circulation to determine the optimal therapeutic window. Intestinal distribution through oral administration with nanoformulation provides several benefits. Therefore, the purpose of this study is to create plumbagin enclosed within niosomes using the quality by design (QbD) strategy for efficient penetration and increased bioavailability. The formulation and optimization of plumbagin-loaded niosomes (P-Ns-Opt) involved the use of a Box–Behnken Design. The particle size (PDI) and entrapment efficiency of the optimized P-Ns-Opt were 133.6 nm, 0.150, and 75.6%, respectively. TEM, DSC, and FTIR were used to analyze the morphology and compatibility of the optimized P-Ns-Opt. Studies conducted in vitro revealed a controlled release system. P-Ns-Opt’s antioxidant activity, α-amylase, and α-glucosidase were evaluated, and the results revealed a dose-dependent efficacy with 60.68 ± 0.02%,90.69 ± 2.9%, and 88.43 ± 0.89%, respectively. In summary, the created P-Ns-Opt demonstrate remarkable potential for antidiabetic activity by inhibiting oxygen radicals, α-amylase, and α-glucosidase enzymes and are, therefore, a promising drug delivery nanocarrier in the management and treatment of diabetes. Full article

(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems 2023)

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13 pages, 3476 KiB

Open AccessReview

Analysis of Giardia lamblia Nucleolus as Drug Target: A Review

by Carlos Gaona-López, Ana Verónica Martínez-Vázquez, Juan Carlos Villalobos-Rocha, Karina Janett Juárez-Rendón and Gildardo Rivera

Pharmaceuticals 2023, 16(8), 1168; https://doi.org/10.3390/ph16081168 - 16 Aug 2023

Cited by 2 | Viewed by 2524

Abstract

Giardia lamblia (G. lamblia) is the main causative agent of diarrhea worldwide, affecting children and adults alike; in the former, it can be lethal, and in the latter a strong cause of morbidity. Despite being considered a predominant disease in low-income [...] Read more.

Giardia lamblia (G. lamblia) is the main causative agent of diarrhea worldwide, affecting children and adults alike; in the former, it can be lethal, and in the latter a strong cause of morbidity. Despite being considered a predominant disease in low-income and developing countries, current migratory flows have caused an increase in giardiasis cases in high-income countries. Currently, there is a wide variety of chemotherapeutic treatments to combat this parasitosis, most of which have potentially serious side effects, such as genotoxic, carcinogenic, and teratogenic. The necessity to create novel treatments and discover new therapeutic targets to fight against this illness is evident. The current review centers around the controversial nucleolus of G. lamblia, providing a historical perspective that traces its apparent absence to the present evidence supporting its existence as a subnuclear compartment in this organism. Additionally, possible examples of ncRNAs and proteins ubiquitous to the nucleolus that can be used as targets of different therapeutic strategies are discussed. Finally, some examples of drugs under research that could be effective against G. lamblia are described. Full article

(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents)

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16 pages, 4670 KiB

Open AccessArticle

Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis

by Marisa Jadna Silva Frederico, Andreza Cipriani, Jocelyn Brice Alexandre Heim, Ana Karla Bittencourt Mendes, Marcela Aragón, Joana Margarida Gaspar, Nylane Maria Nunes De Alencar and Fátima Regina Mena Barreto Silva

Pharmaceuticals 2023, 16(8), 1167; https://doi.org/10.3390/ph16081167 - 16 Aug 2023

Cited by 3 | Viewed by 1113

Abstract

This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN [...] Read more.

This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)

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11 pages, 648 KiB

Open AccessArticle

The Impact of Continuous Veno-Venous Hemodiafiltration on the Efficacy of Administration of Prophylactic Doses of Enoxaparin: A Prospective Observational Study

by Aleksander Aszkiełowicz, Karol P. Steckiewicz, Michał Okrągły, Magdalena A. Wujtewicz and Radosław Owczuk

Pharmaceuticals 2023, 16(8), 1166; https://doi.org/10.3390/ph16081166 - 16 Aug 2023

Cited by 1 | Viewed by 1561

Abstract

Background: Critically ill patients frequently require continuous renal replacement therapy (CRRT). During CRRT, particles up to 10 kDa in size, such as enoxaparin, may be removed. The aim of this study was to determine if patients receiving prophylactic doses of enoxaparin and treated [...] Read more.

Background: Critically ill patients frequently require continuous renal replacement therapy (CRRT). During CRRT, particles up to 10 kDa in size, such as enoxaparin, may be removed. The aim of this study was to determine if patients receiving prophylactic doses of enoxaparin and treated with continuous veno-venous hemodiafiltration (CVVHDF) reach prophylactic values of anti-Xa factor activity. Methods: In this observational trial, we compared two groups: 20 patients treated with CVVHDF and 20 patients not treated with CVVHDF. All of them received prophylactic doses of 40 mg of enoxaparin subcutaneously. Anti-Xa factor activity was determined on the third day of receiving a prophylactic dose of enoxaparin. The first blood sample was taken just before the administration of enoxaparin, and other samples were taken 3 h, 6 h, and 9 h after the administration of a prophylactic dose of enoxaparin. Results: At 3 and 6 h after administration of enoxaparin in both groups, we observed a significant increase in anti-Xa factor activity from baseline, with the peak after 3 h of administration. There were no significant differences in the numbers of patients who had anti-Xa factor activity within the prophylactic range between CVVHDF and control groups. Conclusion: CVVHDF has only a mild effect on the enoxaparin prophylactic effect measured by anti-Xa factor activity. Thus, it seems there is no need to increase the dose of enoxaparin for patients requiring CVVHDF. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 1547 KiB

Open AccessReview

Chemotherapy-Mediated Neuronal Aberration

by Pradip Kumar Jaiswara and Surendra Kumar Shukla

Pharmaceuticals 2023, 16(8), 1165; https://doi.org/10.3390/ph16081165 - 16 Aug 2023

Cited by 3 | Viewed by 2117

Abstract

Chemotherapy is a life-sustaining therapeutic option for cancer patients. Despite the advancement of several modern therapies, such as immunotherapy, gene therapy, etc., chemotherapy remains the first-line therapy for most cancer patients. Along with its anti-cancerous effect, chemotherapy exhibits several detrimental consequences that restrict [...] Read more.

Chemotherapy is a life-sustaining therapeutic option for cancer patients. Despite the advancement of several modern therapies, such as immunotherapy, gene therapy, etc., chemotherapy remains the first-line therapy for most cancer patients. Along with its anti-cancerous effect, chemotherapy exhibits several detrimental consequences that restrict its efficacy and long-term utilization. Moreover, it effectively hampers the quality of life of cancer patients. Cancer patients receiving chemotherapeutic drugs suffer from neurological dysfunction, referred to as chemobrain, that includes cognitive and memory dysfunction and deficits in learning, reasoning, and concentration ability. Chemotherapy exhibits neurotoxicity by damaging the DNA in neurons by interfering with the DNA repair system and antioxidant machinery. In addition, chemotherapy also provokes inflammation by inducing the release of various pro-inflammatory cytokines, including NF-kB, IL-1β, IL-6, and TNF-α. The chemotherapy-mediated inflammation contributes to chemobrain in cancer patients. These inflammatory cytokines modulate several growth signaling pathways and reactive oxygen species homeostasis leading to systemic inflammation in the body. This review is an effort to summarize the available information which discusses the role of chemotherapy-induced inflammation in chemobrain and how it impacts different aspects of therapeutic outcome and the overall quality of life of the patient. Further, this article also discusses the potential of herbal-based remedies to overcome chemotherapy-mediated neuronal toxicity as well as to improve the quality of life of cancer patients. Full article

(This article belongs to the Special Issue Brain Theranostics: Focus on Drug Delivery and Outcomes)

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16 pages, 1551 KiB

Open AccessPerspective

Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report

by Boney Joseph, Nicolas A. Nunez, Simon Kung, Jennifer L. Vande Voort, Vanessa K. Pazdernik, Kathryn M. Schak, Stacey M. Boehm, Brooke Carpenter, Emily K. Johnson, Grigoriy Malyshev, Nathan Smits, Daniel O. Adewunmi, Sarah K. Brown and Balwinder Singh

Pharmaceuticals 2023, 16(8), 1164; https://doi.org/10.3390/ph16081164 - 16 Aug 2023

Cited by 5 | Viewed by 3114 | Correction

Abstract

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with [...] Read more.

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40−100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings. Full article

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

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39 pages, 2276 KiB

Open AccessReview

Use of Nanocarriers Containing Antitrypanosomal Drugs for the Treatment of Chagas Disease

by Diogo de Freitas Paiva, Ana Paula dos Santos Matos, Denise de Abreu Garófalo, Tatielle do Nascimento, Mariana Sato de Souza de Bustamante Monteiro, Ralph Santos-Oliveira and Eduardo Ricci-Junior

Pharmaceuticals 2023, 16(8), 1163; https://doi.org/10.3390/ph16081163 - 15 Aug 2023

Cited by 4 | Viewed by 1622

Abstract

Chagas disease, caused by the Trypanosoma cruzi parasitic protozoan, is a neglected tropical disease (NTD) of significant incidence in Latin America. Transmission to humans and other mammals is mainly via the vector insect from the Reduviidae family, popularly known as the kissing bug. [...] Read more.

Chagas disease, caused by the Trypanosoma cruzi parasitic protozoan, is a neglected tropical disease (NTD) of significant incidence in Latin America. Transmission to humans and other mammals is mainly via the vector insect from the Reduviidae family, popularly known as the kissing bug. There are other transmission means, such as through congenital transmission, blood transfusions, organ transplantations, and the consumption of contaminated food. For more than 50 years, the disease has been treated with benznidazole and nifurtimox, which are only effective during the acute phase of the disease. In addition to their low efficacy in the chronic phase, they cause many adverse effects and are somewhat selective. The use of nanocarriers has received significant attention due to their ability to encapsulate and release therapeutic agents in a controlled manner. Generally, their diameter ranges from 100 to 300 nanometers. The objective of this scoping review was to perform a search of the literature for the use of nanocarriers as an alternative for improving the treatment of Chagas disease and to suggest future research. Bibliographic searches were carried out in the Web of Science and PubMed scientific databases from January 2012 to May 2023, using the “Chagas disease and Trypanosoma cruzi and nanoparticles” keywords, seeking to gather the largest number of articles, which were evaluated using the inclusion and exclusion criteria. After analyzing the papers, the results showed that nanocarriers offer physiological stability and safety for the transport and controlled release of drugs. They can increase solubility and selectivity against the parasite. The in vitro assays showed that the trypanocidal activity of the drug was not impaired after encapsulation. In the in vivo assays, parasitemia reduction and high survival and cure rates in animals were obtained during both phases of the disease using lower doses when compared to the standard treatment. The scoping review showed that nanocarriers are a promising alternative for the treatment of Chagas disease. Full article

(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems 2023)

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Full article ">Figure 1
Chemical structures of nifurtimox and benznidazole. Full article ">Figure 2
Nanocarriers used for the treatment of Chagas disease and cell uptake routes. Full article ">Figure 3
Flowchart corresponding to selection of the articles for the bibliographic review, as PAGE et al. [<a href="#B20-pharmaceuticals-16-01163" class="html-bibr">20</a>]. Full article ">Figure 4
Types of nanocarriers used for delivery of anti-T. cruzi drugs. Others: metallic nanoparticles, composite nanoparticles, and polymerosomes. Full article ">Figure 5
Anti-T. cruzi drugs encapsulated in nanocarriers. Others: Curcumin, ergosterol peroxide, sodium diethyldithiocarbamate, 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyl dithiocarbonate) (H2bdtc), and mercaptosuccinic acid with nitric oxide (NO). Full article ">Figure 6
Methods used by the papers in the syntheses of nanocarriers. Others: Hot homogenization technique, emulsion techniques (O/W), heating and cooling in the formation of crystals, sensitized photo-oxygenation in methanol with eosin, mechanochemistry, ionotropic gelation, anionic polymerization with methanol precipitation and thin film rehydration, green synthesis, condensation hydrolysis and the fluid compression technique called DELOS-SUSP. Full article ">

50 pages, 16501 KiB

Open AccessReview

Chemistry and Pharmacology of Fluorinated Drugs Approved by the FDA (2016–2022)

by Ghulam Shabir, Aamer Saeed, Wajeeha Zahid, Fatima Naseer, Zainab Riaz, Nafeesa Khalil, Muneeba and Fernando Albericio

Pharmaceuticals 2023, 16(8), 1162; https://doi.org/10.3390/ph16081162 - 15 Aug 2023

Cited by 22 | Viewed by 5750

Abstract

Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of [...] Read more.

Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using ¹⁸F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 805 KiB

Open AccessArticle

Reports of Symptoms Associated with Supraventricular Arrhythmias as a Serious Adverse Drug Reaction in the Spanish Pharmacovigilance Database

by Javier Pueyo-Val, Ana Avedillo-Salas, Pablo Berdún-Viñegra, Olga María Pueyo-Val, Ana Fanlo-Villacampa, Cristina Navarro-Pemán, Francisco Javier Lanuza-Giménez, Ignatios Ioakeim-Skoufa and Jorge Vicente-Romero

Pharmaceuticals 2023, 16(8), 1161; https://doi.org/10.3390/ph16081161 - 15 Aug 2023

Viewed by 1249

Abstract

This study aimed to determine the type of drugs reported as suspected of causing severe supraventricular arrhythmias from the Spanish Human Pharmacovigilance System database. A total of 1053 reports were analysed, of which 526 (50%) were on men and 516 (49%) were on [...] Read more.

This study aimed to determine the type of drugs reported as suspected of causing severe supraventricular arrhythmias from the Spanish Human Pharmacovigilance System database. A total of 1053 reports were analysed, of which 526 (50%) were on men and 516 (49%) were on women. The most affected age group was the over-65s, with 593 reports (56%). Of the 1613 drugs, those belonging to the cardiovascular system (ATC Group C) were the most numerous (414 reports, 26%), with digoxin being the most frequent drug (49 reports, 12%). Other common groups were antiinfectives for systemic use (ATC Group J; 306 reports, 19%), antineoplastic and immunomodulating agents (ATC Group L; 198 reports, 12%), and nervous system drugs (ATC Group N; 185 reports, 11%). The most common supraventricular arrhythmia was atrial fibrillation (561 reports, 51%). Regarding outcomes, 730 (66%) patients recovered, 76 (7%) did not recover, 25 (3%) recovered but with sequelae, and 23 (2%) resulted in death. This study revealed that certain drugs have reported to be associated more frequently to supraventricular arrhythmias as serious adverse reactions, especially in the older population. Proper clinical management and effective strategies to ensure medication appropriateness should always be considered to improve patient safety when prescribing drugs. Full article

(This article belongs to the Section Pharmacology)

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81 pages, 15918 KiB

Open AccessSystematic Review

Efficacy and Key Materials of East Asian Herbal Medicine Combined with Conventional Medicine on Inflammatory Skin Lesion in Patients with Psoriasis Vulgaris: A Meta-Analysis, Integrated Data Mining, and Network Pharmacology

by Hee-Geun Jo, Hyehwa Kim, Eunhye Baek, Donghun Lee and Ji Hye Hwang

Pharmaceuticals 2023, 16(8), 1160; https://doi.org/10.3390/ph16081160 - 15 Aug 2023

Cited by 5 | Viewed by 3272

Abstract

Psoriasis is a chronic inflammatory disease that places a great burden on both individuals and society. The use of East Asian herbal medicine (EAHM) in combination with conventional medications is emerging as an effective strategy to control the complex immune-mediated inflammation of this [...] Read more.

Psoriasis is a chronic inflammatory disease that places a great burden on both individuals and society. The use of East Asian herbal medicine (EAHM) in combination with conventional medications is emerging as an effective strategy to control the complex immune-mediated inflammation of this disease from an integrative medicine (IM) perspective. The safety and efficacy of IM compared to conventional medicine (CM) were evaluated by collecting randomized controlled trial literature from ten multinational research databases. We then searched for important key materials based on integrated drug data mining. Network pharmacology analysis was performed to predict the mechanism of the anti-inflammatory effect. Data from 126 randomized clinical trials involving 11,139 patients were used. Compared with CM, IM using EAHM showed significant improvement in the Psoriasis Area Severity Index (PASI) 60 (RR: 1.4280; 95% CI: 1.3783–1.4794; p < 0.0001), PASI score (MD: −3.3544; 95% CI: −3.7608 to −2.9481; p < 0.0001), inflammatory skin lesion outcome, quality of life, serum inflammatory indicators, and safety index of psoriasis. Through integrated data mining of intervention data, we identified four herbs that were considered to be representative of the overall clinical effects of IM: Rehmannia glutinosa (Gaertn.) DC., Isatis tinctoria subsp. athoa (Boiss.) Papan., Paeonia × suffruticosa Andrews, and Scrophularia ningpoensis Hemsl. They were found to have mechanisms to inhibit pathological keratinocyte proliferation and immune-mediated inflammation, which are major pathologies of psoriasis, through multiple pharmacological actions on 19 gene targets and 8 pathways in network pharmacology analysis. However, the quality of the clinical trial design and pharmaceutical quality control data included in this study is still not optimal; therefore, more high-quality clinical and non-clinical studies are needed to firmly validate the information explored in this study. This study is informative in that it presents a focused hypothesis and methodology for the value and direction of such follow-up studies. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products)

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29 pages, 5462 KiB

Open AccessArticle

Cytotoxic and Infection-Controlled Investigations of Novel Dihydropyridine Hybrids: An Efficient Synthesis and Molecular-Docking Studies

by Mallikarjuna R. Guda, Grigory. V. Zyryanov, Amit Dubey, Venkata Subbaiah Munagapati and Jet-Chau Wen

Pharmaceuticals 2023, 16(8), 1159; https://doi.org/10.3390/ph16081159 - 15 Aug 2023

Cited by 1 | Viewed by 1409

Abstract

A sequence of novel 1,4-dihydropyridines (DHP) and their hybrids was developed using a multicomponent strategy under environmentally benign conditions. In addition, computational studies were performed, and the ligand–protein interactions calculated in different bacteria and two fungal strains. Para-hydroxy-linked DHP (5f) showed [...] Read more.

A sequence of novel 1,4-dihydropyridines (DHP) and their hybrids was developed using a multicomponent strategy under environmentally benign conditions. In addition, computational studies were performed, and the ligand–protein interactions calculated in different bacteria and two fungal strains. Para-hydroxy-linked DHP (5f) showed the best binding energies of 3.591, 3.916, 8.499 and 6.895 kcal/mol against various pathogens used and other substances received a good docking score. The pathogen resistance potential of the synthesized targets against four bacteria and two fungi showed that whole DHP substances exhibit different levels of resistance to each microorganism. Gram-positive bacteria, which are highly sensitive to all molecules, and the MTCC-1884-encoded fungus strongly rejected the studied compounds compared to comparator drugs. In particular, the 5f candidate showed remarkable antimicrobial activity, followed by the substances 5a, 5b, 5j, 5k and 5l. Furthermore, MIC and MBC/MFC properties showed that 5f had a minimum bacterial concentration of 12.5 μg/mL against E. coli and against two fungal pathogens, with its killing activity being effective even at low concentrations. On the other hand, whole motifs were tested for their cytotoxic activity, revealing that the methoxy and hydroxy-linked compounds (5h) showed greater cytotoxic potency, followed by the two hydroxy linked compounds (5d and 5f). Overall, this synthetic approach used represents a prototype for future nature-favored synthesis methods and these biological results serve as a guide for future therapeutic drug research. However, the computer results play an important role in the further development of biological experiments. Full article

(This article belongs to the Special Issue Molecular Modification in Designing Next Generation Drug Delivery Systems)

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27 pages, 5870 KiB

Open AccessArticle

Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues

by Daniel Martins, Eva Gil-Martins, Fernando Cagide, Catarina da Fonseca, Sofia Benfeito, Carlos Fernandes, Daniel Chavarria, Fernando Remião, Renata Silva and Fernanda Borges

Pharmaceuticals 2023, 16(8), 1158; https://doi.org/10.3390/ph16081158 - 15 Aug 2023

Cited by 4 | Viewed by 3019

Abstract

Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is [...] Read more.

Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC₅₀ values when compared to their counterparts. Consistently, our data showed a correlation between the drug’s lipophilicity and the EC₅₀ values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood–brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug’s lipophilicity and the EC₅₀ values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs. Full article

(This article belongs to the Special Issue State of the Art of Medicinal Chemistry in Portugal)

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Chemical structures of serotonin and the classic serotonergic psychedelics, psilocybin, and its active metabolite psilocin, N,N-dimethyltryptamine (DMT), mescaline and lysergic acid diethylamide (LSD). Full article ">Figure 2
Phenethylamine-based psychedelics. Chemical structures of 2,5-dimethoxyphenethylamines (2C) drugs and their corresponding N-(2-methoxybenzyl)phenethylamines (NBOMe) drugs. Phenethylamine scaffold is outlined. Full article ">Figure 3
Concentration–response (cell death) curves of the tested drugs (0–1500 µM) obtained, in differentiated SH-SY5Y cells, by the neutral red uptake and the resazurin reduction assays, 24 h after exposure. Results are presented as mean ± 95% CI of at least 4 independent experiments (performed in triplicate). The concentration–response curves were drawn using the least squares method as a fitting method. CI—confidence interval. Full article ">Figure 4
Impact of the cytochrome P450 (CYP)-mediated metabolism on the cytotoxicity of the tested drugs assessed through the neutral red uptake assay, in differentiated SH-SY5Y cells, 24 h after exposure to the drugs in the presence or absence of different CYP inhibitors: 1000 μM ABT (non-selective CYP inhibitor), 10 μM quinidine (CYP2D6 inhibitor) or 1μM ketoconazole (CYP3A4 inhibitor). Results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 5
Effect of monoamine oxidase (MAO) inhibition on the drugs-induced cytotoxicity in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs, in the presence or absence of two MAO inhibitors: 1 μM clorgyline—MAO-A inhibitor or 1 μM rasagiline—MAO-B inhibitor, through the neutral red uptake assay. The results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 6
Mitochondrial membrane potential, evaluated with the JC-1 dye, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. The results were calculated as red/green fluorescence intensity ratios and expressed as percentage of control cells. Results are presented as mean ± SD of at least 3 independent experiments (performed in triplicate). As positive control, carbonyl cyanide m-chlorophenyl hydrazone (100 µM, 4 h) was used. Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [*** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 7
Intracellular levels of total glutathione, evaluated through the DTNB-GSH recycling assay, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. Results are presented as mean ± SD of at least 5 independent experiments (performed in duplicate). Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [*** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 8
Intracellular adenosine triphosphate (ATP) levels, evaluated through an ATP bioluminescence assay, in differentiated SH-SY5Y cells, 24 h after exposure to the tested drugs. Results are presented as mean ± SD of at least 4 independent experiments (performed in duplicate). Statistical comparisons were performed using one-way ANOVA, followed by Dunnett’s multiple comparison post hoc test. [* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 9
Concentration–response (cell death) curves of the tested drugs (0–2000 µM) obtained in HepG2 cells by the neutral red uptake and the resazurin reduction assays, 24 h after exposure. Results are presented as mean ± 95% CI of at least 4 independent experiments (performed in triplicate). The concentration–response curves were drawn using the least squares method as a fitting method. CI—confidence interval. Full article ">Figure 10
Impact of the metabolism via cytochrome P450 (CYP) on the cytotoxicity of the tested drugs assessed through the resazurin reduction uptake assay, in HepG2 cells, 24 h after exposure to the drugs in the presence or absence of different CYP inhibitors: 1000 μM ABT (non-selective CYP inhibitor), 10 μM quinidine (CYP2D6 inhibitor) or 1μM ketoconazole (CYP3A4 inhibitor). Results are presented as mean ± SD of at least 4 independent experiments (performed in triplicate). Statistical comparisons were performed using two-way ANOVA, followed by Tukey’s multiple comparison post hoc test [* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 vs. control (0 μM)]. In all cases, p values < 0.05 were considered statistically significant. Full article ">Figure 11
Correlations between EC50 values obtained in both metabolic and lysosomal activity measurements (cytotoxicity assays) in both cell lines tested with the lipophilicity (A) and calculated passive permeability (B). Full article ">

22 pages, 10428 KiB

Open AccessReview

The Magic Methyl and Its Tricks in Drug Discovery and Development

by Pedro de Sena Murteira Pinheiro, Lucas Silva Franco and Carlos Alberto Manssour Fraga

Pharmaceuticals 2023, 16(8), 1157; https://doi.org/10.3390/ph16081157 - 15 Aug 2023

Cited by 19 | Viewed by 3227

Abstract

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational [...] Read more.

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The “methylation effect”, or the “magic methyl” effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates. Full article

(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)

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