Pharmaceuticals

14 pages, 2804 KiB

Open AccessArticle

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia

by Samia Kalsoom, Muhammad Fawad Rasool, Imran Imran, Hamid Saeed, Tanveer Ahmad and Faleh Alqahtani

Pharmaceuticals 2024, 17(2), 265; https://doi.org/10.3390/ph17020265 - 19 Feb 2024

Viewed by 1916

Abstract

Nadolol is a long-acting non-selective β–adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by [...] Read more.

Nadolol is a long-acting non-selective β–adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (R_pre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration–time curve (AUC_0-t), the maximum concentration in plasma (C_max), and CL (clearance)_. The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the R_pre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

11 pages, 1518 KiB

Open AccessReview

Pharmacological Topical Therapy for Intra-Oral Post Traumatic Trigeminal Neuropathic Pain: A Comprehensive Review

by Yair Sharav, Shimrit Heiliczer, Rafael Benoliel and Yaron Haviv

Pharmaceuticals 2024, 17(2), 264; https://doi.org/10.3390/ph17020264 - 19 Feb 2024

Cited by 1 | Viewed by 1485

Abstract

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review [...] Read more.

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases—MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

► Show Figures

Figure 1

20 pages, 4539 KiB

Open AccessArticle

Shaping the Future of Obesity Treatment: In Silico Multi-Modeling of IP6K1 Inhibitors for Obesity and Metabolic Dysfunction

by Ismail Mondal, Amit Kumar Halder, Nirupam Pattanayak, Sudip Kumar Mandal and Maria Natalia D. S. Cordeiro

Pharmaceuticals 2024, 17(2), 263; https://doi.org/10.3390/ph17020263 - 19 Feb 2024

Viewed by 1612

Abstract

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques [...] Read more.

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure–Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds’ high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models. Full article

(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery)

► Show Figures

Graphical abstract

18 pages, 1712 KiB

Open AccessArticle

Synthesis and Study of the Structure–Activity Relationship of Antiproliferative N-Substituted Isosteviol-Based 1,3-Aminoalcohols

by Dániel Ozsvár, Noémi Bózsity, István Zupkó and Zsolt Szakonyi

Pharmaceuticals 2024, 17(2), 262; https://doi.org/10.3390/ph17020262 - 19 Feb 2024

Viewed by 950

Abstract

Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were prepared via stereoselective transformations. The acid-catalysed hydrolysis and rearrangement of natural stevioside produced isosteviol, which was transformed into the key intermediate methyl ester. In the next step, an 1,3-aminoalcohol library was prepared by [...] Read more.

Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were prepared via stereoselective transformations. The acid-catalysed hydrolysis and rearrangement of natural stevioside produced isosteviol, which was transformed into the key intermediate methyl ester. In the next step, an 1,3-aminoalcohol library was prepared by the reductive amination of the intermediate 3-hydroxyaldehyde obtained from isosteviol in a two-step synthesis. To study the effect of the carboxylate ester function at position 4, the free carboxylic acid, benzyl ester and acryloyl ester analogues were prepared as elongated derivatives in comparison with our earlier results in this field. The antiproliferative activity of compounds against human tumour cell lines (A2780, HeLa, MCF-7 and MDA-MB-231) was investigated. In our preliminary study, the 1,3-aminoalcohol function with N-benzyl or (1H-imidazol-1-yl)-propyl substitution and benzyl ester moiety seemed essential for the reliable antiproliferative activity. The results obtained could be a good starting point to further functionalisation towards more efficient antiproliferative diterpenes. Full article

(This article belongs to the Special Issue Novel Anti-proliferative Agents, 2nd Edition)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Antiproliferative properties showing IC50 values of the prepared isosteviol analogues against cancer cells and NIH/3T3 fibroblasts. The numeric values are given in <a href="#app1-pharmaceuticals-17-00262" class="html-app">Table S1 in the Supplementary Materials</a>. Full article ">Scheme 1
Synthesis of isosteviol-based N-(4-fluorobenzyl)-1,3-aminoalcohol 8. (i) BnBr, K2CO3, dry acetone, 4 h, 60 °C, 87%; (ii) HCHO, NaOEt, dry EtOH, 1 h, 60 °C, 78%; (iii) 10 mol% TEMPO, NBS, TBAB, DCM/H2O, 12 h, reflux, 83%; (iv) (1) 4-FBnNH2, dry EtOH, 3 h, 25 °C; (2) MeOH, NaBH4, 4 h, 25 °C, 70%; (v) Boc2O, dry DCM, 1 h, 25 °C, 79%; (vi) EtOAc/n-hexane, 5% Pd/C, H2 (1 atm), 24 h, 25 °C, 82%; (vii) (1) TFA, dry DCM, 3 h, 25 °C; (2) Et3N, dry DCM, 3 min, 25 °C, 77%. Full article ">Scheme 2
Synthesis of allyl (11, 12) and acetylene derivatives (13, 14). (i) Acrylic acid, K2CO3, 1,4-dibromobutane, dry acetone, 24 h, 25 °C, 61% (9), 26% (10); (ii) 4-bromobutyl acrylate, K2CO3, dry acetone, 24 h, 25 °C, 83%; (iii) 3-(4-bromobutoxy)-3-oxopropyl acrylate, K2CO3, dry acetone, 24 h, 25 °C, 77%; (iv) propargyl bromide, K2CO3, dry acetone, 24 h, 25 °C, 88%; (v) (1) TFA, dry DCM, 3 h, 25 °C; (2) Et3N, dry DCM, 3 min, 25 °C, 79%. Full article ">Scheme 3
Synthesis of isosteviol-based 1,3-aminoalcohols. (i) (1) RNH2 (1 equ.), dry EtOH, 3 h, 25 °C; (2) MeOH, NaBH4 (2 equ.), 4 h, 25 °C, 21–68%. Full article ">Scheme 4
Synthesis of the library of 23–28. (i) EtOAc/n-hexane 1:1, 5% Pd/C, H2 (1 atm), 24 h, 25 °C, 63%; (ii) CH2N2, Et2O, 5 min, 25 °C, 81%; (iii) (1) RNH2 (1 equ.), dry EtOH, 3 h, 25 °C; (2) MeOH, NaBH4 (2 equ.), 4 h, 25 °C, 38–88%. Full article ">

23 pages, 15664 KiB

Open AccessArticle

Integrative Approach for Designing Novel Triazole Derivatives as α-Glucosidase Inhibitors: QSAR, Molecular Docking, ADMET, and Molecular Dynamics Investigations

by Oussama Abchir, Meriem Khedraoui, Hassan Nour, Imane Yamari, Abdelkbir Errougui, Abdelouahid Samadi and Samir Chtita

Pharmaceuticals 2024, 17(2), 261; https://doi.org/10.3390/ph17020261 - 19 Feb 2024

Cited by 6 | Viewed by 1550

Abstract

In response to the increasing prevalence of diabetes mellitus and the limitations associated with the current treatments, there is a growing need to develop novel medications for this disease. This study is focused on creating new compounds that exhibit a strong inhibition of [...] Read more.

In response to the increasing prevalence of diabetes mellitus and the limitations associated with the current treatments, there is a growing need to develop novel medications for this disease. This study is focused on creating new compounds that exhibit a strong inhibition of alpha-glucosidase, which is a pivotal enzyme in diabetes control. A set of 33 triazole derivatives underwent an extensive QSAR analysis, aiming to identify the key factors influencing their inhibitory activity against α-glucosidase. Using the multiple linear regression (MLR) model, seven promising compounds were designed as potential drugs. Molecular docking and dynamics simulations were employed to shed light on the mode of interaction between the ligands and the target, and the stability of the obtained complexes. Furthermore, the pharmacokinetic properties of the designed compounds were assessed to predict their behavior in the human body. The binding free energy was also calculated using MMGBSA method and revealed favorable thermodynamic properties. The results highlighted three novel compounds with high biological activity, strong binding affinity to the target enzyme, and suitability for oral administration. These results offer interesting prospects for the development of effective and well-tolerated medications against diabetes mellitus. Full article

(This article belongs to the Special Issue Triazole and Derivatives in Medicinal Chemistry)

► Show Figures

Figure 1

17 pages, 1959 KiB

Open AccessArticle

Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis

by Yuki Minayoshi, Hitoshi Maeda, Keisuke Hamasaki, Taisei Nagasaki, Mei Takano, Ryo Fukuda, Yuki Mizuta, Motohiko Tanaka, Yutaka Sasaki, Masaki Otagiri, Hiroshi Watanabe and Toru Maruyama

Pharmaceuticals 2024, 17(2), 260; https://doi.org/10.3390/ph17020260 - 19 Feb 2024

Cited by 1 | Viewed by 1336

Abstract

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic [...] Read more.

Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic macrophages. To develop a type-I IFN equipped with the ability to target hepatic macrophages through the macrophage mannose receptor, the present study designed a mouse type-I interferon-mannosylated albumin fusion protein using site-specific mutagenesis and albumin fusion technology. This fusion protein exhibited the induction of anti-inflammatory molecules, such as IL-10, IL-1Ra, and PD-1, in RAW264.7 cells, or hepatoprotective effects on carbon tetrachloride-induced chronic hepatitis mice. As expected, such biological and hepatoprotective actions were significantly superior to those of human fusion proteins. Furthermore, the repeated administration of mouse fusion protein to carbon tetrachloride-induced chronic hepatitis mice clearly suppressed the area of liver fibrosis and hepatic hydroxyproline contents, not only with a reduction in the levels of inflammatory cytokine (TNF-α) and fibrosis-related genes (TGF-β, Fibronectin, Snail, and Collagen 1α2), but also with a shift in the hepatic macrophage phenotype from inflammatory to anti-inflammatory. Therefore, type-I interferon-mannosylated albumin fusion protein has the potential as a new therapeutic agent for chronic hepatitis. Full article

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

► Show Figures

Figure 1

Figure 1
Flow chart describing the creation of the Man-MSA(D494N)-mIFNα2(N78Q) gene using the pPIC9. Full article ">Figure 2
Anti-inflammatory and immunomodulatory effects of Man-MSA-mIFNα2 on RAW264.7 cells. mRNA expression levels of IL-10, IL-1Ra, and PD-L1 were evaluated 3 h after treatment of RAW264.7 cells with Man-HSA-hIFNα2b or Man-MSA-mIFNα2. Full article ">Figure 3
Pathological phenotypes in CCl4-induced hepatitis mice. (A) Schematic summary of the experimental protocol for preparing CCl4-induced hepatitis mice. (B) Plasma ALT values were determined at 0, 2, 4, 6, and 8 weeks after repeated administration of CCl4 (1.0 mL/kg, i.p.). Each value represents the mean ± S.E. (n = 5). * p < 0.05 compared with week 0. (C) The levels of hepatic hydroxyproline were determined at 0, 4, 6, and 8 weeks after repeated administration of CCl4. Each value represents the mean ± S.E. (n = 5). (D) Liver fibrosis was evaluated by picrosirius red staining and immunofluorescence staining of α-SMA (green) with DAPI (blue). Scale bars, 100 µm. Full article ">Figure 4
Effect of Man-MSA-mIFNα2 on hepatocellular damage in CCl4-induced chronic hepatitis mice. (A) Schematic summary of the experimental protocol for evaluation of the effect of Man-MSA-mIFNα2 on hepatocellular damage on CCl4-induced chronic hepatitis mice. (B) Plasma ALT values were determined 8 weeks after repeated administration of CCl4 (1.0 mL/kg, i.p.). Each value represents the mean ± S.E. (n = 5). (C) Sections of liver tissue were prepared 8 weeks after repeated administration of CCl4 and subjected to histopathological examination (HE staining). Scale bars, 100 µm. Full article ">Figure 5
Effects of Man-MSA-mIFNα2 on inflammatory cytokines or macrophage polarization in CCl4-induced chronic hepatitis mice. (A) The expression levels of TNF-α in liver were determined by ELISA. Each value represents the mean ± S.E. (n = 5). (B) Hepatic macrophages were isolated from the livers of CCl4-induced chronic hepatitis mice, and the populations of M1 or M2 macrophages were analyzed using CD80 (M1 marker) or CD206 (M2 marker), respectively. Full article ">Figure 6
Effect of Man-MSA-mIFNα2 on liver fibrosis in CCl4-induced chronic hepatitis mice. (A) Hepatic hydroxyproline contents were determined 8 weeks after repeated administration of CCl4. Each value represents the mean ± S.E. (n = 5). (B) Liver fibrosis was evaluated by picrosirius red staining and immunofluorescence staining of α-SMA (green) with DAPI (blue). Scale bars, 100 µm. (C) The mRNA expression levels of TGF-β, Fibronectin, Snail, and Collagen 1α2 in liver were determined by qRT-PCR. Each value represents the mean ± S.E. (n = 5). Full article ">

19 pages, 5214 KiB

Open AccessArticle

Outlining the Phytoconstituents of Greek Clover Herb Extract and Assessment of Its Effect against Foodborne Infections Caused by Salmonella typhimurium

by Jawaher Alqahtani, Walaa A. Negm, Engy Elekhnawy, Moneerah J. Alqahtani, Ehssan Moglad, Sarah Ibrahim and Suzy A. El-Sherbeni

Pharmaceuticals 2024, 17(2), 259; https://doi.org/10.3390/ph17020259 - 18 Feb 2024

Viewed by 1257

Abstract

Owing to the spread of resistance between pathogenic bacteria, searching for novel compounds with antibacterial activity is essential. Here, we investigated the potential antibacterial activity of Greek clover or Trigonella foenum-graecum herb extract on Salmonella typhimurium clinical isolates. The chemical profile of the [...] Read more.

Owing to the spread of resistance between pathogenic bacteria, searching for novel compounds with antibacterial activity is essential. Here, we investigated the potential antibacterial activity of Greek clover or Trigonella foenum-graecum herb extract on Salmonella typhimurium clinical isolates. The chemical profile of the herb was initially determined using LC-ESI-MS/MS, which explored 36 different compounds. Interestingly, the fenugreek extract possessed antibacterial action in vitro with minimum inhibitory concentrations of 64 to 512 µg/mL. The potential mechanism of action was studied by elucidating the effect of the fenugreek extract on the membrane properties of S. typhimurium bacteria, including the inner and outer membrane permeability and membrane integrity. Remarkably, the fenugreek extract had detrimental effects on the membrane properties in 40–60% of the isolates. Moreover, the in vivo antibacterial action was studied using a gastrointestinal infection model with S. typhimurium bacteria. Interestingly, the fenugreek extract (200 mg/kg) improved the infection outcomes in the tested mice. This was represented by the noteworthy decrease (p < 0.05) in the bacterial count in the small intestine and caecum tissues. The survival rate of the fenugreek-extract-treated mice significantly increased compared to the S. typhimurium-infected group. Additionally, there was an improvement in the histological and immunohistochemical features of tumor necrosis factor-alpha. In addition, using an ELISA and qRT-PCR, there was an improvement in the proinflammatory and oxidative stress markers in the fenugreek-extract-treated group. Consequently, fenugreek extract should be investigated further on other food pathogens. Full article

(This article belongs to the Special Issue Plant- , Microbial- and Marine-Derived Natural Product Research in Drug Discovery: Strengths and Perspectives)

► Show Figures

Graphical abstract

13 pages, 2408 KiB

Open AccessArticle

The Autoxidized Mixture of (-)-Epicatechin Contains Procyanidins and Shows Antiproliferative and Apoptotic Activity in Breast Cancer Cells

by Yazmin Osorio-Cruz, Ivonne María Olivares-Corichi, José Correa-Basurto, José Arnold González-Garrido, Fernando Pereyra-Vergara, Gildardo Rivera and José Rubén García-Sánchez

Pharmaceuticals 2024, 17(2), 258; https://doi.org/10.3390/ph17020258 - 17 Feb 2024

Cited by 1 | Viewed by 1058

Abstract

For this study, procyanidins generated through the autoxidation of (-)-epicatechin (Flavan-3-ol) under mildly acidic conditions (pH = 6.0) were characterized with ultra high-performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS). Two procyanidins (types A and B) and a mix of oligomers [...] Read more.

For this study, procyanidins generated through the autoxidation of (-)-epicatechin (Flavan-3-ol) under mildly acidic conditions (pH = 6.0) were characterized with ultra high-performance liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS). Two procyanidins (types A and B) and a mix of oligomers were generated through the autoxidation of (-)-epicatechin. The antiproliferative activity of this mixture of procyanidins on MDA-MB-231, MDA-MB-436, and MCF-7 breast cancer cells was evaluated. The results indicate that the procyanidin mixture inhibited the proliferation of breast cancer cells, where the activity of the procyanidin mixture was stronger than that of (-)-epicatechin. Moreover, the mechanism underlying the antiproliferative activity of procyanidins was investigated. The resulting data demonstrate that the procyanidins induced apoptotic cell death in a manner selective to cancerous cells. In particular, they caused the activation of intrinsic and extrinsic apoptotic pathways in the breast cancer cells. The findings obtained in this study demonstrate that the generation of procyanidins in vitro by the autoxidation of (-)-epicatechin has potential for the development of anti-breast cancer agents. Full article

(This article belongs to the Special Issue Natural Products for the Treatment of Breast Cancer)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Oxidation of (-)-epicatechin: (A) Conditions of autoxidation of (-)-epicatechin; and (B) TLC pattern of (-)-epicatechin (Lane 1) and (-)-epicatechin oxidized for 72 h (Lane 2). Full article ">Figure 2
HPLC-ESI-MSn spectra of the autoxidation products of (-)-epicatechin: (A) Base peak chromatogram of the autoxidation of (-)-epicatechin; (B) Products generated through the autoxidation of (-)-epicatechin; catechin [<a href="#B36-pharmaceuticals-17-00258" class="html-bibr">36</a>], procyanidin B2 [<a href="#B31-pharmaceuticals-17-00258" class="html-bibr">31</a>,<a href="#B37-pharmaceuticals-17-00258" class="html-bibr">37</a>], procyanidin A [<a href="#B36-pharmaceuticals-17-00258" class="html-bibr">36</a>] and (C) TLC pattern of the PPO mix and ESI-MS of the possible oligomers (peaks 9–15) obtained through the autoxidation of (-)-epicatechin. Full article ">Figure 3
Chemical structures of the compounds present in the autoxidation of (-)-epicatechin. (A) Monomers (<a href="#pharmaceuticals-17-00258-f002" class="html-fig">Figure 2</a>B, peaks 3, 4); (B,C) B2 and A type procyanidin (<a href="#pharmaceuticals-17-00258-f002" class="html-fig">Figure 2</a>B, peaks 5, 6); (D) Type A procyanidin trimer (<a href="#pharmaceuticals-17-00258-f002" class="html-fig">Figure 2</a>C peak 11). Full article ">Figure 4
Antiproliferative activity of (-)-epicatechin and procyanidin mixture in breast cancer cells. The cells were grown in an interval of 0–350 µM: (A) MDA-MB-231; (B) MDA-MB-436; (C) MCF-7; and (D) non-cancerous MCF-10A cells. Each experiment was conducted three times, and each data point was performed in sextuplicate. Data are presented as the mean ± SD and were analyzed using ANOVA followed by Tukey’s test (p ≤ 0.05). Full article ">Figure 5
Effects of (-)-epicatechin and PPO mix in MDA-MB-231 breast cancer cells. Morphology of MDA-MB-231 breast cancer cells in the presence of: (A) Autoxidation buffer; (B) (-)-epicatechin; and (C) PPO mix; the arrows point out membrane blebs; and (D) induction of DNA fragmentation by (-)-epicatechin and PPO mix. Full article ">Figure 6
Human apoptosis array analysis in response to (-)-epicatechin and PPO treatment. Whole-cell lysates were prepared from MDA-MB-231 and MCF-10A cell lines and were left either untreated or exposed to MES-NaOH buffer and hybridized to a human apoptosis array kit (A and C, respectively). The MDA-MB-231 (B) and MCF-10A (D) cell lines were treated with PPO (proanthocyanidins) for 72 h. Each protein was spotted in duplicate. The pair of dots in each corner were positive controls. Each pair of protein dots is indicated with its change in expression. At the same time, no obvious change was observed in MCF-10A cells (C,D). Up and down arrows (Increase or decrease in the expression, respectively), the A-E letters on the left side of each membrane are coordinates for the protein identification. Full article ">

13 pages, 539 KiB

Open AccessArticle

Carbapenems as Antidotes for the Management of Acute Valproic Acid Poisoning

by Nataša Perković Vukčević, Vesna Mijatović Jovin, Gordana Vuković Ercegović, Marko Antunović, Igor Kelečević, Dejan Živanović and Slavica Vučinić

Pharmaceuticals 2024, 17(2), 257; https://doi.org/10.3390/ph17020257 - 17 Feb 2024

Cited by 1 | Viewed by 1740

Abstract

Introduction: Valproic acid (VPA) is a broad-spectrum drug primarily used in the treatment of epilepsy and bipolar disorder. It is not an uncommon occurrence for VPA to cause intoxication. The established treatment of VPA poisoning includes supportive care, multiple doses of activated charcoal, [...] Read more.

Introduction: Valproic acid (VPA) is a broad-spectrum drug primarily used in the treatment of epilepsy and bipolar disorder. It is not an uncommon occurrence for VPA to cause intoxication. The established treatment of VPA poisoning includes supportive care, multiple doses of activated charcoal, levocarnitine and hemodialysis/hemoperfusion. There is a clinically significant interaction between carbapenem antibiotics and VPA. By affecting enterohepatic recirculation, carbapenems can increase the overall VPA clearance from the blood of intoxicated patients. It is suggested that carbapenems could successfully be used as antidotes in the treatment of acute VPA poisonings. The aim: To evaluate the effectiveness of carbapenems in the treatment of patients acutely poisoned by VPA. Patients and methods: This retrospective study included patients acutely poisoned by VPA and treated with carbapenems at the Department of Clinical Toxicology at the Military Medicinal Academy in Serbia for a two-year period. Results: After the admission, blood concentrations of VPA kept increasing, reaching their peak at 114–724 mg/L, while the mental state of the patients continued to decline, prompting a decision to introduce carbapenems. After the introduction of carbapenems, the concentrations of the drug dropped by 46–93.59% (average 72%) followed by rapid recovery of consciousness. Ten out of eleven patients had positive outcomes, while one patient died. The most commonly observed complication in our group of patients was bronchopneumonia. Conclusions: The application of carbapenems for the management of acute VPA poisoning might be a useful and effective treatment option. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

31 pages, 9977 KiB

Open AccessReview

Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands

by Kim E. de Roode, Lieke Joosten and Martin Behe

Pharmaceuticals 2024, 17(2), 256; https://doi.org/10.3390/ph17020256 - 16 Feb 2024

Cited by 5 | Viewed by 2687

Abstract

Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this [...] Read more.

Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys. Full article

(This article belongs to the Special Issue Feature Reviews in Radiopharmaceutical Sciences: Highlights of Two-Decade Development)

► Show Figures

Figure 1

Figure 1
Overview of mechanisms discussed in this review for the reduction of kidney uptake of radioligands. Brown dots represent amino acids assembled into a radioligand, yellow star represents radiolabel. Full article ">Figure 2
(A) Schematic representation of a cross-section of a kidney, showing the renal cortex (light brown) and medulla (dark brown). (B) Autoradiogram of a rat kidney showing accumulation in the renal cortex after administration of radiolabeled minigastrin. This research was originally published in JNM. Gotthardt et al. Indication for Different Mechanisms of Kidney Uptake of Radiolabeled Peptides. J. Nucl. Med. 2007, 48, 596–601. © SNMMI [<a href="#B7-pharmaceuticals-17-00256" class="html-bibr">7</a>]. Full article ">Figure 3
Schematic representation of kidney physiology at different magnification levels and the mechanism of accumulation of radioactivity in the kidneys. (A) Schematic representation of a cross-section of a kidney. The white square indicates the zoom frame of figure (B). (B) Schematic representation of a nephron. In renal excretion, dissolved ions and biomolecules are filtered in the glomerulus (1), after which the formed pre-urine travels through the proximal tubule (2) where reabsorption of organic compounds and water takes place. In the loop of Henle (3), water and subsequently ions are reabsorbed, after which additional reabsorption of water and ions can take place in the distal tubule (4). Urine reaches the collecting duct (5) and is transported towards the bladder. The white rectangle indicates the zoom frame of figure (C). (C) Schematic representation of a proximal tubule cell showing the binding of a radioligand (brown dots with yellow star) to megalin (light brown bar) on the apical site of the membrane (1), followed by association with cubilin (dark brown bar) (2). Subsequent endocytosis (3) internalizes the megalin–cubilin–radioligand complex into the tubular cell. The receptors in the endosome are recycled back to the apical membrane (4), while the radioligand is degraded into its biomolecular building blocks after fused with the lysosome (5). Where the radionuclide–chelator complex (yellow star) is trapped inside the tubular cell, on the basolateral side of the tubule cell, biomolecular building blocks (brown circles) are transported towards the blood circulation for re-use (6). Full article ">Figure 4
Overview of structural changes regarding the chemical design of radioligands for reduced uptake in the kidneys. Full article ">Figure 5
Chemical structures of several chelators discussed in this chapter. R represents conjugation site to (the linker of a) targeting ligand. Full article ">Figure 6
Chemical structures of several albumin-binding entities that have been discussed in this chapter. * indicates stereocenter. Full article ">

22 pages, 4080 KiB

Open AccessArticle

Anti-Bacterial Activity of Green Synthesised Silver and Zinc Oxide Nanoparticles against Propionibacterium acnes

by Hafez Al-Momani, Muhannad I. Massadeh, Muna Almasri, Dua’a Al Balawi, Iman Aolymat, Saja Hamed, Borhan Aldeen Albiss, Lugain Ibrahim, Hadeel Al Balawi and Sameer Al Haj Mahmoud

Pharmaceuticals 2024, 17(2), 255; https://doi.org/10.3390/ph17020255 - 16 Feb 2024

Cited by 1 | Viewed by 1975

Abstract

Propionibacterium acnes plays a critical role in the development of acne vulgaris. There has been a rise in the number of patients carrying P. acnes strains that are resistant to antibiotics. Thus, alternative anti-microbial agents are required. Zinc oxide (ZnO-NPs) and silver (Ag-NPs) [...] Read more.

Propionibacterium acnes plays a critical role in the development of acne vulgaris. There has been a rise in the number of patients carrying P. acnes strains that are resistant to antibiotics. Thus, alternative anti-microbial agents are required. Zinc oxide (ZnO-NPs) and silver (Ag-NPs) nanoparticles can be used against several antibiotic-resistant bacteria. The impact of Ag-NPs and ZnO-NPs against two clinical strains of P. acnes, P1 and P2, and a reference strain, NCTC747, were investigated in this research. A chemical approach for the green synthesis of Ag-NPs and ZnO-NPs from Peganum harmala was employed. The microtiter plate method was used to examine the effects of NPs on bacterial growth, biofilm development, and biofilm eradication. A broth microdilution process was performed in order to determine minimal inhibitory (MIC) concentrations. Ag-NPs and ZnO-NPs had a spherical shape and average dimensions of 10 and 50 nm, respectively. MIC values for all P. acnes strains for Ag-NPs and ZnO-NPs were 125 µg/mL and 250 µg/mL, respectively. Ag-NP and ZnO-NP concentrations of 3.9- 62.5 µg/mL and 15–62.5 µg/mL significantly inhibited the growth and biofilm formation of all P. acnes strains, respectively. ZnO-NP concentrations of 15–62.5 μg/mL significantly inhibited the growth of NCTC747 and P2 strains. The growth of P1 was impacted by concentrations of 31.25 μg/mL and 62.5 μg/mL. Biofilm formation in the NCTC747 strain was diminished by a ZnO-NP concentration of 15 μg/mL. The clinical strains of P. acnes were only affected by ZnO-NP titres of more than 31.25 μg/mL. Established P. acne biofilm biomass was significantly reduced in all strains at a Ag-NP and ZnO-NP concentration of 62.5 µg/mL. The findings demonstrated that Ag-NPs and ZnO-NPs exert an anti-bacterial effect against P. acnes. Further research is required to determine their potential utility as a treatment option for acne. Full article

(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs))

► Show Figures

Figure 1

17 pages, 3296 KiB

Open AccessArticle

Decreased Brain Serotonin in rbfox1 Mutant Zebrafish and Partial Reversion of Behavioural Alterations by the SSRI Fluoxetine

by Maja R. Adel, Ester Antón-Galindo, Edurne Gago-Garcia, Angela Arias-Dimas, Concepció Arenas, Rafael Artuch, Bru Cormand and Noèlia Fernàndez-Castillo

Pharmaceuticals 2024, 17(2), 254; https://doi.org/10.3390/ph17020254 - 16 Feb 2024

Viewed by 1263

Abstract

RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention [...] Read more.

RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention in psychiatric conditions linked to RBFOX1. However, the precise effects of RBFOX1 on the serotonergic system remain largely unexplored. Here we show that homozygous rbfox1^sa15940 zebrafish, which express a shorter, aberrant rbfox1 mRNA, have significantly reduced serotonin levels in telencephalon and diencephalon. We observed that the acute administration of fluoxetine partially reverses the associated behavioural alterations. The hyperactive phenotype and altered shoaling behaviour of the rbfox1^{sa15940/sa15940} zebrafish could be reversed with acute fluoxetine exposure in the Open Field and the Shoaling test, respectively. However, in the other paradigms, hyperactivity was not diminished, suggesting a distinct intrinsic motivation for locomotion in the different paradigms. Acute fluoxetine exposure did not reverse the alterations observed in the aggression and social novelty tests, suggesting the involvement of other neurological mechanisms in these behaviours. These findings underscore the importance of investigating the intricate working mechanisms of RBFOX1 in neurodevelopmental and psychiatric disorders to gain a better understanding of the associated disorders along with their pharmacological treatment. Full article

(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2023)

► Show Figures

Graphical abstract

13 pages, 6473 KiB

Open AccessArticle

Innovative Approach to Producing Palladium-103 for Auger-Emitting Radionuclide Therapy: A Proof-of-Concept Study

by Aicha Nour Laouameria, Mátyás Hunyadi, Attila Csík and Zoltán Szűcs

Pharmaceuticals 2024, 17(2), 253; https://doi.org/10.3390/ph17020253 - 16 Feb 2024

Cited by 1 | Viewed by 1370

Abstract

Auger-emitting radionuclides, exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their high cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive “wet chemistry” methods attributed to the [...] Read more.

Auger-emitting radionuclides, exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their high cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive “wet chemistry” methods attributed to the exceptional chemical inertness of the associated metals. This study proposes an innovative solution to this separation challenge through the design and implementation of a piece of radionuclide separation equipment (RSE). The equipment employs a dry distillation approach, capitalizing on differences in partial vapor pressures between irradiated and resulting radioactive metals, with a diffusion-driven extraction method applied to separate Pd-103 radionuclides generated via the proton irradiation of Rh-103 at cyclotron. Our optimization endeavors focused on determining the optimal temperature for effective metal separation and adjusting the diffusion, evaporation, and deposition rates, as well as addressing chemical impurities. The calculations indicate 17% ± 2% separation efficiency with our RSE. Approximately 77 ± 2% and 49 ± 2% of the deposited Pd-103 were isolated on substrates of Nb foil and ZnO-covered W disc, respectively. The proposed innovative dry distillation method that has been experimentally tested offers a promising alternative to conventional separation techniques, enabling enhanced purity and cost-efficient cancer treatment strategies. Full article

(This article belongs to the Special Issue New Trends in Applications and Production of Metal Radionuclides for Nuclear Medicine)

► Show Figures

Figure 1

Figure 1
(a) Decay scheme of Pd-103 showing the subsequent decay of core–hole states via characteristic X-ray and Auger electrons. (b) Stopping power of electrons in an exemplary organic medium (guanine) for the energy range of typical Auger electrons calculated via the ESTAR code [<a href="#B9-pharmaceuticals-17-00253" class="html-bibr">9</a>]. (c) Illustration of impact range of Auger electrons compared to the dimensions of chromatin strands. Full article ">Figure 2
Partial vapor pressure of palladium and rhodium as a function of the temperature [<a href="#B17-pharmaceuticals-17-00253" class="html-bibr">17</a>]. Full article ">Figure 3
SNMS depth profiling analysis for: (a) the control sample, (b) the annealed sample at 600 °C for 10 min, (c) the annealed sample at 700 °C for 10 min, (d) the annealed sample at 800 °C for 10 min, and (e) the annealed sample at 900 °C for 10 min. (f) Palladium-in-rhodium diffusion coefficient deduced by fitting palladium profiles is plotted as a function of the annealing temperature. The fit (blue curve) results in an activation energy of palladium displacement of 0.55 eV. The extrapolated value of ~4 × 10−14 cm2/s is calculated for 1200 °C, the temperature at which the separation experiment was carried out. Full article ">Figure 4
Elemental composition of the deposited layer on a silicon substrate examined via EDX (energy-dispersive X-ray spectroscopy). Full article ">Figure 5
Simulated evacuation efficiency as the ratio of emitted Pd-103 with respect to the total amount in the rhodium foil. The evacuation efficiency is plotted at varying (a) diffusion coefficients D and (b) foil thicknesses (W). The measured ratio of evaporated-to-produced Pd-103 is also provided (open circle). Full article ">Figure 6
(a) Conceptual layout of the separation equipment incorporating a high-temperature effusion cell. (b) Overhead view of the BN crucible laden with a palladium/rhodium powder mixture for the purity analysis of the separation procedure. (c) Image of the separation equipment and control electronics. Full article ">Figure 7
Comprehensive presentation of experimental data and TENDL predictions for the 103Rh(p,n)103Pd reaction [<a href="#B25-pharmaceuticals-17-00253" class="html-bibr">25</a>] (with permission). Full article ">

21 pages, 307 KiB

Open AccessReview

Immune Checkpoint Inhibitors and Lupus Erythematosus

by Hans Vitzthum von Eckstaedt, Arohi Singh, Pankti Reid and Kimberly Trotter

Pharmaceuticals 2024, 17(2), 252; https://doi.org/10.3390/ph17020252 - 15 Feb 2024

Viewed by 2252

Abstract

Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), [...] Read more.

Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation. Full article

(This article belongs to the Special Issue Immune-Related Adverse Effects of Checkpoint Inhibitors in Cancer Patients)

► Show Figures

Graphical abstract

11 pages, 2931 KiB

Open AccessArticle

Novel Synthesis Approach for Natural Tea Polyphenol-Integrated Hydroxyapatite

by Xiaoxiang Ren, Zeng Yi and Xudong Li

Pharmaceuticals 2024, 17(2), 251; https://doi.org/10.3390/ph17020251 - 15 Feb 2024

Viewed by 1115

Abstract

Hydroxyapatite (HAP) has garnered considerable interest in biomedical engineering for its diverse applications. Yet, the synthesis of HAP integrated with functional natural organic components remains an area ripe for exploration. This study innovatively utilizes the versatile properties of tea polyphenol (TP) to synthesize [...] Read more.

Hydroxyapatite (HAP) has garnered considerable interest in biomedical engineering for its diverse applications. Yet, the synthesis of HAP integrated with functional natural organic components remains an area ripe for exploration. This study innovatively utilizes the versatile properties of tea polyphenol (TP) to synthesize HAP nanomaterials with superior crystallinity and distinct morphologies, notably rod-like structures, via a chemical deposition process in a nitrogen atmosphere. This method ensures an enhanced integration of TP, as confirmed by thermogravimetric (TGA) analysis and a variety of microscopy techniques, which also reveal the dependence of TP content and crystallinity on the synthesis method employed. The research significantly impacts the field by demonstrating how synthesis conditions can alter material properties. It leads the way in employing TP-modified nano-HAP particles for biomedical applications. The findings of this study are crucial as they open avenues for the future development of tailored HAP nanomaterials, aiming at specific medical applications and advancements in nanotechnology. Full article

(This article belongs to the Special Issue Plant-Derived Nanotherapeutics and Nanocarriers: Recent Progress and Future Directions)

► Show Figures

Figure 1

13 pages, 2705 KiB

Open AccessArticle

Advancements in Microfluidic Cassette-Based iMiDEV™ Technology for Production of L-[¹¹C]Methionine and [¹¹C]Choline

by Hemantha Mallapura, Laurent Tanguy, Samin Mahfuz, Lovisa Bylund, Bengt Långström, Christer Halldin and Sangram Nag

Pharmaceuticals 2024, 17(2), 250; https://doi.org/10.3390/ph17020250 - 15 Feb 2024

Viewed by 1231

Abstract

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[¹¹C]methionine [...] Read more.

Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[¹¹C]methionine and [¹¹C]choline, was performed, using a microfluidic cassette and an iMiDEV^TM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[¹¹C]methionine and [¹¹C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [¹¹C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[¹¹C]methionine and >60% for [¹¹C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[¹¹C]methionine and [¹¹C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields. Full article

(This article belongs to the Special Issue Recent Advancements in Radiochemistry and PET Radiotracer Development)

► Show Figures

Graphical abstract

12 pages, 2049 KiB

Open AccessArticle

Disposition of Hexahydrocannabinol Epimers and Their Metabolites in Biological Matrices following a Single Administration of Smoked Hexahydrocannabinol: A Preliminary Study

by Annagiulia Di Trana, Alessandro Di Giorgi, Giorgia Sprega, Jeremy Carlier, Giorgi Kobidze, Eva Montanari, Omayema Taoussi, Giulia Bambagiotti, Maria Sofia Fede, Alfredo Fabrizio Lo Faro, Anastasio Tini, Francesco Paolo Busardò and Simona Pichini

Pharmaceuticals 2024, 17(2), 249; https://doi.org/10.3390/ph17020249 - 15 Feb 2024

Cited by 2 | Viewed by 1327

Abstract

In 2023, hexahydrocannabinol (HHC) attracted the attention of international agencies due to its rapid spread in the illegal market. Although it was discovered in 1940, less is known about the pharmacology of its two naturally occurring epimers, 9(R)-HHC and 9(S)-HHC. Thus, we aimed [...] Read more.

In 2023, hexahydrocannabinol (HHC) attracted the attention of international agencies due to its rapid spread in the illegal market. Although it was discovered in 1940, less is known about the pharmacology of its two naturally occurring epimers, 9(R)-HHC and 9(S)-HHC. Thus, we aimed to investigate the disposition of hexahydrocannabinol epimers and their metabolites in whole blood, urine and oral fluid following a single controlled administration of a 50:50 mixture of 9(R)-HHC and 9(S)-HHC smoked with tobacco. To this end, six non-user volunteers smoked 25 mg of the HHC mixture in 500 mg of tobacco. Blood and oral fluid were sampled at different time points up to 3 h after the intake, while urine was collected between 0 and 2 h and between 2 and 6 h. The samples were analyzed with a validated HPLC-MS/MS method to quantify 9(R)-HHC, 9(S)-HHC and eight metabolites. 9(R)-HHC showed the highest C_max and AUC_0–3h in all the investigated matrices, with an average concentration 3-fold higher than that of 9(S)-HHC. In oral fluid, no metabolites were detected, while they were observed as glucuronides in urine and blood, but with different profiles. Indeed, 11nor-9(R)-HHC was the most abundant metabolite in blood, while 8(R)OH-9(R) HHC was the most prevalent in urine. Interestingly, 11nor 9(S) COOH HHC was detected only in blood, whereas 8(S)OH-9(S) HHC was detected only in urine. Full article

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

► Show Figures

Figure 1

Figure 1
Chemical structures of hexahydrocannabinol epimers and the putative metabolites investigated in this study. Full article ">Figure 2
Time course of 9(R)-HHC and 9(S)-HHC median concentrations (n = 6, median values ± standard error) in blood following the smoking of 25 mg of a mixture of 9(R)-HHC:9(S)-HHC 50:50 w/w in 500 mg tobacco. Full article ">Figure 3
Time course of 8(R)OH-9(R) HHC, 11OH-9(R)-HHC, 11nor-9(R) COOH HHC and 11nor-9(R) COOH HHC median concentrations (n = 6, median values ± standard error) in blood following the smoking of 25 mg of a mixture of 9(R)-HHC:9(S)-HHC 50:50 w/w in 500 mg tobacco. Full article ">Figure 4
Time course of 9(R)-HHC and 9(S)-HHC median concentrations (n = 6, mean values ± standard error) in oral fluid following the smoking of 25 mg of a mixture of 9(R)-HHC:9(S)-HHC 50:50 w/w in 500 mg tobacco. Full article ">Figure 5
Total accumulation (ng) of 9(R)-HHC and 9(S)-HHC glucuronic acid conjugates between 0 and 2 h and between 2 and 6 h following the smoking of 25 mg of a 9(R)-HHC:9(S)-HHC 50:50 w/w mixture with 500 mg tobacco. Full article ">Figure 6
Total accumulation (ng) of 8(R)OH-9(R) HHC, 8(S)OH-9(S)-HHC, 11OH-9(R)-HHC and 11nor-9(R) COOH HHC between 0 and 2 h and between 2 and 6 h following the smoking of 25 mg of a 9(R)-HHC:9(S)-HHC 50:50 w/w mixture with 500 mg tobacco. Full article ">

19 pages, 757 KiB

Open AccessReview

Integrating Nanotechnological Advancements of Disease-Modifying Anti-Rheumatic Drugs into Rheumatoid Arthritis Management

by Sukhbir Singh, Neha Tiwary, Neelam Sharma, Tapan Behl, Anita Antil, Md. Khalid Anwer, Seema Ramniwas, Monika Sachdeva, Gehan M. Elossaily, Monica Gulati and Shreesh Ohja

Pharmaceuticals 2024, 17(2), 248; https://doi.org/10.3390/ph17020248 - 14 Feb 2024

Cited by 1 | Viewed by 2552

Abstract

Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis (RA). Methotrexate, sulfasalazine, hydroxychloroquine, and azathioprine are examples of non-biologic DMARDs that are being used for alleviating pain and preventing disease progression. Biologic [...] Read more.

Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis (RA). Methotrexate, sulfasalazine, hydroxychloroquine, and azathioprine are examples of non-biologic DMARDs that are being used for alleviating pain and preventing disease progression. Biologic DMARDs (bDMARDs) like infliximab, rituximab, etanercept, adalimumab, tocilizumab, certolizumab pegol, and abatacept have greater effectiveness with fewer adverse effects in comparison to non-biologic DMARDs. This review article delineates the classification of DMARDs and their characteristic attributes. The poor aqueous solubility or permeability causes the limited oral bioavailability of synthetic DMARDs, while the high molecular weights along with the bulky structures of bDMARDs have posed few obstacles in their drug delivery and need to be addressed through the development of nanoformulations like cubosomes, nanospheres, nanoemulsions, solid lipid nanoparticles, nanomicelles, liposome, niosomes, and nanostructured lipid carrier. The main focus of this review article is to highlight the potential role of nanotechnology in the drug delivery of DMARDs for increasing solubility, dissolution, and bioavailability for the improved management of RA. This article also focusses on the different aspects of nanoparticles like their applications in biologics, biocompatibility, body clearance, scalability, drug loading, and stability issues. Full article

(This article belongs to the Section Pharmaceutical Technology)

► Show Figures

Graphical abstract

0 pages, 8613 KiB

Open AccessArticle

In Vitro Assessment of Wound-Healing Efficacy of Stabilized Basic Fibroblast Growth Factor (FGF-2) Solutions

by Leah Benington, Jingxin Mo, Mingxin Li, Gunesh Rajan, Cornelia Locher and Lee Yong Lim

Pharmaceuticals 2024, 17(2), 247; https://doi.org/10.3390/ph17020247 - 14 Feb 2024

Cited by 2 | Viewed by 1317 | Correction

Abstract

Chronic tympanic membrane perforations (TMP) pose a significant clinical challenge, but basic fibroblast growth factor (FGF-2) shows promise for their treatment, despite its instability in aqueous solutions which hampers the sustained delivery crucial for the healing process. Addressing this, our research focused on [...] Read more.

Chronic tympanic membrane perforations (TMP) pose a significant clinical challenge, but basic fibroblast growth factor (FGF-2) shows promise for their treatment, despite its instability in aqueous solutions which hampers the sustained delivery crucial for the healing process. Addressing this, our research focused on the development of stabilized FGF-2 formulations, F5 and F6, incorporating dual, generally regarded as safe (GRAS) excipients to enhance stability and therapeutic efficacy. F5 combined FGF-2 (1600 ng/mL) with 0.05% w/v methylcellulose (MC) and 20 mM alanine, while F6 used FGF-2 with 0.05% w/v MC and 1 mg/mL human serum albumin (HSA). Our findings demonstrate that these novel formulations not only significantly improve the cytoproliferation of human dermal fibroblasts but also exhibit the most potent chemoattractant effects, leading to the highest fibroblast monolayer closure rates (92.5% for F5 and 94.1% for F6 within 24 h) compared to other FGF-2 solutions tested. The comparable performance of F5 and F6 underscores their potential as innovative, less invasive, and cost-effective options for developing otic medicinal products aimed at the effective treatment of chronic TMP. Full article

(This article belongs to the Section Biopharmaceuticals)

► Show Figures

Figure 1

4 pages, 192 KiB

Open AccessEditorial

Advances in Non-Small Cell Lung Cancer (NSCLC) Treatment—A Paradigm Shift in Oncology

by Azhar Ali

Pharmaceuticals 2024, 17(2), 246; https://doi.org/10.3390/ph17020246 - 13 Feb 2024

Viewed by 1527

Abstract

Non-Small Cell Lung Cancer (NSCLC) management remains a formidable challenge in the field of oncology, representing a significant global health burden [...] Full article

(This article belongs to the Special Issue Advances in Non-small Cell Lung Cancer Treatment - Current and Future)

8 pages, 1775 KiB

Open AccessCase Report

Cutaneous Alternariosis in Immunosuppressed Patients Treated with Photodynamic Therapy and Oral Antifungals, a Synergistic Strategy

by Pedro Gil-Pallares, Tamara Gracia-Cazaña, Marcial Álvarez-Salafranca, Marcos Antonio Gorgojo, Mar García-García, Antonio Beltrán-Rosel, Manuel Almenara-Blasco, Alba Navarro-Bielsa and Yolanda Gilaberte

Pharmaceuticals 2024, 17(2), 245; https://doi.org/10.3390/ph17020245 - 13 Feb 2024

Viewed by 1153

Abstract

Cutaneous alternariosis is a rare condition, more frequently presented in immunocompromised patients, which usually requires long courses of systemic antifungals that may interact with other medications. The presented series shows three cases of cutaneous alternariosis in immunocompromised patients and organ transplant recipients that [...] Read more.

Cutaneous alternariosis is a rare condition, more frequently presented in immunocompromised patients, which usually requires long courses of systemic antifungals that may interact with other medications. The presented series shows three cases of cutaneous alternariosis in immunocompromised patients and organ transplant recipients that were successfully treated with photodynamic therapy and oral antifungals, allowing a reduction in the systemic treatment duration and therefore decreasing the risk of side effects and drug interactions. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2023)

► Show Figures

Figure 1

Figure 1
Case 1. (a,b) Erythematous verrucous plaques on the left forearm. (c) (H-E 8×) Histopathological analysis showed light acanthosis, with mild hyperkeratosis and foci of parakeratosis; at the dermal layer, there was granulomatous perifollicular inflammation with multinuclear, surrounding broken follicles. (d) (H-E 20×) Some yeast forms can also be identified. Grocott (e) (20×) and PAS staining revealed structures compatible with hyphae, and Ziehl–Nielsen was negative. (g) Macroscopic appearance of the culture showed a grey-olive green color and woolly texture colonies. (f) (40×) The septate, brown hyphae seen microscopically were compatible with Alternaria spp. Alternaria infectoriae was identified by PCR sequencing. Partial improvement was seen five months after Itraconazole (100 mg/12 h for 1 month and Itraconazole 50 mg/12 h for 4 months), which was followed by two sessions of 5-aminolevulinic acid (5-ALA) daylight photodynamic therapy, achieving resolution of the lesions (no photography available). The patient died shortly after due to COPD worsening. Full article ">Figure 2
Case 2. (a) Erythematous-violaceus tumoral lesion on the lateral side of the right ankle. (b) Resolution six months after simultaneous treatment with voriconazole 400 mg/day for three months and photodynamic therapy with methyl-aminolevulinate (Metvix®). Resolution after six months and no recurrence after twelve months follow-up (c). Full article ">Figure 3
Case 3. (a) Ulcerated lesions on the right leg surrounded by grey-blue macules. (b) Partial resolution after 11 sessions of photodynamic therapy with methyl-aminolevulinate (Metvix®) (MAL-PDT) and 10 sessions of photodynamic therapy with methylene blue (MB-PDT). (c) Complete healing after 1.5 months of simultaneous treatment with voriconazole 400 mg/day and MB-PDT (6 sessions), leaving mild erythema and residual hyperpigmentation. Full article ">

27 pages, 2278 KiB

Open AccessReview

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

by Saoirse Elizabeth O’Sullivan, Sanne Skov Jensen, Aditya Reddy Kolli, Gitte Nykjær Nikolajsen, Heidi Ziegler Bruun and Julia Hoeng

Pharmaceuticals 2024, 17(2), 244; https://doi.org/10.3390/ph17020244 - 13 Feb 2024

Cited by 3 | Viewed by 3766

Abstract

The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature [...] Read more.

The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

Figure 1
Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the curve (AUC) for cannabidiol administered by various routes in different species. The raw data used in <a href="#pharmaceuticals-17-00244-f001" class="html-fig">Figure 1</a> are listed in <a href="#pharmaceuticals-17-00244-t001" class="html-table">Table 1</a>, <a href="#pharmaceuticals-17-00244-t002" class="html-table">Table 2</a> and <a href="#pharmaceuticals-17-00244-t003" class="html-table">Table 3</a>. Full article ">Figure 2
Oral delivery efficiency of various cannabidiol formulations in different species based on the PK indices. A dose-normalised systemic delivery rate (Cmax/Tmax/dose) and dose-normalised systemic exposure (AUC/dose) are used to evaluate cannabidiol-based formulation performance. The use of Cmax/Tmax/dose and AUC/dose enables the selectin of CBD formulation with desired rate of systemic delivery and overall exposure. The labels describe the vehicle used for cannabidiol formulation. The PK data of the CBD formulations in different species are listed in <a href="#pharmaceuticals-17-00244-t001" class="html-table">Table 1</a>. Full article ">Figure 3
Box plot of overall dose-normalised systemic exposure (AUC/dose) and dose-normalised rate of systemic delivery (Cmax/Tmax/dose) for various oral formulations of CBD across different species. Full article ">Figure 4
Oral delivery efficiency of different CBD formulations in humans. The efficiencies were compared by deriving the pharmacokinetic indices, i.e., dose (mg/kg)-normalised area under the curve (AUC/dose) and dose-normalised rate of systemic delivery (Cmax/Tmax/dose). The data are provided in <a href="#pharmaceuticals-17-00244-t002" class="html-table">Table 2</a>. Full article ">Figure 5
Multi-route delivery efficiency of CBD in different species based on PK indices. The systemic exposure of CBD is derived using dose-normalised area under the curve (AUC/dose) and the rate of systemic delivery is estimated using dose-normalised Cmax/Tmax (Cmax/Tmax/dose). Cmax (ng/mL) is the maximum plasma concentration; and Tmax (h) is the time to maximum concentration. The data are provided in <a href="#pharmaceuticals-17-00244-t003" class="html-table">Table 3</a>. Full article ">

13 pages, 2218 KiB

Open AccessReview

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

by Danah Al Shaer, Othman Al Musaimi, Fernando Albericio and Beatriz G. de la Torre

Pharmaceuticals 2024, 17(2), 243; https://doi.org/10.3390/ph17020243 - 13 Feb 2024

Cited by 14 | Viewed by 4458

Abstract

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All [...] Read more.

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects. Full article

(This article belongs to the Section Biopharmaceuticals)

► Show Figures

Figure 1

38 pages, 8697 KiB

Open AccessReview

Advances in the Application of Black Phosphorus-Based Composite Biomedical Materials in the Field of Tissue Engineering

by Wanying Qi, Ru Zhang, Zaishang Wang, Haitao Du, Yiwu Zhao, Bin Shi, Yi Wang, Xin Wang and Ping Wang

Pharmaceuticals 2024, 17(2), 242; https://doi.org/10.3390/ph17020242 - 13 Feb 2024

Cited by 2 | Viewed by 1697

Abstract

Black Phosphorus (BP) is a new semiconductor material with excellent biocompatibility, degradability, and optical and electrophysical properties. A growing number of studies show that BP has high potential applications in the biomedical field. This article aims to systematically review the research progress of [...] Read more.

Black Phosphorus (BP) is a new semiconductor material with excellent biocompatibility, degradability, and optical and electrophysical properties. A growing number of studies show that BP has high potential applications in the biomedical field. This article aims to systematically review the research progress of BP composite medical materials in the field of tissue engineering, mining BP in bone regeneration, skin repair, nerve repair, inflammation, treatment methods, and the application mechanism. Furthermore, the paper discusses the shortcomings and future recommendations related to the development of BP. These shortcomings include stability, photothermal conversion capacity, preparation process, and other related issues. However, despite these challenges, the utilization of BP-based medical materials holds immense promise in revolutionizing the field of tissue repair. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

15 pages, 2558 KiB

Open AccessArticle

In Vitro and Ex Vivo Investigation of the Antibacterial Effects of Methylene Blue against Methicillin-Resistant Staphylococcus aureus

by Deniz Gazel, Mehmet Erinmez, Gönenç Çalışkantürk and Khandakar A. S. M. Saadat

Pharmaceuticals 2024, 17(2), 241; https://doi.org/10.3390/ph17020241 - 13 Feb 2024

Viewed by 1648

Abstract

Methylene blue (MB) is a water-soluble dye that has a number of medical applications. Methicillin-resistant Staphylococcus aureus (MRSA) was selected as a subject for research due to the numerous serious clinical diseases it might cause and because there is a significant global resistance [...] Read more.

Methylene blue (MB) is a water-soluble dye that has a number of medical applications. Methicillin-resistant Staphylococcus aureus (MRSA) was selected as a subject for research due to the numerous serious clinical diseases it might cause and because there is a significant global resistance challenge. Our main goal was to determine and analyze the antibacterial effects of MB against S. aureus both in vitro and ex vivo to enhance treatment options. A total of 104 MRSA isolates recovered from various clinical specimens were included in this study. Minimum inhibitory concentration (MIC) values of MB against MRSA isolates were determined by the agar dilution method. One randomly selected MRSA isolate and a methicillin-susceptible S. aureus strain (S. aureus ATCC 25923) were employed for further evaluation of the antibacterial effects of MB in in vitro and ex vivo time-kill assays. A disc diffusion method-based MB + antibiotic synergy assay was performed to analyze the subinhibitory effects of MB on ten isolates. MICs of MB against 104 MRSA isolates, detected by the agar dilution method, ranged between 16 and 64 µg/mL. MB concentrations of 4 and 16 µg/mL showed a bactericidal effect at 24 h in the ex vivo time-kill assays and in vitro time-kill assays, respectively. We observed a significant synergy between cefoxitin and methylene blue at a concentration of 1–2 μg/mL in two (20%) test isolates. Employing MB, which has well-defined pharmacokinetics, bioavailability, and safety profiles, for the treatment of MRSA infections and nasal decolonization could be a good strategy. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
In vitro methylene blue time-kill curves of MRSA isolate no. 1. Full article ">Figure 2
In vitro methylene blue time-kill curves of S. aureus ATCC 25923. Full article ">Figure 3
Ex vivo methylene blue time-kill curves of MRSA isolate no. 1. Full article ">Figure 4
Ex vivo methylene blue time-kill curves of S. aureus ATCC 25923. Full article ">Figure 5
Cumulative descriptive analysis of time-kill studies. Time (0–24 h) and concentration (2–64 μg/mL MB)-dependent mean and SD values of the CFUs are shown as bars and lines in the graphic image. Full article ">Figure 6
Inhibition zone diameters around the antibiotics in the presence and absence of MB. P—benzylpenicillin; FOX—cefoxitin. The inhibition zone diameters to benzylpenicillin and cefoxitin are determined in millimetres. The MHA plate on the left side contains 2 μg/mL MB, while there is no MB inside the MHA plate on the right side. The inhibition zone diameters around the cefoxitin and penicillin disc are significantly increased by the presence of 2 μg/mL methylene blue (left). Full article ">Figure 7
Agar dilution test plates of MRSA isolates. Images of MRSA-inoculated agar plates containing high (64 µg/mL) concentration of MB (top) and low (1 µg/mL) concentration of MB (bottom). The visible colonies (white spots) growing on the agar plate indicate resistance to MB. All MRSA isolates are resistant to 1 µg/mL concentration of MB (bottom), while they are susceptible (no growth) to the higher concentration (64 µg/mL) of MB (top). Full article ">

16 pages, 3475 KiB

Open AccessArticle

Identification of SARS-CoV-2 Main Protease Inhibitors Using Chemical Similarity Analysis Combined with Machine Learning

by Karina Eurídice Juárez-Mercado, Milton Abraham Gómez-Hernández, Juana Salinas-Trujano, Luis Córdova-Bahena, Clara Espitia, Sonia Mayra Pérez-Tapia, José L. Medina-Franco and Marco A. Velasco-Velázquez

Pharmaceuticals 2024, 17(2), 240; https://doi.org/10.3390/ph17020240 - 12 Feb 2024

Cited by 2 | Viewed by 2523

Abstract

SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the viral genome, which is critical for viral replication. Mpro is a target for anti-SARS-CoV-2 drug development. Herein, we performed a large-scale virtual screening by comparing multiple structural descriptors of [...] Read more.

SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the viral genome, which is critical for viral replication. Mpro is a target for anti-SARS-CoV-2 drug development. Herein, we performed a large-scale virtual screening by comparing multiple structural descriptors of reference molecules with reported anti-coronavirus activity against a library with >17 million compounds. Further filtering, performed by applying two machine learning algorithms, identified eighteen computational hits as anti-SARS-CoV-2 compounds with high structural diversity and drug-like properties. The activities of twelve compounds on Mpro’s enzymatic activity were evaluated by fluorescence resonance energy transfer (FRET) assays. Compound 13 (ZINC13878776) significantly inhibited SARS-CoV-2 Mpro activity and was employed as a reference for an experimentally hit expansion. The structural analogues 13a (ZINC4248385), 13b (ZNC13523222), and 13c (ZINC4248365) were tested as Mpro inhibitors, reducing the enzymatic activity of recombinant Mpro with potency as follows: 13c > 13 > 13b > 13a. Then, their anti-SARS-CoV-2 activities were evaluated in plaque reduction assays using Vero CCL81 cells. Subtoxic concentrations of compounds 13a, 13c, and 13b displayed in vitro antiviral activity with IC₅₀ in the mid micromolar range. Compounds 13a–c could become lead compounds for the development of new Mpro inhibitors with improved activity against anti-SARS-CoV-2. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Virtual screening protocol. Identification of potential Mpro inhibitors from a large chemical library combining multiple databases. Similarity analysis was performed with the Tanimoto coefficient and three structural fingerprints (indicated in the figure): MACCS Keys, ECFP4, and ECFP6. ML: machine learning; QSAR: quantitative structure–activity relationship. Full article ">Figure 2
Structure and physicochemical properties of the computational hits. (a) Chemical structure of compounds 1–18, identified by our protocol as potential SARS-CoV-2 Mpro inhibitors. (b) Similarity matrix of the computational hits computed with the Tanimoto coefficient and the ECFP6 fingerprint. (c) Physicochemical properties profiles of the computational hits. The gray area represents the range of values for each property where oral bioavailability is favored. (d) Mpro activity in the presence of 100 µM of the selected computational hits (blue bars) or the positive control GC376 (1 µM; red bar) [<a href="#B18-pharmaceuticals-17-00240" class="html-bibr">18</a>]. The signal was normalized and statistically compared against the corresponding vehicle (Student’s t test; * < 0.05 for inhibitory compounds). Bars show the average ± standard error of the mean (SEM) from two independent experiments. Full article ">Figure 3
Inhibitory activities of compounds 13–13c on Mpro activity. (a) Chemical structure of compound 13 and its three commercially available structural analogs. The maximum common substructure is shown in black. (b) Similarity matrix of compounds 13–13c calculated with the Tanimoto coefficient and the ECFP6 fingerprint. (c) Physicochemical properties of the compounds (13: red; 13a: purple; 13b: brown; 13c green). The gray area represents the range of values where oral bioavailability is favored. TPSA: topological polar surface area. (d) Representative concentration–response curves showing the inhibitory activities of compounds 13–13c on Mpro activity (d). Two independent assays were performed for each compound. Full article ">Figure 4
Binding models of Mpro inhibitors generated by molecular docking employing Molecular Operating Environment software. (a) Surface representation of monomeric Mpro with compounds 13–13c docked into the catalytic site. The insets show each compound bound the sub-pockets S1 and S2. The catalytic residues His41 and Cys145 are shown in green and yellow, respectively. (b) Ribbon representation of the Mpro sub-pocket S2 showing the predicted π-π interactions between the pyridone of compounds 13a–13c and His 41. Full article ">Figure 5
Anti-SARS-CoV-2 effect of Mpro inhibitors. Quantification of the cytopathic effect elicited by SARS-CoV-2 in Vero CCL81 after 72 h in the presence of (a) the positive control, GC376; (b) compound 13; or (c–e) analogs 13a–c. The maximal concentration tested for each compound was determined by evaluating its cytotoxicity in uninfected cells. Graphs show the mean percent reduction in the cytopathic effect from three technical replicates ± SEM. A representative curve is shown from two independent experiments performed. Full article ">

14 pages, 5421 KiB

Open AccessArticle

Integrated UPLC/Q-TOF-MS/MS Analysis and Network Pharmacology to Reveal the Neuroprotective Mechanisms and Potential Pharmacological Ingredients of Aurantii Fructus Immaturus and Aurantii Fructus

by Mingyang Qiu, Jianqing Zhang, Wenlong Wei, Yan Zhang, Mengmeng Li, Yuxin Bai, Hanze Wang, Qian Meng and De-an Guo

Pharmaceuticals 2024, 17(2), 239; https://doi.org/10.3390/ph17020239 - 12 Feb 2024

Cited by 1 | Viewed by 1705

Abstract

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) have been used for thousands of years as traditional Chinese medicine (TCM) with sedative effects. Modern studies have shown that Citrus plants also have protective effects on the nervous system. However, the effective substances and [...] Read more.

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) have been used for thousands of years as traditional Chinese medicine (TCM) with sedative effects. Modern studies have shown that Citrus plants also have protective effects on the nervous system. However, the effective substances and mechanisms of action in Citrus TCMs still remain unclear. In order to explore the pharmacodynamic profiles of identified substances and the action mechanism of these herbs, a comprehensive approach combining ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) analysis and network pharmacology was employed. Firstly, UNIFI 2.1.1 software was used to identify the chemical characteristics of AF and AFI. Secondly, the SwissTargetPrediction database was used to predict the targets of chemical components in AF and AFI. Targets for neuroprotection were also collected from GeneCards: The Human Gene Database (GeneCards-Human Genes|Gene Database|Gene Search). The networks between targets and compounds or diseases were then constructed using Cytoscape 3.9.1. Finally, the Annotation, Visualization and Integrated Discovery Database (DAVID) (DAVID Functional Annotation Bioinformatics Microarray Analysis) was used for GO and pathway enrichment analysis. The results showed that 50 of 188 compounds in AF and AFI may have neuroprotective biological activities. These activities are associated with the regulatory effects of related components on 146 important signaling pathways, derived from the KEGG (KEGG: Kyoto Encyclopedia of Genes and Genomes), such as neurodegeneration (hsa05022), the Alzheimer’s disease pathway (hsa05010), the NF-kappa B signaling pathway (hsa04064), the hypoxia-inducible factor (HIF)-1 signaling pathway (hsa04066), apoptosis (hsa04210), the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance signaling pathway (hsa01521), and others, by targeting 108 proteins, including xanthine dehydrogenase (XDH), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), and glucose-6-phosphate dehydrogenase (G6PD), among others. These targets are thought to be related to inflammation, neural function and cell growth. Full article

► Show Figures

Figure 1

Figure 1
Identification of compounds in AF and AFI. (A) AF-CA; (B) AFI-CA; (C) AF-CAD; (D) AFI-CAD; (E) total ion chromatography of samples in positive ion mode; (F) total ion chromatography of samples in negative ion mode; (G) the identification process of compounds in UNIFI software: No. 142 compound identified as Gardenin A. Full article ">Figure 2
Compound–target networks for AFI and AF. (A) Compound 1 (7-Hydroxycoumarin) compound–target network; (B) Compound 6 (Limonin) compound–target network; (C) Compound 46 ((+/−)-Naringenin) compound–target network; (D) Compound 61 (Helenalin) compound–target network; (E) Compound 63 (Kaempferol) compound–target network. Full article ">Figure 3
Disease–target networks for neuroprotection. (A) Excitotoxicity-associated target network; (B) antioxidation target network. Full article ">Figure 4
Compound–disease–target network. The yellow, red, and green nodes represent the compounds (the numbers represent the serial numbers of the compounds in <a href="#pharmaceuticals-17-00239-t001" class="html-table">Table 1</a>), targets and diseases, respectively, and a node’s size is proportional to its degree. The edges represent the interactions between any two nodes. Full article ">Figure 5
A Venn diagram of neuroprotective candidate compounds among AF-CA, AFI-CA, AF-CAD, and AFI-CAD. Full article ">Figure 6
The top 30 enriched gene ontology terms for the biological processes of potential targets. Full article ">

12 pages, 1786 KiB

Open AccessArticle

Development and Evaluation of a Quantitative Systems Pharmacology Model for Mechanism Interpretation and Efficacy Prediction of Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Patients with Non-Small-Cell Lung Cancer

by Chen-Yu Wang, Hao-Ran Dai, Yu-Ping Tan, Di-Hong Yang, Xiao-Min Niu, Lu Han, Wen Wang, Ling-Ling Ma, Aleksi Julku and Zheng Jiao

Pharmaceuticals 2024, 17(2), 238; https://doi.org/10.3390/ph17020238 - 12 Feb 2024

Viewed by 1847

Abstract

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential [...] Read more.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy. Full article

(This article belongs to the Topic Pharmacokinetic and Pharmacodynamic Modelling in Drug Discovery and Development)

► Show Figures

Figure 1

Figure 1
Parameter sensitivity analysis for tumour volume in (A) carboplatin plus nab-paclitaxel group, and (B) atezolizumab plus carboplatin and nab-paclitaxel group. Parameter sensitivity analysis was performed by varying a set of 26 parameters simultaneously and performing partial correlation analysis to evaluate the effect of those inputs on the model outputs, primarily percentage change in the tumour volume. Kd, binding affinity; mAPC, mature antigen presenting cell; MDSC, myeloid- derived suppressor cells; Nab-P, nab-paclitaxel; Teff, effector T cell; Th, T helper cell; Treg, regulatory T cell; V1, the central compartment; V2, the first peripheral compartment; V3, the second peripheral compartment. Full article ">Figure 2
Rate of response (left) and the best overall response (right) in model-predicted tumour diameter of 500 randomly virtual patients. Response is assessed by RECIST V.1.1 in (A) carboplatin plus nab-paclitaxel group and (B) atezolizumab plus carboplatin and nab-paclitaxel group. Median (thick lines) and individual (thin line) rate of response are shown in PD (red), SD (purple), and PR/CR (blue) subgroups. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Full article ">Figure 3
Pretreatment distributions of potential predictive biomarkers in responders and non-responders in combination therapy. NR, non-responders; R, responders. Full article ">Figure 4
ROC analysis of potential predictive biomarkers in combination therapy. APCs, anti-gen-presenting cells; AUC, areas under curve; NR, non-responders; R, responders; ROC, receiver operating characteristic. Full article ">Figure 5
The dynamics of the major species in the quantitative systems pharmacology model of patients with NSCLC. APC, antigen-presenting cell; Arg-I, arginase I; aT, activated T cell; mAPC, mature antigen presenting cell; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; nT, naïve T cell; Teff, effector T cell; Texh, exhausted T cell; Th, T helper cell; Treg, regulatory T cell. Full article ">

19 pages, 2031 KiB

Open AccessArticle

Use of Quantitative Electroencephalography to Inform Age- and Sex-Related Differences in NMDA Receptor Function Following MK-801 Administration

by Kimberly M. Holter, Alex D. Lekander, Bethany E. Pierce, L. Paul Sands and Robert W. Gould

Pharmaceuticals 2024, 17(2), 237; https://doi.org/10.3390/ph17020237 - 11 Feb 2024

Viewed by 1434

Abstract

Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use [...] Read more.

Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use NMDA receptor antagonists, including MK-801, to model all symptom clusters. Quantitative electroencephalography (qEEG) represents a translational approach to measure neuronal activity, identify targetable biomarkers in neuropsychiatric disorders and evaluate possible treatments. Abnormalities in gamma power have been reported in patients with schizophrenia and correspond to psychosis and cognitive impairment. Further, as gamma power reflects cortical glutamate and GABA signaling, it is highly sensitive to changes in NMDA receptor function, and NMDA receptor antagonists aberrantly increase gamma power in rodents and humans. To evaluate the role of sex and age on NMDA receptor function, MK-801 (0.03–0.3 mg/kg, SC) was administered to 3- and 9-month-old male and female Sprague–Dawley rats that were implanted with wireless EEG transmitters to measure cortical brain function. MK-801-induced elevations in gamma power were observed in 3-month-old male and female and 9-month-old male rats. In contrast, 9-month-old female rats demonstrated blunted maximal elevations across a wide dose range. Importantly, MK-801-induced hyperlocomotor effects, a common behavioral screen used to examine antipsychotic-like activity, were similar across all groups. Overall, sex-by-age-related differences in gamma power support using qEEG as a translational tool to evaluate pathological progression and predict treatment response across a heterogeneous population. Full article

(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)

► Show Figures

Figure 1

Figure 1
Nine-month-old female rats had higher baseline relative high gamma power. qEEG data are shown as a group mean ± SEM of relative power during the 90 min baseline period on each individual’s respective vehicle day. Locomotor activity is expressed as summed activity counts during the baseline period. Data are averaged across the delta [0.5–4 Hz] (A), theta [4–8 Hz] (B), alpha [8–12 Hz] (C), sigma [12–16 Hz] (D), beta [16–24 Hz] (E), low gamma [30–50 Hz] (F), and high gamma [50–100 Hz] (G) frequency bands and summed activity (H) to compare 3-month-old male (n = 9) and female (n = 6) and 9-month-old male (n = 7) and female (n = 9) rats; p < 0.05; b, compared to 9-month-old male rats; c, compared to 3-month-old female rats; circles represent individual datapoints. Full article ">Figure 2
MK-801 differentially affected spectral frequencies in 9-month-old female rats. Data are shown as a group mean ± SEM presented in 1 Hz bins expressed as the average percent change from baseline (average of each individual’s 90 min baseline just prior to compound administration) during the 30–90 min post-dosing period. Gray vertical bars represent frequency bands (delta, Δ 0.5–4 Hz; theta, θ 4–8 Hz; alpha, α 8–13 Hz; sigma, σ 13–15 Hz; beta, β 13–30 Hz; low gamma, γ 30–50 Hz; high gamma, γ 50–100 Hz). All tested doses were examined within each individual group: 3-month old male rats (n = 8–9) (A), 9-month-old male rats (n = 7–8) (B), 3-month-old female rats (n = 6) (C), and 9-month-old female rats (n = 9) (D). Horizontal colored lines matching the color of respective doses represent frequencies at which MK-801-treated groups were significantly different from vehicle-treated groups (p < 0.05) (A–D). Full article ">Figure 3
Nine-month-old females displayed lower MK-801-induced elevations in high gamma power compared to other groups. For direct group comparisons, each individual’s percent change from baseline in the 30–90 min post-dosing period (A) or maximum percent change from baseline over the full 5 h post-dosing period (B) was averaged and graphed as a group mean ± SEM. The effects of MK-801 on high gamma power over time are displayed as group means ± SEM of the percent change from baseline in 10 min bins across the 7 h recording period for 3-month-old male (n = 8–9) (C), 9-month-old male (n = 7–8) (D), 3-month-old female (n = 6) (E), and 9-month-old female rats (n = 9) (F). MK-801 was administered at time point 0, denoted by an arrow. On the x-axis, -2 corresponds to ZT 0, and 5 corresponds to ZT 7 (C–F). In (A,B), p < 0.05; a, compared to the group’s respective vehicle condition; b, compared to 9-month-old male rats; c, compared to 3-month-old female rats. In (C–F), horizontal colored lines matching the respective dose color represent the 10 min bins at which MK-801-treated groups were significantly different from vehicle-treated groups (p < 0.05). Full article ">Figure 4
MK-801 dose-dependently increased locomotor activity in all groups. For direct group comparisons, each individual’s locomotor activity counts in the 30–90 min post-dosing period were summed and graphed as a group mean ± SEM (A). The effects of MK-801 on locomotor activity over time are displayed as group means ± SEM of the summed activity counts in 10 min bins across the 7 h recording period for 3-month-old male (n = 8–9) (B), 9-month-old male (n = 7–8) (C), 3-month-old female (n = 6) (D), and 9-month-old female rats (n = 9) (E). MK-801 was administered at time point 0, denoted by an arrow. On the x-axis, −2 corresponds to ZT 0, and 5 corresponds to ZT 7. In (A), p < 0.05; a, compared to group’s respective vehicle condition; c, compared to 3-month-old male rats. In (B–E), horizontal colored lines matching the respective dose color represent the 10 min bins at which MK-801-treated groups were significantly different from vehicle-treated groups (p < 0.05). Full article ">

17 pages, 1449 KiB

Open AccessReview

Isoflavones Effects on Vascular and Endothelial Outcomes: How Is the Gut Microbiota Involved?

by Samuele Laudani, Justyna Godos, Giovanni Luca Romano, Lucia Gozzo, Federica Martina Di Domenico, Irma Dominguez Azpíroz, Raquel Martínez Diaz, Francesca Giampieri, José L. Quiles, Maurizio Battino, Filippo Drago, Fabio Galvano and Giuseppe Grosso

Pharmaceuticals 2024, 17(2), 236; https://doi.org/10.3390/ph17020236 - 11 Feb 2024

Viewed by 1940

Abstract

Isoflavones are a group of (poly)phenols, also defined as phytoestrogens, with chemical structures comparable with estrogen, that exert weak estrogenic effects. These phytochemical compounds have been targeted for their proven antioxidant and protective effects. Recognizing the increasing prevalence of cardiovascular diseases (CVD), there [...] Read more.

Isoflavones are a group of (poly)phenols, also defined as phytoestrogens, with chemical structures comparable with estrogen, that exert weak estrogenic effects. These phytochemical compounds have been targeted for their proven antioxidant and protective effects. Recognizing the increasing prevalence of cardiovascular diseases (CVD), there is a growing interest in understanding the potential cardiovascular benefits associated with these phytochemical compounds. Gut microbiota may play a key role in mediating the effects of isoflavones on vascular and endothelial functions, as it is directly implicated in isoflavones metabolism. The findings from randomized clinical trials indicate that isoflavone supplementation may exert putative effects on vascular biomarkers among healthy individuals, but not among patients affected by cardiometabolic disorders. These results might be explained by the enzymatic transformation to which isoflavones are subjected by the gut microbiota, suggesting that a diverse composition of the microbiota may determine the diverse bioavailability of these compounds. Specifically, the conversion of isoflavones in equol—a microbiota-derived metabolite—seems to differ between individuals. Further studies are needed to clarify the intricate molecular mechanisms behind these contrasting results. Full article

(This article belongs to the Special Issue Nature Product as Potential Candidates to Improve Cardio-Metabolic Outcomes in Health and Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Pharmaceuticals, Volume 17, Issue 2 (February 2024) – 122 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI