Pharmaceuticals

15 pages, 1761 KiB

Open AccessArticle

Synthesis, Characterization, and Anticancer Activity of Benzothiazole Aniline Derivatives and Their Platinum (II) Complexes as New Chemotherapy Agents

by Md. Kamrul Islam, Ah-Rum Baek, Bokyung Sung, Byeong-Woo Yang, Garam Choi, Hyun-Jin Park, Yeoun-Hee Kim, Minsup Kim, Seongmin Ha, Gang-Ho Lee, Hee-Kyung Kim and Yongmin Chang

Pharmaceuticals 2021, 14(8), 832; https://doi.org/10.3390/ph14080832 - 23 Aug 2021

Cited by 14 | Viewed by 4826

Abstract

We describe the synthesis, characterization, molecular modeling, and in vitro anticancer activity of three benzothiazole aniline (BTA) ligands and their corresponding platinum (II) complexes. We designed the compounds based on the selective antitumor properties of BTA, along with three types of metallic centers, [...] Read more.

We describe the synthesis, characterization, molecular modeling, and in vitro anticancer activity of three benzothiazole aniline (BTA) ligands and their corresponding platinum (II) complexes. We designed the compounds based on the selective antitumor properties of BTA, along with three types of metallic centers, aiming to take advantage of the distinctive and synergistic activity of the complexes to develop anticancer agents. The compounds were characterized using nuclear magnetic resonance spectrometry, Fourier transform infrared spectroscopy, mass spectrometry, elemental analysis, and tested for antiproliferative activity against multiple normal and cancerous cell lines. L1, L2, and L1Pt had better cytotoxicity in the liver, breast, lung, prostate, kidney, and brain cells than clinically used cisplatin. Especially, L1 and L1Pt demonstrated selective inhibitory activities against liver cancer cells. Therefore, these compounds can be a promising alternative to the present chemotherapy drugs. Full article

(This article belongs to the Special Issue Selective Chelators for Metals on Cells and Cancer Chemotherapy)

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17 pages, 1688 KiB

Open AccessArticle

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation

by Diéssica Padilha Dalenogare, Camila Ritter, Fernando Roberto Antunes Bellinaso, Sabrina Qader Kudsi, Gabriele Cheiran Pereira, Maria Fernanda Pessano Fialho, Débora Denardin Lückemeyer, Caren Tatiane de David Antoniazzi, Lorenzo Landini, Juliano Ferreira, Guilherme Vargas Bochi, Sara Marchesan Oliveira, Francesco De Logu, Romina Nassini, Pierangelo Geppetti and Gabriela Trevisan

Pharmaceuticals 2021, 14(8), 831; https://doi.org/10.3390/ph14080831 - 23 Aug 2021

Cited by 10 | Viewed by 3363

Abstract

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and [...] Read more.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients. Full article

(This article belongs to the Special Issue TRPA1 Receptor as a Potential Therapeutic Target in Pain, Inflammation and Neurodegeneration)

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10 pages, 1613 KiB

Open AccessArticle

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Cholic Acid (MT921) after a Subcutaneous Injection in the Submental Area to Humans

by Hyewon Chung, Jin-Woo Park, Dai-Hyun Kim, Soo-Hong Seo, Kyoung-Ah Kim, Woo-Shun Lee and Ji-Young Park

Pharmaceuticals 2021, 14(8), 830; https://doi.org/10.3390/ph14080830 - 23 Aug 2021

Cited by 1 | Viewed by 2072

Abstract

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, [...] Read more.

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, 120 mg, and 150 mg) of MT921. Blood samples were obtained for a 24-h period before and after injecting MT921 to the submental fat area. Plasma concentrations of cholic acid and deoxycholic acid were determined for pharmacokinetic analysis. Levels of free fatty acid, triglyceride, and total cholesterol were measured for pharmacodynamic analysis. Safety and tolerability were assessed until 21 days post-dose. While systemic exposure to cholic acid tended to increase as the MT921 dose increased, pharmacokinetic profiles of deoxycholic acid were similar among dose groups without showing significant changes. Pharmacodynamic profiles were comparable when measured at baseline and post-dose. The most frequent adverse events were injection site pain and edema. All adverse drug reactions resolved without treatment. MT921 appeared to be well-tolerated after an injection to the submental area at a dose up to 150 mg. Systemic exposure to cholic acid increased as the dose increased. Blood lipid profiles and deoxycholic acid levels were not affected by MT921 treatment. Full article

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39 pages, 4082 KiB

Open AccessReview

Extracellular Vesicles: A Double-Edged Sword in Sepsis

by Marlies Burgelman, Charysse Vandendriessche and Roosmarijn E. Vandenbroucke

Pharmaceuticals 2021, 14(8), 829; https://doi.org/10.3390/ph14080829 - 23 Aug 2021

Cited by 26 | Viewed by 4164

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Several studies on mouse and patient sepsis samples have revealed that the level of extracellular vesicles (EVs) in the blood is altered compared to healthy controls, [...] Read more.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Several studies on mouse and patient sepsis samples have revealed that the level of extracellular vesicles (EVs) in the blood is altered compared to healthy controls, but the different functions of EVs during sepsis pathology are not yet completely understood. Sepsis EVs are described as modulators of inflammation, lymphocyte apoptosis, coagulation and organ dysfunction. Furthermore, EVs can influence clinical outcome and it is suggested that EVs can predict survival. Both detrimental and beneficial roles for EVs have been described in sepsis, depending on the EV cellular source and the disease phase during which the EVs are studied. In this review, we summarize the current knowledge of EV sources and functions during sepsis pathology based on in vitro and mouse models, as well as patient samples. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Biology and Emerging Therapeutic Opportunities)

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19 pages, 2995 KiB

Open AccessArticle

New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors

by Andrea Angeli, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Roman M. Vydzhak, Svitlana Y. Panchishin, Volodymyr Brovarets, Viviana De Luca, Clemente Capasso, Athina Geronikaki and Claudiu T. Supuran

Pharmaceuticals 2021, 14(8), 828; https://doi.org/10.3390/ph14080828 - 23 Aug 2021

Cited by 12 | Viewed by 2757

Abstract

Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic [...] Read more.

Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic research efforts are underway to achieve the full pharmacological potential of CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity. Full article

(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)

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1 pages, 163 KiB

Open AccessCorrection

Correction: Zanella et al. Tenofovir, Another Inexpensive, Well Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection. Pharmaceuticals 2021, 14, 454

by Isabella Zanella, Daniela Zizioli, Francesco Castelli and Eugenia Quiros-Roldan

Pharmaceuticals 2021, 14(8), 827; https://doi.org/10.3390/ph14080827 - 23 Aug 2021

Cited by 5 | Viewed by 1782

Abstract

Text Correction [...] Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

12 pages, 757 KiB

Open AccessCommunication

Levetiracetam Therapeutic Drug Monitoring in a Large Cohort of Korean Epileptic Patients

by Changhee Ha, Hyun-Seung Lee, Eun Yeon Joo, Young-Min Shon, Seung Bong Hong, Dae-Won Seo and Soo-Youn Lee

Pharmaceuticals 2021, 14(8), 826; https://doi.org/10.3390/ph14080826 - 23 Aug 2021

Cited by 8 | Viewed by 3426

Abstract

Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam [...] Read more.

Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam TDM status in Korean epilepsy patients. Serum trough levetiracetam concentrations were measured using liquid chromatography–tandem mass spectrometry in 710 samples from 550 patients. The median (range) daily and weight-adjusted levetiracetam doses were 1500 (20–5000) mg and 25.5 (3.03–133.0) mg/kg, respectively. Patients on levetiracetam monotherapy constituted only 19.5% of the population, while 30.1% were on co-medication with valproate and 56.0% with enzyme-inducing AEDs (EIAEDs). Observed levetiracetam concentrations were widely distributed, ranging 0.8–95 mg/L, with a median of 17.3 mg/L. Levetiracetam concentrations were therapeutic, supra-therapeutic, and sub-therapeutic in 58.5% (n = 393), 11.6% (n = 78), and 29.9% (n = 201) of samples, respectively. There was a strong correlation between weight-adjusted levetiracetam dosage and concentrations (ρ = 0.6896, p < 0.0001). In this large-scale clinical study, a large inter-individual difference in levetiracetam pharmacokinetics was observed, and levetiracetam concentrations were influenced by EIAEDs. For individual dose adjustments and monitoring compliance, routine levetiracetam TDM is needed in epilepsy patients. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)

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11 pages, 2085 KiB

Open AccessArticle

Sedative and Immunosuppressive Effects of Dexmedetomidine in Transplantation

by Chen-Fang Lee, Chih-Hsien Cheng, Hao-Chien Hung, Jin-Chiao Lee, Yu-Chiao Wang, Tsung-Han Wu, Ting-Jung Wu, Hong-Shiue Chou, Kun-Ming Chan and Wei-Chen Lee

Pharmaceuticals 2021, 14(8), 825; https://doi.org/10.3390/ph14080825 - 22 Aug 2021

Cited by 4 | Viewed by 2353

Abstract

Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. [...] Read more.

Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. We examined our patients who underwent living donor liver transplantation. Subsequently, we generated a series of mouse models to investigate the effect of dexmedetomidine on sedation-based tolerance post transplantation. A total of 49 liver recipients were enrolled in this study, of which 23 (47%) were administered dexmedetomidine through 24 h infusion on postoperative day 1. A trend toward the improvement of hepatocyte injury along with better liver function was observed in the dexmedetomidine-treated group during the first postoperative week. In animal models, dexmedetomidine inhibited the proliferation of CD4⁺ and CD8⁺ T cells and TNF-α production in a dose-dependent manner. We used dexmedetomidine to treat skin-transplanted mice and observed a significantly prolonged graft survival in mice that were administered a higher dose of dexmedetomidine. Our results revealed that dexmedetomidine exerts a dual effect of sedation and immunosuppression. This light-sedation approach will not only make patients calmer in the intensive care unit but also protect allografts from injury. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)

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12 pages, 783 KiB

Open AccessArticle

Gene Polymorphisms of the Renin-Angiotensin System and Bleeding Complications of Warfarin: Genetic-Based Machine Learning Models

by Joo-Hee Kim, Jeong Yee, Byung-Chul Chang and Hye-Sun Gwak

Pharmaceuticals 2021, 14(8), 824; https://doi.org/10.3390/ph14080824 - 22 Aug 2021

Cited by 1 | Viewed by 2271

Abstract

Background: This study aimed to investigate the effects of genetic variants and haplotypes in the renin–angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Methods: Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of [...] Read more.

Background: This study aimed to investigate the effects of genetic variants and haplotypes in the renin–angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Methods: Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. Results: The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02–0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8–14.1) and 3.2-fold (95% CI 1.1–8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)–linear kernel, and SVM–radial kernel models were 0.732 (0.694–0.771), 0.741 (0.612–0.870), 0.723 (0.589–0.857), 0.673 (0.517–0.828), and 0.680 (0.528–0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1–46.7) increased risk of bleeding, compared to the 25–75th percentile group, respectively. Conclusion: This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding. Full article

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13 pages, 3439 KiB

Open AccessArticle

In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

by Tsung-Ying Yang, Sung-Pin Tseng, Heather Nokulunga Dlamini, Po-Liang Lu, Lin Lin, Liang-Chun Wang and Wei-Chun Hung

Pharmaceuticals 2021, 14(8), 823; https://doi.org/10.3390/ph14080823 - 21 Aug 2021

Cited by 8 | Viewed by 2785

Abstract

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 [...] Read more.

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents 2022)

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19 pages, 4855 KiB

Open AccessArticle

Melatonin Attenuates Dextran Sodium Sulfate Induced Colitis in Obese Mice

by Shijia Pan, Fan Hong, Letong Li, Yuan Guo, Xiaoxiao Qiao, Jia Zhang, Pengfei Xu and Yonggong Zhai

Pharmaceuticals 2021, 14(8), 822; https://doi.org/10.3390/ph14080822 - 21 Aug 2021

Cited by 5 | Viewed by 2965

Abstract

Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism [...] Read more.

Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals. Full article

(This article belongs to the Section Pharmacology)

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31 pages, 1703 KiB

Open AccessReview

Exploring the Role of Nutraceuticals in Major Depressive Disorder (MDD): Rationale, State of the Art and Future Prospects

by Miguel A. Alvarez-Mon, Miguel A. Ortega, Cielo García-Montero, Oscar Fraile-Martinez, Jorge Monserrat, Guillermo Lahera, Fernando Mora, Alberto Rodriguez-Quiroga, Sonia Fernandez-Rojo, Javier Quintero and Melchor Alvarez-Mon

Pharmaceuticals 2021, 14(8), 821; https://doi.org/10.3390/ph14080821 - 21 Aug 2021

Cited by 17 | Viewed by 6679

Abstract

Major depressive disorder (MDD) is a complex and common disorder, with many factors involved in its onset and development. The clinical management of this condition is frequently based on the use of some pharmacological antidepressant agents, together with psychotherapy and other alternatives in [...] Read more.

Major depressive disorder (MDD) is a complex and common disorder, with many factors involved in its onset and development. The clinical management of this condition is frequently based on the use of some pharmacological antidepressant agents, together with psychotherapy and other alternatives in most severe cases. However, an important percentage of depressed patients fail to respond to the use of conventional therapies. This has created the urgency of finding novel approaches to help in the clinical management of those individuals. Nutraceuticals are natural compounds contained in food with proven benefits either in health promotion or disease prevention and therapy. A growing interest and economical sources are being placed in the development and understanding of multiple nutraceutical products. Here, we summarize some of the most relevant nutraceutical agents evaluated in preclinical and clinical models of depression. In addition, we will also explore less frequent but interest nutraceutical products which are starting to be tested, also evaluating future roads to cover in order to maximize the benefits of nutraceuticals in MDD. Full article

(This article belongs to the Special Issue Psychopharmacology of Affective Disorders)

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13 pages, 2205 KiB

Open AccessArticle

The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

by Angéla Takács, Zsófia Szász, Márton Kalabay, Péter Bárány, Antal Csámpai, Hargita Hegyesi, Orsolya Láng, Eszter Lajkó and László Kőhidai

Pharmaceuticals 2021, 14(8), 820; https://doi.org/10.3390/ph14080820 - 20 Aug 2021

Cited by 3 | Viewed by 2688

Abstract

Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of [...] Read more.

Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro. Full article

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16 pages, 331 KiB

Open AccessReview

Pharmacological Interactions of Nintedanib and Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis in Times of COVID-19 Pandemic

by José M. Serra López-Matencio, Manuel Gómez, Esther F. Vicente-Rabaneda, Miguel A. González-Gay, Julio Ancochea and Santos Castañeda

Pharmaceuticals 2021, 14(8), 819; https://doi.org/10.3390/ph14080819 - 20 Aug 2021

Cited by 13 | Viewed by 5646

Abstract

The discovery of antifibrotic agents have resulted in advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF). Currently, nintedanib and pirfenidone have become the basis of IPF therapy based on the results of large randomized clinical trials showing their safety and efficacy [...] Read more.

The discovery of antifibrotic agents have resulted in advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF). Currently, nintedanib and pirfenidone have become the basis of IPF therapy based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease advancement. However, the goal of completely halting disease progress has not been reached yet. Administering nintedanib with add-on pirfenidone is supposed to enhance the therapeutic benefit by simultaneously acting on two different pathogenic pathways. All this becomes more important in the context of the ongoing global pandemic of coronavirus disease 2019 (COVID-19) because of the fibrotic consequences following SARS-CoV-2 infection in some patients. However, little information is available about their drug–drug interaction, which is important mainly in polymedicated patients. The aim of this review is to describe the current management of progressive fibrosing interstitial lung diseases (PF-ILDs) in general and of IPF in particular, focusing on the pharmacokinetic drug-drug interactions between these two drugs and their relationship with other medications in patients with IPF. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations)

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11 pages, 1623 KiB

Open AccessArticle

Labelling via [Al¹⁸F]²⁺ Using Precomplexed Al-NODA Moieties

by Daniel Kang, Ulrich Simon, Felix M. Mottaghy and Andreas T. J. Vogg

Pharmaceuticals 2021, 14(8), 818; https://doi.org/10.3390/ph14080818 - 20 Aug 2021

Cited by 4 | Viewed by 2336

Abstract

Over the past 20 years, ⁶⁸Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with ⁶⁸Ge/⁶⁸Ga generators is limited as well as the number of patient doses per batch of ⁶⁸Ga radiopharmaceutical. In [...] Read more.

Over the past 20 years, ⁶⁸Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with ⁶⁸Ge/⁶⁸Ga generators is limited as well as the number of patient doses per batch of ⁶⁸Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with ⁶⁸Ga but using ¹⁸F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al¹⁸F]²⁺. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [¹⁸F]fluoride. Hence, no free Al³⁺ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH₂-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses. Full article

(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)

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21 pages, 2358 KiB

Open AccessArticle

Pharmacokinetic Investigation of Commercially Available Edible Marijuana Products in Humans: Potential Influence of Body Composition and Influence on Glucose Control

by Taylor Russell Ewell, Kieran Shay Struebin Abbotts, Natasha N. Bondareva Williams, Hannah Michelle Butterklee, Matthew Charles Bomar, Kole Jerel Harms, Jordan Douglas Rebik, Sarah Margaret Mast, Natalie Akagi, Gregory P. Dooley and Christopher Bell

Pharmaceuticals 2021, 14(8), 817; https://doi.org/10.3390/ph14080817 - 20 Aug 2021

Cited by 9 | Viewed by 8384

Abstract

The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana [...] Read more.

The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana on glucose tolerance. Seven regular users of marijuana self-administered five edible products in a randomized crossover design; each product contained 10 mg of delta-9-tetrahydrocannabinol (THC). Thirty minutes following marijuana ingestion, participants imbibed a 75 g glucose beverage. Time-to-peak plasma THC concentration ranged between 35 and 90 min; maximal plasma THC concentration (C_max) ranged between 3.2 and 5.5 ng/mL. Differences between products in plasma THC concentration during the first 20–30 min were detected (p = 0.019). Relations were identified between body composition and pharmacokinetic parameters for some products; however, none of these body composition characteristics were consistently related to pharmacokinetics across all five of the products. Edible marijuana had no effect on oral glucose tolerance compared with a marijuana-free control (Matsuda Index; p > 0.395). Commercially available edible marijuana products evoke different plasma THC concentrations shortly after ingestion, but do not appear to influence acute glucose regulation. These data may allow recreational marijuana users to make informed decisions pertaining to rates of edible marijuana ingestion and avoid overdose. Full article

(This article belongs to the Special Issue Pharmacokinetics and Pharmacodynamics of Psychoactive Substances: Clinical and Forensic Aspects)

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17 pages, 2756 KiB

Open AccessArticle

A Design of Experiment (DoE) Approach to Model the Yield and Chemical Composition of Ajowan (Trachyspermum ammi L.) Essential Oil Obtained by Microwave-Assisted Extraction

by Eugenia Mazzara, Serena Scortichini, Dennis Fiorini, Filippo Maggi, Riccardo Petrelli, Loredana Cappellacci, Giuseppe Morgese, Mohammad Reza Morshedloo, Giovanni Filippo Palmieri and Marco Cespi

Pharmaceuticals 2021, 14(8), 816; https://doi.org/10.3390/ph14080816 - 19 Aug 2021

Cited by 7 | Viewed by 2764

Abstract

Ajowan (Trachyspermum ammi L.) is a spice traditionally used in Middle Eastern medicine and contains a valuable essential oil (EO) exploited in different fields, such as pharmaceutics, agrochemicals and food additives. This EO is mostly characterized by the thymol to which most [...] Read more.

Ajowan (Trachyspermum ammi L.) is a spice traditionally used in Middle Eastern medicine and contains a valuable essential oil (EO) exploited in different fields, such as pharmaceutics, agrochemicals and food additives. This EO is mostly characterized by the thymol to which most of its biological properties are related. Given the economic value of ajowan and its increasing demand across the globe, the extraction method used for its EO is of paramount importance in terms of quality and quantity of the final product. In the present study, we used the design of experiment (DoE) approach to study and optimize the extraction of the ajowan EO using the microwave-assisted extraction (MAE), a novel extraction technique with high efficiency, low energy consumption, short process length and low environmental impact. A two-step DoE (screening followed by surface response methodology) was used to reduce the number of experiments and to improve the cost/benefit ratio. Reliable mathematical models, relating the more relevant EO features with the extraction conditions, were obtained and used to identify the best experimental conditions able to maximize the yield and thymol concentration. The optimized MAE procedure assures an EO with a higher yield and thymol amount compared with the standard hydrodistillation procedure. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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17 pages, 29664 KiB

Open AccessArticle

Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2H-indazole Hybrids

by Jaime Pérez-Villanueva, Félix Matadamas-Martínez, Lilián Yépez-Mulia, Vadim Pérez-Koldenkova, Martha Leyte-Lugo, Karen Rodríguez-Villar, Francisco Cortés-Benítez, Ana Perla Macías-Jiménez, Ignacio González-Sánchez, Ariana Romero-Velásquez, Juan Francisco Palacios-Espinosa and Olivia Soria-Arteche

Pharmaceuticals 2021, 14(8), 815; https://doi.org/10.3390/ph14080815 - 19 Aug 2021

Cited by 6 | Viewed by 2646

Abstract

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious [...] Read more.

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC₅₀ of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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13 pages, 5287 KiB

Open AccessArticle

New 2,3-Benzodiazepine Derivative: Synthesis, Activity on Central Nervous System, and Toxicity Study in Mice

by Amal Amaghnouje, Serhii Bohza, Nathalie Bohdan, Imane Es-Safi, Andrii Kyrylchuk, Sanae Achour, Hinde El Fatemi, Dalila Bousta and Andriy Grafov

Pharmaceuticals 2021, 14(8), 814; https://doi.org/10.3390/ph14080814 - 19 Aug 2021

Cited by 2 | Viewed by 3010

Abstract

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and [...] Read more.

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and novel object recognition tests under oral administration for acute and sub-acute treatment. We tested the VBZ102 toxicity in mice through a determination of LD₅₀ values and examination of the biochemical and histopathological parameters. The VBZ102 induced an anxiolytic effect at different doses both in the light–dark box and open field tests. Unlike other benzodiazepines (e.g., bromazepam), a sedative effect was noted only after administration of the VBZ102 at 10.0 mg/kg. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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18 pages, 5338 KiB

Open AccessArticle

Formulation and Evaluation of Helichrysum italicum Essential Oil-Based Topical Formulations for Wound Healing in Diabetic Rats

by Marijana Andjić, Biljana Božin, Nevena Draginić, Aleksandar Kočović, Jovana N. Jeremić, Marina Tomović, Andjela Milojević Šamanović, Nebojša Kladar, Ivan Čapo, Vladimir Jakovljević and Jovana V. Bradić

Pharmaceuticals 2021, 14(8), 813; https://doi.org/10.3390/ph14080813 - 19 Aug 2021

Cited by 23 | Viewed by 6182

Abstract

As proper wound management is crucial to reducing morbidity and improving quality of life, this study evaluated for the first time the wound healing potential of H. italicum essential oil (HIEO) prepared in the form of ointment and gel in streptozotocin-induced diabetic wound [...] Read more.

As proper wound management is crucial to reducing morbidity and improving quality of life, this study evaluated for the first time the wound healing potential of H. italicum essential oil (HIEO) prepared in the form of ointment and gel in streptozotocin-induced diabetic wound models in rats. After creating full-thickness cutaneous wounds, forty-eight diabetic rats were divided into six groups: (1) negative control; (2) positive control; (3) ointment base; (4) gel base; (5) 0.5% HIEO ointment (6) 0.5% HIEO gel. Wound healing potential was determined by the percentage of wound contraction, hydroxyproline content, redox status, and histological observation. A significant decrease in the wound size was observed in animals treated with HIEO formulations compared with other groups. The HIEO groups also showed a higher level of total hydroxyproline content, and more pronounced restitution of adnexal structures with only the underlying muscle defect indicating the incision site. Hence, our results legitimate the traditional data of the pro-healing effect of HIEO because HIEO in both formulations such as gel and ointment exhibited the significant wound repairing effect in the incision wound model. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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21 pages, 5195 KiB

Open AccessArticle

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

by Thammarat Aree

Pharmaceuticals 2021, 14(8), 812; https://doi.org/10.3390/ph14080812 - 18 Aug 2021

Cited by 9 | Viewed by 2742

Abstract

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water [...] Read more.

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (K_as) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH₂–CH₂- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔE_stbs), although the complex stability orders based on K_as and ΔE_stbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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45 pages, 5569 KiB

Open AccessReview

Extracellular Vesicles in Skin Wound Healing

by Deimantė Narauskaitė, Gabrielė Vydmantaitė, Justina Rusteikaitė, Revathi Sampath, Akvilė Rudaitytė, Gabija Stašytė, María Isabel Aparicio Calvente and Aistė Jekabsone

Pharmaceuticals 2021, 14(8), 811; https://doi.org/10.3390/ph14080811 - 18 Aug 2021

Cited by 52 | Viewed by 10835

Abstract

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, [...] Read more.

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, EV-based signaling takes part in all four wound healing phases: hemostasis, inflammation, proliferation, and remodeling. Such an extensive involvement of EVs suggests exploiting their action to modulate the impaired healing phase. Furthermore, next to their natural wound healing capacity, EVs can be engineered for better defined pharmaceutical purposes, such as carrying specific cargo or targeting specific destinations by labelling them with certain surface proteins. This review aims to promote scientific awareness in basic and translational research of EVs by summarizing the current knowledge about their natural role in each stage of skin repair and the most recent findings in application areas, such as wound healing, skin regeneration, and treatment of dermal diseases, including the stem cell-derived, plant-derived, and engineered EVs. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Biology and Emerging Therapeutic Opportunities)

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18 pages, 1451 KiB

Open AccessReview

Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role

by Irina Giralt, Gabriel Gallo-Oller, Natalia Navarro, Patricia Zarzosa, Guillem Pons, Ainara Magdaleno, Miguel F. Segura, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma

Pharmaceuticals 2021, 14(8), 810; https://doi.org/10.3390/ph14080810 - 18 Aug 2021

Cited by 12 | Viewed by 3666

Abstract

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in [...] Read more.

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)

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23 pages, 5292 KiB

Open AccessArticle

A High-Content Screen for the Identification of Plant Extracts with Insulin Secretion-Modulating Activity

by Roland Hager, Johannes Pitsch, Jakob Kerbl-Knapp, Cathrina Neuhauser, Nicole Ollinger, Marcus Iken, Josef Ranner, Verena Mittermeier-Kleßinger, Corinna Dawid, Peter Lanzerstorfer and Julian Weghuber

Pharmaceuticals 2021, 14(8), 809; https://doi.org/10.3390/ph14080809 - 17 Aug 2021

Cited by 11 | Viewed by 3564

Abstract

Bioactive plant compounds and extracts are of special interest for the development of pharmaceuticals. Here, we describe the screening of more than 1100 aqueous plant extracts and synthetic reference compounds for their ability to stimulate or inhibit insulin secretion. To quantify insulin secretion [...] Read more.

Bioactive plant compounds and extracts are of special interest for the development of pharmaceuticals. Here, we describe the screening of more than 1100 aqueous plant extracts and synthetic reference compounds for their ability to stimulate or inhibit insulin secretion. To quantify insulin secretion in living MIN6 β cells, an insulin–Gaussia luciferase (Ins-GLuc) biosensor was used. Positive hits included extracts from Quillaja saponaria, Anagallis arvensis, Sapindus mukorossi, Gleditsia sinensis and Albizia julibrissin, which were identified as insulin secretion stimulators, whereas extracts of Acacia catechu, Myrtus communis, Actaea spicata L., Vaccinium vitis-idaea and Calendula officinalis were found to exhibit insulin secretion inhibitory properties. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to characterize several bioactive compounds in the selected plant extracts, and these bioactives were retested for their insulin-modulating properties. Overall, we identified several plant extracts and some of their bioactive compounds that may be used to manipulate pancreatic insulin secretion. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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11 pages, 680 KiB

Open AccessArticle

Extracorporeal Photopheresis in Children with Chronic Graft-Versus-Host Disease

by Andrey Kozlov, Maria Estrina, Olesia Paina, Tatiana Bykova, Anna Osipova, Polina Kozhokar, Zhemal Rakhmanova, Irina Solodova, Elena Morozova, Alexander Alyansky, Irina Kulagina, Asmik Gevorgian, Anna Dotsenko, Ivan Moiseev, Alexey Chukhlovin, Alexander Kulagin, Sergey Bondarenko, Elena Semenova and Ludmila Zubarovskaya

Pharmaceuticals 2021, 14(8), 808; https://doi.org/10.3390/ph14080808 - 17 Aug 2021

Cited by 1 | Viewed by 2449

Abstract

Chronic graft versus host disease (cGVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It significantly decreases survival and quality of life. The present study demonstrates retrospective data on extracorporeal photopheresis (ECP) in children with cGVHD. A total of 42 [...] Read more.

Chronic graft versus host disease (cGVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It significantly decreases survival and quality of life. The present study demonstrates retrospective data on extracorporeal photopheresis (ECP) in children with cGVHD. A total of 42 children with steroid-refractory cGVHD were enrolled in the study. The majority of patients had acute leukemia (n = 32, 76%). All patients received ECP as second (n = 18, 43%) or third (n = 24, 57%) line of therapy. Initial ECP schedule consisted of bimonthly regimen for two consecutive days with possibility of further tapering according to response. Any concurrent treatment administered before ECP could be continued if considered necessary. Complete response to ECP was registered in seven (17%) patients and partial response in 24 (57%). Overall response according to organ involvement was as follows: skin (n = 24, 75%), mucous membranes (n = 16, 73%), liver (n = 8, 80%), gut (n = 4, 80%), lungs (n = 2, 22%) and joints (n = 2, 67%). Five-year overall, progression-free and failure-free survival was 57%, 56% and 30%, respectively. Non-relapse mortality at 5 years was 14%. We didn’t observe any clinically significant complications in children that could be attributed to the procedure. ECP remains important and safe treatment option in children with cGVHD. Full article

(This article belongs to the Special Issue Pharmaceutical and Cellular Strategies to Treat GVHD)

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16 pages, 328 KiB

Open AccessEditor’s ChoiceReview

Lung Fibrosis after COVID-19: Treatment Prospects

by Evgeny Bazdyrev, Polina Rusina, Maria Panova, Fedor Novikov, Ivan Grishagin and Vladimir Nebolsin

Pharmaceuticals 2021, 14(8), 807; https://doi.org/10.3390/ph14080807 - 17 Aug 2021

Cited by 97 | Viewed by 18202

Abstract

At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global [...] Read more.

At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5–10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2–6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage. Full article

(This article belongs to the Special Issue Lung Injury and Repair)

32 pages, 2038 KiB

Open AccessEditor’s ChoiceReview

Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus

by Jana Blahova, Monika Martiniakova, Martina Babikova, Veronika Kovacova, Vladimira Mondockova and Radoslav Omelka

Pharmaceuticals 2021, 14(8), 806; https://doi.org/10.3390/ph14080806 - 17 Aug 2021

Cited by 97 | Viewed by 14638

Abstract

Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin [...] Read more.

Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium–glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided. Full article

(This article belongs to the Special Issue Multitarget Drug Discovery and Pharmacology)

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15 pages, 2853 KiB

Open AccessFeature PaperReview

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

by Enrique Ambrocio-Ortiz, Gloria Pérez-Rubio, Alma D. Del Ángel-Pablo, Ivette Buendía-Roldán, Leslie Chávez-Galán, Rafael de Jesús Hernández-Zenteno, Alejandra Ramírez-Venegas, Jorge Rojas-Serrano, Mayra Mejía, Rogelio Pérez-Padilla, Cristóbal Guadarrama-Pérez and Ramcés Falfán-Valencia

Pharmaceuticals 2021, 14(8), 805; https://doi.org/10.3390/ph14080805 - 17 Aug 2021

Cited by 7 | Viewed by 4233

Abstract

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1–7) from angiotensin II (Ang II). The [...] Read more.

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1–7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1–7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases. Full article

(This article belongs to the Special Issue Pharmacogenetics and Genomic Biomarkers and Their Application in Clinical Practice)

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17 pages, 2060 KiB

Open AccessArticle

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

by Maud Velev, Alicja Puszkiel, Benoit Blanchet, Sixtine de Percin, Nicolas Delanoy, Jacques Medioni, Claire Gervais, David Balakirouchenane, Nihel Khoudour, Patricia Pautier, Alexandra Leary, Zahra Ajgal, Laure Hirsch, François Goldwasser, Jerome Alexandre and Guillaume Beinse

Pharmaceuticals 2021, 14(8), 804; https://doi.org/10.3390/ph14080804 - 16 Aug 2021

Cited by 14 | Viewed by 2924

Abstract

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients [...] Read more.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients. Full article

(This article belongs to the Special Issue Precision Medicine in Oncology: Controlling the Pharmacokinetics Variability)

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16 pages, 982 KiB

Open AccessReview

Xenograft Zebrafish Models for the Development of Novel Anti-Hepatocellular Carcinoma Molecules

by Federica Tonon, Rossella Farra, Cristina Zennaro, Gabriele Pozzato, Nhung Truong, Salvatore Parisi, Flavio Rizzolio, Mario Grassi, Bruna Scaggiante, Fabrizio Zanconati, Deborah Bonazza, Gabriele Grassi and Barbara Dapas

Pharmaceuticals 2021, 14(8), 803; https://doi.org/10.3390/ph14080803 - 16 Aug 2021

Cited by 4 | Viewed by 2880

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is [...] Read more.

Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is the most common form of the disease at diagnosis. New therapeutic strategies are therefore urgently needed. The use of animal models represents a relevant tool for preclinical screening of new molecules/strategies against HCC. However, several issues, including animal husbandry, limit the use of current models (rodent/pig). One animal model that has attracted the attention of the scientific community in the last 15 years is the zebrafish. This freshwater fish has several attractive features, such as short reproductive time, limited space and cost requirements for husbandry, body transparency and the fact that embryos do not show immune response to transplanted cells. To date, two different types of zebrafish models for HCC have been developed: the transgenic zebrafish and the zebrafish xenograft models. Since transgenic zebrafish models for HCC have been described elsewhere, in this review, we focus on the description of zebrafish xenograft models that have been used in the last five years to test new molecules/strategies against HCC. Full article

(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)

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