Pharmaceuticals

14 pages, 990 KiB

Open AccessArticle

The Application of Inosine 5′-Monophosphate Dehydrogenase Activity Determination in Peripheral Blood Mononuclear Cells for Monitoring Mycophenolate Mofetil Therapy in Children with Nephrotic Syndrome

by Joanna Sobiak, Alicja Jóźwiak, Honorata Wziętek, Jacek Zachwieja and Danuta Ostalska-Nowicka

Pharmaceuticals 2020, 13(8), 200; https://doi.org/10.3390/ph13080200 - 18 Aug 2020

Cited by 4 | Viewed by 2471

Abstract

In pediatric nephrotic syndrome, recommended mycophenolic acid (MPA) pharmacokinetics are higher than those for transplant recipients. In MPA therapeutic monitoring, inosine-5′-monophosphate dehydrogenase (IMPDH) activity may be useful. We modified the method established for renal transplant recipients and determined IMPDH activity in peripheral blood [...] Read more.

In pediatric nephrotic syndrome, recommended mycophenolic acid (MPA) pharmacokinetics are higher than those for transplant recipients. In MPA therapeutic monitoring, inosine-5′-monophosphate dehydrogenase (IMPDH) activity may be useful. We modified the method established for renal transplant recipients and determined IMPDH activity in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and children (4–16 years) with nephrotic syndrome treated with mycophenolate mofetil (MMF). From children, four blood samples were collected, and MPA concentrations were also determined. IMPDH activity was calculated using xanthosine monophosphate (XMP) normalized with adenosine monophosphate (AMP), both determined with the HPLC-UV method. The modified method was accurate, precise, and linear for AMP and XMP within 0.50–50.0 μmoL/L. Mean IMPDH activity in volunteers was 45.97 ± 6.24 µmoL·s⁻¹·moL⁻¹ AMP, whereas for children, the values were variable and amounted to 39.23 ± 27.40 µmoL·s⁻¹·moL⁻¹ AMP and 17.97 ± 15.24 µmoL·s⁻¹·moL⁻¹ AMP before the next MMF dose and 1 h afterward, respectively. The modified method may be applied to IMPDH activity determination in children with nephrotic syndrome treated with MMF. IMPDH activity should be determined after one thawing of PBMCs due to the change in AMP and XMP concentrations after subsequent thawing. For children, the lowest IMPDH activity was observed concomitantly with the highest MPA concentration. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 3813 KiB

Open AccessReview

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors

by Joseph Lau, Julie Rousseau, Daniel Kwon, François Bénard and Kuo-Shyan Lin

Pharmaceuticals 2020, 13(8), 199; https://doi.org/10.3390/ph13080199 - 17 Aug 2020

Cited by 27 | Viewed by 5144

Abstract

Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R [...] Read more.

Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors. Full article

(This article belongs to the Special Issue Kinins and Their Receptors as Potential Therapeutic Targets —— A Tribute to Professor Domenico Regoli, A Key Figure in the Field of Kinins)

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12 pages, 3908 KiB

Open AccessArticle

Total Synthesis of Natural Disaccharide Sambubiose

by Simone Lucarini, Maria Gessica Ciulla, Paola Mestichelli and Andrea Duranti

Pharmaceuticals 2020, 13(8), 198; https://doi.org/10.3390/ph13080198 - 17 Aug 2020

Cited by 3 | Viewed by 3763

Abstract

A practical and robust synthetic method to obtain the natural disaccharide sambubiose (2-O-β-D-xylopyranosyl-D-glucopyranose) is reported, exploring the key step in the synthesis, i.e., stereoselective O-glycosylation. Specifically, the best combinations of glycoside donors and acceptors were identified, stereospecific control of the [...] Read more.

A practical and robust synthetic method to obtain the natural disaccharide sambubiose (2-O-β-D-xylopyranosyl-D-glucopyranose) is reported, exploring the key step in the synthesis, i.e., stereoselective O-glycosylation. Specifically, the best combinations of glycoside donors and acceptors were identified, stereospecific control of the reaction was achieved by screening several catalysts and protection/deprotection steps were evaluated and improved. The best result was obtained by coupling allyl 3,5,6-tri-O-benzyl-β-D-glucofuranoside with 2,3,4-tri-O-acetyl-D-xylopiranosyl-α-trichloro acetimidate in the presence of trimethylsilyl triflate as a catalyst giving the corresponding protected target compound as a correct single isomer. The latter was transformed accordingly into the desired final product by deprotection steps (deallylation, deacetylation, and debenzylation). Sambubiose was synthesized into a satisfactory and higher overall yield than previously reported and was also characterized. Full article

(This article belongs to the Section Natural Products)

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16 pages, 6291 KiB

Open AccessArticle

New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding

by Bahareh Rasaeifar, Patricia Gomez-Gutierrez and Juan J. Perez

Pharmaceuticals 2020, 13(8), 197; https://doi.org/10.3390/ph13080197 - 17 Aug 2020

Cited by 4 | Viewed by 2817

Abstract

Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, [...] Read more.

Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, only a few small molecule binders have been disclosed so far, hampering a deeper understanding of their pharmacology. In order to have a deeper understanding of the stereochemical features characterizing binding to the BB1 receptor, we performed the molecular modeling study consisting of the construction of a 3D model of the receptor by homology modeling followed by a docking study of the peptoids PD168368 and PD176252 onto it. Analysis of the complexes permitted us to propose prospective bound conformations of the compounds, consistent with the experimental information available. Subsequently, we defined a pharmacophore describing minimal stereochemical requirements for binding to the BB1 receptor that was used in silico screening. This exercise yielded a set of small molecules that were purchased and tested, showing affinity to the BB1 but not to the BB2 receptor. These molecules exhibit scaffolds of diverse chemical families that can be used as a starting point for the development of novel BB1 antagonists. Full article

(This article belongs to the Special Issue GPCRs: Ligands and beyond 2022)

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37 pages, 2598 KiB

Open AccessReview

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

by Gaber El-Saber Batiha, Ali Alqahtani, Omotayo B. Ilesanmi, Abdullah A. Saati, Amany El-Mleeh, Helal F. Hetta and Amany Magdy Beshbishy

Pharmaceuticals 2020, 13(8), 196; https://doi.org/10.3390/ph13080196 - 17 Aug 2020

Cited by 101 | Viewed by 17762

Abstract

Avermectins are a group of drugs that occurs naturally as a product of fermenting Streptomyces avermitilis, an actinomycetes, isolated from the soil. Eight different structures, including ivermectin, abamectin, doramectin, eprinomectin, moxidectin, and selamectin, were isolated and divided into four major components (A1a, [...] Read more.

Avermectins are a group of drugs that occurs naturally as a product of fermenting Streptomyces avermitilis, an actinomycetes, isolated from the soil. Eight different structures, including ivermectin, abamectin, doramectin, eprinomectin, moxidectin, and selamectin, were isolated and divided into four major components (A1a, A2a, B1a and B2a) and four minor components (A1b, A2b, B1b, and B2b). Avermectins are generally used as a pesticide for the treatment of pests and parasitic worms as a result of their anthelmintic and insecticidal properties. Additionally, they possess anticancer, anti-diabetic, antiviral, antifungal, and are used for treatment of several metabolic disorders. Avermectin generally works by preventing the transmission of electrical impulse in the muscle and nerves of invertebrates, by amplifying the glutamate effects on the invertebrates-specific gated chloride channel. Avermectin has unwanted effects or reactions, especially when administered indiscriminately, which include respiratory failure, hypotension, and coma. The current review examines the mechanism of actions, biosynthesis, safety, pharmacokinetics, biological toxicity and activities of avermectins. Full article

(This article belongs to the Special Issue Antiparasitics)

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10 pages, 593 KiB

Open AccessArticle

Juvenile Hemochromatosis: A Case Report and Review of the Literature

by Akiyoshi Takami, Yasuaki Tatsumi, Katsuhisa Sakai, Yasumichi Toki, Katsuya Ikuta, Yuka Oohigashi, Junko Takagi, Koichi Kato and Kazuhisa Takami

Pharmaceuticals 2020, 13(8), 195; https://doi.org/10.3390/ph13080195 - 15 Aug 2020

Cited by 6 | Viewed by 4070

Abstract

Juvenile hemochromatosis (JH), type 2A hemochromatosis, is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2), which encodes hemojuvelin, an essential regulator of the hepcidin expression, causing liver fibrosis, diabetes, and heart failure before [...] Read more.

Juvenile hemochromatosis (JH), type 2A hemochromatosis, is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2), which encodes hemojuvelin, an essential regulator of the hepcidin expression, causing liver fibrosis, diabetes, and heart failure before 30 years of age, often with fatal outcomes. We report two Japanese sisters of 37 and 52 years of age, with JH, who showed the same homozygous HJV I281T mutation and hepcidin deficiency and who both responded well to phlebotomy on an outpatient basis. When all reported cases of JH with homozygous HJV mutations in the relevant literature were reviewed, we found—for the first time—that JH developed in females and males at a ratio of 3:2, with no age difference in the two groups. Furthermore, we found that the age of onset of JH may depend on the types of HJV mutations. In comparison to patients with the most common G320V/G320V mutation, JH developed earlier in patients with L101P/L101P or R385X/R385X mutations and later in patients with I281T/I281T mutations. Full article

(This article belongs to the Section Pharmacology)

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30 pages, 1166 KiB

Open AccessReview

Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

by Malgorzata Sztiller-Sikorska and Malgorzata Czyz

Pharmaceuticals 2020, 13(8), 194; https://doi.org/10.3390/ph13080194 - 14 Aug 2020

Cited by 62 | Viewed by 5253

Abstract

Primary and acquired resistance of cancer to therapy is often associated with activation of nuclear factor kappa B (NF-κB). Parthenolide (PN) has been shown to inhibit NF-κB signaling and other pro-survival signaling pathways, induce apoptosis and reduce a subpopulation of cancer stem-like cells [...] Read more.

Primary and acquired resistance of cancer to therapy is often associated with activation of nuclear factor kappa B (NF-κB). Parthenolide (PN) has been shown to inhibit NF-κB signaling and other pro-survival signaling pathways, induce apoptosis and reduce a subpopulation of cancer stem-like cells in several cancers. Multimodal therapies that include PN or its derivatives seem to be promising approaches enhancing sensitivity of cancer cells to therapy and diminishing development of resistance. A number of studies have demonstrated that several drugs with various targets and mechanisms of action can cooperate with PN to eliminate cancer cells or inhibit their proliferation. This review summarizes the current state of knowledge on PN activity and its potential utility as complementary therapy against different cancers. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest)

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18 pages, 5113 KiB

Open AccessArticle

Bactericidal and In Vitro Cytotoxicity of Moringa oleifera Seed Extract and Its Elemental Analysis Using Laser-Induced Breakdown Spectroscopy

by Reem K. Aldakheel, Suriya Rehman, Munirah A. Almessiere, Firdos A. Khan, Mohammed A. Gondal, Ahmed Mostafa and Abdulhadi Baykal

Pharmaceuticals 2020, 13(8), 193; https://doi.org/10.3390/ph13080193 - 13 Aug 2020

Cited by 43 | Viewed by 4441

Abstract

In the current study, we present the correlation between the capability of laser-induced breakdown spectroscopy (LIBS) to monitor the elemental compositions of plants and their biological effects. The selected plant, Moringa oleifera, is known to harbor various minerals and vitamins useful for [...] Read more.

In the current study, we present the correlation between the capability of laser-induced breakdown spectroscopy (LIBS) to monitor the elemental compositions of plants and their biological effects. The selected plant, Moringa oleifera, is known to harbor various minerals and vitamins useful for human health and is a potential source for pharmaceutical interventions. From this standpoint, we assessed the antibacterial and in vitro cytotoxicity of the bioactive components present in Moringa oleifera seed (MOS) extract. Detailed elemental analyses of pellets of MOSs were performed via LIBS. Furthermore, the LIBS outcome was validated using gas chromatography–mass spectrometry (GC-MS). The LIBS signal was recorded, and the presence of the essential elements (Na, Ca, Se, K, Mg, Zn, P, S, Fe and Mn) in the MOSs were examined. The bactericidal efficacy of the alcoholic MOS extract was examined against Escherichia coli (E. coli) and Staphylococcus aureus(S. aureus) by agar well diffusion (AWD) assays and scanning electron microscopy (SEM), which depicted greater inhibition against Gram-positive bacteria. The validity and DNA nuclear morphology of human colorectal carcinoma cells (HCT-116) cells were evaluated via an MTT assay and DAPI staining. The MTT assay results manifested a profoundly inhibitory action of MOS extract on HCT116 cell growth. Additionally, MOS extracts produced inhibitory action in colon cancer cells (HCT-116), whereas no inhibitory action was seen using the same concentrations of MOS extract on HEK-293 cells (non-cancerous cells), suggesting that MOS extracts could be non-cytotoxic to normal cells. The antibacterial and anticancer potency of these MOS extracts could be due to the presence of various bioactive chemical complexes, such as ethyl ester and D-allose and hexadecenoic, oleic and palmitic acids, making them an ideal candidate for pharmaceutical research and applications. Full article

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

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18 pages, 2557 KiB

Open AccessReview

Gold Nanoparticles: A New Golden Era in Oncology?

by Clara Gerosa, Guido Crisponi, Valeria Marina Nurchi, Luca Saba, Rosita Cappai, Flaviana Cau, Gavino Faa, Peter Van Eyken, Mario Scartozzi, Giuseppe Floris and Daniela Fanni

Pharmaceuticals 2020, 13(8), 192; https://doi.org/10.3390/ph13080192 - 12 Aug 2020

Cited by 28 | Viewed by 4637

Abstract

In recent years, the spectrum of possible applications of gold in diagnostics and therapeutic approaches in clinical practice has changed significantly, becoming surprisingly broad. Nowadays, gold-based therapeutic agents are used in the therapy of multiple human diseases, ranging from degenerative to infectious diseases [...] Read more.

In recent years, the spectrum of possible applications of gold in diagnostics and therapeutic approaches in clinical practice has changed significantly, becoming surprisingly broad. Nowadays, gold-based therapeutic agents are used in the therapy of multiple human diseases, ranging from degenerative to infectious diseases and, in particular, to cancer. At the basis of these performances of gold, there is the development of new gold-based nanoparticles, characterized by a promising risk/benefit ratio that favors their introduction in clinical trials. Gold nanoparticles appear as attractive elements in nanomedicine, a branch of modern clinical medicine, which combines high selectivity in targeting tumor cells and low toxicity. Thanks to these peculiar characteristics, gold nanoparticles appear as the starting point for the development of new gold-based therapeutic strategies in oncology. Here, the new gold-based therapeutic agents developed in recent years are described, with particular emphasis on the possible applications in clinical practice as anticancer agents, with the aim that their application will give rise to a new golden age in oncology and a breakthrough in the fight against cancer. Full article

(This article belongs to the Special Issue Applications of Medicinal Bioinorganic Chemistry)

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22 pages, 576 KiB

Open AccessArticle

Profile and Content of Phenolic Compounds in Leaves, Flowers, Roots, and Stalks of Sanguisorba officinalis L. Determined with the LC-DAD-ESI-QTOF-MS/MS Analysis and Their In Vitro Antioxidant, Antidiabetic, Antiproliferative Potency

by Sabina Lachowicz, Jan Oszmiański, Andrzej Rapak and Ireneusz Ochmian

Pharmaceuticals 2020, 13(8), 191; https://doi.org/10.3390/ph13080191 - 12 Aug 2020

Cited by 26 | Viewed by 4065

Abstract

The aim of this study was to accurately determine the profile of polyphenols using the highly sensitive LC-DAD-ESI-QTOF-MS/MS technique and to determine in vitro antioxidant activity, the ability of inhibition of α-amylase, α-glucoamylase, and pancreatic lipase activity, and antiproliferative activity in leaves, flowers, [...] Read more.

The aim of this study was to accurately determine the profile of polyphenols using the highly sensitive LC-DAD-ESI-QTOF-MS/MS technique and to determine in vitro antioxidant activity, the ability of inhibition of α-amylase, α-glucoamylase, and pancreatic lipase activity, and antiproliferative activity in leaves, flowers, roots, and stalks of medical plant Sanguisorba officinalis L. The results of the analysis of the morphological parts indicated the presence of 130 polyphenols, including 62 that were detected in S. officinalis L. for the first time. The prevailing group was tannins, with contents ranging from 66.4% of total polyphenols in the flowers to 43.3% in the stalks. The highest content of polyphenols was identified in the flowers and reached 14,444.97 mg/100 g d.b., while the lowest was noted in the stalks and reached 4606.33 mg/100 g d.b. In turn, the highest values of the antiradical and reducing capacities were determined in the leaves and reached 6.63 and 0.30 mmol TE/g d.b, respectively. In turn, a high ability to inhibit activities of α-amylase and α-glucoamylase was noted in the flowers, while a high ability to inhibit the activity of pancreatic lipase was demonstrated in the leaves of S. officinalis L. In addition, the leaves and the flowers showed the most effective antiproliferative properties in pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, bladder cancer, and T-cell leukemia cells, whereas the weakest activity was noted in the stalks. Thus, the best dietetic material to be used when composing functional foods were the leaves and the flowers of S. officinalis L., while the roots and the stalks were equally valuable plant materials. Full article

(This article belongs to the Special Issue Applications of Liquid Chromatography in Analysis of Pharmaceuticals and Natural Products)

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20 pages, 9087 KiB

Open AccessArticle

Reversal of Increase in Intestinal Permeability by Mangifera indica Seed Kernel Extract in High-Fat Diet-Induced Obese Mice

by Pavan Kumar Mujawdiya, Pravesh Sharma, Shashwat Sharad and Suman Kapur

Pharmaceuticals 2020, 13(8), 190; https://doi.org/10.3390/ph13080190 - 11 Aug 2020

Cited by 13 | Viewed by 3784

Abstract

Obesity and hyper-intestinal permeability are interconnected. This study is designed to evaluate the ability of Mangifera indica seed kernel extract (MESK) in restoring the intestinal barrier and preventing obesity and associated metabolic complications in a high-fat diet-induced obese mouse model. Four groups of [...] Read more.

Obesity and hyper-intestinal permeability are interconnected. This study is designed to evaluate the ability of Mangifera indica seed kernel extract (MESK) in restoring the intestinal barrier and preventing obesity and associated metabolic complications in a high-fat diet-induced obese mouse model. Four groups of Swiss albino mice: (1) normal diet (ND), (2) high-fat diet (HFD), (3) HFD + Orlistat (100 µg/kg), and (4) HFD + MESK (75 µg/kg), were used to monitor various biochemical parameters associated with metabolic syndrome (glucose, total cholesterol, triglycerides) and body weight in an eight-week-long study. In vivo intestinal permeability was determined by the FITC-dextran method. Interestingly, MESK significantly reduced HFD-induced body weight gain, hepatic lipid accumulation, hepatic fibrosis, hyperglycemia, and dyslipidemia. Additionally, MESK treatment restored the expression of tight junction protein Zonula Occludens-1 (ZO-1) and Claudin-1 and hence prevented increased intestinal permeability induced by a high-fat diet. Moreover, it also increased the expression of potent satiety molecule Nesfatin-1 in the mouse jejunum. Our results, for the first time, establish MESK as a nutraceutical which prevents disruption of the intestinal barrier and thereby intercepts the adverse consequences of compromised intestinal permeability such as obesity, hyperglycemia, dyslipidemia, and systemic inflammation. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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24 pages, 379 KiB

Open AccessReview

Antibacterials in Aquatic Environment and Their Toxicity to Fish

by Bartosz Bojarski, Barbara Kot and Małgorzata Witeska

Pharmaceuticals 2020, 13(8), 189; https://doi.org/10.3390/ph13080189 - 09 Aug 2020

Cited by 82 | Viewed by 7505

Abstract

Antibacterial agents are commonly present in aquatic environment at low concentrations. Terrestrial animal farms, human medicine and aquaculture are main sources of water contamination with antibacterials. Antibiotics were proved to be directly toxic to fish causing oxidative stress, general stress response, histopathological lesions, [...] Read more.

Antibacterial agents are commonly present in aquatic environment at low concentrations. Terrestrial animal farms, human medicine and aquaculture are main sources of water contamination with antibacterials. Antibiotics were proved to be directly toxic to fish causing oxidative stress, general stress response, histopathological lesions, hematological, metabolic, and reproductive disorders, as well as immunosuppressive and genotoxic effects. Environmentally realistic low concentrations of antibiotics also disturb aquatic bacterial communities causing alterations in fish symbiotic microbiota and induce emergence of antibiotic-resistant pathogenic bacteria by exerting selective pressure on spread of antibiotic-resistance genes. Full article

(This article belongs to the Section Pharmacology)

32 pages, 2554 KiB

Open AccessReview

Emerging Therapeutic Modalities against COVID-19

by Shipra Malik, Anisha Gupta, Xiaobo Zhong, Theodore P. Rasmussen, Jose E. Manautou and Raman Bahal

Pharmaceuticals 2020, 13(8), 188; https://doi.org/10.3390/ph13080188 - 08 Aug 2020

Cited by 19 | Viewed by 10365

Abstract

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. [...] Read more.

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials. Full article

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

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15 pages, 1398 KiB

Open AccessArticle

Physicochemical Compatibility Investigation of Mesalazine and Folic Acid Using Chromatographic and Thermoanalytical Techniques

by Mario-Livio Jeličić, Edvin Brusač, Daniela Amidžić Klarić, Biljana Nigović, Sabina Keser and Ana Mornar

Pharmaceuticals 2020, 13(8), 187; https://doi.org/10.3390/ph13080187 - 08 Aug 2020

Cited by 8 | Viewed by 3799

Abstract

Inflammatory bowel disease is a common name for Crohn’s disease and ulcerative colitis. These inflammatory states cause damage in the sidewalls of the gastrointestinal tract, resulting in malabsorption of food and vitamins. Folic acid (Vitamin B9) is often associated with inflammatory bowel diseases [...] Read more.

Inflammatory bowel disease is a common name for Crohn’s disease and ulcerative colitis. These inflammatory states cause damage in the sidewalls of the gastrointestinal tract, resulting in malabsorption of food and vitamins. Folic acid (Vitamin B9) is often associated with inflammatory bowel diseases since reduced overall folate concentration in the human body may lead to the development of colorectal cancer and megaloblastic anaemia. However, its deficiency is easily compensated by taking an additional folic acid pill during regular therapy. At the moment, there are no studies that have examined the compatibility of folic acid with 5-aminosalicylate drugs used in the treatment of inflammatory bowel diseases. In this work, differential scanning calorimetry, forced degradation studies, isothermal stress testing and dissolution stability testing were used to determine the stability of folic acid and one of the most commonly used 5-aminosalicylates, mesalazine, when present in the same solution or blend. To monitor the assay of folic acid, mesalazine and nine of its related impurities, a single HPLC method was developed. Results of compatibility studies showed that no physicochemical interaction between mesalazine and folic acid occurs when combined, opening the path to the development of new formulations, such as a mesalazine/folic acid fixed-dose combination. Full article

(This article belongs to the Section Pharmaceutical Technology)

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32 pages, 5271 KiB

Open AccessArticle

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

by Nicolas Lebouvier, Fabrice Pagniez, Young Min Na, Da Shi, Patricia Pinson, Mathieu Marchivie, Jean Guillon, Tarek Hakki, Rita Bernhardt, Sook Wah Yee, Claire Simons, Marie-Pierre Lézé, Rolf W. Hartmann, Angélique Mularoni, Guillaume Le Baut, Isabelle Krimm, Ruben Abagyan, Patrice Le Pape and Marc Le Borgne

Pharmaceuticals 2020, 13(8), 186; https://doi.org/10.3390/ph13080186 - 08 Aug 2020

Cited by 13 | Viewed by 4493

Abstract

A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key [...] Read more.

A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (−)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC₈₀ = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (−)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated. Full article

(This article belongs to the Special Issue Featured Papers to Celebrate the New Era of the Journal Pharmaceuticals)

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15 pages, 1395 KiB

Open AccessArticle

The In Vitro Anti-amyloidogenic Activity of the Mediterranean Red Seaweed Halopithys Incurva

by Marzia Vasarri, Matteo Ramazzotti, Bruno Tiribilli, Emanuela Barletta, Carlo Pretti, Nadia Mulinacci and Donatella Degl’Innocenti

Pharmaceuticals 2020, 13(8), 185; https://doi.org/10.3390/ph13080185 - 07 Aug 2020

Cited by 2 | Viewed by 3110

Abstract

Neurodegenerative diseases are generally characterized by the presence of neurotoxic amyloid aggregates underlying progressive neuronal death. Since ancient times, natural compounds have been used as curative agents for human health. Amyloid research is constantly looking for safe natural molecules capable of blocking toxic [...] Read more.

Neurodegenerative diseases are generally characterized by the presence of neurotoxic amyloid aggregates underlying progressive neuronal death. Since ancient times, natural compounds have been used as curative agents for human health. Amyloid research is constantly looking for safe natural molecules capable of blocking toxic amyloid aggregates’ formation. From the marine environment, seaweeds are recognized as rich reservoirs of molecules with multiple bioactivities, including the anti-amyloidogenic activity. Here, hydroalcoholic extracts of two seasonal samples of the Mediterranean red seaweed Halophytis incurva (HIEs) were characterized by the HPLC-DAD-MS analysis. The H. incurva anti-amyloidogenic role was explored by incubating both HIEs with hen egg white lysozyme (HEWL), a well-known protein model widely used in amyloid aggregation experiments. The aggregation kinetics and morphological analysis of amyloid aggregates were performed by ThT and AFM analysis, respectively, while their cytotoxicity on SH-SY5Y human neuroblastoma cells was examined by MTT assay. HIEs showed a different efficacy, probably dependent on their metabolic composition, both in inhibiting amyloid fibrillation and in obtaining short and less toxic pre-fibrillary aggregates. Overall, this work sheds light, for the first time, on a Mediterranean red seaweed as a promising renewable resource of bioactive compounds, potentially useful in preventing the formation of toxic amyloid aggregates. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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20 pages, 4646 KiB

Open AccessArticle

Comparative In Vitro Toxicology of Novel Cytoprotective Short-Chain Naphthoquinones

by Zikai Feng, Mohammed Sedeeq, Abraham Daniel, Monika Corban, Krystel L. Woolley, Ryan Condie, Iman Azimi, Jason A. Smith and Nuri Gueven

Pharmaceuticals 2020, 13(8), 184; https://doi.org/10.3390/ph13080184 - 07 Aug 2020

Cited by 4 | Viewed by 2807

Abstract

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which largely depends on the reversible redox characteristics of the active quinone core. We recently identified 11 naphthoquinone derivatives, 1–11, from a library of SCQs that demonstrated enhanced [...] Read more.

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which largely depends on the reversible redox characteristics of the active quinone core. We recently identified 11 naphthoquinone derivatives, 1–11, from a library of SCQs that demonstrated enhanced cytoprotection and improved metabolic stability compared to the clinically used benzoquinone idebenone. Since the toxicity properties of our promising SCQs were unknown, this study developed multiplex methods and generated detailed toxicity profiles from 11 endpoint measurements using the human hepatocarcinoma cell line HepG2. Overall, the toxicity profiles were largely comparable across different assays, with simple standard assays showing increased sensitivity compared to commercial toxicity assays. Within the 11 naphthoquinones tested, the L-phenylalanine derivative 4 consistently demonstrated the lowest toxicity across all assays. The results of this study not only provide useful information about the toxicity features of SCQs but will also enable the progression of the most promising drug candidates towards their clinical use. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 3662 KiB

Open AccessArticle

Deciphering the Pharmacological Properties of Methanol Extract of Psychotria calocarpa Leaves by In Vivo, In Vitro and In Silico Approaches

by Tahmina Akter Bristy, Niloy Barua, Abu Montakim Tareq, Shahenur Alam Sakib, Saida Tasnim Etu, Kamrul Hasan Chowdhury, Mifta Ahmed Jyoti, Md. Arfin Ibn Aziz, A.S.M. Ali Reza, Elisabetta Caiazzo, Barbara Romano, Syed Mohammed Tareq, Talha Bin Emran and Raffaele Capasso

Pharmaceuticals 2020, 13(8), 183; https://doi.org/10.3390/ph13080183 - 06 Aug 2020

Cited by 44 | Viewed by 6301

Abstract

The present study explores the neuropharmacological, antinociceptive, antidiarrheal, antioxidant, thrombolytic and cytotoxic activity of methanol extract of Psychotria calocarpa leaves (MEPC). In anxiolytic activity testing of MEPC by elevated plus maze test, hole–board test and light–dark test, the extract exhibited a dose-dependent reduction [...] Read more.

The present study explores the neuropharmacological, antinociceptive, antidiarrheal, antioxidant, thrombolytic and cytotoxic activity of methanol extract of Psychotria calocarpa leaves (MEPC). In anxiolytic activity testing of MEPC by elevated plus maze test, hole–board test and light–dark test, the extract exhibited a dose-dependent reduction of anxiety while the open field test observed a decreased locomotion. The administration of MEPC revealed a significant dose-dependent reduction of depressant behavior in forced swimming and tail suspension test. Additionally, the antinociceptive and antidiarrheal activity exposed a significant reduction of nociception and diarrheal behavior at the highest dose. In addition, a strong antioxidant activity was observed in DPPH-free radical-scavenging assay (IC₅₀ = 461.05 μg/mL), total phenol content (118.31 ± 1.12 mg) and total flavonoid content (100.85 ± 0.97 mg). The significant clot–lysis activity was also observed with moderate toxicity (LC₅₀ = 247.92 μg/mL) level in the lethality assay of brine shrimp. Moreover, in silico molecular docking study showed that the compound Psychotriasine could offer promising active site interactions for binding proteins. Furthermore, ADME/T and toxicological properties of the compound satisfied the Lipinski’s rule of five and Veber rules for drug-like potential and toxicity level. Overall, MEPC had a potential neuropharmacological, antinociceptive, antidiarrheal and antioxidant activity that warranted further investigation. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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13 pages, 5000 KiB

Open AccessArticle

Layered Silicate-Alginate Composite Particles for the pH-Mediated Release of Theophylline

by Uttom Nandi, Vivek Trivedi, Dennis Douroumis, Andrew P. Mendham and Nichola J. Coleman

Pharmaceuticals 2020, 13(8), 182; https://doi.org/10.3390/ph13080182 - 06 Aug 2020

Cited by 5 | Viewed by 2663

Abstract

Numerous natural and synthetic clay minerals have proven to be excellent drug carriers for high drug-loaded and sustained release formulations due to their considerable ion exchange, adsorption, and swelling capacities. Moreover, the synthetic smectite clays have added advantages in terms of compositional purity [...] Read more.

Numerous natural and synthetic clay minerals have proven to be excellent drug carriers for high drug-loaded and sustained release formulations due to their considerable ion exchange, adsorption, and swelling capacities. Moreover, the synthetic smectite clays have added advantages in terms of compositional purity and controlled cation exchange capacity in comparison to natural clays. This study involves the intercalation of theophylline (TP) in a synthetic clay, Laponite^® (LP), followed by the inclusion of the resulting intercalates into sodium alginate (SA) beads to achieve pH-controlled drug release. Maximum intercalated drug incorporation of 68 mg/g was obtained by ion exchange at pH 1.2 and confirmed by an increase in basal spacing of the clay from 12.9 to 15.5 Å. TP release from the binary LP-TP intercalates in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) was found to be 40% and 70%, respectively. LP-TP particles were also incorporated in an SA matrix via polymer crosslinking using CaCl_2(aq) to improve the pH selective release. The ternary polymer-clay-drug composite particles effectively prevented the release of TP at low pH in SGF and resulted in sustained release in SIF, with 40% dissolution within 120 min. Full article

(This article belongs to the Section Pharmaceutical Technology)

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9 pages, 201 KiB

Open AccessOpinion

Financial Toxicity Encountered in Therapeutic Radiopharmaceutical Clinical Development for Ovarian Cancer

by Charles A. Kunos and Rita Abdallah

Pharmaceuticals 2020, 13(8), 181; https://doi.org/10.3390/ph13080181 - 05 Aug 2020

Cited by 2 | Viewed by 2805

Abstract

Financial toxicity or the debt a cancer survivor incurs from the costs of their medical cancer care is an understudied aspect in the clinical development of experimental therapeutic agents. The United States National Cancer Institute (NCI) Cancer Therapy Evaluation Program studies experimental therapeutic [...] Read more.

Financial toxicity or the debt a cancer survivor incurs from the costs of their medical cancer care is an understudied aspect in the clinical development of experimental therapeutic agents. The United States National Cancer Institute (NCI) Cancer Therapy Evaluation Program studies experimental therapeutic agents like radiopharmaceuticals in both early and late phase trials, which provide opportunities to comprehend more clearly the possible sources of financial toxicity incurred by cancer survivors. We reviewed the academic scholarship describing fiscal and social costs involved in the development of therapeutic radiopharmaceuticals. Because many ovarian cancer survivors outlive their disease through initial and, perhaps, multiple treatment courses, these women and their treatments provide context for our discussion on financial toxicity. 16 (27%) of 60 articles discuss financial toxicity incurred by women with ovarian cancer; none described financial toxicity associated with regulatory agency-approved or experimental therapeutic radiopharmaceuticals. Fiscal costs of radiopharmaceutical dose and schedule and social costs of individual productivity loss or asset expenditure arose as primary financial toxicities. The development of radiopharmaceuticals for women with ovarian cancer remains a high priority for the NCI Cancer Therapy Evaluation Program. Weighing radiopharmaceutical clinical benefit against measures of financial toxicity is challenging and warrants further study in prospective radiopharmaceutical clinical trials. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers)

18 pages, 1518 KiB

Open AccessReview

Uncovering the Exosomes Diversity: A Window of Opportunity for Tumor Progression Monitoring

by Domenico Maisano, Selena Mimmi, Rossella Russo, Antonella Fioravanti, Giuseppe Fiume, Eleonora Vecchio, Nancy Nisticò, Ileana Quinto and Enrico Iaccino

Pharmaceuticals 2020, 13(8), 180; https://doi.org/10.3390/ph13080180 - 04 Aug 2020

Cited by 32 | Viewed by 5236

Abstract

Cells can communicate through special “messages in the bottle”, which are recorded in the bloodstream inside vesicles, namely exosomes. The exosomes are nanovesicles of 30–100 nm in diameter that carry functionally active biological material, such as proteins, messanger RNA (mRNAs), and micro RNA [...] Read more.

Cells can communicate through special “messages in the bottle”, which are recorded in the bloodstream inside vesicles, namely exosomes. The exosomes are nanovesicles of 30–100 nm in diameter that carry functionally active biological material, such as proteins, messanger RNA (mRNAs), and micro RNA (miRNAs). Therefore, they are able to transfer specific signals from a parental cell of origin to the surrounding cells in the microenvironment and to distant organs through the circulatory and lymphatic stream. More and more interest is rising for the pathological role of exosomes produced by cancer cells and for their potential use in tumor monitoring and patient follow up. In particular, the exosomes could be an appropriate index of proliferation and cancer cell communication for monitoring the minimal residual disease, which cannot be easily detectable by common diagnostic and monitoring techniques. The lack of unequivocal markers for tumor-derived exosomes calls for new strategies for exosomes profile characterization aimed at the adoption of exosomes as an official tumor biomarker for tumor progression monitoring. Full article

(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)

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18 pages, 2315 KiB

Open AccessArticle

The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations

by J. Daniel Martínez, Angela S. Infantino, Pablo Valverde, Tammo Diercks, Sandra Delgado, Niels-Christian Reichardt, Ana Ardá, Francisco Javier Cañada, Stefan Oscarson and Jesús Jiménez-Barbero

Pharmaceuticals 2020, 13(8), 179; https://doi.org/10.3390/ph13080179 - 04 Aug 2020

Cited by 10 | Viewed by 3909

Abstract

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein–ligand complexes. We herein present a new methodology based [...] Read more.

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein–ligand complexes. We herein present a new methodology based on the synergic combination of experimental ¹⁹F-based saturation transfer difference (STD) NMR data with computational protocols, applied to analyze the interaction between DC-SIGN, a key lectin involved in inflammation and infection events with the trifluorinated glycomimetic of the trimannoside core, ubiquitous in human glycoproteins. A novel 2D-STD-TOCSYreF NMR experiment was employed to obtain the experimental STD NMR intensities, while the Complete Relaxation Matrix Analysis (CORCEMA-ST) was used to predict that expected for an ensemble of geometries extracted from extensive MD simulations. Then, an in-house built computer program was devised to find the ensemble of structures that provide the best fit between the theoretical and the observed STD data. Remarkably, the experimental STD profiles obtained for the ligand/DC-SIGN complex could not be satisfactorily explained by a single binding mode, but rather with a combination of different modes coexisting in solution. Therefore, the method provides a precise view of those ligand–receptor complexes present in solution. Full article

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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17 pages, 1236 KiB

Open AccessArticle

Resistance to Acetylsalicylic Acid in Patients with Coronary Heart Disease Is the Result of Metabolic Activity of Platelets

by Yuriy I. Grinshtein, Andrei A. Savchenko, Aleksandra A. Kosinova and Maxim D. Goncharov

Pharmaceuticals 2020, 13(8), 178; https://doi.org/10.3390/ph13080178 - 01 Aug 2020

Cited by 3 | Viewed by 2877

Abstract

Sensitivity to acetylsalicylic acid (ASA) is important in the treatment of patients with coronary heart disease (CHD) after coronary artery bypass grafting (CABG). Patients were divided into ASA sensitive (sASA) and ASA resistant (rASA) by the activity of platelet aggregation induced arachidonic acid [...] Read more.

Sensitivity to acetylsalicylic acid (ASA) is important in the treatment of patients with coronary heart disease (CHD) after coronary artery bypass grafting (CABG). Patients were divided into ASA sensitive (sASA) and ASA resistant (rASA) by the activity of platelet aggregation induced arachidonic acid (ARA) together with ASA. Induced platelet aggregation activity was studied in sASA and rASA patients with CHD before and after CABG. The level of synthesis of primary and secondary reactive oxygen species (ROS) by platelets was determined using chemiluminescent analysis. The activity of NAD- and NADP-dependent dehydrogenases in platelets was determined by the bioluminescent method. It was found that the aggregation activity of platelets depended on the sensitivity of CHD patients to ASA and decreased during postoperative ASA therapy. The most pronounced differences in metabolic parameters of platelets in sASA and rASA patients were detected by Nox2 activity. The synthesis of secondary ROS by platelets of CHD patients did not depend on the sensitivity of patients to ASA but increased during postoperative treatment with ASA. The activity of NAD(P)-dependent dehydrogenases in platelets did not differ in sASA and rASA patients with CHD. Full article

(This article belongs to the Special Issue Novel Translational Approaches to the Treatment of Coronary Artery Disease and Congenital Heart Disease in Comorbid Patients)

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21 pages, 5200 KiB

Open AccessArticle

Adenosine Receptor Agonists Increase the Inhibition of Platelet Function by P2Y₁₂ Antagonists in a cAMP- and Calcium-Dependent Manner

by Nina Wolska, Hassan Kassassir, Boguslawa Luzak, Cezary Watala and Marcin Rozalski

Pharmaceuticals 2020, 13(8), 177; https://doi.org/10.3390/ph13080177 - 31 Jul 2020

Cited by 5 | Viewed by 4792

Abstract

We have shown previously that platelet activity can be lowered through the simultaneous inhibition of P2Y₁₂ receptor and activation of adenosine receptors (AR). This work explores this concept by testing the antiplatelet potential of nine AR agonists in combination with P2Y₁₂ [...] Read more.

We have shown previously that platelet activity can be lowered through the simultaneous inhibition of P2Y₁₂ receptor and activation of adenosine receptors (AR). This work explores this concept by testing the antiplatelet potential of nine AR agonists in combination with P2Y₁₂ receptor antagonists—cangrelor and prasugrel metabolite. A panel of in vitro methods was used to assess platelet viability, P-selectin expression, GPIIb-IIIa activation, fibrinogen binding, calcium ion mobilization, VASP-P level, and cAMP formation, utilizing whole blood or isolated platelets from healthy volunteers. The AR agonists demonstrated anti-platelet effects, but stimulated signaling pathways to varying degrees. AR agonists and P2Y₁₂ antagonists reduced expression of both P-selectin and the activated form of GPIIb-IIIa on platelets; however, the combined systems (AR agonist + P2Y₁₂ antagonist) demonstrated stronger effects. The antiplatelet effects of AR when combined with P2Y₁₂ were more pronounced with regard to exogenous fibrinogen binding and calcium mobilization. The cAMP levels in both resting and ADPactivated platelets were increased by AR agonist treatment, and more so when combined with P2Y₁₂ inhibitor. In conclusion, as AR agonists are fast-acting compounds, the methods detecting early activation events are more suitable for assessing their antiplatelet action. The exogenous fibrinogen binding, calcium mobilisation and cAMP level turned out to be sensitive markers for detecting the inhibition caused by AR agonists alone or in combination with P2Y₁₂ receptor antagonists. Full article

(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)

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16 pages, 1904 KiB

Open AccessArticle

Automated GMP-Compliant Production of [⁶⁸Ga]Ga-DO3A-Tuna-2 for PET Microdosing Studies of the Glucagon Receptor in Humans

by Michael Wagner, Johan G. Doverfjord, Joachim Tillner, Gunnar Antoni, Torsten Haack, Martin Bossart, Iina Laitinen, Lars Johansson, Stefan Pierrou, Olof Eriksson and Irina Velikyan

Pharmaceuticals 2020, 13(8), 176; https://doi.org/10.3390/ph13080176 - 31 Jul 2020

Cited by 3 | Viewed by 3608

Abstract

Introduction: [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 (previously published as [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-S01-GCG) has shown high-affinity specific binding to the glucagon receptor (GCGR) in vitro and in vivo in rats and non-human primates in our previous studies, confirming the suitability of [...] Read more.

Introduction: [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 (previously published as [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-S01-GCG) has shown high-affinity specific binding to the glucagon receptor (GCGR) in vitro and in vivo in rats and non-human primates in our previous studies, confirming the suitability of the tracer for drug development applications in humans. The manufacturing process of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 was automated for clinical use to meet the radiation safety and good manufacturing practice (GMP) requirements. Methods: The automated synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler, Eurotope, Germany), disposable cassettes for ⁶⁸Ga-labeling, and pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator (GalliaPharm^®) used in the study were purchased from Eckert & Ziegler. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, and pH, as well as product purification step, were investigated and optimized. Process optimization was conducted with regard to product quality and quantity, as well as process reproducibility. The active pharmaceutical ingredient starting material DO3A-VS-Cys⁴⁰-Tuna-2 (GMP-grade) was provided by Sanofi Aventis. Results: The reproducible and GMP-compliant automated production of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 with on-line documentation was developed. The non-decay-corrected radiochemical yield was 45.2 ± 2.5% (n = 3, process validation) at the end of the synthesis with a labeling synthesis duration of 38 min and a quality controlincluding release procedure of 20 min. The radiochemical purity of the product was 98.9 ± 0.6% (n = 17) with the total amount of the peptide in the preparation of 48 ± 2 µg (n = 3, process validation). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity tests met the acceptance criteria. The product was stable at ambient temperature for at least 2 h. Conclusion: The fully automated GMP-compliant manufacturing process was developed and thoroughly validated. The resulting [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 was used in a clinical study for accurate quantification of GCGR occupancy by a dual anti-diabetic drug in vivo in humans. Full article

(This article belongs to the Section Pharmaceutical Technology)

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23 pages, 1398 KiB

Open AccessReview

Ducrosia spp., Rare Plants with Promising Phytochemical and Pharmacological Characteristics: An Updated Review

by Javad Mottaghipisheh, Anahita Boveiri Dehsheikh, Mohammad Mahmoodi Sourestani, Tivadar Kiss, Judit Hohmann and Dezső Csupor

Pharmaceuticals 2020, 13(8), 175; https://doi.org/10.3390/ph13080175 - 31 Jul 2020

Cited by 8 | Viewed by 3852

Abstract

The rare genus Ducrosia (Apiaceae family) consists of six species, which are mainly native to Asia, specifically to Iran and Iraq. The aerial parts of D. anethifolia, as the most common species, have been traditionally consumed to relieve headache, backache and colic pain, [...] Read more.

The rare genus Ducrosia (Apiaceae family) consists of six species, which are mainly native to Asia, specifically to Iran and Iraq. The aerial parts of D. anethifolia, as the most common species, have been traditionally consumed to relieve headache, backache and colic pain, and have also been used as an anxiolytic, an antidepressant, and for treating insomnia. The antispasmodic and carminative effects of D. assadii, and the analgesic activity of D. flabellifolia, along with the insecticidal activities and use as a remedy of skin infections of D. ismaelis, have been previously documented. Among the 49 non-volatile secondary metabolites identified from D. anethifolia and D. ismaelis, 17 linear furanocoumarins and 8 flavonoids have been characterized. The essential oil compositions of four species, including D. anethifolia, D. assadii, D. flabellifolia and D. ismaelis, have been analyzed, whereby aldehyde hydrocarbons, including decanal (10.1–74.0%) and dodecanal (7.2–33.41%), and α-pinene (4.0–70.3%), were identified as the main aroma constituents. From the species of the genus, the bioactivities of D. anethifolia, as well as D. ismaelis, D. assadii and D. flabellifolia, have been previously investigated. Except one clinical trial, all the pharmacological data are derived from preclinical tests, predominantly focusing on antimicrobial, antioxidant, antiproliferative and cytotoxic activities in vitro, and neuroprotective, antidiabetic and analgesic effects in vivo. Considering the vast ethnobotanical uses of the plants in Iranian folk medicine, the phytochemical and pharmacological analysis of un-investigated species might be promising. Furthermore, due to extensive consumption of the Ducrosia genus, more scientific data are needed to support the safety and efficacy of these plants. Full article

(This article belongs to the Special Issue Medicinal Plants 2020)

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22 pages, 1188 KiB

Open AccessReview

Receptors and Channels Possibly Mediating the Effects of Phytocannabinoids on Seizures and Epilepsy

by Lara Senn, Giuseppe Cannazza and Giuseppe Biagini

Pharmaceuticals 2020, 13(8), 174; https://doi.org/10.3390/ph13080174 - 30 Jul 2020

Cited by 33 | Viewed by 7872

Abstract

Epilepsy contributes to approximately 1% of the global disease burden. By affecting especially young children as well as older persons of all social and racial variety, epilepsy is a present disorder worldwide. Currently, only 65% of epileptic patients can be successfully treated with [...] Read more.

Epilepsy contributes to approximately 1% of the global disease burden. By affecting especially young children as well as older persons of all social and racial variety, epilepsy is a present disorder worldwide. Currently, only 65% of epileptic patients can be successfully treated with antiepileptic drugs. For this reason, alternative medicine receives more attention. Cannabis has been cultivated for over 6000 years to treat pain and insomnia and used since the 19th century to suppress epileptic seizures. The two best described phytocannabinoids, (−)-trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) are claimed to have positive effects on different neurological as well as neurodegenerative diseases, including epilepsy. There are different cannabinoids which act through different types of receptors and channels, including the cannabinoid receptor 1 and 2 (CB₁, CB₂), G protein-coupled receptor 55 (GPR55) and 18 (GPR18), opioid receptor µ and δ, transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), type A γ-aminobutyric acid receptor (GABA_AR) and voltage-gated sodium channels (VGSC). The mechanisms and importance of the interaction between phytocannabinoids and their different sites of action regarding epileptic seizures and their clinical value are described in this review. Full article

(This article belongs to the Section Medicinal Chemistry)

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31 pages, 2691 KiB

Open AccessReview

Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy

by Benedikt Judmann, Diana Braun, Björn Wängler, Ralf Schirrmacher, Gert Fricker and Carmen Wängler

Pharmaceuticals 2020, 13(8), 173; https://doi.org/10.3390/ph13080173 - 30 Jul 2020

Cited by 17 | Viewed by 3878

Abstract

Over the past few years, an approach emerged that combines different receptor-specific peptide radioligands able to bind different target structures on tumor cells concomitantly or separately. The reason for the growing interest in this special field of radiopharmaceutical development is rooted in the [...] Read more.

Over the past few years, an approach emerged that combines different receptor-specific peptide radioligands able to bind different target structures on tumor cells concomitantly or separately. The reason for the growing interest in this special field of radiopharmaceutical development is rooted in the fact that bispecific peptide heterodimers can exhibit a strongly increased target cell avidity and specificity compared to their corresponding monospecific counterparts by being able to bind to two different target structures that are overexpressed on the cell surface of several malignancies. This increase of avidity is most pronounced in the case of concomitant binding of both peptides to their respective targets but is also observed in cases of heterogeneously expressed receptors within a tumor entity. Furthermore, the application of a radiolabeled heterobivalent agent can solve the ubiquitous problem of limited tumor visualization sensitivity caused by differential receptor expression on different tumor lesions. In this article, the concept of heterobivalent targeting and the general advantages of using radiolabeled bispecific peptidic ligands for tumor imaging or therapy as well as the influence of molecular design and the receptors on the tumor cell surface are explained, and an overview is given of the radiolabeled heterobivalent peptides described thus far. Full article

(This article belongs to the Special Issue Forward Thinking towards Theranostic (Radio)ligands Targeting the Tumor Microenvironment (TME))

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13 pages, 2466 KiB

Open AccessArticle

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

by Cansu de Muijnck, Yoren van Gorkom, Maurice van Duijvenvoorde, Mina Eghtesadi, Geeske Dekker-Ensink, Shadhvi S. Bhairosingh, Alessandra Affinito, Peter J. K. Kuppen, Alexander L. Vahrmeijer and Cornelis F. M. Sier

Pharmaceuticals 2020, 13(8), 172; https://doi.org/10.3390/ph13080172 - 30 Jul 2020

Cited by 1 | Viewed by 3970

Abstract

Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible [...] Read more.

Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. Methods: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. Results: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. Conclusion: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases. Full article

(This article belongs to the Special Issue Targeting the Eph–ephrin System)

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13 pages, 2718 KiB

Open AccessArticle

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

by Daniele Florio, Maria Cuomo, Ilaria Iacobucci, Giarita Ferraro, Ahmed M. Mansour, Maria Monti, Antonello Merlino and Daniela Marasco

Pharmaceuticals 2020, 13(8), 171; https://doi.org/10.3390/ph13080171 - 29 Jul 2020

Cited by 19 | Viewed by 2886

Abstract

Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)_264–277, a model amyloidogenic system, [...] Read more.

Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)_264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC₅₀) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents. Full article

(This article belongs to the Section Biopharmaceuticals)

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