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Sci. Pharm., Volume 90, Issue 1 (March 2022) – 21 articles

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Article
Temperature and pH-Dependent Behaviors of mAb Drugs: A Case Study for Trastuzumab
Sci. Pharm. 2022, 90(1), 21; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010021 - 21 Mar 2022
Cited by 1 | Viewed by 1263
Abstract
The distortions in the high-order structure of therapeutic monoclonal antibodies (mAbs) under different environmental conditions acutely affect mAb stability, resulting in altered safety, efficacy, and shelf-life profiles. The overall stability of mAbs depends on many factors, and it requires complementary techniques for an [...] Read more.
The distortions in the high-order structure of therapeutic monoclonal antibodies (mAbs) under different environmental conditions acutely affect mAb stability, resulting in altered safety, efficacy, and shelf-life profiles. The overall stability of mAbs depends on many factors, and it requires complementary techniques for an in-depth analysis. The stability of mAbs can be characterized by differential centrifugal sedimentation (DCS), differential scanning calorimetry (DSC), differential scanning fluorimetry (DSF), and size exclusion chromatography (SEC) techniques. In this report, temperature-ramped dynamic light scattering (DLS), and circular dichroism (CD) spectroscopy were employed as complementary tools to show how temperature and pH affect the aggregation of a model mAb, trastuzumab, in solution. The results showed that the aggregation onset temperature of trastuzumab defined by DLS was 75 °C, which decreases the amount of β-sheets and causes a slight increase in helix structures. Moreover, the melting temperature of trastuzumab was determined to be between 80–83 °C by temperature-ramped CD spectrophotometry, which is in line with the Tm of trastuzumab’s Fab region tested with DSC. Thus, unfolding and aggregation of trastuzumab start simultaneously at 75 °C, and unfolding triggers the aggregation. The temperature-ramped CD and DLS methods are robust tools to determine the thermal behavior of biosimilars in various solution conditions. Their complementary usage provides solid scientific background for regulatory applications and a better understanding of mAb instability and its relationship with structural changes. Full article
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Review
Nanocarrier Systems in Taste Masking
Sci. Pharm. 2022, 90(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010020 - 04 Mar 2022
Viewed by 1350
Abstract
Taste is the most crucial organoleptic parameter affecting patient compliance in the case of drugs with poor palatability. Taste masking is a major challenge for the development of orally ingested active pharmaceutical constituents in the pharmaceutical industry. Numerous conventional taste-masking techniques have been [...] Read more.
Taste is the most crucial organoleptic parameter affecting patient compliance in the case of drugs with poor palatability. Taste masking is a major challenge for the development of orally ingested active pharmaceutical constituents in the pharmaceutical industry. Numerous conventional taste-masking techniques have been extensively studied. In parallel, affecting the drug solubility or release is a major concern of conventional taste-masking techniques. Recently, many nanocarrier systems have been introduced, claiming the advantage of effective taste masking without affecting either the drug solubility or its release. In this review, we will present new techniques for taste masking, including taste-masking techniques utilizing nanocarrier systems such as liposomes, polymeric and solid lipid nanoparticles, polymeric micelles, submicron lipid emulsions, and nanogels. We will chiefly highlight the composition of these systems and their applications in designing oral therapeutic delivery systems successful in masking the taste of bitter molecules. Full article
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Article
Application of Quality by Design Approach to the Pharmaceutical Development of Anticancer Crude Extracts of Crocus sativus Perianth
Sci. Pharm. 2022, 90(1), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010019 - 03 Mar 2022
Viewed by 1386
Abstract
The application of the Quality by Design (QbD) concept to extracts obtained from Crocus sativus perianth with potential anticancer activity will ensure the safety, efficiency, and quality control of the entire technological process, as well as determine the critical factors affecting the quality [...] Read more.
The application of the Quality by Design (QbD) concept to extracts obtained from Crocus sativus perianth with potential anticancer activity will ensure the safety, efficiency, and quality control of the entire technological process, as well as determine the critical factors affecting the quality of extracts. Potentially critical points of the production of the plant extracts, including the cultivation and processing of the plant materials, the extraction process, and the choice of solvents, were identified using the Ishikawa diagram and FMEA risk assessment methods as well as the corrective actions proposed. The Herbal Chemical Marker Ranking System (HerbMars) approach was used to justify the Q-markers choice of Crocus, which takes into account bioavailability, pharmacological activity, and the presence of the selected standard. An experimental design (DoE) was used to assess the influence of potentially critical factors on the efficiency of the compound extraction from raw materials with water or ethanol. The presence of 16 compounds in Crocus perianth was determined by HPLC and their quantitative assessment was established. Selected compounds (ferulic acid, mangiferin, crocin, rutin, isoquercitrin) can be used for the quality control of Crocus perianth. In addition, the stigmas from the Volyn region met the requirements of ISO 3632 for saffron as a spice (category I). The cytotoxic activity against melanoma (IGR39) and triple-negative breast cancer (MDA-MB-231) cell lines of the hydroethanolic extract of C. sativus perianth was significantly more pronounced than the water extract, probably due to the chemical composition of the constituent components. The results show that the QbD approach is a powerful tool for process development for the production of quality herbal drugs. Full article
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Article
Purple Corn Silk Extract Attenuates UVB-Induced Inflammation in Human Keratinocyte Cells
Sci. Pharm. 2022, 90(1), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010018 - 01 Mar 2022
Viewed by 1213
Abstract
UVB is a causative factor for severe skin damage, such as cell aging, death, and inflammation. UVB easily permeates into the epidermis layer of human skin, which is mainly composed of keratinocyte cells. In previous results, we found that purple corn silk (PCS) [...] Read more.
UVB is a causative factor for severe skin damage, such as cell aging, death, and inflammation. UVB easily permeates into the epidermis layer of human skin, which is mainly composed of keratinocyte cells. In previous results, we found that purple corn silk (PCS) extract showed the potential to inhibit keratinocyte damages of UVB-treated cells. Thus, in this study, we aimed to evaluate the preventive effects of PCS extract against the inflammation of UVB-induced keratinocyte cells using the HaCaT cell line. HaCaT cells were treated with PCS extract at various concentrations for 1 h, then exposed to 25 mJ/cm2 UVB before subsequent experiments. Fragmented DNA was observed using flow cytometry. The inflammatory response was investigated through NF-κB activity by immunofluorescence staining and related protein expression by Western blotting. The results demonstrated that PCS extract decreased the sub-G1 DNA content. Interestingly, PCS extract attenuated NF-κB activity via suppressed NF-κB nuclear translocation and protein expression. Moreover, PCS extract remarkably decreased c-Jun phosphorylation and decreased proinflammatory cytokines, along with iNOS and COX-2 levels in UVB-treated cells compared to the UVB-control group. This finding exhibited that PCS extract minimized inflammation in keratinocyte cells induced by UVB radiation. Full article
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Article
Evaluation of Liposome-Loaded Microbubbles as a Theranostic Tool in a Murine Collagen-Induced Arthritis Model
Sci. Pharm. 2022, 90(1), 17; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010017 - 28 Feb 2022
Viewed by 1251
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe inflammation of the synovial tissue. Here, we assess the feasibility of liposome-loaded microbubbles as theranostic agents in a murine arthritis model. First, contrast-enhanced ultrasound (CEUS) was used to quantify neovascularization in this model [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe inflammation of the synovial tissue. Here, we assess the feasibility of liposome-loaded microbubbles as theranostic agents in a murine arthritis model. First, contrast-enhanced ultrasound (CEUS) was used to quantify neovascularization in this model since CEUS is well-established for RA diagnosis in humans. Next, the potential of liposome-loaded microbubbles and ultrasound (US) to selectively enhance liposome delivery to the synovium was evaluated with in vivo fluorescence imaging. This procedure is made very challenging by the presence of hard joints and by the limited lifetime of the microbubbles. The inflamed knee joints were exposed to therapeutic US after intravenous injection of liposome-loaded microbubbles. Loaded microbubbles were found to be quickly captured by the liver. This resulted in fast clearance of attached liposomes while free and long-circulating liposomes were able to accumulate over time in the inflamed joints. Our observations show that murine arthritis models are not well-suited for evaluating the potential of microbubble-mediated drug delivery in joints given: (i) restricted microbubble passage in murine synovial vasculature and (ii) limited control over the exact ultrasound conditions in situ given the much shorter length scale of the murine joints as compared to the therapeutic wavelength. Full article
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Communication
Compatibility of Different Formulations in TrichoConceptTM Vehicles for Hair Treatments
Sci. Pharm. 2022, 90(1), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010016 - 25 Feb 2022
Viewed by 1181
Abstract
The wide variety of potential pathogeneses for alopecia and the wide variety of active pharmaceutical ingredients (APIs) to treat and manage those pathogeneses highlight the importance of the development of stable and effective topical treatments. Topical options for alopecia on the market remain [...] Read more.
The wide variety of potential pathogeneses for alopecia and the wide variety of active pharmaceutical ingredients (APIs) to treat and manage those pathogeneses highlight the importance of the development of stable and effective topical treatments. Topical options for alopecia on the market remain limited and oral products may result in unwanted systemic adverse effects. This study is meant to fill the gap by determining compatibility in terms of beyond-use date (BUD) of APIs with theoretical or demonstrated benefits for topical use for alopecia. The compatibility of seven formulations was tested: F1 = clobetasol 0.05% in TrichoWashTM; F2 = ketoconazole 2% in TrichoWashTM; F3 = spironolactone 1% in TrichoWashTM; F4 = latanoprost 0.1% in TrichoCreamTM; F5 = pyridoxine HCl 0.5%, vitamin A acetate 1%, and vitamin E succinate 12.1 IU in TrichoCondTM; F6 = Caffeine 2%, menthol 1%, and pyridoxine HCl 0.5% in TrichoWashTM; F7 = Latanoprost 0.1%, minoxidil 5%, and finasteride 0.25% in TrichoSolTM. All formulations presented a BUD of 6 months, except for F4 and F7, which showed compatibility for 3 months. This validates the compatibility of the APIs with the TrichotechTM vehicles, and that they are highly convenient for compounding pharmacies. Full article
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Article
Formulation Optimization of Extemporaneous Oral Liquids Containing Naloxone and Propranolol for Pediatric Use
Sci. Pharm. 2022, 90(1), 15; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010015 - 22 Feb 2022
Viewed by 1112
Abstract
There is a need to develop dosage forms suitable for children to improve drug treatment. Extemporaneous compounding of drugs for children is one way to meet these needs. However, excipients generally considered as safe in adults may not be appropriate in dosage forms [...] Read more.
There is a need to develop dosage forms suitable for children to improve drug treatment. Extemporaneous compounding of drugs for children is one way to meet these needs. However, excipients generally considered as safe in adults may not be appropriate in dosage forms intended for children. The aim was to optimize the composition of two pediatric liquid preparations by substituting paraben as a microbiological preservative and ethanol as a solubilizer, with excipients more suitable for pediatric use. The oral liquids were Naloxone 1 mg/mL and Propranolol 10 mg/mL. Twelve different formulations were tested with propranolol and naloxone, respectively, during the screening process to select appropriate formulations. Sodium benzoate and glycerol were used as a preservative and solubilizer, respectively, and different pH of the formulations were evaluated. The formulations were characterized according to dispensed dose (dosing accuracy), viscosity and osmolality. The optimized formulations from the screening process were tested with two amounts of sodium benzoate and microbiological assays were performed. These formulations were shown to have satisfactory preservative properties and dosing accuracy. The results showed that the oral liquids could be prepared without the addition of solubilizer and with lower osmolality (naloxone), thus reducing the risk of gastrointestinal side effects. Full article
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Review
Systematic Review on the Effectiveness of Essential and Carrier Oils as Skin Penetration Enhancers in Pharmaceutical Formulations
Sci. Pharm. 2022, 90(1), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010014 - 19 Feb 2022
Cited by 1 | Viewed by 1637
Abstract
Oils, including essential oils and their constituents, are widely reported to have penetration enhancement activity and have been incorporated into a wide range of pharmaceutical formulations. This study sought to determine if there is an evidence base for the selection of appropriate oils [...] Read more.
Oils, including essential oils and their constituents, are widely reported to have penetration enhancement activity and have been incorporated into a wide range of pharmaceutical formulations. This study sought to determine if there is an evidence base for the selection of appropriate oils for particular applications and compare their effectiveness across different formulation types. A systematic review of the data sources, consisting of Google Scholar, EMBASE, PubMed, Medline, and Scopus, was carried out and, following screening and quality assessment, 112 articles were included within the analysis. The research was classified according to the active pharmaceutical ingredient, dosage form, in vitro/in vivo study, carrier material(s), penetration enhancers as essential oils, and other chemical enhancers. The review identified four groups of oils used in the formulation of skin preparations; in order of popularity, these are terpene-type essential oils (63%), fatty acid-containing essential oils (29%) and, finally, 8% of essential oils comprising Vitamin E derivatives and miscellaneous essential oils. It was concluded that terpene essential oils may have benefits over the fatty acid-containing oils, and their incorporation into advanced pharmaceutical formulations such as nanoemulsions, microemulsions, vesicular systems, and transdermal patches makes them an attractive proposition to enhance drug permeation through the skin. Full article
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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Article
Amphiphilic Alkylated Pectin Hydrogels for Enhanced Topical Delivery of Fusidic Acid: Formulation and In Vitro Investigation
Sci. Pharm. 2022, 90(1), 13; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010013 - 14 Feb 2022
Cited by 2 | Viewed by 1084
Abstract
Hydrogels constructed of amphiphilically modified polysaccharides have attracted a lot of interest because of their potential to augment drug diffusion over the skin. This research describes the synthesis of amphiphilic alkylated pectin via glycidyl tert-butyl ether modification (alkylation degree 15.7%), which was [...] Read more.
Hydrogels constructed of amphiphilically modified polysaccharides have attracted a lot of interest because of their potential to augment drug diffusion over the skin. This research describes the synthesis of amphiphilic alkylated pectin via glycidyl tert-butyl ether modification (alkylation degree 15.7%), which was characterized using spectroscopic and thermal analysis techniques and then formulated into hydrogels for the study of their potential in regulating fusidic acid diffusion topically. The hydrogels were formulated by the ionic interaction of negatively charged pectin and positively charged crosslinker CaCl2, with a reported fusidic acid loading degree of 93–95%. Hydrogels made of alkylated pectin showed a lower swelling percentage than that of native pectin, resulting in a slower fusidic acid release. The influence of pH on the swelling percentage and drug release was also investigated, with results revealing that greater pH enhanced swelling percentage and drug release. The in vitro interactions with HaCaT cells revealed negligible cytotoxicity under application-relevant settings. Utilizing Franz diffusion cells, the alkylated pectin hydrogels caused fusidic acid to penetrate the Strat-M® membrane at a 1.5-fold higher rate than the native pectin hydrogels. Overall, the in vitro results showed that alkylated pectin hydrogels have a lot of promise for topical distribution, which needs further investigation. Full article
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Review
Repurposing of Anti-Malarial Drug Quinacrine for Cancer Treatment: A Review
Sci. Pharm. 2022, 90(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010012 - 08 Feb 2022
Viewed by 1085
Abstract
Quinacrine (QC), a synthetic drug belonging to the 9-aminoacridine family, has been used extensively to treat malaria and multiple ailments over the past several decades. Following its discovery in the 1920s and extensive use for the treatment of malaria for nearly two decades, [...] Read more.
Quinacrine (QC), a synthetic drug belonging to the 9-aminoacridine family, has been used extensively to treat malaria and multiple ailments over the past several decades. Following its discovery in the 1920s and extensive use for the treatment of malaria for nearly two decades, numerous studies have explored its antineoplastic potential in both preclinical and clinical settings. Multiple studies spanning over seven decades have examined a wide range of QC anticancer activities across various types of cancers, along with the underlying mechanisms. Many of these mechanisms, including activation of the p53 signaling cascade and simultaneous NF-κB signaling inhibition, have been reported in various studies, bringing QC to a unique polypharmacological category drug possessing the potential to treat a wide variety of diseases, including cancer. This article summarizes most of the research conducted over several decades to uncover new molecular mechanisms activated or inactivated and directly correlate with antineoplastic activity QC. Full article
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Article
Proof-of-Concept Preclinical Use of Drosophila melanogaster in the Initial Screening of Immunomodulators
Sci. Pharm. 2022, 90(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010011 - 08 Feb 2022
Viewed by 1123
Abstract
Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action. This research was carried out to determine whether Drosophila melanogaster can serve as an appropriate model organism [...] Read more.
Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action. This research was carried out to determine whether Drosophila melanogaster can serve as an appropriate model organism in the initial screening of drug candidates with immunomodulatory activities. To test this, we performed phenotypic assay and molecular analysis to investigate the immunomodulatory activities of aspirin, dexamethasone, curcumin, and epigallocatechin gallate (EGCG), that have been reported to yield such effects in the mammalian model system. In vivo survival analysis demonstrated that all drugs/compounds were relatively safe at the tested concentrations. In the infection assay, curcumin and EGCG showed a protective signature to bacterial infection in flies lacking Toll-mediated immune responses. Furthermore, dexamethasone and aspirin, drugs with immunosuppressive activity, could improve the survival of PGRP-LBΔ mutant flies with hyperactivated immune system. These phenotypes were supported by RT-qPCR-based molecular analysis, revealing that drugs/compounds used in this study could modulate the expression level of genes related to the immune system. In conclusion, while curcumin and EGCG could promote the improvement of fly survival against infection, aspirin and dexamethasone were able to suppress overactivation of immune responses in D. melanogaster. These results are in line with the ones observed in the mammalian model system, further emphasizing the notion that flies would serve as a prospective model organism in the initial screening of drug candidates for their immunomodulatory activities prior to further checking in the mammalian animal models. In the end, this will reduce the use of mammalian animal models for preliminary experiments in an effort to discover/repurpose drugs with immunomodulatory activity. Full article
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Article
Antioxidant Activity, Sun Protection Activity, and Phytochemical Profile of Ethanolic Extracts of Daemonorops acehensis Resin and Its Phytosomes
Sci. Pharm. 2022, 90(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010010 - 03 Feb 2022
Viewed by 1094
Abstract
Daemonorops (Indonesian: jernang) resin is one of Indonesia’s leading non-timber forest products and can be developed as a source of natural antioxidants and sun protection. This study aimed to select promising solvents for extracting a Daemonorops acehensis resin and phytosome formulation with [...] Read more.
Daemonorops (Indonesian: jernang) resin is one of Indonesia’s leading non-timber forest products and can be developed as a source of natural antioxidants and sun protection. This study aimed to select promising solvents for extracting a Daemonorops acehensis resin and phytosome formulation with high antioxidant capacities and sun protection factor (SPF) values. Jernang resin was extracted using a water–ethanol mixture in five different ratios. The promising extract was then mixed with soy lecithin in three different formulations. A promising extract and phytosome were then selected based on their antioxidant capacities and sun protection factor (SPF) values. A liquid chromatography mass spectrometry/mass spectrometry (LC–MS/MS) analysis was also performed on five extracts to identify the components in the extracts that might be responsible for the biological activity. The results showed that the ethanol solvent variation and phytosome formulation influenced the antioxidant capacity and SPF value. A hundred-percent ethanolic extract and F1 phytosome exhibited the highest antioxidant capacities and SPF values. A qualitative analysis revealed the various classes of compounds in the extract and phytosome. A flavylium chromophore, dracorhodin, dominated the resin extract and was presumed to be the marker compound responsible for their antioxidant capabilities and SPF values. These findings are important for manufacturing sunscreens containing active compounds of bioactive natural resins. Full article
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Editorial
Acknowledgment to Reviewers of Scientia Pharmaceutica in 2021
Sci. Pharm. 2022, 90(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010009 - 27 Jan 2022
Viewed by 1007
Abstract
Rigorous peer-reviews are the basis of high-quality academic publishing [...] Full article
Article
Pharmacokinetic Study of Mucoadhesive Itopride Hydrochloride In Situ Nasal Gel Formulations in a Comparative In Vivo Study and Histopathological Safety Evaluation
Sci. Pharm. 2022, 90(1), 8; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010008 - 21 Jan 2022
Viewed by 1156
Abstract
Hepatic first-pass metabolism has been a major cause of reduced bioavailability for many drugs. Using the nasal route as an alternative route to deliver drugs to the systemic circulation provided the solution to this problem. One of the drugs which are highly affected [...] Read more.
Hepatic first-pass metabolism has been a major cause of reduced bioavailability for many drugs. Using the nasal route as an alternative route to deliver drugs to the systemic circulation provided the solution to this problem. One of the drugs which are highly affected by first-pass metabolism is itopride hydrochloride (ITO HCl). It is a prokinetic agent used for the treatment of various gastrointestinal motility disorders, mainly gastroesophageal reflux. The objective of this study was to determine the pharmacokinetic parameters of selected mucoadhesive in situ nasal gel formulations (F1 and F17) of itopride hydrochloride (ITO HCl) and to evaluate their safety after topical application on the nasal mucosa. The tested formulations contained 18% w/v poloxamer 407 with 0.5% w/v of HPMC K4M (F1), or with 0.5% w/v MC (F17). A randomized cross-over study was done on six rabbits after administration of F1, F17, and commercial oral tablets (Ganaton®). Plasma levels were assessed using high-performance liquid chromatography (HPLC) to compare the nasal gel formulations with the conventional oral tablets. Histopathological study of the nasal mucosa was performed in rats after nasal application of both in situ gel formulas. The in vivo pharmacokinetic profiles of in situ nasal gel formulas F1 and F17 provided showed improvement in Cmax, Ke, t1/2, AUC0–24, AUC24–inf, AUC0–inf, AUMC24–inf, AUMC0–inf, MRT, Vd, and Cmax/AUC0–24 values over commercial tablets (p < 0.05). No statistically significant difference was found between both nasal gel formulas (F1 and F17). The percentage relative bioavailability of ITO HCl nasal in situ gel F1 and F17 was found to be 171.22% and 178.91%, respectively, in comparison with the commercial tablet. Histopathological study of the nasal mucosa revealed the safety of nasal in situ gel formulations to the nasal mucosa after 14 days of application. The study showed that the formulation of itopride hydrochloride as a mucoadhesive in situ nasal gel has enhanced the drug bioavailability due to avoidance of first-pass metabolism. The study points to the potential of mucoadhesive nasal in situ gel in terms of safety and efficiency. Full article
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Article
Antineoplastic Activity of Water-Soluble Form of Novel Kinase Inhibitor 1-(4-Chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione immobilized on Polymeric Poly(PEGMA-co-DMM) Carrier
Sci. Pharm. 2022, 90(1), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010007 - 21 Jan 2022
Viewed by 1170
Abstract
The maleimide derivative 1-(4-chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione (MI-1) was synthesized as inhibitor of several protein kinases, however, its application is hindered by its poor water solubility. In this study, the mechanisms of the antineoplastic action of MI-1 and its MI-1/M5 complex with M5 carrier [...] Read more.
The maleimide derivative 1-(4-chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione (MI-1) was synthesized as inhibitor of several protein kinases, however, its application is hindered by its poor water solubility. In this study, the mechanisms of the antineoplastic action of MI-1 and its MI-1/M5 complex with M5 carrier (poly (PEGMA-co-DMM)) towards human colon carcinoma HCT116 cells were investigated by using the MTT and clonogenic assays, DNA intercalation with methyl green replacement, alkaline DNA comet assay, and Western-blot analysis. MI-1 compound and its MI-1/M5 complex possessed high toxicity towards colon (HCT116), cervical (HeLa) carcinoma cells and melanoma (SK-MEL-28) cells with GI50 value in a range of 0.75–7.22 µg/mL, and demonstrated high selectivity index (SI ˃ 6.9). The p53 status of colon cancer cells did not affect the sensitivity of these cells to the treatment with MI-1 and its MI-1/M5 complex. M5 polymer possessed low toxicity towards studied cells. The MI-1, MI-1/M5, and M5 only slightly inhibited growth of the pseudo-normal HaCaT and Balb/c 3T3 cell lines (GI50 ˃ 50 μg/mL). The MI-1 and its MI-1/M5 complex induced mitochondria-dependent pathway of apoptosis, damage of the DNA, and morphological changes in HCT116 cells, and affected the G2/M transition checkpoint. The MI-1 intercalated into the DNA molecule, while such capability of MI-1/M5 complex and M5 polymer was much lower. Thus, poly (PEGMA-co-DMM) might be a promising carrier for delivery of the maleimide derivative, MI-1, a novel kinase inhibitor, through improving its solubility in aqueous media and enhancing its antiproliferative action towards human tumor cells. Studies are in progress on the treatment of Nemeth-Kellner lymphoma (NK/Ly)-bearing mice with the MI-1 and MI-1/M5 complex. Full article
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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Article
Dehydroepiandrosterone (DHEA) Improves the Metabolic and Haemostatic Disturbances in Rats with Male Hypogonadism
Sci. Pharm. 2022, 90(1), 6; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010006 - 20 Jan 2022
Viewed by 1078
Abstract
Objectives: The current work was designed to study the effect of dehydroepiandrosterone (DHEA) on glucose homeostasis, liver functions and hemostatic disturbances in a rat model of bilateral orchidectomy (ORCH). Methods: 32 male rats (n = 8) were randomly assigned into 4 groups; [...] Read more.
Objectives: The current work was designed to study the effect of dehydroepiandrosterone (DHEA) on glucose homeostasis, liver functions and hemostatic disturbances in a rat model of bilateral orchidectomy (ORCH). Methods: 32 male rats (n = 8) were randomly assigned into 4 groups; (i) control (sham operated) group; were normal rats in which all surgical procedures were done without ORCH, (ii) Control + DHEA group: as control group but rats were treated with DHEA for 12 weeks, (iii) orchiectomized (ORCH) group: rats had bilateral orchidectomy and (iv) ORCH + DHEA group: orchiectomized rats treated with DHEA for 12 weeks. Four weeks after ORCH, DHEA treatment began and lasted for twelve weeks. By the end of the experiment, the parameters of glucose homeostasis, lipid profile, liver enzymes, bleeding and clotting times (B.T. and C.T.), prothrombin time (P.T.), activated partial thromboplastin time (aPTT), platelet count and aggregation, von-Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor (PAI-1), fibrin degradation products (FDP), intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelin-1 were measured. Results: ORCH caused significant deteriorations in the parameters of glucose homeostasis, lipid profile, and liver functions (p < 0.05). In addition, lower androgenicity-induced by ORCH caused a significant rise in PAI-1, fibrinogen, FDPs, ET-1 (p < 0.01) with significant shortening of bleeding and clotting times. DHEA replacement therapy significantly decreased glucose, insulin, PAI-1, fibrinogen, ICAM-1, and VCAM-1 when compared to ORCH rats. Conclusion: DHEA ameliorated the metabolic, hepatic, hypercoagulable, and hypofibrinolysis disturbances induced by ORCH. Full article
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Article
A New Practice to Monitor the Fabrication Process of Fab-Targeting Ligands from Bevacizumab by LC-MS: Preparation and Analytical Characterization
Sci. Pharm. 2022, 90(1), 5; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010005 - 04 Jan 2022
Viewed by 1067
Abstract
The objective of this study was to qualitatively evaluate a Fab-targeting ligand preparation containing free thiol groups in the hinge region by using bevacizumab as a model. The evaluation focused on the purification of fragments through a nonaffinity-based process using a centrifugal ultrafiltration [...] Read more.
The objective of this study was to qualitatively evaluate a Fab-targeting ligand preparation containing free thiol groups in the hinge region by using bevacizumab as a model. The evaluation focused on the purification of fragments through a nonaffinity-based process using a centrifugal ultrafiltration technique and mild reduction conditions for the intact production of F(ab’) fragments with specific inter-heavy-chain disulfide bonds cleavage. Under these conditions, F(ab’) fragments with a defined chemical composition were successfully obtained via proteolytic digestion followed by a controlled reduction reaction process maintaining the integrity of the binding sites. The ultrafiltration purification technique appears to be suitable for the removal of the digestive enzyme but inefficient for the removal of Fc fragments, thus requiring additional processing. A suitable analytical strategy was developed, allowing us to demonstrate the reformation of disulfide bridges between the two reduced cysteines within F(ab’) fragments. Full article
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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Review
Traditional Uses, Phytochemistry, and Pharmacology of Elegia Species: A Review
Sci. Pharm. 2022, 90(1), 4; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010004 - 27 Dec 2021
Cited by 1 | Viewed by 1192
Abstract
In South Africa, plants belonging to the Restionaceae family possess an ecological dominance. As a result, they have been the subject of numerous morphological, anatomical, and evolutionary studies. However, few studies have focused on their phytochemical profile and their potential pharmacological activities. The [...] Read more.
In South Africa, plants belonging to the Restionaceae family possess an ecological dominance. As a result, they have been the subject of numerous morphological, anatomical, and evolutionary studies. However, few studies have focused on their phytochemical profile and their potential pharmacological activities. The genus Elegia L. is the second largest of this family comprising 52 species, which are mainly used as materials for thatching. Limited studies on the chemical constituents of Elegia species and their importance as medicinal plants have been undertaken. This review provides constructive and extensive information about the botanical characterization, distribution, traditional uses, phytochemistry and pharmacology of the genus Elegia. A comprehensive search of previously published literature was performed for studies on this genus, using databases with different key search words. This survey documented 52 Elegia species summarizing their previous taxonomic classification. In addition, 14 species were found to be studied for their phytochemical profile, revealing 14 chemical compounds. Concerning their biological activities, only one species (E. tectorum (L.f.) Moline and H.P.Linder) is reported for its anti-wrinkle activity. Moreover, two species are locally used for thatching and as materials for brooms. The present review highlights the Elegia genus as an important source of bioactive phytochemicals with flavonol glycosides being the main metabolites and reveals the uncharted territory of this genus for new research studies. Full article
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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Article
The Development and the Validation of a Novel Dissolution Method of Favipiravir Film-Coated Tablets
Sci. Pharm. 2022, 90(1), 3; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010003 - 24 Dec 2021
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Abstract
The aim of this study was to develop and validate a dissolution test for favipiravir release in a tablet dosage form using ultra-high performance liquid chromatography (UHPLC). The dissolution method was developed by testing the solubility of favipiravir in media with different pH [...] Read more.
The aim of this study was to develop and validate a dissolution test for favipiravir release in a tablet dosage form using ultra-high performance liquid chromatography (UHPLC). The dissolution method was developed by testing the solubility of favipiravir in media with different pH values. The results demonstrated that the best dissolution was achieved in phosphate buffer with a pH of 6.8. The amount of favipiravir that was released was about 100% after 30 min. The UHPLC method presented linearity (R = 1.000) in the concentration range of 0.044–0.44 mg/mL. The recovery parameter that was achieved ranged from 102.5% to 104.2%. The system suitability, repeatability, and intermediate precision RSD% results were found to be 0.36%, 1.99%, and 2.49%, respectively. In addition to these parameters and results, an F-test was performed using the Minitab 18 Statistical Software program for the intermediate precision and repeatability results. The standard and sample solutions were found to be stable for 2 days in their respective dissolution medium. This analytical method was also found to be selective for favipiravir. In conclusion, a simple and feasible dissolution method with a short run time of 2.5 min was developed and validated successfully. The obtained results demonstrated that the dissolution test developed here is adequate for its purpose and can be applied as the dissolution method for favipiravir in film-coated tablets for release analyses. Full article
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Article
The Search for New Antibacterial Agents among 1,2,3-Triazole Functionalized Ciprofloxacin and Norfloxacin Hybrids: Synthesis, Docking Studies, and Biological Activity Evaluation
Sci. Pharm. 2022, 90(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010002 - 22 Dec 2021
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Abstract
Among all modern antibiotics, fluoroquinolones are well known for their broad spectrums of activity and efficiency toward microorganisms and viruses. However, antibiotic resistance is still a problem, which has encouraged medicinal chemists to modify the initial structures in order to combat resistant strains. [...] Read more.
Among all modern antibiotics, fluoroquinolones are well known for their broad spectrums of activity and efficiency toward microorganisms and viruses. However, antibiotic resistance is still a problem, which has encouraged medicinal chemists to modify the initial structures in order to combat resistant strains. Our current work is aimed at synthesizing novel hybrid derivatives of ciprofloxacin and norfloxacin and applying docking studies and biological activity evaluations in order to find active promising molecules. We succeeded in the development of a synthetic method towards 1,2,3-triazole-substituted ciprofloxacin and norfloxacin derivatives. The structure and purity of the obtained compounds were confirmed by 1H NMR, 13C NMR, 19F NMR, LC/MS, UV-, IR- spectroscopy. Docking studies, together with in vitro research against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus subtilis ATCC 6633, Pseudomonas aeruginosa ATCC 27853, Candida albicans NCTC 885-653 revealed compounds in which activity exceeded the initial molecules. Full article
(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design 2.0)
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Review
Using Metabolite Data to Develop Patient Centric Specification for Amide Impurity in Vildagliptin Tablets
Sci. Pharm. 2022, 90(1), 1; https://0-doi-org.brum.beds.ac.uk/10.3390/scipharm90010001 - 22 Dec 2021
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Abstract
Many specified impurities in vildagliptin’s finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level [...] Read more.
Many specified impurities in vildagliptin’s finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found ≥1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of ≤0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities. Full article
(This article belongs to the Special Issue Feature Papers in Scientia Pharmaceutica)
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