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Drugs Drug Candidates, Volume 2, Issue 4 (December 2023) – 8 articles

Cover Story (view full-size image): Multiple agonists of the kappa opioid receptor (KOR) have recently been approved as safe and effective therapeutic agents for itching conditions (pruritis). Exciting recent findings by several different investigative teams have demonstrated consistent robust effectiveness in animal models of demyelinating disorders, including experimental autoimmune encephelomyelitis. The precise mechanisms underlying the effectiveness of KOR agonists in ameliorating the clinical effects in animal demyelination models require further investigation, but KOR-induced remyelination has been shown to be involved in several of the studies. This summary of the published work on KOR agonists in demyelination disorder models presents the diverse structural classes of KOR agonists investigated, with comparisons of effects, and discussion of potential future directions. View this paper
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14 pages, 1512 KiB  
Review
The Effects of Vitamin D on Preventing Hyperglycemia and a Novel Approach to Its Treatment
by Suchitra Monapati, Pavani Kaki, Mary Stella Gurajapu, Prathibha Guttal Subhas and Harinadha Baba Kudipudi
Drugs Drug Candidates 2023, 2(4), 923-936; https://doi.org/10.3390/ddc2040046 - 28 Nov 2023
Viewed by 1396
Abstract
The dietary reference levels for vitamin D were established with an emphasis on its role in bone health; however, with the identification of vitamin D receptors in all body tissues novel associations with other metabolic disorders, such as diabetes, are being researched. Aside [...] Read more.
The dietary reference levels for vitamin D were established with an emphasis on its role in bone health; however, with the identification of vitamin D receptors in all body tissues novel associations with other metabolic disorders, such as diabetes, are being researched. Aside from its standard function as the main regulator of calcium absorption, vitamin D also controls the calcium pool, mediates the activity of beta cell calcium-dependent endopeptidases, encourages the conversion of proinsulin to insulin, increases insulin output, and raises insulin activity in peripheral insulin target tissues. Both immune cells and pancreatic beta cells include vitamin D receptors. A deficiency of vitamin D causes glucose intolerance and affects insulin secretion. Different pathogenic characteristics of the disease are linked to a number of vitamin D-related genes. It has been proven that vitamin D supplementation lowers the risk of type 1 and type 2 diabetes and its associated problems. In this article, we discussed a few prospective clinical trials on vitamin D that are necessary to clearly demonstrate the role of vitamin D in the prevention and management of diabetes. Full article
(This article belongs to the Section Clinical Research)
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25 pages, 3004 KiB  
Review
Nanoscale Self-Assemblies from Amphiphilic Block Copolymers as Proficient Templates in Drug Delivery
by Dhruvi Patel, Ketan Kuperkar, Shin-ichi Yusa and Pratap Bahadur
Drugs Drug Candidates 2023, 2(4), 898-922; https://doi.org/10.3390/ddc2040045 - 22 Nov 2023
Cited by 1 | Viewed by 1120
Abstract
This review article emphasizes the current enlargements in the formation and properties of the various nanostructured aggregates resulting from the self-assembly of a variety of block copolymers (BCPs) in an aqueous solution. The development of the different polymerization techniques which produce polymers with [...] Read more.
This review article emphasizes the current enlargements in the formation and properties of the various nanostructured aggregates resulting from the self-assembly of a variety of block copolymers (BCPs) in an aqueous solution. The development of the different polymerization techniques which produce polymers with a desired predetermined molecular weight and low polydispersity is investigated with regard to their technological and biomedical applications; in particular, their applications as vehicles for drug delivery systems are considered. The solution behavior of amphiphilic BCPs and double-hydrophilic block copolymers (DHBCs), with one or both blocks being responsive to any stimulus, is discussed. Polyion complex micelles (PICMs)/polymersomes obtained from the electrostatic interaction of a polyelectrolyte-neutral BCP with oppositely charged species are also detailed. Lastly, polymerization-induced self-assembly (PISA), which forms nanoscale micellar aggregates with controlled size/shape/surface functionality, and the crystallization-driven self-assembly of semicrystalline BCPs facilitated when one block of the BCP is crystallizable, are also revealed. The scalability of the copolymeric micelles in the drug delivery systems and pharmaceutical formations that are currently being used in clinical trials, research, or preclinical testing is emphasized as these micelles could be used in the future to create novel nanomedicines. The updated literature and the future perspectives of BCP self-assembly are considered. Full article
(This article belongs to the Section Preclinical Research)
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15 pages, 1041 KiB  
Review
The Kappa Opioid Receptor: Candidate Pharmacotherapeutic Target for Multiple Sclerosis
by Brian Reed and Surya Dutta
Drugs Drug Candidates 2023, 2(4), 883-897; https://doi.org/10.3390/ddc2040044 - 10 Nov 2023
Cited by 1 | Viewed by 921
Abstract
Multiple sclerosis (MS) afflicts millions of people worldwide. While multiple therapeutics have recently been developed and approved as treatment agents, they are not 100% effective. Recent developments investigating the endogenous opioid system involvement in MS has revealed that agonists of the kappa opioid [...] Read more.
Multiple sclerosis (MS) afflicts millions of people worldwide. While multiple therapeutics have recently been developed and approved as treatment agents, they are not 100% effective. Recent developments investigating the endogenous opioid system involvement in MS has revealed that agonists of the kappa opioid receptor (KOR) have beneficial effects in both animal models of MS (and demyelinating disorders more generally) as well as in vitro models of remyelination. Several groups have contributed to this development. We summarize here the findings of these published studies, with comparisons of the effects and discussion of similarities and differences. The effects of KOR agonists involve both neuroimmunomodulation as well as remyelination, in different populations of cells. The compelling findings in MS model systems using KOR agonists strongly indicate that further investigations at both mechanistic and translational therapeutic levels are warranted. Full article
(This article belongs to the Section Preclinical Research)
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18 pages, 5219 KiB  
Review
Repositioning Oxybutynin Hydrochloride: State of the Art in Synthesis, Mode of Action, Metabolism, and Formulations
by Jean Jacques Vanden Eynde
Drugs Drug Candidates 2023, 2(4), 865-882; https://doi.org/10.3390/ddc2040043 - 24 Oct 2023
Viewed by 1172
Abstract
For decades, oxybutynin hydrochloride has been prescribed to improve bladder control in cases of incontinence and excessive urination frequency. This review summarizes synthetic methods enabling the preparation of the racemic drug and, in a detailed manner, preparation of (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid, a [...] Read more.
For decades, oxybutynin hydrochloride has been prescribed to improve bladder control in cases of incontinence and excessive urination frequency. This review summarizes synthetic methods enabling the preparation of the racemic drug and, in a detailed manner, preparation of (S)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid, a key intermediate in the synthesis of (S)-oxybutynin. The mode of action and metabolism are briefly addressed in order to explain the main adverse effects associated with its use and to justify the evolution observed in the diverse commercial formulations. Repositioning opportunities are discussed in terms of clinical trials for the management of hyperhidrosis, hot flashes, and obstructive sleep apnea. Full article
(This article belongs to the Section Marketed Drugs)
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38 pages, 6413 KiB  
Review
Ethnomedicinal Uses, Phytochemistry, and Pharmacological Activity of the Irvingia Species
by Branly-Natalien Nguena-Dongue, Boniface Pone Kamdem, Paul Keilah Lunga and Fabrice Fekam Boyom
Drugs Drug Candidates 2023, 2(4), 827-864; https://doi.org/10.3390/ddc2040042 - 17 Oct 2023
Cited by 1 | Viewed by 1064
Abstract
Plants belonging to the genus Irvingia are widespread across the African and Southeast Asian regions of the world. Irvingia gabonensis, Irvingia malayana, and Irvingia grandifolia are among the commonly used species in ethnomedicine, especially in Africa. Fever, scabies, toothache, inflammation, and [...] Read more.
Plants belonging to the genus Irvingia are widespread across the African and Southeast Asian regions of the world. Irvingia gabonensis, Irvingia malayana, and Irvingia grandifolia are among the commonly used species in ethnomedicine, especially in Africa. Fever, scabies, toothache, inflammation, and liver and gastrointestinal disorders are among the pathological conditions that are reverted by Irvingia plants upon traditional preparations. Modern pharmacological investigations have substantiated the ethnomedicinal uses of Irvingia spp. Reports on the phytochemical analysis of Irvingia plants have revealed the presence of a number of secondary metabolites such as flavonoids, phenolic compounds, tannins, saponins, and alkaloids. Based on the foregoing, the present study provides a comprehensive evaluation of reports on the ethnomedicinal use, phytochemistry, pharmacology, and toxicity of plants from the genus Irvingia. Relevant information on Irvingia plants was mostly obtained from major scientific databases from their inception until July 2023. As a result, more than forty compounds have been identified in Irvingia spp., proving the abundance of secondary metabolites in these plants. Reports have pointed out modern pharmacological activities such as antiprotozoal, antimicrobial, antioxidant, antidiabetic, anti-inflammatory, and hepatoprotective activities. The present study provides more insights for the successful utilization of Irvingia plants and may guide further research on their therapeutic potential in the treatment of various diseases. Full article
(This article belongs to the Section Drug Candidates from Natural Sources)
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17 pages, 2822 KiB  
Article
In Vitro Study of the Effects of Five Chemically Modified Tetracycline (CMT) Analogs on Human Epidermal Melanogenesis: Potential as Novel Anti-Melanogenic Agents
by Shilpi Goenka and Lorne M. Golub
Drugs Drug Candidates 2023, 2(4), 810-826; https://doi.org/10.3390/ddc2040041 - 15 Oct 2023
Viewed by 861
Abstract
Treatment of hyperpigmented skin disorders by novel drug candidates without side effects remains an ongoing area of research. Chemically modified tetracyclines (CMTs) are a group of nonantimicrobial tetracycline drugs that have been shown to possess multiple pharmacological activities. We have previously documented the [...] Read more.
Treatment of hyperpigmented skin disorders by novel drug candidates without side effects remains an ongoing area of research. Chemically modified tetracyclines (CMTs) are a group of nonantimicrobial tetracycline drugs that have been shown to possess multiple pharmacological activities. We have previously documented the anti-melanogenic effects of CMT-3 and its 9-amino derivative, CMT-308. Herein, we have extended our analysis to evaluate other CMT analogs, namely CMT-1, CMT-4, CMT-5, CMT-6, and CMT-8, for their impact on melanogenesis using primary human epidermal melanocytes (HEMn-DP cells). CMT analogs were screened using a tetrazolium-based assay to identify nontoxic concentration ranges that were further used to analyze the effects of CMTs on cellular melanin content and morphology (via quantitation of dendricity). Cellular tyrosinase (TYR) activity and levels of melanogenesis proteins, TYR, and microphthalmia transcription factor (MITF) were also evaluated to elucidate the mechanisms underlying their effects on melanogenesis. The findings demonstrated that exposure to CMT-8 resulted in notable cytotoxic effects at concentrations >10 µM; hence, all five analogs were further evaluated and compared at 10 µM. None of the five CMT analogs exhibited any impact on intracellular melanin in HEMn-DP cells at the concentration of 10 µM. However, CMT-1, CMT-4, and CMT-8 robustly suppressed dendricity parameters in HEMn-DP cells, while CMT-5 and CMT-6 showed no effect, suggesting that only a subset of CMT analogs can attenuate melanocyte dendricity. Moreover, the analog CMT-5, which has β-diketone blocked, was ineffective, thus confirming the role of this moiety in suppressing dendrite formation. CMT-1 and CMT-8 did not affect cellular tyrosinase activity, while CMT-4 suppressed TYR activity at 10 µM. The capacity of CMT-4 and CMT-8 to suppress dendricity was partly associated with their ability to downregulate MITF protein levels, while CMT-1 had no effect on MITF but suppressed TYR protein levels. The results of this study indicate that CMT-1, CMT-4, and CMT-8 merit further investigation using in vivo studies as potential drug candidates for the treatment of hyperpigmentation disorders. Full article
(This article belongs to the Section Preclinical Research)
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14 pages, 2321 KiB  
Article
Identification of Potential Non-Systemic Therapeutics for Hyperammonemia
by Brad Nicklas, Simon Velasquez Morales, Jian Qian, Kyle J. Stephens, David R. Corbin, Mark B. Shiflett, Cory J. Berkland and Alan M. Allgeier
Drugs Drug Candidates 2023, 2(4), 796-809; https://doi.org/10.3390/ddc2040040 - 30 Sep 2023
Viewed by 956
Abstract
A non-absorbable therapeutic candidate for the treatment of hyperammonemia has been identified and characterized. Conventional approaches to reducing ammonia concentration in the blood and colon include acidifying the colon, inhibiting the bacterial production of ammonia, and activation of the urea cycle. Addressing gaps [...] Read more.
A non-absorbable therapeutic candidate for the treatment of hyperammonemia has been identified and characterized. Conventional approaches to reducing ammonia concentration in the blood and colon include acidifying the colon, inhibiting the bacterial production of ammonia, and activation of the urea cycle. Addressing gaps in the literature around therapeutic ammonia adsorption, this study established assays for ammonia uptake from both NH4OH and NH4Cl solutions as well as interference and selectivity for potassium absorption. Performance was characterized for a large number and variety of materials, spanning zeolites, ion-exchange resins, metallopolymers, metal–organic frameworks (MOFs), and polymeric carboxylic acids. The latter class showed low potassium capacity (poly(acrylic acid): 10 mg/g, poly(maleic-co-acrylic acid): 4 mg/g) and a therapeutically relevant depression of pH in buffered simulated intestinal fluid (SIF) (poly(acrylic acid): −2.01 and poly(maleic-co-acrylic acid): −3.23) compared to lactulose (−3.46), an approved therapeutic for hyperammonemia that works by acidifying the colon. In the polymeric organic acids evaluated, pH depression correlated well with pKa and acid site density. Additionally, this class of candidates should avoid the undesirable side effects of lactulose, such as the potential for hyperglycemia in diabetic patients and incompatible use with galactosemic patients. Full article
(This article belongs to the Section Preclinical Research)
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15 pages, 2986 KiB  
Article
Bioactive Components of Myracrodruon urundeuva against SARS-CoV-2: A Computational Study
by Sabrina Kelly Silva Alves, Cássio Silva Sousa, Edilanne Katrine Amparo Viana, Hellen Cris Araújo Souza, Maycon Douglas Araújo Souza, Arthur Serejo Neves Ribeiro, Vanessa de Sousa do Vale, Muhammad Torequl Islam, Joabe Lima Araújo and Jefferson Almeida Rocha
Drugs Drug Candidates 2023, 2(4), 781-795; https://doi.org/10.3390/ddc2040039 - 27 Sep 2023
Viewed by 1228
Abstract
SARS-CoV-2 (severe acute respiratory distress syndrome coronavirus 2) is the causative agent for the novel coronavirus disease 2019 (COVID-19). It raises serious biosecurity questions due to its high contagious potential, thereby triggering rapid and efficient responses by the scientific community to take necessary [...] Read more.
SARS-CoV-2 (severe acute respiratory distress syndrome coronavirus 2) is the causative agent for the novel coronavirus disease 2019 (COVID-19). It raises serious biosecurity questions due to its high contagious potential, thereby triggering rapid and efficient responses by the scientific community to take necessary actions against viral infections. Cumulative scientific evidence suggests that natural products remain one of the main sources for pharmaceutical consumption. It is due to their wide chemical diversity that they are able to fight against almost all kinds of diseases and disorders in humans and other animals. Knowing the overall facts, this study was carried out to investigate the chemical interactions between the active constituents of a promising medicinal plant, Myracrodruon urundeuva, and some specific proteins of SARS-CoV-2. For this, we used molecular docking to predict the most appropriate orientation by binding a molecule (a ligand) to its receptor (a protein). The best results were evaluated by screening their pharmacokinetic properties using the online tool pkCSM. Findings suggest that among 44 chemical compounds of M. urundeuva, agathisflavone, which is abundantly present in its leaf, exhibited excellent molecular affinity (−9.3 to −9.7 kcal.mol−1) with three functional proteins, namely, Spike, MPro, and RBD of SARS-CoV-2. In conclusion, M. urundeuva might be a good source of antiviral agents. Further studies are required to elucidate the exact mechanism of action of the bioactive compounds of M. urundeuva acting against SARS-CoV-2. Full article
(This article belongs to the Special Issue Fighting SARS-CoV-2 and Related Viruses)
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