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In Vitro and In Silico Biological Evaluation of the Essential Oil from Syzigium cumini Leaves as a Source of Novel Antifungal and Trichomonacidal Agents
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Ocular Drug Delivery into the Eyes Using Drug-Releasing Soft Contact Lens
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Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy
Journal Description
Future Pharmacology
Future Pharmacology
is an international, peer-reviewed, open access journal on pharmacology, drug discovery, and therapeutics published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within ESCI (Web of Science), EBSCO, and other databases.
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 25 days after submission; acceptance to publication is undertaken in 4.6 days (median values for papers published in this journal in the first half of 2024).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
- Future Pharmacology is a companion journal of Pharmaceutics.
Latest Articles
Beyond One-Size-Fits-All: Personalized Medicine and Future Directions in Sex-Based Psychopharmacological Treatment
Future Pharmacol. 2024, 4(3), 541-563; https://doi.org/10.3390/futurepharmacol4030030 (registering DOI) - 20 Aug 2024
Abstract
Sex-related differences in psychopharmacology present unique challenges in both clinical and research settings. Recognition of sex differences in psychopharmacological treatment has increased in recent years, but a significant research gap regarding variations between men and women still exists. Biological factors, including hormonal fluctuations,
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Sex-related differences in psychopharmacology present unique challenges in both clinical and research settings. Recognition of sex differences in psychopharmacological treatment has increased in recent years, but a significant research gap regarding variations between men and women still exists. Biological factors, including hormonal fluctuations, genetic factors, and brain structure differences, contribute significantly to differential drug responses. Moreover, social determinants can influence the differential burden of psychiatric disorders between the sexes and may impact treatment plans. Incorporating sex as a key variable in personalized treatment programs and plans holds the potential to optimize efficacy and minimize adverse effects in psychopharmacology. Sex-related challenges in psychopharmacology necessitate a nuanced approach to treatment. Further research is needed to fully understand these differences and to develop guidelines for personalized medication management. By addressing these challenges, clinicians can improve treatment outcomes and enhance the quality of life of patients with psychiatric disorders.
Full article
Open AccessReview
Insights for Future Pharmacology: Exploring Phytochemicals as Potential Inhibitors Targeting SARS-CoV-2 Papain-like Protease
by
Jawaria Jabeen, Nabeel Ahmed, Zunaira Shahzad, Maida Shahid and Taseer Ahmad
Future Pharmacol. 2024, 4(3), 510-540; https://doi.org/10.3390/futurepharmacol4030029 - 17 Aug 2024
Abstract
(1) Background: The SARS-CoV-2 papain-like protease (PLpro) remains an underexplored antiviral target so far. The reduced efficacy of approved treatments against novel variants highlights the importance of developing new agents. This review aims to provide a comprehensive understanding of phytochemicals as inhibitors of
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(1) Background: The SARS-CoV-2 papain-like protease (PLpro) remains an underexplored antiviral target so far. The reduced efficacy of approved treatments against novel variants highlights the importance of developing new agents. This review aims to provide a comprehensive understanding of phytochemicals as inhibitors of PLpro, identify gaps, and propose novel insights for future reference. (2) Methods: A thorough literature search was conducted using Google Scholar, ScienceDirect, and PubMed. Out of 150 articles reviewed, 57 met inclusion criteria, focusing on SARS-CoV-2 PLpro inhibitors, excluding studies on other coronaviruses or solely herbal extracts. Data were presented class-wise, and phytochemicals were grouped into virtual, weak, modest, and potential inhibitors. (3) Results: Approximately 100 phytochemicals are reported in the literature as PLpro inhibitors. We classified them as virtual inhibitors (70), weak inhibitors (13), modest inhibitors (11), and potential inhibitors (6). Flavonoids, terpenoids, and their glycosides predominated. Notably, six phytochemicals, including schaftoside, tanshinones, hypericin, and methyl 3,4-dihydroxybenzoate, emerged as potent PLpro inhibitors with favorable selectivity indices and disease-mitigation potential; (4) Conclusions: PLpro stands as a promising therapeutic target against SARS-CoV-2. The phytochemicals reported in the literature possess valuable drug potential; however, certain experimental and clinical gaps need to be filled to meet the therapeutic needs.
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(This article belongs to the Special Issue Feature Papers in Future Pharmacology 2024)
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Open AccessArticle
Preclinical Pharmacology of the Low-Impact Ampakine CX717
by
Daniel P. Radin, Sheng Zhong, Rok Cerne, Jodi L. Smith, Jeffrey M. Witkin and Arnold Lippa
Future Pharmacol. 2024, 4(3), 494-509; https://doi.org/10.3390/futurepharmacol4030028 - 16 Aug 2024
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Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and
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Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression.
Full article
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Open AccessReview
Substance Delivery across the Blood-Brain Barrier or the Blood-Retinal Barrier Using Organic Cation Transporter Novel Type 2 (OCTN2)
by
Toshihiko Tashima
Future Pharmacol. 2024, 4(3), 479-493; https://doi.org/10.3390/futurepharmacol4030027 - 4 Aug 2024
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The membrane impermeability of a drug poses a significant challenge in drug research and development, preventing effective drug delivery to the target site. Specifically, the blood-brain barrier (BBB) presents a formidable obstacle to the delivery of drugs targeting the central nervous system (CNS)
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The membrane impermeability of a drug poses a significant challenge in drug research and development, preventing effective drug delivery to the target site. Specifically, the blood-brain barrier (BBB) presents a formidable obstacle to the delivery of drugs targeting the central nervous system (CNS) into the brain, whereas the blood-retinal barrier (BRB) presents a tremendous obstacle to the delivery of drugs targeting the ocular diseases into the eyes. The development of drugs for Alzheimer’s or Parkinson’s disease targeting the CNS and for diabetic retinopathy and age-related macular degeneration targeting the eyes remains an unmet medical need for patients. Transporters play a crucial physiological role in maintaining homeostasis in metabolic organs. Various types of solute carrier (SLC) transporters are expressed in the capillary endothelial cells of the BBB, facilitating the delivery of nutrients from the blood flow to the brain. Therefore, carrier-mediated transport across the BBB can be achieved using SLC transporters present in capillary endothelial cells. It is well-known that CNS drugs typically incorporate N-containing groups, indicating that cation transporters facilitate their transport into the brain. In fact, carrier-mediated transport across the BBB can be accomplished using glucose transporter type 1 (Glut1) as a glucose transporter, L-type amino acid transporter 1 (LAT1) as a large neutral amino acid transporter, and H+/cation antiporter as a cation transporter. Surprisingly, although organic cation transporter novel type 2 (OCTN2) is expressed in the capillary endothelial cells, there has been limited investigation into OCTN2-mediated substance delivery into the brain across the BBB. Furthermore, it is suggested that OCTN2 is expressed at the BRB. In this prospective review, I present the advantages and possibilities of substance delivery into the brain across the BBB or into the eyes across the BRB, mediated by OCTN2 via carrier-mediated transport or receptor-mediated transcytosis.
Full article
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Open AccessReview
Deciphering the Complex Interplay of Long Noncoding RNAs and Aurora Kinases: Novel Insights into Breast Cancer Development and Therapeutic Strategies
by
Mona Kamal Saadeldin, Giuseppe Curigliano and Amal Kamal Abdel-Aziz
Future Pharmacol. 2024, 4(3), 466-478; https://doi.org/10.3390/futurepharmacol4030026 - 30 Jul 2024
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Breast cancer is the most common type of cancer globally and presents an escalating problem and a huge burden on societies. Several strategies are implemented in clinics to treat patients and prevent disease incidence. Efforts to understand the underlying causes of disease emergence
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Breast cancer is the most common type of cancer globally and presents an escalating problem and a huge burden on societies. Several strategies are implemented in clinics to treat patients and prevent disease incidence. Efforts to understand the underlying causes of disease emergence are pivotal, and the latest examination of human transcriptomic studies showed the involvement of the noncoding RNA regulatory molecules in influencing both pathological and physiological conditions. Several molecular mechanisms are involved in the process and collaborate to develop tumor plasticity and drug resistance. In this review, we highlight for the first time the interplay between long noncoding RNAs and Aurora kinases in breast cancer and review the latest advances in the field in an attempt to pave the way for a better understanding of the course of the disease and to delineate the targets for treatment strategies in the clinic.
Full article
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Open AccessArticle
Eugenol-Rich Essential Oils from Flower Buds and Leaves of Syzygium aromaticum Show Antifungal Activity against Candida and Cryptococcus Species
by
Evariste Josué Momo, François Nguimatsia, Laure Ateufouet Ngouango, Paul Keilah Lunga, Boniface Pone Kamdem and Pierre Michel Jazet Dongmo
Future Pharmacol. 2024, 4(3), 449-465; https://doi.org/10.3390/futurepharmacol4030025 - 27 Jul 2024
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Plants from the Myrtaceae family are known to contain considerable quantities of volatile compounds, ranging from oxygenated monoterpenes to hydrogenated sesquiterpenes, and others, which exhibit antimicrobial activity. One such plant includes Syzygium aromaticum, which has been extensively used to treat a number
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Plants from the Myrtaceae family are known to contain considerable quantities of volatile compounds, ranging from oxygenated monoterpenes to hydrogenated sesquiterpenes, and others, which exhibit antimicrobial activity. One such plant includes Syzygium aromaticum, which has been extensively used to treat a number of disorders, including bacterial and fungal infections. Thus, the scientific validation of the essential oil (EO) of Syzygium aromaticum vis-à-vis Candida and Cryptococcus species is valuable. To this end, the present study sought to investigate the antifungal activity of EO from S. aromaticum (clove) leaves and flower buds against Candida and Cryptococcus species. The antioxidant activity of S. aromaticum’s essential oils was also elucidated. The EO was extracted from fresh leaves and floral buds of S. aromaticum using a Clevenger-type apparatus. The as-prepared essential oils were further evaluated for antifungal activity against Candida and Cryptococcus species using a microdilution method. The phytochemical analysis of the EOs was assessed by gas chromatography/mass spectrometry (GC-MS). Antioxidant activities of the EOs were evaluated using standard methods. As a result, the GC-MS analysis revealed the presence of volatile compounds, such as eugenol (87.08%), β-caryophyllene (6.40%) and acetyleugenol (4.45%) as the major constituents of EO from the flower buds, and eugenol (90.54%) and β-caryophyllene (8.42%) as the major components of the leaf’s EO. The eugenol-rich essential oils exhibited significant antifungal effects against Candida species (common MIC value: 200 ppm) and Cryptococcus neoformans (MIC value: 50 ppm), as well as antioxidant activity. Overall, essential oils of S. aromaticum demonstrated antioxidant and antifungal effects, thus validating the ethnopharmacological use of this plant in the treatment of fungal infections. However, antifungal mechanisms of action, in-depth toxicity and in vivo experiments, and pharmacokinetics are warranted to support the use of this plant in ethnomedicine.
Full article
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Open AccessArticle
Lipid Composition-, Medium pH-, and Drug-Concentration-Dependent Membrane Interactions of Ibuprofen, Diclofenac, and Celecoxib: Hypothetical Association with Their Analgesic and Gastrointestinal Toxic Effects
by
Maki Mizogami and Hironori Tsuchiya
Future Pharmacol. 2024, 4(2), 437-448; https://doi.org/10.3390/futurepharmacol4020024 - 20 Jun 2024
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Among nonsteroidal anti-inflammatory drugs, ibuprofen, diclofenac, and celecoxib have been frequently used in multimodal analgesia. Recent studies challenge the conventional theory that they exhibit activity and toxicity by acting on cyclooxygenase selectively. We compared their membrane interactions that may be associated with analgesic
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Among nonsteroidal anti-inflammatory drugs, ibuprofen, diclofenac, and celecoxib have been frequently used in multimodal analgesia. Recent studies challenge the conventional theory that they exhibit activity and toxicity by acting on cyclooxygenase selectively. We compared their membrane interactions that may be associated with analgesic and gastrointestinal toxic effects. Biomimetic membranes suspended in buffers of different pH were prepared with 1-palmitoyl-2-oleoylphosphatidylcholine, sphingomyelin, and cholesterol to mimic neuronal membranes and with 1,2-dipalmitoylphosphatidylcholine to mimic gastrointestinal mucosae. The membrane interactivity was determined by measuring fluorescence polarization. At pH 7.4, the drugs interacted with neuro-mimetic membranes to decrease membrane fluidity at pharmacokinetically-relevant 0.5–100 μM. Celecoxib was most potent, followed by ibuprofen and diclofenac. At pH 4.0 and 2.5, however, the drugs increased the fluidity of 1,2-dipalmitoylphosphatidylcholine membranes at 0.1–1 mM, corresponding to gastroduodenal lumen concentrations after administration. Their membrane fluidization was greater at gastric pH 2.5 than at duodenal pH 4.0. Low-micromolar ibuprofen, diclofenac, and celecoxib structure specifically decrease neuronal membrane fluidity, which hypothetically could affect signal transmission of nociceptive sensory neurons. Under gastroduodenal acidic conditions, high-micromolar ibuprofen, diclofenac, and celecoxib induce fluidity increases of membranous phosphatidylcholines that are hypothetically associated with gastrointestinal toxic effects, which would enhance acid permeability of protective mucosal membranes.
Full article
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Open AccessArticle
Repurposing Synthetic Acetaminophen Derivatives Containing a Benzothiazole Scaffold as an Alternative Therapy for Infectious Diarrhea Caused by Drug-Resistant Shigella Species
by
Boniface Pone Kamdem, Brice Rostan Pinlap, Bijou-Lafortune Noumboue Kouamou, Aubin Youbi Kamche, Boris Arnaud Kuate, Joseph Tsemeugne, Orleans Ngomo, Pierre Mkounga and Fabrice Fekam Boyom
Future Pharmacol. 2024, 4(2), 420-436; https://doi.org/10.3390/futurepharmacol4020023 - 20 Jun 2024
Abstract
Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance
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Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance against current drugs justifies the pressing need to search for alternative medications. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing a benzothiazole backbone, and their combination with certain antibiotics. As a result, two acetaminophen derivatives containing a benzothiazole backbone (4a and 4b) inhibited the growth of Shigella flexneri with a common MIC value of 12.5 µg/mL. These compounds were established through a time-kill kinetics study to be potentially bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a and b) were found to be poorly active (MIC: 100 µg/mL) against this pathogen. Combination studies of 4a and 4b with the least effective antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity with MIC values decreasing from 12.5 to 0.781 μg/ mL. The present study demonstrates that the azobenzothiazole dyes 4 (a and b) can be repurposed as potential anti-Shigella compounds, thus providing potential chemical pharmacophores for the discovery of drugs against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.
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(This article belongs to the Special Issue Feature Papers in Future Pharmacology 2024)
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Open AccessReview
A Narrative Review of Pharmacotherapy of Glaucoma
by
Shalini Virani and Parveen Rewri
Future Pharmacol. 2024, 4(2), 395-419; https://doi.org/10.3390/futurepharmacol4020022 - 27 May 2024
Cited by 1
Abstract
Progressive loss of retinal ganglionic cells (RGC) causes degeneration of optic nerve axons, which leads to blindness in glaucoma. Elevated intraocular pressure (IOP) is the most important, treatable risk factor. Currently, the management of glaucoma is centred on reducing the IOP, and drugs
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Progressive loss of retinal ganglionic cells (RGC) causes degeneration of optic nerve axons, which leads to blindness in glaucoma. Elevated intraocular pressure (IOP) is the most important, treatable risk factor. Currently, the management of glaucoma is centred on reducing the IOP, and drugs in the form of topical drops are the first line of management. Drugs reduce IOP either by suppressing aqueous humour secretion or improving the aqueous humour outflow. Newer drugs added during the past three decades to the armamentarium of glaucoma treatment have targeted the aqueous outflow. With an evolving understanding of the pathogenesis of glaucoma, the role of 24-h IOP control and other IOP-independent risk factors affecting ocular blood flow and RGC toxicity is also being actively studied in clinical and pre-clinical models of glaucoma. The role of available drugs in controlling IOP over 24 h is being evaluated. Improvement of ocular blood flow and neuroprotection are seen as potential drug targets for preventing the loss of RGC. In this article, we review the pharmacotherapy of glaucoma based on current therapeutic principles.
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(This article belongs to the Special Issue Feature Papers in Future Pharmacology 2024)
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Open AccessArticle
In Vitro and In Silico Biological Evaluation of the Essential Oil from Syzigium cumini Leaves as a Source of Novel Antifungal and Trichomonacidal Agents
by
José Thyálisson da Costa Silva, Fabio Caboclo Moreira, José Jailson Lima Bezerra, Naiza Saraiva Farias, Aparecida Vitória Silva Menêses, Andressa Guilhermino dos Santos, Mariana dos Santos Santana, Maria Elenilda Paulino da Silva, Victor Juno Alencar Fonseca, Adrielle Rodrigues Costa, Saulo Almeida Menezes, Rafael Pereira da Cruz, Maria Flaviana Bezerra Morais-Braga, Tiana Tasca, Cícera Datiane de Morais Oliveira-Tintino, Henrique Douglas Melo Coutinho and José Weverton Almeida-Bezerra
Future Pharmacol. 2024, 4(2), 380-394; https://doi.org/10.3390/futurepharmacol4020021 - 1 May 2024
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As microbes develop resistance to various drugs, the treatment of infections becomes increasingly challenging, leading to prolonged illness, heightened severity of infections, elevated mortality rates, and increased healthcare costs. Essential oils are lipophilic and volatile mixtures of compounds that have gained attention in
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As microbes develop resistance to various drugs, the treatment of infections becomes increasingly challenging, leading to prolonged illness, heightened severity of infections, elevated mortality rates, and increased healthcare costs. Essential oils are lipophilic and volatile mixtures of compounds that have gained attention in research for novel antimicrobial agents. Therefore, the present study evaluated the essential oil of Syzygium cumini leaves (EOSC) in order to prospect its antifungal and trichomonacidal activities. The essential oil from the leaves was extracted by steam distillation and analyzed by GC-MS. Antifungal activity was evaluated using the serial microdilution method. Additionally, the potential of the EOSC as an enhancer of fluconazole (FCZ) action was tested at subinhibitory concentrations. To assess anti-Trichomonas vaginalis activity, concentrations ranging from 15.6 to 500 μg/mL of EOSC were tested. Finally, the SwissADME platform was employed to analyze the physicochemical and pharmacokinetic characteristics of the major component of EOSC. The GC-MS analysis identified 94.24% of the components of EOSC, with α-pinene (51.11%) and nerol (8.25%) as major constituents. EOSC exhibited low antifungal activity against the evaluated Candida strains. However, the combination of EOSC and FCZ reduced the IC50 against Candida krusei from 45.29 to 0.30 μg/mL. EOSC also demonstrated significant activity against T. vaginalis (IC50 = 88.2 μg/mL). In silico prediction with α-pinene showed low toxic action and important physicochemical aspects for drug production. The essential oil of Syzygium cumini emerges as a promising candidate for the discovery of molecules with potential antifungal and anti-Trichomonas vaginalis applications.
Full article
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Open AccessReview
Nanotechnology-Driven Therapeutic Innovations in Neurodegenerative Disorders: A Focus on Alzheimer’s and Parkinson’s Disease
by
Antea Krsek and Lara Baticic
Future Pharmacol. 2024, 4(2), 352-379; https://doi.org/10.3390/futurepharmacol4020020 - 30 Apr 2024
Abstract
Neurodegenerative disorders entail a progressive loss of neurons in cerebral and peripheral tissues, coupled with the aggregation of proteins exhibiting altered physicochemical properties. Crucial to these conditions is the gradual degradation of the central nervous system, manifesting as impairments in mobility, aberrant behaviors,
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Neurodegenerative disorders entail a progressive loss of neurons in cerebral and peripheral tissues, coupled with the aggregation of proteins exhibiting altered physicochemical properties. Crucial to these conditions is the gradual degradation of the central nervous system, manifesting as impairments in mobility, aberrant behaviors, and cognitive deficits. Mechanisms such as proteotoxic stress, neuroinflammation, oxidative stress, and programmed cell death contribute to the ongoing dysfunction and demise of neurons. Presently, neurodegenerative diseases lack definitive cures, and available therapies primarily offer palliative relief. The integration of nanotechnology into medical practices has significantly augmented both treatment efficacy and diagnostic capabilities. Nanoparticles, capable of traversing the blood–brain barrier, hold considerable potential for diagnosing and treating brain pathologies. By combining gene therapy with nanotechnology, the therapeutic effectiveness against neurodegenerative diseases can be substantially enhanced. Recent advancements in nano-biomaterial-based methodologies have fortified existing approaches to neural stem cell (NSC) differentiation therapies. NSC-targeting technologies offer a promising, potentially safe method for treating neurodegenerative diseases. This review endeavors to summarize current insights and perspectives on nanotechnology-driven therapeutic innovations in neurodegenerative disorders, with a particular emphasis on Alzheimer’s and Parkinson’s disease.
Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology 2024)
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Open AccessReview
Ocular Drug Delivery into the Eyes Using Drug-Releasing Soft Contact Lens
by
Toshihiko Tashima
Future Pharmacol. 2024, 4(2), 336-351; https://doi.org/10.3390/futurepharmacol4020019 - 29 Apr 2024
Cited by 2
Abstract
The impact of visual impairment, such as blindness, on quality of life is immeasurable. However, effective ocular drug delivery into the eyes has not yet been established, primarily due to the impermeability imposed by the blood–retinal barrier (BRB) based on the tight junctions
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The impact of visual impairment, such as blindness, on quality of life is immeasurable. However, effective ocular drug delivery into the eyes has not yet been established, primarily due to the impermeability imposed by the blood–retinal barrier (BRB) based on the tight junctions and efflux transporters at the endothelium or the epithelium in oral or intravenous administration, as well as the dilution with tear fluid and excretion through the nasolacrimal duct in eye drop administration. Furthermore, intravitreous injections induce pain and fear in patients. Unmet medical needs persist in ocular diseases such as age-related macular degeneration and diabetic retinopathy. Therefore, innovative non-invasive administration methods should be developed. Drug-releasing soft contact lenses (DR-SCLs) affixed to the eye’s surface can continuously and locally deliver their loaded drugs to the eyes. The use of DR-SCLs is expected to greatly enhance the bioavailability and patient adherence to the drug regimen. It is known that several solute carrier (SLC) transporters are expressed in various parts of the eyes, including the cornea, the ciliary body, and the bulbar conjunctiva. Carrier-mediated transport through SLC transporters may occur in addition to passive diffusion. Moreover, nanoparticles can be loaded into DR-SCLs, offering various intelligent approaches based on modifications to induce receptor-mediated endocytosis/transcytosis or to control the loaded drug release within this delivery system. In this perspective review, I discuss the implementation and potential of DR-SCL-mediated ocular drug delivery, particularly focusing on low-molecular-weight compounds because of their fine distribution in living body, ease of handling, and ease of manufacturing.
Full article
(This article belongs to the Special Issue Unveiling New Insights and Treatment Options for Ocular Surface Diseases)
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Open AccessArticle
Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy
by
Monika Berezowska, Paola Coppola, Venkatesh Pilla Reddy and Pradeep Sharma
Future Pharmacol. 2024, 4(2), 317-335; https://doi.org/10.3390/futurepharmacol4020018 - 10 Apr 2024
Cited by 1
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Pregnancy is associated with various physiological changes that can significantly impact the disposition of drugs. To further the insight into how pregnancy affects the pharmacokinetics of drugs at different stages, clinical studies can be simulated using Physiologically Based Pharmacokinetic modelling. PBPK modelling of
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Pregnancy is associated with various physiological changes that can significantly impact the disposition of drugs. To further the insight into how pregnancy affects the pharmacokinetics of drugs at different stages, clinical studies can be simulated using Physiologically Based Pharmacokinetic modelling. PBPK modelling of drugs metabolised by Phase I enzymes (CYPs) in pregnant population models had been reported in the past, while its use in Phase II (UGTs) is not known. In this study, based on the results of a recent meta-analysis, lamotrigine (UGT1A4) and raltegravir (UGT1A1) were selected as candidate drugs, and pregnancy-specific models were developed for both using the Simcyp v.21 simulator. A middle-out strategy was used where previously published drug parameters were adapted from a minimal to a full PBPK model to allow their application for the pregnancy population models using Simcyp PBPK software. Adapted models were successfully validated against observed clinical data both qualitatively (visual overlay of plasma concentrations on graphs) and quantitatively (calculating the predicted/observed ratios for AUC, Cmax and CL as well as statistical analysis using model prediction power metrics). They were then applied to predict the PKs of both drugs in pregnancy population models. The temporal changes in maternal enzymatic activities during gestation were modelled based on in vitro data reported in literature and default relationships encoded in the Simcyp platform for UGT1A1 and UGT1A4, respectively. Our study demonstrates the successful development and validation of a PBPK model for LTG and RTG in pregnancy population models. Future work with additional UGT1A4 substrate drugs using the proposed changes in UGT1A4 activity may enable validating the pregnancy population model and its subsequent use for the prospective prediction of PK.
Full article
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Open AccessReview
Biologics, Small Molecules and More in Inflammatory Bowel Disease: The Present and the Future
by
Manish Manrai, Atul Abhishek Jha, Saurabh Dawra and Aditya Vikram Pachisia
Future Pharmacol. 2024, 4(1), 279-316; https://doi.org/10.3390/futurepharmacol4010017 - 14 Mar 2024
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Inflammatory bowel disease (IBD) is a group of heterogeneous chronic inflammatory diseases of the gut presenting with intestinal and extraintestinal manifestations. Most cases fit in predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily in
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Inflammatory bowel disease (IBD) is a group of heterogeneous chronic inflammatory diseases of the gut presenting with intestinal and extraintestinal manifestations. Most cases fit in predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily in the past three decades. Focused research has resulted in many therapeutic options. Biologics (derived from humans or animals) and small molecules have emerged as the cornerstone in the management of IBD and have become widely available. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab), along with small molecules (tofacitinib), are approved for use. This article summarizes various aspects of these drugs, like clinical pharmacology, indications for use in IBD, safety in pregnancy and lactation, and the adverse effects profile based on the studies leading to their approval. This review also focuses on the recent advances and future perspectives specific to biologics in IBD.
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Open AccessArticle
Comparative Study of the Effects of Curcuminoids and Tetrahydrocurcuminoids on Melanogenesis: Role of the Methoxy Groups
by
Shilpi Goenka
Future Pharmacol. 2024, 4(1), 256-278; https://doi.org/10.3390/futurepharmacol4010016 - 8 Mar 2024
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Curcuminoids are naturally occurring yellow-colored compounds that, when hydrogenated to remove their conjugated double bond, become colorless and are referred to as tetrahydrocurcuminoids. Curcuminoids consist of pure curcumin (PC) in major amounts and demethoxycurcumin (DC) and bisdemethoxycurcumin (BDC) in minor amounts. Tetrahydrocurcuminoids similarly
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Curcuminoids are naturally occurring yellow-colored compounds that, when hydrogenated to remove their conjugated double bond, become colorless and are referred to as tetrahydrocurcuminoids. Curcuminoids consist of pure curcumin (PC) in major amounts and demethoxycurcumin (DC) and bisdemethoxycurcumin (BDC) in minor amounts. Tetrahydrocurcuminoids similarly consist mainly of tetrahydrocurcumin (THC), along with minor amounts of tetrahydrodemethoxycurcumin (THDC) and tetrahydrobisdemethoxycurcumin (THBDC). Previous studies have shown the inhibitory effects of PC, DC, and BDC on melanin production, but there are contradictory findings about THC. In addition, there are currently no reports on the effects of THDC and THBDC on melanogenesis. Our previous report described that, in contrast to PC, which suppressed melanin production, THC stimulated melanin production in B16F10 and MNT-1 cells; this effect was ascribed to the loss of the conjugated heptadiene moiety of PC. However, whether this finding can be generalized to the two curcumin derivatives (DC and BDC), such that THDC and THBDC might also stimulate melanogenesis, has not been addressed. Herein, a comparative study of six curcumin derivatives (PC, DC, BDC, THC, THDC, and THBDC) was undertaken to identify their effects on melanogenesis with the goal of elucidating the structure–activity relationships (SARs) focused on assessing the two regions of the parent curcumins’ structure: (i) the hydrogenation of the two double bonds bridging the phenyl rings to the β-diketone moiety, and (ii) the effect of the ortho-methoxy substituent (-OCH3) on the two phenyl rings. To determine the direct effects of the six compounds, antioxidant activity and tyrosinase activity were assessed in cell-free systems before cellular experiments utilizing the B16F10 mouse melanoma cells, MNT-1 human melanoma cells, and primary cells. Evaluations were made on cytotoxicity, melanin concentration, and cellular tyrosinase activity. The results showed that BDC inhibited melanogenesis in B16F10 and MNT-1 cells. However, it was ineffective in primary human melanocytes, while THBDC continued to exhibit anti-melanogenic capacity in normal human melanocytes. Moreover, these findings provide a novel perspective into the role of the methoxy groups of PC on the biological effects of melanogenesis and also confirm that the removal of the conjugated double bonds abolishes the anti-melanogenic capacity of PC and DC only, but not BDC, as THBDC maintained anti-melanogenic activity that was greater than BDC. However, the outcome is contingent upon the specific kind of cell involved. To the best of our knowledge, this work presents novel findings indicating that the anti-melanogenic capacity of the colored BDC is not only intact but enhanced after its hydrogenation as observed in THBDC. The findings show potential for using colorless THBDC as a pharmacological candidate to diminish the increased pigmentation characteristic of skin hyperpigmentation disorders. Future pharmacological therapeutics that incorporate pure THBDC or THBDC-enriched extracts, which retain both a colorless appearance and potent anti-melanogenic activity, can be applied to compounds for anti-melanoma therapeutics where the demand for nontoxic novel molecules is desired for established efficacies.
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Open AccessReview
Using 5-Nitroimidazole Derivatives against Neglected Tropical Protozoan Diseases: Systematic Review
by
Micheel M. Vichi-Ramírez, Edgar López-López, Catalina Soriano-Correa and Carolina Barrientos-Salcedo
Future Pharmacol. 2024, 4(1), 222-255; https://doi.org/10.3390/futurepharmacol4010015 - 5 Mar 2024
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Neglected tropical diseases (NTDs) are a significant global health problem. Additionally, anti-protozoan treatments are toxic, and their therapeutic regimens require prolonged treatment times and high concentrations of the drugs. Additionally, multi-resistant protozoan strains represent an important global emergency that must be addressed. For
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Neglected tropical diseases (NTDs) are a significant global health problem. Additionally, anti-protozoan treatments are toxic, and their therapeutic regimens require prolonged treatment times and high concentrations of the drugs. Additionally, multi-resistant protozoan strains represent an important global emergency that must be addressed. For these reasons, global efforts are being made to identify new drug candidates that are capable of combating these kinds of diseases. This systematic review shows that 5-nitroimidazole derivatives have been successfully used against neglected tropical protozoan diseases (NTPDs), with a specific focus on three diseases: malaria, leishmaniasis, and human trypanosomiasis. Some nitroimidazole derivatives have been repurposed, and an important group of new drugs is available for the treatment of NTPDs. Finally, we address 5-nitroimidazoles using chemoinformatics and medicinal chemistry tools to describe the most recent and promising 5-nitroimidazole derivatives associated with anti-protozoal activity using their published in vitro and in vivo data. We show that 5-nitroimidazoles offer a broader spectrum of activity against a variety of protozoal pathogens. More importantly, these compounds demonstrate a significantly reduced systemic toxicity compared to other nitroimidazoles. This makes them a more favorable option in the treatment of protozoal infections, particularly in scenarios where the patient’s tolerance to drug side effects is a critical concern.
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Open AccessReview
The Role of Lysophosphatidic Acid in Neuropsychiatric and Neurodegenerative Disorders
by
Simona Dedoni, Chiara Camoglio, Carlotta Siddi, Maria Scherma, Walter Fratta and Paola Fadda
Future Pharmacol. 2024, 4(1), 199-221; https://doi.org/10.3390/futurepharmacol4010014 - 4 Mar 2024
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Individuals suffering from diverse neuropsychiatric and neurodegenerative disorders often have comparable symptoms, which may underline the implication of shared hereditary influences and the same biological processes. Lysophosphatidic acid (LPA) is a bioactive phospholipid and a crucial regulator of the development of adult neuronal
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Individuals suffering from diverse neuropsychiatric and neurodegenerative disorders often have comparable symptoms, which may underline the implication of shared hereditary influences and the same biological processes. Lysophosphatidic acid (LPA) is a bioactive phospholipid and a crucial regulator of the development of adult neuronal systems; hence, it may play an important role in the onset of certain diseases such as Alzheimer’s, Parkinson’s disease, and schizophrenia. During development, LPA signaling regulates many cellular processes such as proliferation, survival, migration, differentiation, cytoskeleton reorganization, and DNA synthesis. So far, six lysophosphatidic acid receptors that respond to LPA have been discovered and categorized based on their homology. Despite the abundance of evidence relating LPA cellular activities to different pathological conditions, little is known about the involvement of LPA in the field of neuropsychiatric and neurodegenerative diseases. The purpose of this review is to define LPA activities related to the illnesses stated above in order to better understand these pathologies and provide future novel treatment strategies based on the latest data.
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Open AccessArticle
Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro
by
Darline Dize, Mariscal Brice Tchatat Tali, Cyrille Armel Njanpa Ngansop, Rodrigue Keumoe, Eugenie Aimée Madiesse Kemgne, Lauve Rachel Tchokouaha Yamthe, Patrick Valere Tsouh Fokou, Boniface Pone Kamdem, Katsura Hata and Fabrice Fekam Boyom
Future Pharmacol. 2024, 4(1), 188-198; https://doi.org/10.3390/futurepharmacol4010013 - 28 Feb 2024
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Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR])
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Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.
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Open AccessArticle
Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents
by
Daniel Pierce Radin, Sheng Zhong, Rok Cerne, Mohammed Shoaib, Jeffrey M. Witkin and Arnold Lippa
Future Pharmacol. 2024, 4(1), 173-187; https://doi.org/10.3390/futurepharmacol4010012 - 26 Feb 2024
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AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are
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AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms.
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Open AccessCase Report
Atazanavir/Ritonavir Increased Tizoxanide Exposure from Oral Nitazoxanide through Pharmacokinetic Interaction in Healthy Volunteers
by
Abdulafeez Akinloye, Timothy Oyedeji, Oluwasegun Eniayewu, Babatunde Adeagbo, Oluseye Bolaji, Steve Rannard, Andrew Owen and Adeniyi Olagunju
Future Pharmacol. 2024, 4(1), 163-172; https://doi.org/10.3390/futurepharmacol4010011 - 22 Feb 2024
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Nitazoxanide use is limited by gastrointestinal side effects associated with increasing dose. In this drug repurposing study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. In this crossover drug–drug interaction study, 18 healthy
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Nitazoxanide use is limited by gastrointestinal side effects associated with increasing dose. In this drug repurposing study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. In this crossover drug–drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alone and in combination with 300/100 mg atazanavir/ritonavir in period 1 and 2 respectively. On both days, blood samples for intensive pharmacokinetic analyses were collected at 0–12 h post-dose. To explore the utility of dried blood spots (DBS) as an alternative to plasma for tizoxanide quantification, 50 µL of blood from some participants was spotted on DBS cards and correlated with plasma concentrations. Pharmacokinetic parameters were derived by non-compartmental analysis and compared between both periods. Co-administration of nitazoxanide with atazanavir/ritonavir resulted in a significant increase in tizoxanide plasma exposure [GMR (90% CI) of AUC0–12h, Cmax and C12h being 1.872 (1.870–1.875), 2.029 (1.99–2.07) and 3.14 (2.268–4.352), respectively]. DBS concentration (%CV) was 46.3% (5.6%) lower than plasma concentrations, and there was strong correlation (R = 0.95, p < 0.001) between DBS-derived plasma concentration and plasma concentrations. Co-administration with atazanavir/ritonavir enhanced tizoxanide exposure with no report of adverse events in healthy volunteers.
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