Journal Description
Pharmaceuticals
Pharmaceuticals
is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is partners of Pharmaceuticals and their members receive a discount on the article processing charge.
- Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.6 days after submission; acceptance to publication is undertaken in 3.6 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Testimonials: See what our editors and authors say about Pharmaceuticals.
- International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
- Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.
Impact Factor:
4.3 (2023);
5-Year Impact Factor:
4.6 (2023)
Latest Articles
Changes in Quality of Life, Adherence, and Kinesiophobia in Patients with Hemophilia Treated with Extended Half-Life Treatment: Final Results of the LongHest Project
Pharmaceuticals 2024, 17(7), 835; https://doi.org/10.3390/ph17070835 (registering DOI) - 25 Jun 2024
Abstract
(1) Background: Hemophilia is a bleeding disorder characterized by hemarthrosis. Prophylaxis is the gold standard for bleeding prevention. Extended half-life (EHL) recombinant FVIII replacement products have shown to be associated with low bleeding rates. The aim was to evaluate the efficacy of EHL
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(1) Background: Hemophilia is a bleeding disorder characterized by hemarthrosis. Prophylaxis is the gold standard for bleeding prevention. Extended half-life (EHL) recombinant FVIII replacement products have shown to be associated with low bleeding rates. The aim was to evaluate the efficacy of EHL prophylaxis in improving perceived quality of life, adherence to treatment, and kinesiophobia in patients with hemophilia. (2) Methods: This was a prospective cohort study. Forty-six patients from different regions, who had started EHL FVIII concentrate prophylactic treatment, were evaluated at baseline and at 12-month follow-up. The study variables were as follows: perceived quality of life (36-Item Short Form Health Survey), adherence to treatment (Validated Hemophilia Regimen Treatment Adherence Scale—Prophylaxis), and kinesiophobia (Tampa Scale of Kinesiophobia). (3) Results: There were statistically significant differences in the domains Role-Physical (p < 0.001), Bodily Pain (p < 0.001), Role-Emotional (p < 0.001), Vitality (p = 0.04), and Social Functioning (p = 0.01) and the total scores, Physical Health (p < 0.001) and Mental Health (p < 0.001) on perceived quality of life. There were significant differences in the domains Skipping (p < 0.01), Communicating (p < 0.001), and the total score (p = 0.01) in terms of adherence. There were also significant differences in kinesiophobia (p = 0.02) after the study period. (4) Conclusions: EHL prophylaxis can improve the perceived quality of life of people with hemophilia. This prophylactic regimen, which requires fewer infusions, may improve adherence to treatment in adult patients with hemophilia over a 12-month period. The administration of extended half-life factor VIII concentrates can reduce kinesiophobia in adult patients with hemophilic arthropathy.
Full article
(This article belongs to the Special Issue Recent Developments of Coagulation Factor Products in Hemophilia Treatment)
Open AccessCase Report
Impact of Cannabidiol and Exercise on Clinical Outcomes and Gut Microbiota for Chemotherapy-Induced Peripheral Neuropathy in Cancer Survivors: A Case Report
by
MariaLuisa Vigano, Sarah Kubal, Yao Lu, Sarah Habib, Suzanne Samarani, Georgina Cama, Charles Viau, Houman Farzin, Nebras Koudieh, Jianguo Xia, Ali Ahmad, Antonio Vigano and Cecilia T. Costiniuk
Pharmaceuticals 2024, 17(7), 834; https://doi.org/10.3390/ph17070834 (registering DOI) - 25 Jun 2024
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus
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Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3). Clinical outcomes and gut microbiota composition were assessed at baseline and after each phase. We present the case of a 52-year-old female with a history of triple-negative breast cancer in remission for over five years presenting with CIPN. She showed decreased monocyte counts, c-reactive protein, and systemic inflammatory index after each phase. Duloxetine provided moderate benefits and intolerable side effects (hyperhidrosis). She experienced the best improvement and least side effects with the combined (CBD plus MME) phase. Noteworthy were clinically meaningful improvements in CIPN symptoms, quality of life (QoL), and perceived physical function, as well as improvements in pain, mobility, hand/finger dexterity, and upper and lower body strength. CBD and MME altered gut microbiota, showing enrichment of genera that produce short-chain fatty acids. CBD and MME may improve CIPN symptoms, QoL, and physical function through anti-inflammatory and neuroprotective effects in cancer survivors suffering from long-standing CIPN.
Full article
(This article belongs to the Special Issue Therapeutic Potential for Cannabinoid and Its Receptor)
Open AccessArticle
Automated Radiosynthesis of [18F]FluoFAPI and Its Dosimetry and Single Acute Dose Toxicological Evaluation
by
Jason A. Witek, Allen F. Brooks, Sahil M. Kapila, Wade P. Winton, Jenelle R. Stauff, Peter J. H. Scott and Benjamin L. Viglianti
Pharmaceuticals 2024, 17(7), 833; https://doi.org/10.3390/ph17070833 (registering DOI) - 25 Jun 2024
Abstract
Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on
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Background: Cancer-associated fibroblasts have become a new target for therapy. Fibroblasts present within malignancies express the fibroblast activation protein (FAP). Inhibitors to FAP (FAPI) are small molecules recently developed as a theranostic agents for imaging and radiotherapy. All currently used FAPI rely on a linker–chelator complex attached to the ‘inhibitor’. We describe a new automated method of the direct attachment of the radioisotope to the inhibitor, resulting in a >50% MW reduction with the hope of an improved tumor-to-background ratio and tumor uptake. Methods: [18F]FluroFAPI was developed from a Sn precursor. This allowed for subsequent automated radioflourination. We obtained the biodistribution of [18F]FluroFAPI in rats, performed estimated human radiation dosimetry, and performed a 100× expected single dose toxicology analysis for eventual first-in-human experiments. Results: The synthesis of the Sn precursor for FluorFAPI and the automated synthesis of [18F]FluroFAPI was demonstrated. [18F]FluroFAPI had favorable estimated human radiation dosimetry, and demonstrated no adverse effects when injected at a dose of 100× that planned for [18F]FluroFAPI. Conclusions: With the successful development of an automated synthesis of [18F]FluroFAPI, first-in-human testing can be planned with the hope of an improved tumor-to-background performance compared to other FAPI agents.
Full article
(This article belongs to the Section Radiopharmaceutical Sciences)
Open AccessReview
Targeted Delivery Strategies for Multiple Myeloma and Their Adverse Drug Reactions
by
Shuting Li, Hongjie Wang, Shijun Xiong, Jing Liu and Shuming Sun
Pharmaceuticals 2024, 17(7), 832; https://doi.org/10.3390/ph17070832 (registering DOI) - 25 Jun 2024
Abstract
Currently, multiple myeloma (MM) is a prevalent hematopoietic system malignancy, known for its insidious onset and unfavorable prognosis. Recently developed chemotherapy drugs for MM have exhibited promising therapeutic outcomes. Nevertheless, to overcome the shortcomings of traditional clinical drug treatment, such as off-target effects,
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Currently, multiple myeloma (MM) is a prevalent hematopoietic system malignancy, known for its insidious onset and unfavorable prognosis. Recently developed chemotherapy drugs for MM have exhibited promising therapeutic outcomes. Nevertheless, to overcome the shortcomings of traditional clinical drug treatment, such as off-target effects, multiple drug resistance, and systemic toxicity, targeted drug delivery systems are optimizing the conventional pharmaceuticals for precise delivery to designated sites at controlled rates, striving for maximal efficacy and safety, presenting a promising approach for MM treatment. This review will delve into the outstanding performance of antibody–drug conjugates, peptide–drug conjugates, aptamer–drug conjugates, and nanocarrier drug delivery systems in preclinical studies or clinical trials for MM and monitor their adverse reactions during treatment.
Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions)
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Graphical abstract
Open AccessReview
Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder
by
Shilu Deepa Thomas, Sabna Abdalla, Nermin Eissa, Amal Akour, Niraj Kumar Jha, Shreesh Ojha and Bassem Sadek
Pharmaceuticals 2024, 17(7), 831; https://doi.org/10.3390/ph17070831 (registering DOI) - 25 Jun 2024
Abstract
Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3
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Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3 receptor (H3R) antagonists and inverse agonists potentiate the endogenous release of brain histamine and have been shown to enhance cognitive abilities in animal models of several brain disorders. Microglial activation and subsequent neuroinflammation are implicated in impacting embryonic and adult neurogenesis, contributing to the development of Alzheimer’s disease (AD), Parkinson’s disease (PD), and autism spectrum disorder (ASD). Acknowledging the importance of microglia in both neuroinflammation and neurodevelopment, as well as their regulation by histamine, offers an intriguing therapeutic target for these disorders. The inhibition of brain H3Rs has been found to facilitate a shift from a proinflammatory M1 state to an anti-inflammatory M2 state, leading to a reduction in the activity of microglial cells. Also, pharmacological studies have demonstrated that H3R antagonists showed positive effects by reducing the proinflammatory biomarkers, suggesting their potential role in simultaneously modulating crucial brain neurotransmissions and signaling cascades such as the PI3K/AKT/GSK-3β pathway. In this review, we highlight the potential therapeutic role of the H3R antagonists in addressing the pathology and cognitive decline in brain disorders, e.g., AD, PD, and ASD, with an inflammatory component.
Full article
(This article belongs to the Special Issue Pharmacological Therapies for Stress-Related Disorders and Autism Spectrum Disorder)
Open AccessArticle
An In Silico Study Based on QSAR and Molecular Docking and Molecular Dynamics Simulation for the Discovery of Novel Potent Inhibitor against AChE
by
Meriem Khedraoui, Oussama Abchir, Hassan Nour, Imane Yamari, Abdelkbir Errougui, Abdelouahid Samadi and Samir Chtita
Pharmaceuticals 2024, 17(7), 830; https://doi.org/10.3390/ph17070830 (registering DOI) - 25 Jun 2024
Abstract
Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer’s disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors of AChE. We explored a 2D QSAR study using the statistical method of multiple linear regression
[...] Read more.
Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer’s disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors of AChE. We explored a 2D QSAR study using the statistical method of multiple linear regression based on a set of substituted 5-phenyl-1,3,4-oxadiazole and N-benzylpiperidine analogs, which were recently synthesized and proved their inhibitory activities against acetylcholinesterase (AChE). The molecular descriptors, polar surface area, dipole moment, and molecular weight are the key structural properties governing AChE inhibition activity. The MLR model was selected based on its statistical parameters: R2 = 0.701, R2test = 0.76, Q2CV = 0.638, and RMSE = 0.336, demonstrating its predictive reliability. Randomization tests, VIF tests, and applicability domain tests were adopted to verify the model’s robustness. As a result, 11 new molecules were designed with higher anti-Alzheimer’s activities than the model molecule. We demonstrated their improved pharmacokinetic properties through an in silico ADMET study. A molecular docking study was conducted to explore their AChE inhibition mechanisms and binding affinities in the active site. The binding scores of compounds M1, M2, and M6 were (−12.6 kcal/mol), (−13 kcal/mol), and (−12.4 kcal/mol), respectively, which are higher than the standard inhibitor Donepezil with a binding score of (−10.8 kcal/mol). Molecular dynamics simulations over 100 ns were used to validate the molecular docking results, indicating that compounds M1 and M2 remain stable in the active site, confirming their potential as promising anti-AChE inhibitors.
Full article
(This article belongs to the Special Issue Application of 2D and 3D-QSAR Models in Drug Design)
Open AccessArticle
Synthesis and Psychotropic Properties of Novel Condensed Triazines for Drug Discovery
by
Ervand G. Paronikyan, Shushanik Sh. Dashyan, Suren S. Mamyan, Ruzanna G. Paronikyan, Ivetta M. Nazaryan, Kristine V. Balyan, Hrachik V. Gasparyan, Sona A. Buloyan, Lernik S. Hunanyan and Nina G. Hobosyan
Pharmaceuticals 2024, 17(7), 829; https://doi.org/10.3390/ph17070829 (registering DOI) - 25 Jun 2024
Abstract
The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest
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The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest for new neurotropic drugs among derivatives of these heterocycles with pharmacophore groups remains a significant research challenge. The aim of this research work was to develop a synthesis method for new heterocyclic compounds, evaluate their neurotropic and neuroprotective activities, study histological changes, and perform docking analysis. Classical organic synthesis methods were used in the creation of novel heterocyclic systems containing pharmacophore rings. To evaluate the neurotropic activity of these synthesized compounds, a range of biological assays were employed. Docking analysis was conducted using various software packages and methodologies. The neuroprotective activity of compound 13 was tested in seizures with and without pentylenetetrazole (PTZ) administration. Histopathological examinations were performed in different experimental groups in the hippocampus and the entorhinal cortex. As a result of chemical reactions, 16 new, tetra- and pentacyclic heterocyclic compounds were obtained. The biologically studied compounds exhibited protection against PTZ seizures as well as some psychotropic effects. The biological assays evidenced that 13 of the 16 studied compounds showed a high anticonvulsant activity by antagonism with PTZ. The toxicity of the compounds was low. According to the results of the study of psychotropic activity, it was found that the selected compounds have a sedative effect, except compound 13, which exhibited activating behavior and antianxiety effects (especially compound 13). The studied compounds exhibited antidepressant effects, especially compound 13, which is similar to diazepam. Histopathological examination showed that compound 13 produced moderate changes in the brain and exhibited neuroprotective effects in the entorhinal cortex against PTZ-induced damage, reducing gliosis and neuronal loss. Docking studies revealed that out of 16 compounds, 3 compounds bound to the γ-aminobutyric acid type A (GABAA) receptor. Thus, the selected compounds demonstrated anticonvulsant, sedative, and activating behavior, and at the same time exhibited antianxiety and antidepressant effects. Compound 13 bound to the GABAA receptor and exhibited antianxiety, antidepressant, and neuroprotective effects in the entorhinal cortex against PTZ-induced changes.
Full article
(This article belongs to the Special Issue New Perspectives on Chemoinformatics and Drug Design)
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Scheme 1
Open AccessSystematic Review
Comparative Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity or Overweight: A Systematic Review and Network Meta-Analysis
by
Ligang Liu, Hekai Shi, Yufei Shi, Anlin Wang, Nuojin Guo, Heqing Tao and Milap C. Nahata
Pharmaceuticals 2024, 17(7), 828; https://doi.org/10.3390/ph17070828 - 24 Jun 2024
Abstract
Four glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used in children and adolescents with obesity or overweight. This network meta-analysis was conducted to compare the efficacy and safety of these regimens. Embase, PubMed, and Scopus were searched on March 2023 and updated
[...] Read more.
Four glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used in children and adolescents with obesity or overweight. This network meta-analysis was conducted to compare the efficacy and safety of these regimens. Embase, PubMed, and Scopus were searched on March 2023 and updated in June 2024 for eligible randomized controlled trials (RCTs). The primary efficacy outcomes were mean difference in actual body weight, BMI (body mass index), BMI z score, and waist circumference. Safety outcomes included nausea, vomiting, diarrhea, abdominal pain, injection-site reaction, and hypoglycemia. Eleven RCTs with 953 participants were eligible. Semaglutide exhibited greater effects in reducing weight, BMI, and BMI z score versus the placebo. Semaglutide was associated with greater weight loss and BMI z score reduction in comparison with exenatide, liraglutide, and dulaglutide. Semaglutide also significantly decreased BMI than exenatide. None of the four GLP-1 RAs were associated with higher risks of diarrhea, headache, and abdominal pain versus the placebo. Liraglutide was more likely to cause nausea, vomiting, hypoglycemia, and injection-site reactions than the placebo. Liraglutide also had higher odds of causing injection-site reactions than other GLP-1 RAs. Semaglutide appeared to be the most effective and safe option among four GLP-1 RAs in children and adolescents with obesity or overweight.
Full article
(This article belongs to the Section Pharmacology)
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Open AccessReview
Endometriosis: Molecular Pathophysiology and Recent Treatment Strategies—Comprehensive Literature Review
by
Marcin Sadłocha, Jakub Toczek, Katarzyna Major, Jakub Staniczek and Rafał Stojko
Pharmaceuticals 2024, 17(7), 827; https://doi.org/10.3390/ph17070827 - 24 Jun 2024
Abstract
Endometriosis is an enigmatic disease, with no specific cause or trigger yet discovered. Major factors that may contribute to endometriosis in the pelvic region include environmental, epigenetic, and inflammatory factors. Most experts believe that the primary mechanism behind the formation of endometrial lesions
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Endometriosis is an enigmatic disease, with no specific cause or trigger yet discovered. Major factors that may contribute to endometriosis in the pelvic region include environmental, epigenetic, and inflammatory factors. Most experts believe that the primary mechanism behind the formation of endometrial lesions is associated with Sampson’s theory of “retrograde menstruation”. This theory suggests that endometrial cells flow backward into the peritoneal cavity, leading to the development of endometrial lesions. Since this specific mechanism is also observed in healthy women, additional factors may be associated with the formation of endometrial lesions. Current treatment options primarily consist of medical or surgical therapies. To date, none of the available medical therapies have proven effective in curing the disorder, and symptoms tend to recur once medications are discontinued. Therefore, there is a need to explore and develop novel biomedical targets aimed at the cellular and molecular mechanisms responsible for endometriosis growth. This article discusses a recent molecular pathophysiology associated with the formation and progression of endometriosis. Furthermore, the article summarizes the most current medications and surgical strategies currently under investigation for the treatment of endometriosis.
Full article
(This article belongs to the Special Issue Current Therapies for Endometriosis, Adenomyosis and Endometrial Cancer)
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Open AccessArticle
Sexual Dysfunction Induced by Antidepressants—A Pharmacovigilance Study Using Data from VigiBaseTM
by
Rene Zeiss, Kathrin Malejko, Bernhard Connemann, Maximilian Gahr, Verena Durner and Heiko Graf
Pharmaceuticals 2024, 17(7), 826; https://doi.org/10.3390/ph17070826 - 24 Jun 2024
Abstract
Sexual dysfunction is a common side effect of antidepressants, significantly impacting patients’ quality of life and treatment adherence. This study investigates the relationship between sexual dysfunction and antidepressants by analyzing data from VigiBase™, the World Health Organization’s global database of individual case safety
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Sexual dysfunction is a common side effect of antidepressants, significantly impacting patients’ quality of life and treatment adherence. This study investigates the relationship between sexual dysfunction and antidepressants by analyzing data from VigiBase™, the World Health Organization’s global database of individual case safety reports. In this study, we examined, for the first time, reports related to sexual response—desire, arousal, and orgasm—by grouping appropriate side effect terms and calculated the reporting odds ratios (RORs) for various antidepressants. The findings of this study highlight a high disproportional reporting of sexual dysfunction, particularly with selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. In contrast, agents such as agomelatine, bupropion, and mirtazapine showed a lower association. Furthermore, we investigated the correlation between reporting odds ratios and the binding affinities of antidepressants to specific neurotransmitter receptors and transporters, unveiling significant relationships that provide insights into the pharmacodynamic pathways underlying these adverse effects. For instance, a positive correlation was observed between the serotonin transporter and side effects in the category desire: r (19) = 0.67, p = 0.001 These insights underscore the necessity for clinicians to consider sexual side effects when prescribing antidepressants and to monitor and address these issues to improve patient outcomes.
Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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Open AccessArticle
Interplay between Electric Field Strength and Number of Short-Duration Pulses for Efficient Gene Electrotransfer
by
Ernestas Urbanskas, Baltramiejus Jakštys, Justinas Venckus, Paulina Malakauskaitė, Ingrida Šatkauskienė, Inga Morkvėnaitė-Vilkončienė and Saulius Šatkauskas
Pharmaceuticals 2024, 17(7), 825; https://doi.org/10.3390/ph17070825 - 23 Jun 2024
Abstract
Electroporation is a method that shows great promise as a non-viral approach for delivering genes by using high-voltage electric pulses to introduce DNA into cells to induce transient gene expression. This research aimed to evaluate the interplay between electric pulse intensity and 100
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Electroporation is a method that shows great promise as a non-viral approach for delivering genes by using high-voltage electric pulses to introduce DNA into cells to induce transient gene expression. This research aimed to evaluate the interplay between electric pulse intensity and 100 µs-duration pulse numbers as an outcome of gene electrotransfer efficacy and cell viability. Our results indicated a close relationship between pulse number and electric field strength regarding gene electrotransfer efficacy; higher electric pulse intensity resulted in fewer pulses needed to achieve the same gene electrotransfer efficacy. Subsequently, an increase in pulse number had a more negative impact on overall gene electrotransfer by significantly reducing cell viability. Based on our data, the best pulse parameters to transfect CHO cells with the pMax-GFP plasmid were using 5 HV square wave pulses of 1000 V/cm and 2 HV of 1600 V/cm, correspondingly resulting in 55 and 71% of transfected cells and maintaining 79 and 54% proliferating cells. This shows ESOPE-like 100 µs-duration pulse protocols can be used simultaneously to deliver cytotoxic drugs as well as immune response regulating genetically encoded cytokines.
Full article
(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Prof. Jolanta Saczko: Pharmaceutical Science in Electrochemotherapy)
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Open AccessArticle
Prognostic Significance of Pan-Immune-Inflammation Value in Patients with HER2-Positive Metastatic Breast Cancer Treated with Trastuzumab Emtansine
by
Taha Koray Sahin, Arif Akyildiz, Osman Talha Dogan, Gozde Kavgaci, Deniz Can Guven and Sercan Aksoy
Pharmaceuticals 2024, 17(7), 824; https://doi.org/10.3390/ph17070824 - 23 Jun 2024
Abstract
Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in
[...] Read more.
Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan–Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569–0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408–3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585–3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.
Full article
(This article belongs to the Section Biopharmaceuticals)
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Open AccessArticle
IL-1β-Induced CXCL10 Expression in THP-1 Monocytic Cells Involves the JNK/c-Jun and NF-κB-Mediated Signaling
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Shihab Kochumon, Amnah Al-Sayyar, Texy Jacob, Hossein Arefanian, Fatemah Bahman, Nourah Almansour, Fawaz Alzaid, Fahd Al-Mulla, Sardar Sindhu and Rasheed Ahmad
Pharmaceuticals 2024, 17(7), 823; https://doi.org/10.3390/ph17070823 - 22 Jun 2024
Abstract
CXCL10 (IP-10) plays a key role in leukocyte homing to the inflamed tissues and its increased levels are associated with the pathophysiology of various inflammatory diseases including obesity and type 2 diabetes. IL-1β is a key proinflammatory cytokine that is found upregulated in
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CXCL10 (IP-10) plays a key role in leukocyte homing to the inflamed tissues and its increased levels are associated with the pathophysiology of various inflammatory diseases including obesity and type 2 diabetes. IL-1β is a key proinflammatory cytokine that is found upregulated in meta-inflammatory conditions and acts as a potent activator, inducing the expression of cytokines/chemokines by immune cells. However, it is unclear whether IL-1β induces the expression of CXCL10 in monocytic cells. We, therefore, determined the CXCL10 induction using IL-1β in THP1 monocytic cells and investigated the mechanisms involved. Monocytes (human monocytic THP-1 cells) were stimulated with IL-1β. CXCL10 gene expression was determined with real-time RT-PCR. CXCL10 protein was determined using ELISA. Signaling pathways were identified by using Western blotting, inhibitors, siRNA transfections, and kinase assay. Our data show that IL-1β induced the CXCL10 expression at both mRNA and protein levels in monocytic cells (p = 0.0001). Notably, only the JNK inhibitor (SP600125) significantly suppressed the IL-1β-induced CXCL10 expression, while the inhibitors of MEK1/2 (U0126), ERK1/2 (PD98059), and p38 MAPK (SB203580) had no significant effect. Furthermore, IL-1β-induced CXCL10 expression was decreased in monocytic cells deficient in JNK/c-Jun. Accordingly, inhibiting the JNK kinase activity markedly reduced the IL-1β-induced JNK/c-Jun phosphorylation in monocytic cells. NF-κB inhibition by Bay-117085 and resveratrol also suppressed the CXCL10 expression. Our findings provide preliminary evidence that IL-1β stimulation induces the expression of CXCL10 in monocytic cells which requires signaling via the JNK/c-Jun/NF-κB axis.
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(This article belongs to the Special Issue Chemokines and Chemokine Receptors)
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Open AccessArticle
Predicting Drugs Suspected of Causing Adverse Drug Reactions Using Graph Features and Attention Mechanisms
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Jinxiang Yang, Zuhai Hu, Liyuan Zhang and Bin Peng
Pharmaceuticals 2024, 17(7), 822; https://doi.org/10.3390/ph17070822 - 22 Jun 2024
Abstract
Background: Adverse drug reactions (ADRs) refer to an unintended harmful reaction that occurs after the administration of a medication for therapeutic purposes, which is unrelated to the intended pharmacological action of the drug. In the United States, ADRs account for 6% of all
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Background: Adverse drug reactions (ADRs) refer to an unintended harmful reaction that occurs after the administration of a medication for therapeutic purposes, which is unrelated to the intended pharmacological action of the drug. In the United States, ADRs account for 6% of all hospital admissions annually. The cost of ADR-related illnesses in 2016 was estimated at USD 528.4 billion. Increasing the awareness of ADRs is an effective measure to prevent them. Assessing suspected drugs in adverse events helps to enhance the awareness of ADRs. Methods: In this study, a suspect drug assisted judgment model (SDAJM) is designed to identify suspected drugs in adverse events. This framework utilizes the graph isomorphism network (GIN) and an attention mechanism to extract features based on patients’ demographic information, drug information, and ADR information. Results: By comparing it with other models, the results of various tests show that this model performs well in predicting the suspected drugs in adverse reaction events. ADR signal detection was conducted on a group of cardiovascular system drugs, and case analyses were performed on two classic drugs, Mexiletine and Captopril, as well as on two classic antithyroid drugs. The results indicate that the model can accomplish the task of predicting drug ADRs. Validation using benchmark datasets from ten drug discovery domains shows that the model is applicable to classification tasks on the Tox21 and SIDER datasets. Conclusions: This study applies deep learning methods to construct the SDAJM model for three purposes: (1) identifying drugs suspected to cause adverse drug events (ADEs), (2) predicting the ADRs of drugs, and (3) other drug discovery tasks. The results indicate that this method can offer new directions for research in the field of ADRs.
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(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions)
Open AccessArticle
Identification of South African Plant-Based Bioactive Compounds as Potential Inhibitors against the SARS-CoV-2 Receptor
by
Nqobile Monate Mkolo, Clarissa Marcelle Naidoo, Rose Kadye, Chikwelu Lawrence Obi, Benson Chucks Iweriebor, Oyinlola Oluwunmi Olaokun, Earl Prinsloo and Muhammad Sulaiman Zubair
Pharmaceuticals 2024, 17(7), 821; https://doi.org/10.3390/ph17070821 - 22 Jun 2024
Abstract
The expected progress in SARS-CoV-2 vaccinations, as anticipated in 2020 and 2021, has fallen short, exacerbating global disparities due to a lack of universally recognized “safe and effective” vaccines. This study focuses on extracts of South African medicinal plants, Artemisia annua and Artemisia
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The expected progress in SARS-CoV-2 vaccinations, as anticipated in 2020 and 2021, has fallen short, exacerbating global disparities due to a lack of universally recognized “safe and effective” vaccines. This study focuses on extracts of South African medicinal plants, Artemisia annua and Artemisia afra, to identify metabolomic bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors. The extracts were monitored for cytotoxicity using a resazurin cell viability assay and xCELLigence real-time cell analyzer. Chemical profiling was performed using UPLC-MS/MS, orthogonal projection to latent structures (OPLS), and evaluated using principle component analysis (PCA) models. Identified bioactive compounds were subjected to in vitro SARS-CoV-2 enzyme inhibition assay using standard methods and docked into the spike (S) glycoprotein of SARS-CoV-2 using Schrodinger® suite followed by molecular dynamics simulation studies. Cell viability assays revealed non-toxic effects of extracts on HEK293T cells at lower concentrations. Chemical profiling identified 81 bioactive compounds, with compounds like 6″-O-acetylglycitin, 25-hydroxyvitamin D3-26,23-lactone, and sesaminol glucoside showing promising binding affinity. Molecular dynamics simulations suggested less stable binding, but in vitro studies demonstrated the ability of these compounds to interfere with SARS-CoV-2 spike protein’s binding to the human ACE2 receptor. Sesaminol glucoside emerged as the most effective inhibitor against this interaction. This study emphasizes the importance of multiplatform metabolite profiling and chemometrics to understand plant extract composition. This finding is of immense significance in terms of unravelling metabolomics bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors and holds promise for phytotherapeutics against SARS-CoV-2.
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(This article belongs to the Section Natural Products)
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