Future Pharmacol., Volume 3, Issue 4 (December 2023) – 17 articles

Palmitoylethanolamine (PEA) is an endocannabinoid-like compound first encountered within the lipid fractions of specific foods and has intrigued researchers since the 1950s due to its therapeutic effects. This survey aims to explore the therapeutic promise held by PEA as an anti-inflammatory and immunomodulatory agent. The therapeutic impact of PEA reverberates across diverse physiological systems, such as the central nervous system, gastrointestinal tract, vascular network, and the digestive and respiratory system. Additionally, it is effective in pain management and reducing inflammation and immune responses. These attributes have fostered collaborations targeting conditions such as Alzheimer’s disease, multiple sclerosis, cerebral ischemia, neuroinflammation, general inflammation, pain, coagulopathy, steatohepatitis, and acute lung injury. PEA operates both independently and in synergy with other compounds, like paracetamol, luteolin, and oxymetazoline. This efficacy stems from its interactions with pivotal targets, including PPARα, PPAR-δ, PPAR-γ, CB1, CB2, GPR55, and TRPV1. Additionally, PEA exerts a direct influence on the inflammatory cascade, orchestrating precise adjustments in immune responses. Numerous animal studies have elucidated the inherent potential of PEA. Nevertheless, the imperative of reinforcing clinical investigation is evident. This review notably underscores the pivotal necessity for methodologically rigorous clinical trials to definitively establish the translational efficacy of PEA in ameliorating diverse inflammatory pathologies within the human milieu. Full article

Feline population control remains a concern as to whether it is intended for the short- or long-term. Induced sterilization of felids is critical in the case of feral, free-roaming cats, or the management of wild populations in Zoos or sanctuaries. This narrative review explores the shifting paradigm in induced sterilization methods, driven by the development of gene editing approaches recently applied to control felid reproductive activity. Although gene therapy approaches have gained attention as alternatives to more traditional methods, their clinical applications remain in the realm of thought. The objective of this study was to provide a comprehensive overview of the current state and most recent advances in gene-based contraception options, consolidate current research and evidence, and share some considerations on its potential effectiveness, advantages or limitations, and implications for animal welfare and population control strategies. Gene-based contraception therapy tested in felines, targeting the AMH pathway, was unable to suppress the estrous cycle and follicular development. However, at an experimental level, preliminary results hint at the need to change towards different molecular targets. Moreover, their side effects remain largely unknown, and several questions remain unanswered, such as the regularity of treatment applications or cost. Full article

Tenosynovial giant cell tumor (TGCT) is a rare and locally aggressive benign tumor arising from the synovium of joints, bursae, and tendon sheaths. It is classified into localized (L-TGCT) and diffuse (D-TGCT) forms based on the extent of involvement. Surgical resection is the primary treatment, though achieving a definitive cure remains challenging due to the high recurrence rates, especially in D-TGCT. Systemic therapies targeting the CSF1-CSF1R axis have emerged as promising treatment options. CSF1R tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, pexidartinib, and vimseltinib, alongside anti-CSF1R antibodies like emactuzumab, cabiralizumab, and lacnotuzumab, have shown encouraging results in managing TGCT, particularly when surgery is not feasible or poses significant morbidity. Other potential therapies, including local treatments and anti-inflammatory drugs, are being explored for TGCT management. This review provides an overview of systemic treatment options for D-TGCT, highlighting emerging therapeutic modalities and their potential implications. Effective management is crucial due to TGCT’s significant morbidity despite its non-life-threatening nature, necessitating novel approaches to improve patient prognosis and quality of life. Full article

As one of the leading causes of death in childhood, cancer also causes discomfort to pediatric patients. Even with guidelines for pain management, more than half of hospitalized children have intense and unrelieved pain. The present work aims to describe the intensity of pain and its pharmacological management in a pediatric oncology population. Patients aged 0 to 17 years old, diagnosed with cancer, who were admitted to a children’s oncology hospital and had well-documented data on pain management in their medical records were included. A total of 333 patients were included, mostly male (55.8%) with a mean age of 7.9 years. A substantial portion of the patient cohort (51.4%) initially reported experiencing pain of moderate intensity during the first assessment. Subsequently, following the pharmacological intervention, a significant proportion of patients (90.1%) reported complete alleviation of pain. The predominant pharmaceutical agents utilized for pain management encompassed metamizole (76.6%) and morphine (10.2%). All pharmacological interventions used were able to significantly reduce patients’ pain. This study underscores the utilization of different pharmacological classes to achieve notable reductions in pain intensity among patients grappling with severe pain. Full article

This case report was conducted by searching for the following keywords on PubMed: High Functioning Autism, Autism Spectrum Disorder, cariprazine, aripiprazole, partial agonist antipsychotic, DRD2/DRD3. High Functioning Autism (HFA) is a neurodevelopmental disorder characterized by the core symptoms of autism spectrum disorder (ASD) with average intellectual abilities, behavioral symptoms such as irritability, hyperactivity, aggressiveness and mood symptoms. HFA is not a term used in the Diagnostic and Statistical Manual of mental disorders (DSM), but it is commonly used to identify patients diagnosed with Autistic Disorder (AD) or Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) with average or above average intellectual abilities. Several factors are involved in HFA development, including environmental and genetic factors. In particular, over the last several decades, dopaminergic signaling system dysfunction has been highlighted as being responsible for behavioral patterns. Nowadays, symptoms of ASD lack a specific pharmacological treatment. The only medications approved by the Food and Drug Administration (FDA) for symptoms associated with ASD, in particular the irritability, are risperidone and aripiprazole. According to the hypothesis that dopamine receptor DRD2 and DRD3 might be involved in impulsive behavior, stereotypy, repetitive behaviors and language impairment, cariprazine could be a therapeutic option. This molecule is primarily characterized by DRD3 partial agonism and serotonin 5-HT1A partial agonism, with a lower ability to activate DRD2 than other third-generation antipsychotics, such as aripiprazole. We have reported here a case study of treatment of HFA with cariprazine. Full article

Alzheimer’s disease (AD) is a progressive, multifactorial, and unremitting neurodegenerative disease characterized by memory loss, personality changes, and cognitive impairment. It has become more prevalent in recent years. Therefore, understanding the pathophysiology of AD and developing efficient therapeutic strategies are essential. Moreover, the progression of the disease is unaffected by the pharmaceutical approaches discovered to date. Additionally, the failure of over 200 potential drug candidates in clinical trials over the past decade suggests the complexity and difficulty of both the disease and its underlying causes. Therefore, research focused on medicinal plant-based natural products in the search for novel neuroprotective therapeutic candidates for AD is essential. Indeed, several scientific investigations have demonstrated the efficacy of many medicinal plants and their principal phytochemicals in the treatment of AD. This review article covered the pathophysiological mechanisms of AD, the necessity for natural products as anti-AD treatments, and the most recent preclinical studies revealing the function of neuroprotective medicinal plants and their bioactive compounds in the effective management of AD. In addition, the review also presents clinical trial data of promising anti-AD formulations/agents of plant origin. Revealing recent findings and highlighting the clinical trial data related to the development of new treatments for AD would promote further research in this field and pave the way for the development of more effective and safe treatments for this debilitating disease. Full article

In recent decades, the roles of tacrolimus and mycophenolate mofetil (MMF) in hypertension have been under discussion. However, the question of whether there are sex-specific responses to these agents has not received enough attention. Aim: To evaluate sex-specific differences in the responses to tacrolimus and mycophenolate mofetil in female (F) and male (M) spontaneously hypertensive rats (SHRs) and evaluate whether T cells contribute to mean arterial pressure (MAP) changes. Methods: Male and female SHRs received either tacrolimus or MMF for 14 days. The rats were implanted with radiotelemeters. MAP was measured chronically; then, circulating and renal infiltrated CD4⁺, CD8⁺, T helper 17 (Th17), and T regulatory (Treg) cells were quantified using flow cytometry. Key Findings: Tacrolimus increased MAP only in males, and it decreased CD4⁺ and CD8⁺ T cells in both males and females (p < 0.05). The tacrolimus-induced reduction of renal CD4⁺ and Treg cells was more profound in males. MMF reduced MAP and circulating and renal CD4⁺ and CD8⁺ T cells in the male and female rats. MMF also decreased Th17 and Treg cells in both sexes, but the decrease in Th17 was higher in males (p < 0.05) and the reduction in Treg cells was higher in females (p < 0.05). Our findings indicate that the effects of tacrolimus and MMF on renal T cell subsets are sex-specific. Significance: Targeting T cells in hypertension using therapeutic agents may have different effects on men and women; so, the management of hypertension and post-transplant hypertension using these agents should be specified by gender. Full article

The complex life cycle of the malaria parasite Plasmodium requires the parasite to adequately adapt to different conditions. For this reason, Plasmodium strictly controls its gene expression, and given its evolutionary distance from the human host, the involved factors may figure as attractive potential drug targets. In recent years, several unique transcription factors and chromatin modifiers have been identified and partially characterized in Plasmodium falciparum and in the murine species P. yoelii and P. berghei. This review unites data from studies focusing on drug development against enigmatic plant-like AP2-transcription factors and chromatin modifiers, such as histone acetyl transferases and deacetylases and histone methyltransferases and demethylases. Considering the reported success of inhibition of both factors, these may be included as targets to effectively combat the parasite by perturbing its control of gene expression. Full article

Oral candidiasis is an opportunistic infection usually related to predisposing factors. Oral manifestations in patients affected by COVID-19 have been reported, as the oral mucosa is the gateway to this viral infection. Xerostomia, as well as other oral symptoms, are predisposing factors for the emergence of oral candidiasis after the COVID-19 pandemic. It is a common pathology, but fatal if left untreated. Nystatin (NYS) is the drug of first choice in the treatment of oral candidiasis. Herein, we reviewed the epidemiology of oral candidiasis and its treatments, focusing on the mechanism of action, dosage forms, and NYS efficacy. NYS is an effective drug against oral candidiasis and belongs to Class IV of the biopharmaceutical classification system; however, its low solubility and low permeability may compromise its availability in the oral cavity and, consequently, its pharmacological action. Future perspectives to overcome drug limitations were also addressed and discussed in our review. Full article

Methotrexate (MTX) is the cornerstone of therapy in the treatment of rheumatoid arthritis (RA). However, its efficacy and toxicity are variable and remain unpredictable. Interindividual variation in the metabolism of MTX by the enzyme folyl polyglutamate synthetase (FPGS) has been associated with response variability in RA. In this work, we propose the development of a FPGS phenotyping assay that can be evaluated as a tool for the prediction of efficacy and toxicity in patients with RA prior to initiating MTX therapy. FPGS activity was measured in erythrocyte lysate by monitoring methotrexate polyglutamate (MTX + Glu_n) formation using ultra-performance liquid chromatography tandem–mass spectrometry (UPLC/MS/MS). Erythrocyte FPGS activity was measured in newly diagnosed RA (n = 35) and osteoarthritis (n = 7) patients. The enzymatic assay was optimized for measuring FPGS activity in 25 µL of packed erythrocytes over two hours. The coefficient of variation for intra- and inter-day analysis was found to be 5% and 12%, respectively. The method was used to measure FPGS enzyme kinetics, resulting in a mean (SD) K_m of 30.3 (4.8) µM and a V_max of 612 (193) pmol MTX + Glu₂/h/mL of packed erythrocytes. Mean (SD) erythrocyte FPGS activity in patients with RA was found to be 445.93 (344.50) pmol MTX + Glu₂/h/mL and with a 26-fold difference in the range (range: 83–2179 pmol MTX + Glu₂/h/mL) whereas for patients with OA, it was found to be 409.80 (157.66) pmol MTX + Glu₂/h/mL with a 3.5-fold difference in the range (range: 200.95–683.93 pmol MTX + Glu₂/h/mL). Monitoring erythrocyte FPGS activity may be a feasible strategy of phenotyping for methotrexate efficacy and toxicity in patients with RA. Full article

Inflammasomes, a group of multiprotein complexes, are essential in regulating inflammation and immune responses. Several inflammasomes, including nucleotide-binding domain leucine-rich repeat-containing protein 1 (NLRP1), NLRP3, NLRP6, NLRP7, NLRP12, interferon-inducible protein 16 (IFI16), NOD-like receptor family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and pyrin, have been studied in various inflammatory diseases. Activating inflammasomes leads to the processing and production of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is the most extensively studied and well characterized. Consequently, targeting inflammasomes (particularly NLRP3) with several compounds, including small molecule inhibitors and natural compounds, has been studied as a potential therapeutic strategy. This review provides a comprehensive overview of different inflammasomes and their roles in six inflammatory diseases, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, atherosclerosis, type 2 diabetes, and obesity. We also discussed different strategies that target inflammasomes to develop effective therapeutics. Full article

Antibiotic resistance requires alternatives to fight multi-drug resistant strains. Antimicrobial peptides (AMPs) act by disrupting or solubilizing microbial cell walls or membranes in accordance with mechanisms difficult to counteract from the microbe’s point of view. In this review, structure–activity relationships for AMPs and their assemblies are discussed, considering not only their self-assembly but also their interactions with their carriers for optimal delivery or their combinations with other complementary antimicrobials or moieties covalently bound to their chemical structure. The effect of the formulations on AMP activity is also evaluated, revealing a myriad of possibilities. Depending on the interaction forces between the AMP, the carrier, or the elements added to the formulations, AMP activity can be reduced, enhanced, or remain unaffected. Approaches protecting AMPs against proteolysis may also reduce their activity. Full article

While it is true that pharmacotherapy has achieved desired health outcomes, significant unmet medical needs persist in the field of central nervous system (CNS) drugs, particularly for neurodegenerative diseases such as Alzheimer’s disease, as well as ocular diseases such as diabetic retinopathy and age-related macular degeneration. Drugs cannot enter the brain from the bloodstream due to the presence of the blood–brain barrier (BBB). Similarly, they cannot enter the eyes from the bloodstream due to the blood–retina barrier (BRB), which is composed of the endothelium or the epithelium. Thus, innovative drug delivery systems that can overcome these barriers based on efflux transporters, hydrophobic lipid bilayer membranes, and tight junctions should be developed using patient-friendly techniques distinct from craniotomy procedures or intravitreal injections. Brain-penetrating CNS drugs and antihistamine drugs commonly share N-containing groups. These findings suggest that certain types of cation transporters are involved in their transportation across the cell membrane. Indeed, the proton-coupled organic cation (H⁺/OC) antiporter, whose specific characteristics remain unidentified, is responsible for transporting compounds with N-containing groups, such as clonidine and pyrilamine, at the BBB, and likely at the BRB as well. Therefore, well-designed low-molecular-weight drugs containing N-containing groups as transporter recognition units can enter the brain or the eyes through carrier-mediated transport. In this perspective review, I introduce the implementation and potential of H⁺/OC antiporter-mediated transport across the endothelium at the BBB or the BRB using drugs consciously designed with N-containing groups as their substrates. Full article

Alzheimer’s disease is one of the leading causes of death globally, significantly impacting countless families and communities. In parallel, recent advancements in molecular biology and network approaches, guided by the Network Medicine perspective, offer promising outcomes for Alzheimer’s disease research and treatment. In this study, we aim to discover candidate therapies for AD through drug repurposing. We combined a protein-protein interaction (PPI) network with drug-target interactions. Experimentally validated PPI data were collected from the PICKLE meta-database, while drugs and their protein targets were sourced from the DrugBank database. Then, based on RNA-Seq data, we first assigned weights to edges to indicate co-expression, and secondly, estimated differential gene expression to select a subset of genes potentially related to the disease. Finally, small subgraphs (modules) were extracted from the graph, centered on the genes of interest. The analysis revealed that even if there is no drug targeting several genes of interest directly, an existing drug might target a neighboring node, thus indirectly affecting the aforementioned genes. Our approach offers a promising method for treating various diseases by repurposing existing drugs, thereby reducing the cost and time of experimental procedures and paving the way for more precise Network Medicine strategies. Full article

Green tea extract, rich in polyphenols like catechins, has been reported to have pharmacological benefits in patients with hyperlipidemia. The minimal membrane permeability of green tea limits its use in terms of bioavailability. To improve the permeability of green tea catechins in order to enhance theiranti-hyperlipidemia activity, a surfactant-based polymer was used to formulate a solid dispersion of green tea and convert it into commercially acceptable pellets. Green tea extract solid dispersions (GTE-SDs) were prepared withsolvent evaporation method using Soluplus^® as a carrier. The GTE-SDs were evaluated for ex vivo permeation studies and characterized using FTIR, DSC, and XRD for confirming the formation of SD. The GTE-SDs exhibiting enhanced ex vivo permeation of EGCG were converted into a pellet formulation using the extrusion spheronization technique while being optimized using a 32 full factorial design. Soluplus^® exhibited a four-fold improvement in the ex vivo permeation of EGCG from GTE-SD pellets (33.27%) as compared to GTE (10.43%) (p-value < 0.0001). In male Wistar rats, optimized GTE-SD pellets reduced the lipid blood profiles as compared to GTE (p-value < 0.0001). Thus, GTE-SD pellets can serve as an effective drug delivery platform for hyperlipidemia. Full article

Breast cancer is a complex disease for which pharmacological treatment does not guarantee success or cure. In addition, current pharmacological therapies induce unwanted side effects due to their lack of specificity or selectivity. Therefore, it is necessary to develop new therapeutic options to improve these aspects. Currently, phytochemicals with antineoplastic properties have been identified from a wide variety of plant sources, and new therapeutic options have been developed based on the conjugation of drugs with polymeric matrices, resulting in nanoparticles or hydrogels with improved properties. Some antineoplastic drugs have been conjugated with antibodies to improve their selectivity and specificity. One of the most important advances in the treatment of breast cancer has been the development of cyclin inhibitors and gene therapy. This review provides an overview of drugs derived from medicinal plants and polymeric matrices with high potential for use in the treatment of breast cancer. We also highlight the clinical evidence for the use of anti-HER2 monoclonal antibodies and cyclin inhibitors in breast cancer, as well as the advantages of using conjugated antibodies. Finally, we mention some considerations that should be taken into account in the search for new therapeutic agents from phytochemicals, polymers, antibodies, cyclin inhibitors, and gene therapy focused on the treatment of breast cancer. Full article

The screening of rare plants from the Yucatan region and the known native plants in Mexico, that have been successfully introduced worldwide, has been conducted. Based on a literature analysis and a search of English and Spanish scientific information regarding botanical, plant biochemical, and antioxidant potential in databases such as Google Scholar, Scopus, Web of Knowledge, as well as the national databases of Mexico (Flora: Yucatan Peninsula (cicy.mx) and Especies endémicas|Biodiversidad Mexicana), rare or underutilized plants from the Yucatan region with antioxidant potential have been selected. The formulas of the most studied secondary metabolites of these selected rare plants are shown. Among the selected rare plants with antioxidant potential, the families Sapidaceae and Anacardiaceae had the highest number of representatives. Additionally, representatives from the families Annonaceae, Moraceae, Malpighiaceae, Solanaceae, Ebenaceae, Asteraceae, Ranunculaceae, and Leguminosae were also presented. The current scientific data analysis of selected rare plants from the Yucatan region, Mexico, provides significant background for their further use and introduction in not only the Yucatan region of Mexico, but also worldwide. Full article