Future Pharmacology

Obsessive slowness is described as a complex and disabling clinical syndrome that causes extreme slowness in performing tasks, with potential personal and functional impairment. It is a rare condition with a challenging differential diagnosis with obsessive-compulsive disorders, mental retardation and catatonia, and its existence as an independent syndrome is still debated by authors and not included by classification systems. Therefore, its treatment management is not well-defined and it still represents a clinical challenge for clinicians. Currently, the main proposal is a mix of antidepressant, antipsychotic, psychoeducation, psychotherapy and biological non-pharmacological interventions. Hereby, we describe a case of an 18-year-old male patient who presented debilitating slowness and severe impairment. Managing his treatment was particularly challenging for clinicians and was ultimately improved with escitalopram 30 mg/day combined with memantine 10 mg/day and amisulpride 400 mg/day. Full article

Pharmacogenetics (PGx) is an emerging field of pharmacology focusing on how gene variations affect the patient’s response to treatment. Pharmacogenetics is a promising tool to optimize the selection and dosing of medications, including urate-lowering therapies (ULTs) among patients with gout. The global prevalence of gout is rising, and it disproportionately affects specific racial groups and individuals with select socioeconomic status. Genetic and experimental findings have provided evidence that genetic polymorphisms associated with serum urate pathology are also of pharmacogenetic interest. Patients with gout present with several comorbidities, warranting the use of several acute and long-term medications that increase their pill burden and the risk of adverse drug events. Implementing PGx testing can identify individuals who are more or less likely to benefit from a given treatment, improve medication adherence, and reduce pill burden. The purpose of this non-systematic review was to evaluate the contemporary evidence for PGx use in gout management, especially treatment modalities associated with specific genetic polymorphisms that could impact medication safety and efficacy. Strong evidence suggests that individuals carrying the HLA-B*58:01 allele are at a higher risk of serious and life-threatening skin reactions when taking allopurinol. Additionally, racial disparities in the frequency of HLA-B*58:01 warrant genetic screening in high-risk populations, specifically some Asian subgroups and African Americans. Individuals that are G6PD-deficient can develop hemolytic anemia and methemoglobinemia with pegloticase and probenecid use. Patients with the less active form of the drug-metabolizing CYP2C9 are at higher risk for NSAID-related upper gastrointestinal (GI) bleeding. Emerging evidence of clinically significant drug-gene pairs among various gout therapies is growing. Genes found to modulate the response to allopurinol include AOX, ABCG2, and SLC22A12. Meanwhile, UGT1A1 appears to modulate the response to Febuxostat. While CYP2C9 may modulate the toxicity of benzbromarone, SLC22A12 and ABCB1 were found to modulate the response to both benzbromarone and probenecid. The genes CYP2D6, ABCB1, gene cluster (rs6916345 G>A), and SEPHS1 were recently reported to modulate the safety and efficacy of colchicine. Finally, HCG22 and IL1RN are linked with the response to corticosteroid and anakinra, respectively. This review examines and synthesizes the most current level of evidence for using PGx to maximize gout pharmacotherapy. Full article

Single cell of vegetative microspore from spore-bearing plant field Equisetum arvense L. has been presented as a single-cell experimental model for the screening of native compounds acting as antihistamine agents. The effects of azulene, sesquiterpene lactones austricine, gaillardine, grosshemine, inulicine, and desacetylinulicine as well as sesquiterpene alcohol ledol, on the content of histamine in germinating horsetail microspores has been investigated by the fluorescent method. It has been shown using microspectrofluorimetry that these compounds are able to regulate the germination of microspores to varying degrees, as assessed by the autofluorescence of chlorophyll, in a medium without and in the presence of 0.5–1% sodium sulfate as a salt stress factor. A fluorescent histochemical reaction to histamine with ortho-phthalic aldehyde in cells and secretory mucilage revealed the ability of the compounds studied to reduce the level of this biogenic amine depending on their structure in the following order: grosshemine > azulene > austricine > ledol. Gaillardine, inulicine, and desacetylinulicine showed weak antihistamine activity Full article

Snake venoms are a natural biological source of bioactive compounds, mainly composed of proteins and peptides with specific pathophysiological functions. The diversity of protein families found in snake venoms is reflected by the range of targets and toxicological effects observed, and consequently, a wide variety of potential pharmacological activities. In this context, in vitro biomimetic models such as spheroid and organoid systems, which are three-dimensional (3D) cell culture models, enable extensive screening and identification of substances with pharmacological potential and the determination of the mechanisms underlying their activities. In this review we summarize the main findings of 3D microenvironment cell culture as a promising model for snake venom research, from producing snake toxins on venom gland organoids to screening pharmacological active compounds on spheroids for drug development. Full article

Zolpidem is a non-benzodiazepine agonist at the benzodiazepine binding site in GABAA receptors. It is a hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. This study aimed to perform an in silico study to assess both EMA and FDA positions on the dose adjustment of Zolpidem based on sex. Both agencies based their position on clinical studies but endorsed different approaches to the need for dose adjustments between men and females. Clinical studies of Zolpidem tablets in single-and multiple-dose regimens were gathered and digitized from the literature. The collected profiles were used for model building, evaluation, and simulation. A 2-compartment model with first-order absorption, lag-time, and linear elimination best described the data. To minimize bias, the distribution of data on females and males were balanced, comprising, respectively, four and eight patients. Simulation of dose regimen comparing the efficacy and safety of 10 and 12.5 mg zolpidem tablets showed that with the 10 mg tablets there was a 69% chance of being more efficient for an individual of the population simulated, for the selected dose of regimen, while the 12.5 mg tablet there was only a 42% chance of being more efficient. Moreover, the safety target for 12.5 mg was very low, with only a 14% of chance of being a safe treatment for an individual of this population. Based on these differences, this study compared the results gathered in simulations with the rationale behind EMA and FDA positions. It is very important that all health care professionals and patients have access to the same and most up-to-date safety and efficacy information, especially in this situation where the discussion focuses on the same active substance, same formulations, same treatment indications, and same target populations. Full article

During the SARS-CoV-2 pandemic, hydroxychloroquine (HCQ), was among the first drugs to be tested due to demonstrated in vitro antiviral activity against SARS-CoV-2. Pharmacokinetic variability was expected due to the frequent comorbidities and pathophysiological modifications observed in severe COVID-19 patients hospitalized in intensive care units (ICUs). The aim of this study was to describe HCQ plasmatic concentrations in ICUs and assess variability factors. A multicentric retrospective study was carried in four ICUs in Marseille from March to April 2020. There were two dosing regimens: 400 mg after a 400 mg loading dose (DR1); and 600 mg without a loading dose (DR2). HCQ concentrations were determined every 2 or 3 days. The impacts of demo-graphic, biological, and clinical covariates were investigated. The median HCQ concentration was: 0.096 mg/L on day (D) 2, 0.129 mg/L on D3 to D5, 0.140 mg/L on D6 to D10 for DR1 versus 0.116 mg/L, 0.261 mg/L, and 0.30 mg/L, respectively, for DR2. At D2, 53.9% and 46.2% of patients with DR1 and DR2, respectively, presented HCQP concentrations <0.1µg/mL and 48.2% versus 10.7% at D3 to D5. Time post-initiation, dosing regimen, nasogastric administration, and weight showed significant association with HCQ variability. The high proportion of suboptimal HCQ concentrations can be explained by a lack of optimized dosing regimen and numerous pathophysiological changes in the COVID-19/ICU population. Full article

Bergenin (BER), a key constituent of Bergenia crassifolia (Saxifragaceae), has gained extensive attention, owing to its array of pharmacological actions, including anti-infective, anti-cancer, anti-diabetic, neuroprotective, hepatoprotective, anti-urolithiatic, anti-hyperuricemic, and anti-bradykinin properties. Despite ever-intensifying support for its therapeutic features, the poor solubility, lower oral bioavailability, shorter half-life, and more intestinal pH degradation (pH 6.8 or above) of BER have puzzled researchers. To circumvent these pharmaceutical challenges, and to improve its therapeutic efficacy, newer approaches have been adopted by research scientists. Thus, a discussion of the existing literature may provide complete information about the advances in delivery strategies for enhancing its utility. This paper summarizes up-to-date works on the design and development of novel delivery carriers of this bioactive compound, such as phospholipid complexes, extended-release core tablets, prodrugs, herbal gels, polyherbal ointments, nanoparticles, and poly (lactic acid) polymers, with the objective of harnessing its full potential. This review also provides a deep insight into its bioactivities, along with mechanisms. Additionally, the physicochemical attributes, chemistry, and pharmacokinetics of BER are discussed herein. Hence, the comprehensive information documented in this review may introduce new avenues for research advancements of BER. Full article

Patients in the intensive care unit often lose a considerable fraction of their gut microbiome due to exposure to broad-spectrum antibiotics and other reasons. Dysbiosis often results in prolonged diarrhea and increase occurrence of multi-drug resistant pathogens in the colon with clinical consequences not yet well understood. Restoring the microbiome by fecal microbial transplantation (FMT) is a plausible therapeutic possibility, so far only documented in case reports and case series using very heterogeneous methodologies. Before FMT with critically ill patients can be tested in randomized controlled trials, there is a burning need to describe a standardized operating procedure (SOP) of the whole process, respecting the specifics of the critically ill population, such as the risk of the disrupted intestinal barrier and time-critical nature of the procedure. We describe the SOP that has been developed for experimental use in critically ill patients by a multidisciplinary team of intensivists, gastroenterologists, and microbiologists based on feedback from regulatory authority (State Institute for Drug Control of the Czech Republic). The hallmarks of these SOPs are multi-donor freshly frozen transplants guaranteed for 2 months consisting of seven aliquots from seven unrelated healthy donors and administered by a rectal tube. In this paper we discuss the rationale for this SOP and the process of its development in detail and release the full proposed SOP is in the form of an online appendix. Full article

The objectives of this study were to investigate whether elicitors induce the production of taxoids in Taxus globosa by testing the hypothesis that the cells induce a greater accumulation of taxoids depending on the type and concentration of the elicitor treatment tested. Cell cultures were initiated from Taxus globosa friable calli for producing taxoids using the Gamborg medium supplemented with different initial combinations of growth regulators as follows: naphthaleneacetic acid, benzylaminopurine, picloram, and polyvinylpyrrolidone. The cell suspension cultures were then used for evaluating taxoid production through different elicitor treatments, such as methyl jasmonate, ethanol, buthionine sulphoximine, and hydrogen peroxide. The cell suspension cultures showing the best growth characteristics were found in the medium supplemented with 10.74 µM of naphthaleneacetic acid and 3.33 µM of picloram. The highest biomass for the cell cultures was obtained in the EtOH-2 treatment (0.12 ± 0.005 mg·g⁻¹ of dry weight) after 8 days, while the biomass in the control treatment at that time was 0.095 ± 0.2 mg·g⁻¹ of dry weight. The exogenous application of a combination of elicitors buthionine and hydrogen peroxide in the cell suspension cultures significantly increased the concentration of the 10-deacetylbaccatin (1662 µg·g⁻¹ of dry weight), cephalomannine (334.32 µg·g⁻¹ of dry weight), and the production of taxol (157.0 µg·g⁻¹ of dry weight). Full article

The availability of systematic drug response registries for hundreds cell lines, coupled with the comprehensive profiling of their genomes/transcriptomes enabled the development of computational methods that investigate the molecular basis of drug responsiveness. Herein, we propose an automated, multi-omics systems pharmacology method that identifies genomic markers of anti-cancer drug response. Given a cancer type and a therapeutic compound, the method builds two cell line groups on the antipodes of the drug response spectrum, based on the outer quartiles of the maximum micromolar screening concentration. The method intersects cell lines that share common features in their mutation status, gene expression levels or copy number variants, and a pool of drug response biomarkers (core genes) is built, using genes with mutually exclusive alterations in the two cell line groups. The relevance with the drug target pathways is then quantified, using the combined interaction score of the core genes and an accessory protein network having strong, physical/functional interactions. We demonstrate the applicability and effectiveness of our methodology in three use cases that end up in known drug-gene interactions. The method steps into explainable bioinformatics approaches for novel anticancer drug-gene interactions, offering high accuracy and increased interpretability of the analysis results. Availability: https://github.com/PGxAUTH/PGxGDSC. Full article

The chemical composition of the Cynophalla flexuosa hydroethanolic extract (CFHEE) was identified and its antioxidant, antifungal and antipleomorphic activities against C. albicans and C. tropicalis strains were evaluated. Phytochemical prospecting evidenced polyphenolic and triterpenoid compounds while UPLC-MS analysis revealed the presence of Isopropyl/n-propyl-GLS; Methylpropyl-GLS/butyl-GLS; Methylbutyl-GLS; Quercetin O-di-hexoside; Quercetin-pentosyl-hexoside; Rutin; Quercetin O-glucoside; Kaempferol O-rhamnosyl-hexoside; Kaempferol O-pentosyl-hexoside and Lariciresinol hexoside. The CFHEE inhibited the effect of the DPPH^● free radical, both when evaluated individually and in combination with the antifungal fluconazole. When associated with 256 μg/mL fluconazole, the extract, at concentrations from 128 μg/mL, reduced the effect of the DPPH^● free radical with values ranging from 37.7% to 95.8%. The extract’s antifungal effect was considered clinically irrelevant and its combination with the antifungal triggered an antagonistic effect against the two strains, thus indicating the popular use of bravo beans in the form of teas or infusions should not be combined with the intake of the drug Fluconazole as this may lead to a reduction of its clinical effect. The extract, however, inhibited morphological changes (pleomorphism) in Candida species, preventing the development of hyphae. The CFHEE possesses an antioxidant effect and a potential pharmacological activity for the inhibition of one of the Candida spp. virulence factors. Full article

Glycyrrhizic acid (GA) is the main active component of the licorice root, which has been known in traditional medicine since the ancient times. It is a molecule composed of a hydrophilic part, two glucuronic acid molecules, and a hydrophobic part, glycyrrhetinic acid. GA, when subjected to acid hydrolysis, releases 18β- and 18α-glycyrrhetinic acids. Glycyrrhetinic acid is most responsible for the pharmacological activities of licorice. GA has been reported to have multiple therapeutic properties: anti-viral, anti-inflammatory, antitumor, antimicrobial and hepatoprotective. Different approaches have revealed similar anti-inflammatory mechanisms of action of GA, such as the inhibition of translocation of nuclear factor-κB (NF-κB) and suppression of Tumour Necrosis Factor alpha (TNF-α) and interleukins. In this sense, several in vitro and in vivo studies have described the use of GA in the prevention and treatment of several complications, especially microbial/viral infection, and as a novel chemo-preventive agent for liver injury. Recent studies postulated that GA nanoparticles (GANPs) can be a promising strategy for the treatment of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infections. This mini-review summarizes the pharmacological activities of GA and its beneficial effects against various health problems and provides perspectives on the development of versatile nanoplatforms to overcome some limiting physicochemical properties and for enhancing the therapeutic benefits of GA. Full article

Skin and soft tissue infections (SSTIs) have increased problematically in hospital and ambulatory settings due to the poor immunity of hosts and multidrug-resistant pathogens. Mupirocin (MUP), a global topical antibiotic, is used for the treatment of SSTIs caused by various pathogens due to its unique mechanism of action. However, the therapeutic efficiency of MUP is hampered due to the protein binding and drug resistance caused by frequent use. A combined report covering the various aspects of MUP, such as the synthesis of the novel formulation, loading of the drug, and application against various skin infections, is missing. This comprehensive review focuses on various novel drug delivery strategies such as composite biomaterials/scaffold, hydrogel dressings, liposomes, liposomal hydrogel, microparticles/microspheres, microsponges, nanocapsules, nanofibers, silicone-based adhesive patches, and topical sprays. The therapeutic effect of the MUP can be synergized by combining with other agents and using novel strategies. The objective is to enhance patient compliance, decrease the resistance, magnify the delivery of MUP, and overcome the limitations of conventional formulations. Moreover, the carriers/dressing materials are biocompatible, biodegradable, stimulate wound healing, protect the wound from external environmental contamination, adsorb the wound exudates, and are permeable to oxygen and moisture. This review will help researchers to explore further the treatment of various bacterial skin infections by using MUP-loaded novel formulations with better efficacy, utilizing the novel nanostructures or combinatorial methods. Full article

Adenylate kinase 3 (AK3) is an enzyme located in the mitochondrial matrix involved in purine homeostasis. This protein has been considered a potential therapeutic target in chronic lymphocytic leukemia (CLL), because the silencing of the AK3 gene has inhibited cell growth in CLL in vitro models. This study aimed to design potential AK3 inhibitors by applying molecular modeling techniques. Through the mapping of AK3 binding sites, essential interaction fields for pharmacophore design were identified. Online libraries were virtually screened by using a pharmacophore model, and 6891 compounds exhibited the functional groups for interaction with the target. These compounds underwent molecular docking simulations through Surflex and GOLD programs. After visual inspection, we selected 13 compounds for pharmacokinetic properties toxicology prediction via admetSAR and Protox web servers. Finally, six compounds were chosen for further analysis. Full article

A new tablet system was examined for an intestinal delivery system using hydroxypropyl methylcellulose (HPMC) and shellac. HPMC was incorporated into the inside of the tablet, and shellac was coated on the surface, which was evaluated for its controlled-release property through several dissolution tests, firstly in vitro and then via two kinds of clinical studies with healthy volunteers. The clinical studies were originally designed by employing X-ray photography for the movements of the tablets in the gastrointestinal tract and an electronical device to easily analyze the absorption profile of glucose, a model compound. It was found that the dissolution of the tablet was strongly suppressed in a simulated gastric fluid (pH 1.2) and subsequently started to disintegrate in a simulated intestinal fluid (pH 6.8). The first human study with X-ray photography revealed that the model tablets could pass through the stomach without disintegrating. The controlled release of the tablets was further confirmed via analyses of the AUC, C_max, and T_max for the blood glucose concentration with other volunteers. The AUC and C_max were significantly reduced by using our system, thus concluding that the delivery system combined with the addition of HPMC and a shellac coating unequivocally leads to controlled release in the human gastrointestinal tract. Full article

Glutaminase is a critical enzyme that catalyzes the process of glutaminolysis for energy synthesis. Meanwhile, glutaminase also contributes to the pathological process of various diseases, such as cancer, neurodegenerative diseases, and inflammation. This leads to the discovery of glutaminase inhibitors for therapeutical uses. However, the mechanisms of the beneficial therapeutical effect of glutaminase inhibitors are still unclear. This pilot study aimed to determine the impact of a well-characterized glutaminase inhibitor, compound 968 (C968), on Nrf2 signaling. We performed molecular docking, luciferase assay, and quantitative PCR to determine the activation of Nrf2 and the expression of several Nrf2-related genes. These experiments found that C968 induced the Nrf2 activation and promoted the expression of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H Quinone Dehydrogenase-1 (NQO-1). All findings provide evidence that Nrf2 activation could be one of the mechanisms contributing to the therapeutical activity of C968, but more studies are warranted to further confirm this mechanism. Full article

The aim of this systematic review is to understand if kiwifruit dietary consumption can effectively improve constipation and intestinal function. PubMed, EMBASE, and Cochrane Library were systematically searched for relevant studies from inception up to September 2021. After database search, nine clinical studies were considered eligible for inclusion. Most trials were characterised by a limited number of study participants (median: 20, min: 11, max: 79) and had a cross-over design. On average, study participants ate from two to four kiwifruits a day for a period varying from three days to four weeks. Included trials almost exclusively involved young or middle-aged adults with a high female-to-male ratio, whereas direct evidence for elderly people (>65 years old) is scant. Moderate quality evidence indicated that kiwifruit dietary consumption can improve complete bowel movements per week and decrease stool consistency in both healthy subjects and patients with constipation due to irritable bowel syndrome, probably owing to the fruit fibre and water content. Kiwifruit dietary consumption can also have beneficial effects beyond intestinal motility, such as a mild anti-inflammatory and antioxidant effect on the gut barrier, due to a combined activity of all its nutrients (enzymes, vitamins, minerals). When only patients affected by constipation were considered, kiwifruit consumption was likely associated with a short-term significant increase in defecation frequency but not always with significant changes in stool consistency. These results were also supported by studies characterised by the highest methodological quality and confirmed by the meta-analysis about the effects of kiwifruit-based interventions on defecation frequency (g = 0.576; 95% CI: (0.174; 0.978); p = 0.012). Further investigations on the topic are recommended to strengthen the consistency of current evidence with larger trials. Full article

Mitochondrial transplantation (MT) is a new experimental approach that has demonstrated positive results reverting mitochondrial alterations in cardiac and kidney dysfunction mainly mediated by oxidative stress. On the other hand, cisplatin is an effective and widely used antineoplastic drug in treating several cancers; however, cisplatin has notorious side effects in different organs, such as the heart, kidneys, liver, and brain; the kidney being one of the most affected. The genitourinary system is the principal excretion pathway of cisplatin, since it is removed from the blood primarily by glomerular filtration and tubular secretion, and it may cause a sudden reduction in the renal function (acute kidney injury “AKI”), in part, by inducing mitochondrial dysfunction and the consequent oxidative stress in the tubular segment. In addition, AKI may associate with cardiac alterations, as occurs in acute cardiorenal syndrome. Due to the high prevalence of renal and cardiac side effects produced by cisplatin, here we discuss the possible use of MT as a novel therapy that could protect tissues by alleviating mitochondrial dysfunction and reducing reactive oxygen species (ROS) production. Full article