Future Pharmacol., Volume 2, Issue 2 (June 2022) – 6 articles

This work reports on a complex in silico assessment of the ADME properties of Salubrinal (S1) and 54 of its structural analogues containing a cinnamic acid residue (S2–S40) or a quinoline ring (S41–S55). In the work for (Q)SAR forecast, the online servers SwissADME, ADMETlab, admetSAR 2.0, Molinspiration, ALOGPS 2.1, pkCSM, SuperCYPsPred, and Vienna LiverTox were used. In addition, using AutoDock Vina, molecular docking studies were performed with transporter proteins and metabolic enzymes, which were intended to interact with the test compounds. In silico assessment of the ability of the S1–S55 compounds to be absorbed in the intestine was carried out using the SAR classification models implemented in these servers, as well as on the basis of two empirical rules—Lipinski’s and Veber’s. Most of the studied compounds had moderate lipophilicity (MLogP ˂ 4.15) and a polar surface area of less than 140 Ų. They complied with Lipinski’s and Veber’s rules, and are predicted to have good intestinal absorption. In silico analysis of the distribution of the S1–S55 compounds throughout the body, the volume of distribution at steady-state (V_dss), the ability to bind to blood plasma proteins and cross the blood-brain barrier (BBB) were taken into account. Most compounds are predicted to have low or medium V_dss and the ability to cross the BBB. Molecular docking studies were carried out with the structures most important for drug binding of blood plasma proteins, human serum albumin (HSA), and alpha-1-acid glycoprotein (AGP). The studies showed that these substances can effectively bind to blood plasma proteins. When assessing metabolism, the prediction of inhibitory and substrate activity to cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was carried out. For most of these enzymes, the analyzed compounds are likely to be potential inhibitors, as indicated by the molecular docking data. For all studied compounds, a low total clearance (CL_tot. ˂ 5 mL/min/kg) and a half-life time (T_1/2 ˂ 3 h) are predicted. Full article

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