Search Results (16)

Background/Objectives: Pain—whether acute, chronic, or neuropathic—remains a leading cause of disability and reduced quality of life worldwide. Despite advances in pharmacologic options, interindividual variability in response and susceptibility to adverse effects continues to challenge clinicians. In recent years, pharmacogenetics has emerged as a promising approach to optimize analgesic selection and dosing based on patient-specific genetic profiles. This perspective examines current pharmacogenetic evidence in pain management, focusing on validated biomarkers and their clinical implications. Methods: A narrative review was conducted of recent literature addressing the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of analgesic agents. Particular focus was given to genes involved in drug metabolism and transport as well as receptor signaling, along with the clinical applications of genotype-informed prescribing. Results: Substantial evidence indicates that genetic variants significantly influence patient responses to analgesics, contributing to both inadequate pain relief and heightened sensitivity to adverse effects. The main pharmacogenetic biomarkers appear to be CYP2C9 (for NSAIDs), CYP2D6 (for opioids and tricyclic antidepressants), CYP2C19 (for tricyclic antidepressants) and HLA-B*15:02 and HLA-A*31:01 for carbamazepine. PGx-informed strategies have shown promise in improving analgesic effectiveness, reducing opioid-related complications, and supporting opioid-sparing protocols. Conclusions: Pharmacogenetic screening represents a valuable tool for personalizing pain management. Incorporating validated pharmacogenetic biomarkers into clinical practice could improve treatment outcomes and patient safety. Further research, infrastructure development, and clinician education are essential for scaling PGx implementation in pain care. Full article

Background: Antimicrobial resistance (AMR) poses significant risks to human and animal health, while the environment can contribute to its spread. National AMR surveillance programs are pivotal for assessing AMR prevalence, trends, and intervention outcomes; however, integrating advanced surveillance tools can be difficult. This pilot study, conducted by FAO ECTAD Indonesia and DGLAHS, the Indonesian Ministry of Agriculture, evaluated the costs and benefits of integrating the Nanopore MinION, Illumina MiSeq, and Sensititre system into a culture-based slaughterhouse–river surveillance system. Methods: Water samples were collected from six chicken slaughterhouses and adjacent rivers (pre- and post-treatment effluent, upstream, and downstream). Culture-based ESBL and general E. coli concentrations were estimated via the WHO Tricycle Protocol, while isolates (n = 42) were sequenced (MinION, MiSeq) and antimicrobial susceptibility testing conducted (Sensititre). Results: The Tricycle Protocol results provided estimates of effluent and river concentrations of ESBL and general E. coli identifying ESBL-to-general E. coli ratios of 13.8% and 6.2%, respectively. Compared to hybrid sequencing assemblies, MinION had a higher concordance than MiSeq for ARG identification (98%), virulence genes (96%), and locations for both (predominately plasmids). Furthermore, MinION concordance with Sensititre AST was 91%. Conclusions: Cost–benefit comparisons suggest sequencing can complement culture-based methods but is dependent on the value placed on the additional information gained. Full article

A new protocol for the synthesis of N-vinyl azoles using vinyl selenones and azoles in the presence of potassium hydroxide was developed. This reaction proceeded under mild and transition metal-free conditions through an addition/elimination cascade process. Both aromatic and aliphatic vinyl selenones and various mono-, bi- and tri-cyclic azoles can be tolerated and give terminal N-vinyl azoles in moderate to high yields. A plausible mechanism is also proposed. Full article

A practical method was developed for the convenient synthesis of isoxazole-fused tricyclic quinazoline alkaloids. This procedure accesses diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives via intramolecular cycloaddition of methyl azaarenes with tert-butyl nitrite (TBN). In this method, TBN acts as the radical initiator and the source of N–O. Moreover, this protocol forms new C–N, C–C, and C–O bonds via sequence nitration and annulation in a one-pot process with broad substrate scope and functionalization of natural products. Full article

A mild and efficient strategy for the synthesis of tricyclic 1,2,4-oxadiazolines-fused tetrahydro-isoquinolines derivatives via [3 + 2] cycloaddition reaction is reported. The reactions provided the functionalized tricyclic 1,2,4-oxadiazolines in high yields (up to 96%). This protocol is simple and easy to handle. Moreover, a gram-scale experiment further highlights the synthetic utility. The chemical structure of the product was determined by X-ray single-crystal structure analysis. A possible mechanism for this transformation is proposed to explain the reaction process. Full article

A series of novel 1,4-dihydrobenzo[1,2,4][e]triazines bearing an acetyl or ester moiety as a functional group at the C(3) atom of the 1,2,4-triazine ring were synthesized. The synthetic protocol is based on an oxidative cyclization of functionally substituted amidrazones in the presence of DBU and Pd/C. It was found that the developed approach is suitable for the preparation of 1,4-dihydrobenzo[e][1,2,4]triazines, but the corresponding Blatter radicals were isolated only in few cases. In addition, a previously unknown dihydrobenzo[e][1,2,4]triazolo[3,4-c][1,2,4]triazine tricyclic open-shell derivative was prepared. Studies of thermal behavior of the synthesized 1,4-dihydrobenzo[1,2,4][e]triazines revealed their high thermal stability (up to 240–250 °C), which enables their application potential as components of functional organic materials. Full article

Many nitrogen- and sulfur-containing heterocyclic compounds exhibit biological activity. Among these heterocycles are benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles for which two main synthetic approaches exist. Here we report a new synthetic protocol that allows the preparation of these tricyclic compounds via the oxidation of a mercaptophenyl moiety to its corresponding disulfide. Subsequent C-H bond functionalization is thought to enable an intramolecular ring closure, thus forming the desired benzo[4,5]thiazolo[2,3-c][1,2,4]triazole. This method combines a high functional group tolerance with short reaction times and good to excellent yields. Full article

Infections by Extended-Spectrum Beta-Lactamase producing Escherichia coli (ESBL-Ec) are on the increase in Ghana, but the level of environmental contamination with this organism, which may contribute to growing Antimicrobial Resistance (AMR), is unknown. Using the WHO OneHealth Tricycle Protocol, we investigated the contamination of E. coli (Ec) and ESBL-Ec in two rivers in Ghana (Odaw in Accra and Okurudu in Kasoa) that receive effluents from human and animal wastewater hotspots over a 12-month period. Concentrations of Ec, ESBL-Ec and percent ESBL-Ec/Ec were determined per 100 mL sample. Of 96 samples, 94 (98%) were positive for ESBL-Ec. concentrations per 100 mL (MCs100) of ESBL-Ec and %ESBL-Ec from both rivers were 4.2 × 10⁴ (IQR, 3.1 × 10³–2.3 × 10⁵) and 2.79 (IQR, 0.96–6.03), respectively. MCs100 were significantly lower in upstream waters: 1.8 × 10⁴ (IQR, 9.0 × 10³–3.9 × 10⁴) as compared to downstream waters: 1.9 × 10⁶ (IQR, 3.7 × 10⁵–5.4 × 10⁶). Both human and animal wastewater effluents contributed to the increased contamination downstream. This study revealed high levels of ESBL-Ec in rivers flowing through two cities in Ghana. There is a need to manage the sources of contamination as they may contribute to the acquisition and spread of ESBL-Ec in humans and animals, thereby contributing to AMR. Full article

In electroconvulsive therapy (ECT), ictal characteristics predict treatment response and can be modified by changes in seizure threshold and in the ECT technique. We aimed to study the impact of ECT procedure-related variables that interact during each session and might influence the seizure results. Two hundred and fifty sessions of bilateral ECT in forty-seven subjects were included. Seizure results were evaluated by two different scales of combined ictal EEG parameters (seizure quality index (SQI) and seizure adequacy markers sum (SAMS) scores) and postictal suppression rating. Repeated measurement regression analyses were performed to identify predictors of each session’s three outcome variables. Univariate models identified age, physical status, hyperventilation, basal oxygen saturation, days between sessions, benzodiazepines, lithium, and tricyclic antidepressants as predictors of seizure quality. Days elapsed between sessions, higher oxygen saturation and protocolized hyperventilation application were significant predictors of better seizure quality in both scales used in multivariate models. Additionally, lower ASA classification influenced SQI scores as well as benzodiazepine use and lithium daily doses were predictors of SAMS scores. Higher muscle relaxant doses and lower applied stimulus intensities significantly influenced the postictal suppression rating. The study found several modifiable procedural factors that impacted the obtained seizure characteristics; they could be adjusted to optimize ECT session results. Full article

Background: Research findings regarding the association between tricyclic antidepressant (TCA) treatment and the risk of fracture are not consistent; we aimed to assess whether people who take TCAs are at an increased fracture risk. Methods: Relevant studies published through June 2020 were identified through database searches of MEDLINE, EMBASE, Scopus, PsycINFO, ISI Web of Science, WorldCat Dissertations and Theses from each database’s inception, as well as through manual searches of relevant reference lists. Two researchers independently performed literature searches, study selection, data abstraction and study appraisal by using a standardized protocol. Frequentist and Bayesian hierarchical random-effects models were used for the analysis. The heterogeneity and publication bias were evaluated in this study. Results: Eight studies met the inclusion criteria. Overall, TCA use was associated with a significantly increased risk of fracture in both the frequentist approach (Risk Ratio (RR), 1.23; 95% CI, 1.06−1.42; p = 0.007) and the Bayesian method (RR, 1.24, 95% Credible Interval (CrI), 1.01−1.56). These results were consistent in multiple sensitivity and subgroup analyses. Significant heterogeneity was observed in the meta-analysis; however, no significant publication bias was detected. Conclusion: TCA medication may indicate an increased risk of fracture. TCA should be prescribed with caution in the clinic. Full article

The term cylindrospermopsins (CYNs) refers to a structurally related class of cyanobacterial metabolites comprised of a tricyclic guanidine group and a hydroxymethyluracil moiety. Most reports in environmental aquatic samples refer to cylindrospermopsin (CYN), and reports on other CYN alkaloids are scarce, due, in part, to a lack of versatile isolation protocols. Thus, using commercially available solid phase extraction (SPE) cartridges, we optimized an isolation protocol for the complete recovery of CYN, 7-deoxy-cylindrospermopsin (7D-CYN) and 7-deoxy-desulfo-cylindrospermopsin (7D-desulfo-CYN) from the same aliquot. The isolation protocol was adaptable depending on the nature of the sample (solid biomass, culture broth or environmental water sample) and tolerates up to 4 L of dense culture broth or 400 mg of lyophilized biomass. To quantitate the CYN alkaloids, we validated an LC-DAD-MS² method, which takes advantage of the UV absorption of the uracil group (λ 262 nm). Using electrospray ionization (ESI) in a positive ion mode, the high-resolution MS¹ data confirms the presence of the protonated alkaloids, and the MS² fragment assignment is reported as complementary proof of the molecular structure of the CYNs. We isolated three CYN alkaloids with different water solubility using the same lyophilized sample, with a purity that ranged from 95% to 99%. The biological activity of the purified CYNs, along with a synthetic degradation product of CYN (desulfo-cylindrospermopsin), was evaluated by assessing necrosis and apoptosis in vitro using flow cytometry. CYN’s lethal potency in HepG2 cells was greater than the other analogs, due to the presence of all four functional groups: guanidine, uracil, C-7 hydroxyl and the sulfate residue. Full article

Unsymmetrically N-substituted and N,N’-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[b]thieno[3,4-f][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30—human fibroblasts) and three tumor cells (U87—human primary glioblastoma, HeLa—cervix adenocarcinoma, BICR18—laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs. Full article

Major depressive disorder is a psychiatric disease having approximately a 20% lifetime prevalence in adults in the United States (U.S.), as reported by Hasin et al. in JAMA Psichiatry 2018 75, 336–346. Symptoms include low mood, anhedonia, decreased energy, alteration in appetite and weight, irritability, sleep disturbances, and cognitive deficits. Comorbidity is frequent, and patients show decreased social functioning and a high mortality rate. Environmental and genetic factors favor the development of depression, but the mechanisms by which stress negatively impacts on the brain are still not fully understood. Several recent works, mainly published during the last five years, aim at investigating the correlation between treatment with fluoxetine, a non-tricyclic antidepressant drug, and the amelioration of oxidative stress. In this work, the antioxidant activity of fluoxetine was investigated using a computational protocol based on the density functional theory approach. Particularly, the scavenging of five radicals (HO^•, HOO^•, CH₃OO^•, CH₂=CHOO^•, and CH₃O^•) was considered, focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) mechanisms. Thermodynamic as well as kinetic aspects are discussed, and, for completeness, two metabolites of fluoxetine and serotonin, whose extracellular concentration is enhanced by fluoxetine, are included in our analysis. Indeed, fluoxetine may act as a radical scavenger, and exhibits selectivity for HO^• and CH₃O^•, but is inefficient toward peroxyl radicals. In contrast, the radical scavenging efficiency of serotonin, which has been demonstrated in vitro, is significant, and this supports the idea of an indirect antioxidant efficiency of fluoxetine. Full article

Terpenes are valuable starting materials for the synthesis of molecules that are of interest to the flavor, fragrance, and pharmaceutical industries. However, most processes involve the use of mineral acids or homogeneous Lewis acid catalysts. Here, we report results obtained in the liquid-phase reaction of citronellal with anilines under heterogeneous catalysis conditions to give tricyclic compounds with interesting pharmacological activity. The terpenic aldehyde could be converted into octahydroacridines with a 92% yield through an intramolecular imino Diels–Alder reaction of the imine initially formed in the presence of an acidic clay such as Montmorillonite KSF. Selectivity to the desired product strongly depended on the acid sites distribution, with Brønsted acids favoring selectivity to octahydroacridine and formation of the cis isomer. Pure Lewis acids such as silica–alumina with a very low amount of alumina gave excellent results with electron-rich anilines like toluidine and p-anisidine. This protocol can be applied starting directly from essential oils such as kaffir lime oil, which has a high citronellal content. Full article

Readily available chiral ammonium salts derived from cinchona alkaloids have proven to be effective phase transfer catalysts in the asymmetric Michael reaction of 3-substituted isoindolinones. This protocol provides a convenient method for the construction of valuable asymmetric 3,3-disubstituted isoindolinones in high yields and moderate to good enantioselectivity. Diastereoselectivity was also investigated in the construction of contiguous tertiary and quaternary stereocenters. The use of acrolein as Michael acceptor led to an interesting tricyclic derivative, a pyrroloisoindolinone analogue, via a tandem conjugated addition/cyclization reaction. Full article