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Paddlanes are tricyclic molecules with four bridging chains that share the same two bridgehead carbon atoms. The smallest known paddlane containing only carbon atoms in the main framework has a total of 18 atoms. We utilized computational chemistry (MP2/cc‐pVTZ) to locate the smallest possible all‐carbon paddlanes that meet the criterion suggested by Hoffmann, Schleyer, and Schaefer as being "fleeting," meaning frequency calculations suggest the structures are energy minima on their respective potential energy surfaces (PES). Our results suggest that paddlane compounds with a total of 10 or fewer atoms can be considered to be non‐viable either because they are not energy minima on the PES or due to strain in the system that manifests as especially long carbon–carbon bonds. Some paddlanes with a total of 11 carbon atoms proved to be energy minima but still exhibited longer carbon–carbon bonds than normal. Finally, several paddlanes with a total of 12 carbons appear to be the least strained since carbon–carbon bond lengths remain reasonable. [ABSTRACT FROM AUTHOR]

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Objective: Management of emergency care. Background: Tricyclic antidepressant (TCA) drugs are a common cause of fatal poisoning because of their cardiotoxic and arrhythmogenic effects. Classic supportive management includes sodium bicarbonate, gastrointestinal chelating agents, and vasopressors. Recently, intravenous lipid emulsion (supported by a low evidence level) has also been used. Case Report: We report the case of a 55-year-old woman admitted to our Intensive Care Unit (ICU) with acute imipramine self-poisoning. She arrived at the emergency department 7 hours after imipramine ingestion; she had severe rhabdomyolysis upon admission, with creatine phosphokinase levels at about 52 500 IU/L (normal, <200 IU/L). She quickly developed cardiogenic shock and malign arrhythmia requiring veno-arterial extra corporeal membrane oxygenation (VA-ECMO). Continuous renal replacement therapy (CRRT) with CytoSorb® (CytoSorbents, Monmouth Junction, New York, United Sates of America) was started 19 hours after admission. We performed serial blood measurements of imipramine and its active metabolite desipramine as well as viewing the levels on the CRRT-circuit monitor. Cardiac function improved and ECMO was explanted after 4 days. She also had severe acute respiratory distress syndrome, which resolved spontaneously. The neurologic outcome was favorable despite early myoclonus. The patient regained consciousness on the fifth day. Her clinical evolution was marked by acute ischemia of the lower left limb due to the arterial ECMO cannula. Conclusions: These measurements document the efficacy of the CytoSorb® adsorber in removing a lipophilic drug from a patient's bloodstream. To our knowledge, this is the first published case of CytoSorb® extracorporeal blood purification therapy for acute TCA poisoning. [ABSTRACT FROM AUTHOR]

We report a short synthetic approach to various tricyclic systems that are present in several diquinane‐based natural products starting with a readily available exo‐dicyclopentadiene‐1‐one. To this end, we have successfully assembled a fused 5/5/7‐tricyclic enone via ring‐rearrangement metathesis as a key step. The strategy has been further extended to synthesize the 1,3‐dihydroxy and then 1‐keto‐3‐hydroxy derivatives by utilizing regio‐ and stereoselective epoxidation and ring‐rearrangement metathesis reactions as key steps. All these target compounds are found to be present in diquinane‐based natural products such as longeracinphyllins A, himalenine D and daphnipaxianine A, etc. Moreover, the newly synthesized tricyclic compounds matches the exact ring‐junction stereochemistry (5/5‐exo) of these natural products. Hence, the synthetic studies disclosed here may be useful in the synthesis of biologically significant natural products and in the drug design. The newly synthesized molecules were characterized by NMR and HRMS data. Some of these structures were confirmed by a single crystal X‐ray diffraction studies. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate and categorize the survival benefit of tricyclic antidepressants (TCAs) in lung cancer patients based on systematic computational drug repositioning data. METHODS: Data were retrospectively extracted from the medical records of non-small cell lung cancer (NSCLC) patients from the University of Cincinnati Cancer Medical Center database. Patients receiving antidepressants during their course of anti-cancer treatment were compared with those without antidepressants. Data were analyzed using Kaplan–Meier survival curves with the log-rank test, and overall survival (OS) was calculated from the date of diagnosis until last follow-up or death. RESULTS: The median OS at 2 and 5 years for patients on antidepressants was 20.3 months (54.7% and 42%) vs 44.3 months (47.6% and 43.2%), which was not significant. The median OS for patients receiving TCAs, selective serotonin reuptake inhibitors, and other antidepressants was 3.17 months, 31.33 months, and 18.50 months, respectively. CONCLUSION: We found no significant survival benefit for TCA use in combination with anti-cancer agents in NSCLC patients.

Herein, a short synthetic approach to linearly fused tricyclic enone 1 and cis‐anti‐cis type hydroxy‐triquinane 2 has been described in an efficient manner by employing tandem‐metathesis as a key step. The triquinane‐based enone 1 is prepared by a Babler–Dauben oxidation of hydroxy‐triquinane 2, which is assembled by following a three‐step sequence involving a regio‐ and stereoselective allylation, vinyl Grignard addition, and tandem‐metathesis. Our strategy relies on exo‐tricyclic ketone, which is derived from readily available exo‐dicyclopentadiene‐1‐one. The newly synthesized molecules were identified and characterized by nuclear magnetic resonance spectroscopy (NMR), and high‐resolution mass spectrometry (HRMS) data. It is worth mentioning that tricyclic enone 1 is present as a core unit of many naturally occurring polyquinanes, particularly xeromphalinone family members. Hence, our approach may be useful in the synthesis of such bioactive molecules. [ABSTRACT FROM AUTHOR]

Here, we report a new synthetic approach to a highly strained 1,3‐fused cis‐cis‐cis‐5/5/6 tricyclic system that appeared among the presilphiperfolanol analogues. The cis‐fusion of six‐membered ring to a diquinane moiety is accomplished by substrate‐controlled regio‐ and stereoselective epoxidation, and ring‐rearrangement metathesis (RRM) sequence. In this regard, both early‐, and late‐stage epoxidation and RRM reactions were studied. The target compound, cis‐cis‐cis‐5/5/6 tricyclic ketone with an α,β‐oxirane ring can serve as a key building block to produce various presilphiperfolanol analogues. The cis‐cis‐cis‐5/5/6‐tricyclic‐α,β‐epoxyketone can also act as masked enone and therefore useful for various chemical transformations in organic synthesis. The short synthetic sequence disclosed here may be useful to design various biologically important molecules. The newly reported molecules are well‐characterized by NMR, HRMS, and IR spectral data. [ABSTRACT FROM AUTHOR]

PurposeDepression strongly predicts stroke incidence, suggesting that treating depression may reduce stroke risk. Antidepressant medications, however, may increase stroke risk via direct pathways. Previous evidence on antidepressant medication and stroke incidence is mixed. We evaluated associations between antidepressant use and incident stroke.MethodsFor 2302 Adult Changes in Thought cohort participants with no stroke at study entry, we characterized antidepressant use from pharmacy records, biennial depressive symptoms with a 10-item Centers for Epidemiologic Study-Depression scale, and incident strokes from ICD codes. We used discrete-time survival models with inverse probability weighting to compare stroke risk associated with filling antidepressant prescriptions and by medication category: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, or other.ResultsOver an average 8.4-year follow-up, 441 incident strokes occurred. Filling antidepressant medications 3+ times versus 0-2 times predicted 35% increased odds of stroke (OR = 1.35; 95% CI: 0.98, 1.66). Use of TCAs was associated with stroke onset (OR per 10 fills = 1.28; CI: 1.04, 1.57), but use of selective serotonin reuptake inhibitors (OR = 0.98; CI: 0.80, 1.20) or other antidepressants (OR = 0.99; CI: 0.67, 1.45) was not.ConclusionsAlthough patients who received antidepressant medication were at higher risk of stroke, this association appeared specific to TCA prescriptions.

Herein, we describe new synthetic approaches to fused 5/5/6‐carbocyclic frameworks present in various polycyclic natural products such as presilphiperfolanols, lycopodium alkaloids, and cyclopiane diterpenes. Our work features, a strategically introduced hydroxy group at the tert‐carbon center of the tricyclic system which is present in presilphiperfolanols. In addition, one presilphiperfolanol analogue is reported to show the potential of strategies disclosed in this work. All the new compounds are characterized by high‐resolution NMR spectral data. The structures of critical compounds were confirmed by various chemical transformations and further supported by single‐crystal X‐ray diffraction data. Overall, our approach is simple and rely on readily available starting materials and involves a tandem‐metathesis sequence. The synthetic studies disclosed here are applicable to the synthesis of natural products and to design medicinally important targets. [ABSTRACT FROM AUTHOR]

BackgroundAntidepressant use is very common in the elderly, but the effects of antidepressants on cognition in the elderly are controversial with some studies suggesting harm and others protection. We aimed to investigate the association between different antidepressant use and change in cognition and risk of mild cognitive impairment (MCI) or dementia in very old women.MethodsWe examined 1,234 community-dwelling women (mean age 83.2 years) from the Study of Osteoporotic Fractures. Baseline antidepressant use was reported and verified by medication containers, and medications were coded with computerized dictionary. Cognitive status (normal, MCI, or dementia) was adjudicated by an expert clinical panel 5 years later. Change in a short-form Mini-Mental State Examination and Trails B were evaluated over 5 years.ResultsEleven per cent of the women were taking antidepressants. Users of selective serotonin reuptake inhibitors (SSRIs) had the greatest cognitive decline over 5 years, after adjustment for demographics, medical comorbidities, benzodiazepine use, and baseline cognition. Multivariable logistic regression shows that the users of SSRIs were more than twice (OR = 2.69, 95% CI = 1.64-4.41) and trazodone users more than three times (3.48, 1.12-10.81) as likely to develop MCI or dementia compared with the nonusers. Further adjustment for baseline cognition or depressive symptoms did not appreciably alter the results, and the association remained after excluding women with high depressive symptoms. The use of tricyclic antidepressants or other antidepressants was not significantly associated with cognitive outcomes.ConclusionsThe use of antidepressants, especially SSRIs and trazodone, was associated with an increased risk of cognitive impairment 5 years later among the oldest old women.

Chagas disease is caused by the etiological agent Trypanosoma cruzi that impacts negatively on society and mainly affects the poorest populations of the community. The treatment is restricted to two drugs that have been on the market since the 1960s: nifurtimox and benznidazole. However, both have a high incidence of unwanted side effects and low efficiency in the chronic phase of the disease. Therefore, in this context, the objective of this work was to synthesize chromenopyrazole derivatives and to evaluate their antiparasitic activity in vitro against the intracellular forms of T. Cruzi. Chromenopyrazoles are heterocyclic compounds having as a basic core a benzene ring fused to a pyran ring and a pyrazole ring, thus forming a tricyclic compound with a 6, 6, 5 arrangement. Reaction of 3-benzoyl-flavanone with hydrazine was expected to afford the target compounds, but for a similar synthetic route described in the literature, the proposed product was a pyrazole derivative in an open form that had not undergone the final conjugate addition step. Based on NMR and X-ray crystallography analysis, it has been demonstrated that a tricyclic chromenopyrazole is the correct structural representation for the product of this reaction. This study resulted in the synthesis of 15 novel chromenopyrazoles compounds displaying significant trypanocidal activity. The majority of the chromenepyrazoles satisfied Lipinski rules, without any violations, whilst only two compounds showed at least one violation of the rule, due to the log P being greater than 5.6. All chromenepyrazoles exhibited anti-T. cruzi activity, and improved potency was observed when comparing them to the precursor 3-benzoyl-flavanone. The introduction of an anisole moiety at the pyrazole ring and the inclusion of 3,4,5-trimethoxybenzene at the pyranone resulted in a doubling of potency and improvement in selectivity. The lead compound bearing methoxyl groups was the most active and displayed comparable anti-T. Cruzi activity to the control drug benznidazole. This result, once again, reinforces the same observations reported in the literature in which the introduction of the methoxy groups favoured either more active or more selective trypanocidal compounds. [ABSTRACT FROM AUTHOR]

Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB 1 and CB 2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB 1 and CB 2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

BackgroundIncreased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.Methods and resultsWe conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.ConclusionsAmong Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

A 32-year-old woman with anorexia nervosa experienced ventricular tachycardia while on therapeutic-dose amitriptyline despite normal blood tests, imaging, and intracardiac recordings. Electrocardiograms over several years featured the Type 1 Brugada pattern. Careful electrocardiogram monitoring should be made if using high doses of amitriptyline, especially in those with low body weight. (Level of Difficulty: Intermediate.)

Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance. [ABSTRACT FROM AUTHOR]

A recent study has found that phenothiazine, anthraquinone and related tricyclic derivatives are good potency inhibitors of the monoamine oxidase (MAO) enzymes. Based on these findings, the present study investigated the possibility that these compounds may also inhibit another oxidase enzyme, d-amino acid oxidase (DAAO). The results show that seven of the study compounds exhibit good potency inhibition of DAAO with IC50 values that range from 0.309 to 6.27 µM. These values are comparable to that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.34 µM). The most potent inhibitors are 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.309 µM), 2-chlorophenothiazine (IC50 = 0.332 µM) and quinizarin (IC50 = 0.367 µM). It may be concluded that active DAAO inhibitors may serve as novel lead compounds for the design of DAAO inhibitors, compounds that may find future application in the treatment of neuropsychiatric disorders such as schizophrenia.

BackgroundNew drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.MethodsBetween April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.Findings229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.InterpretationOur results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.FundingNeuPSIG of the International Association for the Study of Pain.

In the present study, we reported the synthesis of benzimidazole‐containing tricyclic systems and evaluated their antimicrobial efficacy against some Gram‐positive, Gram‐negative strains, and their anti‐inflammatory activity as well as a hemolytic assay in terms of percentage. The antimicrobial study of the synthesized compounds revealed that most of them showed significant activity, and compound 5b displayed excellent antimicrobial efficacy among all. Results showed that the hydroxyl group at the fourth position on the aromatic ring has a substantial role in the biological activity. Synthesized compounds showed promising minimum inhibitory concentration (μg/mL) values in the range of 1.2–12.8 μg/mL against the tested strains. The in vitro anti‐inflammatory activity of these compounds was evaluated by denaturation of bovine serum albumin method and showed the inhibition in the range of IC50 value 31.16–94.63 μg/mL. Among all the tested compounds, compound 5b has a significant IC50 value. The percentage of hemolysis of the target compounds ranged from 1.14 to 52.8 at a concentration of 100 μg/mL. Molecular docking study revealed the good binding interactions against Escherichia coli, and it is best suited with in vitro studies. Pharmacokinetic studies showed the safe profiles for the title compounds. [ABSTRACT FROM AUTHOR]

The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined methodology, the subgroup responsible for this poison reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed in person at a meeting. A second vote determined the final recommendations. Seventy-seven articles met inclusion criteria. Only case reports, case series, and one poor-quality observational study were identified yielding a very low quality of evidence for all recommendations. Data on 108 patients, including 12 fatalities, were abstracted. The workgroup concluded that TCAs are not dialyzable and made the following recommendation: ECTR is not recommended in severe TCA poisoning (1D). The workgroup considers that poisoned patients with TCAs are not likely to have a clinical benefit from extracorporeal removal and recommends it NOT to be used in TCA poisoning.

UnlabelledSmall cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.SignificanceOur work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells.

The iota energy of an n-vertex digraph D is defined by Ec (𝐷) = ∑ 􀀀1 |Im(𝑧 k)|, where z1, . . ., zn are eigenvalues of D and Im(zk) is the imaginary part of eigenvalue zk . The iota energy of an n-vertex sidigraph can be defined analogously. In this paper, we define a class Fn of n-vertex tricyclic digraphs containing five linear subdigraphs such that one of the directed cycles does not share any vertex with the other two directed cycles and the remaining two directed cycles are of same length sharing at least one vertex. We find the digraphs in Fn with minimal and maximal iota energy. We also consider a similar class of tricyclic sidigraphs and find extremal values of iota energy among the sidigraphs in this class.

Parotid gland plays the most critical role in saliva secretion in the oral cavity. Parotid gland injuries due to facial trauma can cause various complications such as formation of a fistula or sialocele. Thus, such saliva-related complications can interfere with wound healing and increase the risk of infection. Several previous studies have discussed the treatment of fistula or sialocele. Nonetheless, prevention of such complications is of utmost importance. We present a case of parotid gland injury due to trauma to the cheeks that was surgically treated, with early postoperative management involving oral administration of nortriptyline and closed drainage, without complications. [ABSTRACT FROM AUTHOR]

Promutagenic O6-alkylguanine adducts in DNA are repaired in humans by O6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic. [ABSTRACT FROM AUTHOR]

Objective: A restrictive use of tricyclic antidepressants (TCA) in patients with dementia (PwD) is recommended due to the hazard of anticholinergic side effects. We evaluated the frequency of TCA dispensing in PwD over a period of 1 year and the use of TCA before and after the incident diagnosis of dementia.Methods: This analysis was based on administrative data from a German statutory health insurance for a period of 2 years. Totally, 20,357 patients with an incident diagnosis of dementia in 2014 were included. We evaluated the dispensing of TCA in 2015. Subgroup analyses were conducted to evaluate associations between the incident diagnosis of dementia and modifications in TCA dispensing.Results: In 2015, 1,125 dementia patients (5.5%) were treated with TCA and 31% were medicated with TCA in all four quarters of 2015. Most dispensings were conducted by general practitioners (67.9%). On average, patients received 3.7 ± 2.6 dispensings per year. Amitriptyline (56.3%), doxepin (26.8%), and trimipramine (16.8%) were dispensed most often. Subgroup analyses revealed that the dispensing of TCA remained mainly unchanged following the incident diagnosis.Conclusion: A relevant number of PwD were treated with TCA. To maintain the patients’ safety, an improved implementation of guidelines for the pharmaceutical treatment of PwD in healthcare institutions might be required. Since 68% of the patients suffered from depression, future studies should further evaluate the indications for TCA.

Background Falls are a common cause of morbidity and mortality in older adults, with most being caused by identifiable risk factors. This study aimed to assess demographics and clinical characteristics of patients who had recurrent falls attending the medicine for the older person (MFTOP) outpatient department at a tertiary centre. Methods Retrospective analysis of patients seen at MFTOP OPD between January 2018 and December 2018. Data were obtained from clinical notes. Age, gender, blood pressure, cognitive tests, blood tests, diagnoses and medications that could contribute to falls were recorded. Results 100 patients were reviewed. 60% were female (60). Mean and median ages were 83. Causes of falls included; gait/balance disorders or weakness 36.0%, environment-related/'accident' 19.0%, alcohol 5.0%, dizziness/vertigo 5.0%, visual disorder 4.0%, confusion 4.0%, others 3.0%, drop attack 1.0%, unknown 5.0%. 18.4% (18/98) had orthostatic hypotension (OH), of which 44.4% (8/18) had low standing systolic BP <120 P=0.0205 compared to the non-OH group. Median HbA1c was 39 (30 - 83) for 80 patients 95% CI 39.5-43.4. 11.9% (11/92) had low serum sodium (<135) (95% CI 137.7-139.3). 29.0% (29/100) had impaired cognition of which 13.4% (4/29) were at risk of vitamin D deficiency P=0.5767. Other medical conditions potentially contributing to falls included; arthritis 16.0%, Parkinson's disease 7% and incontinence 3.0%. Medications that can contribute to falls included; antihypertensive agents 67 (66.3%), tricyclic antidepressants 19 (18.8%), antianxiety agents 15 (14.9%), opiates 12 (11.9%), hypnotics/ tranquilizers 27(26.7%) and diuretics 28 (27.7%). Conclusion There is a high prevalence of co-morbidities and polypharmacy in patients with recurrent falls. Identifying modifiable causes may reduce the risk of falls in the future. Tighter glycaemic control was observed and relaxed glucose control in high-risk older adults are recommended. [ABSTRACT FROM AUTHOR]

Objective: A restrictive use of tricyclic antidepressants (TCA) in patients with dementia (PwD) is recommended due to the hazard of anticholinergic side effects. We evaluated the frequency of TCA dispensing in PwD over a period of 1 year and the use of TCA before and after the incident diagnosis of dementia. Methods: This analysis was based on administrative data from a German statutory health insurance for a period of 2 years. Totally, 20,357 patients with an incident diagnosis of dementia in 2014 were included. We evaluated the dispensing of TCA in 2015. Subgroup analyses were conducted to evaluate associations between the incident diagnosis of dementia and modifications in TCA dispensing. Results: In 2015, 1,125 dementia patients (5.5%) were treated with TCA and 31% were medicated with TCA in all four quarters of 2015. Most dispensings were conducted by general practitioners (67.9%). On average, patients received 3.7 ± 2.6 dispensings per year. Amitriptyline (56.3%), doxepin (26.8%), and trimipramine (16.8%) were dispensed most often. Subgroup analyses revealed that the dispensing of TCA remained mainly unchanged following the incident diagnosis. Conclusion: A relevant number of PwD were treated with TCA. To maintain the patients' safety, an improved implementation of guidelines for the pharmaceutical treatment of PwD in healthcare institutions might be required. Since 68% of the patients suffered from depression, future studies should further evaluate the indications for TCA. [ABSTRACT FROM AUTHOR]

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants. [ABSTRACT FROM AUTHOR]

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp 113 in gp120, the antiviral potency of several analogues met or exceeded that of 3 , demonstrating that engaging Asp 113 is not a prerequisite for potent antiviral activity. [ABSTRACT FROM AUTHOR]

Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side‐effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti‐T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays. Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people. We describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase were carried out, and 10 compounds were found to be more active than the reference drug benznidazole. [ABSTRACT FROM AUTHOR]

The cellular delivery of cell-impermeable and water-insoluble molecules remains an ongoing challenge to overcome. Previously, we reported amphipathic cyclic peptides c[WR]4 and c[WR]5 consisting of alternate arginine and tryptophan residues as nuclear-targeting molecular transporters. These peptides contain an optimal balance of positive charge and hydrophobicity, which is required for interactions with the phospholipid bilayer to facilitate their application as a drug delivery system. To further optimize them, we synthesized and evaluated a multivalent tricyclic peptide as an efficient molecular transporter. The monomeric cyclic peptide building blocks were synthesized using Fmoc/tBu solid-phase chemistry and cyclization in the solution and conjugated with each other through an amide bond to afford the tricyclic peptide, which demonstrated modest antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli (E. coli) with a minimum inhibitory concentration (MIC) of 64–128 µg/mL. The tricyclic peptide was found to be nontoxic up to 30 µM in the breast cancer cell lines (MDA-MB-231). The presence of tricyclic peptide enhanced cellular uptakes of fluorescently-labeled phosphopeptide (F’-GpYEEI, 18-fold), anti-HIV drugs (lamivudine (F’-3TC), emtricitabine (F’-FTC), and stavudine (F’-d4T), 1.7–12-fold), and siRNA (3.3-fold) in the MDA-MB-231 cell lines.