Precision dosing for patients on tricyclic antidepressants.

OBJECTIVE: We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect. METHODS: The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs. RESULTS: The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect. CONCLUSION: To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion.

False-positive results for pheochromocytoma associated with norepinephrine reuptake blockade.

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.

Antidepressants as Autophagy Modulators for Cancer Therapy.

Cancer is a major global public health problem with high morbidity. Depression is known to be a high-frequency complication of cancer diseases that decreases patients' life quality and increases the mortality rate. Therefore, antidepressants are often used as a complementary treatment during cancer therapy. During recent decades, various studies have shown that the combination of antidepressants and anticancer drugs increases treatment efficiency. In recent years, further emerging evidence has suggested that the modulation of autophagy serves as one of the primary anticancer mechanisms for antidepressants to suppress tumor growth. In this review, we introduce the anticancer potential of antidepressants, including tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). In particular, we focus on their autophagy-modulating mechanisms for regulating autophagosome formation and lysosomal degradation. We also discuss the prospect of repurposing antidepressants as anticancer agents. It is promising to repurpose antidepressants for cancer therapy in the future.

NITROSOGENESIS OF SKIN CANCER: THE NITROSAMINE CONTAMINATION IN THE CALCIUM CHANNEL BLOCKERS (AMLODIPINE), BETA BLOCKERS (BISOPROLOL), SARTANS (VALSARTAN/LOSARTAN), ACE INHIBITORS (PERINDOPRIL/ENALAPRIL), TRICYCLIC ANTIDEPRESSANTS (MELITRACEN), SSRIS (PAROXETINE), SNRIS (VENLAFAXINE) AND METFORMIN: THE MOST PROBABLE EXPLANATION FOR THE RISING SKIN CANCER INCIDENCE.

The Nitrosogenesis of skin cancer is a newly introduced concept in medical science, the significance of which is yet to be the subject of detailed analyses and discussions. Contamination of the most commonly used drugs for systemic treatment worldwide (such as Angiotensin receptor II blockers/ARBs, ACE inhibitors, Beta blockers, Thiazide diuretics, Metformin, Ranitidine, Nizatidine, tricyclic antidepressants, anticoagulants/dabigatran, Rifampicin, calcium channel blockers, SSRIs/ selective serotonin reuptake inhibitors, Varenicline) is already a fact and is more than worrying but also indicative. It is "this relationship" that has been repeatedly described in the medical literature (initially) as an association, and subsequently now increasingly as a causal relationship, a pathogenetic relationship. Observational data from clinicians over the past year increasingly speak in favour of a pathogenetic link and associate every single drug declared as contaminated with the development of heterogeneous forms of skin cancer gradually and surely. New drugs are added monthly that have not yet been declared as actually/potentially contaminated but are probably known to regulatory authorities or are in the process of being clarified. In parallel, the number of nitrosamines identified as contaminants in medicines is growing. This should not be surprising to anyone: ˝You take 3 drugs contaminated with mutagens- you subsequently develop skin cancer˝. Polymorbidity and multimedication against the background of polycontamination with nitrosamines appears to be the most serious problem at present. While until recently polymorbidity was considered to be a key factor in carcinogenesis (generator, trigger, inducer), today this dogma should be re-examined or looked at from another, radically different angle: from the angle of polycontamination to multimedication within polymorbidity. It is this that could provide a good explanation for the pandemic concerning skin cancer, for example. The development of relatively identical patterns of manifestation of skin tumors after concomitant intake of drugs declared as contaminated (drugs from the classes already mentioned above/ with radically different mechanism of action) supports unequivocally the thesis that: the nitrosogenesis of skin cancer is an undeniable fact that should be studied in detail. Studied because it could be eliminated. The analysis presented within this scientific thesis concerns 4 polymorbid patients who developed skin tumors within the framework of the multimedication they were assigned. The concomitant intake of medications declared as contaminated (in the presented patients) led to the manifestation of single or multiple skin neoplasms that were successfully treated surgically. Once again, the importance of potential/actual contamination of beta blockers, ACE inhibitors, oral antidiabetic drugs, and sartans in the generation of 1) non-melanocytic forms of skin cancer, and 2) melanoma precursor lesions or so-called dysplastic moles is established and validated. The possible contamination with nitrosamines of 1) other types of tricyclic antidepressant- Melitracen; 2) antidepressant of the selective serotonin reuptake inhibitor (SSRI) class: Paroxetine; 3) antidepressant of the serotonin and noradrenaline reuptake inhibitor (SNRIs) class: Venlafaxine, as well as of the systemic anticoagulant: apixaban is highlighted for the first time in the world literature.

Acid sphingomyelinase expression is associated with survival in resectable pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC.

In-situ growth of covalent organic framework on stainless steel needles as solid-phase microextraction probe coupled with electrospray ionization mass spectrometry for rapid and sensitive determination of tricyclic antidepressants in biosamples.

Tricyclic antidepressants (TCAs) including amitriptyline (AT), doxepin (DOX) and nortriptyline (NT) are the first-line drugs for the clinical treatment of depression; however, monitoring TCA concentrations in biological fluids and tissues is necessary to improve therapeutic effect and determine the cause of death in patients. It is of great significance to develop a rapid and sensitive method for real-time monitoring of TCAs in various biosamples. In this work, we fabricated a novel covalent organic framework (COF) based solid-phase microextraction (SPME) probe by an in-situ step-by-step strategy, which was obtained by sequentially modifying 1,3,5-tri (4-aminophenyl) benzene (TPB) and 2, 5-divinylbenzaldehyde (DVA) on the surface of polydopamine layer. The TPB-DVA-COF-SPME probe possessed high specific surface area (1244 m2·g - 1), regular pores (3.23 nm), good hydrophobicity and stability, resulting in efficient enrichment for TCAs. Furthermore, the combination of TPB-DVA-COF-SPME probe and ambient electrospray ionization mass spectrometry system (ESI/MS) was firstly proposed for rapid and sensitive determination of TCAs in biosamples. As a result, the developed method exhibited low limits of detection (LODs) (0.1-0.5 µg∙L - 1), high enrichment factors (39-218), and low relative standard deviations (RSDs) for one probe (1.2-3.8%) and probe-to-probe (2.0-3.7%). Benefiting from these outstanding performance, TPB-DVA-COF-SPME probe was further successfully applied to biosamples (i.e., serum, liver, kidney, and brain) with excellent reusability, indicating the promising applicability of the TPB-DVA-COF-SPME-ESI/MS as a powerful tool for drug monitoring.

Antidepressants for the treatment of depression in people with cancer.

BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have a negative impact in terms of quality of life, compliance with anticancer treatment, suicide risk and possibly the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results. OBJECTIVES: To evaluate the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage). SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was November 2022. SELECTION CRITERIA: We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. efficacy as a continuous outcome. Our secondary outcomes were 2. efficacy as a dichotomous outcome, 3. Social adjustment, 4. health-related quality of life and 5. dropouts. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 14 studies (1364 participants), 10 of which contributed to the meta-analysis for the primary outcome. Six of these compared antidepressants and placebo, three compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update, we included four additional studies, three of which contributed data for the primary outcome. For acute-phase treatment response (six to 12 weeks), antidepressants may reduce depressive symptoms when compared with placebo, even though the evidence is very uncertain. This was true when depressive symptoms were measured as a continuous outcome (standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.92 to -0.12; 7 studies, 511 participants; very low-certainty evidence) and when measured as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; 5 studies, 662 participants; very low-certainty evidence). No studies reported data on follow-up response (more than 12 weeks). In head-to-head comparisons, we retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) and for mirtazapine versus TCAs. There was no difference between the various classes of antidepressants (continuous outcome: SSRI versus TCA: SMD -0.08, 95% CI -0.34 to 0.18; 3 studies, 237 participants; very low-certainty evidence; mirtazapine versus TCA: SMD -4.80, 95% CI -9.70 to 0.10; 1 study, 25 participants). There was a potential beneficial effect of antidepressants versus placebo for the secondary efficacy outcomes (continuous outcome, response at one to four weeks; very low-certainty evidence). There were no differences for these outcomes when comparing two different classes of antidepressants, even though the evidence was very uncertain. In terms of dropouts due to any cause, we found no difference between antidepressants compared with placebo (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low-certainty evidence), and between SSRIs and TCAs (RR 0.83, 95% CI 0.53 to 1.22; 3 studies, 237 participants). We downgraded the certainty of the evidence because of the heterogeneous quality of the studies, imprecision arising from small sample sizes and wide CIs, and inconsistency due to statistical or clinical heterogeneity. AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were few and of low quality. This review found a potential beneficial effect of antidepressants against placebo in depressed participants with cancer. However, the certainty of evidence is very low and, on the basis of these results, it is difficult to draw clear implications for practice. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which drug to prescribe may be based on the data on antidepressant efficacy in the general population of people with major depression, also taking into account that data on people with other serious medical conditions suggest a positive safety profile for the SSRIs. Furthermore, this update shows that the usage of the newly US Food and Drug Administration-approved antidepressant esketamine in its intravenous formulation might represent a potential treatment for this specific population of people, since it can be used both as an anaesthetic and an antidepressant. However, data are too inconclusive and further studies are needed. We conclude that to better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.

Ozone in Chemotherapy-Induced Peripheral Neuropathy-Current State of Art, Possibilities, and Perspectives.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most detrimental toxicity to a patient's quality of life. Pathophysiological mechanisms involved in CIPN pathogenesis are complex, multifactorial, and only partially examined. They are suspected to be associated with oxidative stress (OS), mitochondrial dysfunction, ROS-induced apoptosis, myelin sheath and DNA damage, and immunological and inflammatory processes. Unfortunately, medications commonly used for the management of other neuropathic pain syndromes, including gabapentinoids, opioids, and tricyclic antidepressants (such as desipramine and nortriptyline), do not bring satisfactory results in CIPN. The aim of this review is to evaluate the existing literature on the potential use of medical ozone as a treatment for CIPN. This paper would explore the potential therapeutic benefits of medical ozone. The review would evaluate the existing literature on the use of medical ozone in other contexts, as well as its potential application in treating CIPN. The review would also suggest possible research methods, such as randomized controlled trials, to evaluate the efficacy of medical ozone as a treatment for CIPN. Medical ozone has been used to disinfect and treat diseases for over 150 years. The effectiveness of ozone in treating infections, wounds, and a variety of diseases has been well documented. Ozone therapy is also documented to inhibit the growth of human cancer cells and has antioxidative and anti-inflammatory effects. Due to its ability to modulate oxidative stress, inflammation, and ischemia/hypoxia, ozone may have a potentially valuable effect on CIPN.

Anticancer effect of paroxetine and amitriptyline on HT29 and A549 cell lines.

INTRODUCTION: Paroxetine is functionally classified as a selective serotonin reuptake inhibitor. Paroxetine can induce mitochondria-dependent apoptosis through the ROS-MAPK pathway.Amitriptyline is a tricyclic antidepressant. This drug induces the expression of p53, thereby activating caspase-3. Amitriptyline has also been studied as a potential candidate for inducing oxidative stress and cytotoxicity in cancer cells, which may be more effective than other chemotherapy drugs. This study aims to to investigate the anticancer effects of paroxetine and amitriptyline and their combination treatment on HT29 and A549 cell lines for the first time. METHODS: In order to investigate the anticancer effect of two drugs, paroxetine and amitriptyline, on inhibiting the growth of A549 and HT29 cancer cells, oxidative stress factors and LDH enzyme and apoptosis tests were performed. RESULTS: Two drugs, amitriptyline and paroxetine alone, inhibited the growth of cancer cells in such a way that the inhibitory effect of the cells increased with the increase in the dose of the drug. In the simultaneous exposure of these two drugs, the inhibitory effect was much greater than the effect of single drug exposure. Also, these two drugs have caused LDH leakage and induction of apoptosis. CONCLUSION: According to the results of the study, it was found that these two drugs have the necessary ability to inhibit the growth of cancer cells by inducing apoptosis and LDH leakage and inducing oxidative stress.

Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition.

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.

Antidepressant Use and Risk of Myocardial Infarction: A Longitudinal Investigation of Sex-Specific Associations in the HUNT Study.

OBJECTIVE: Antidepressants are thought to affect the risk of cardiovascular disease, although the nature of the association is unclear. Men and women have unique cardiovascular risk factors, and sex differences in depression as well as the efficacy of antidepressants are important to consider. We examined whether antidepressant use was associated with risk of having a myocardial infarction (MI) and whether this association was sex-specific. METHODS: Data from The Trøndelag Health Study were used, gathered from a population in Norway ( N = 31,765), collected from 1995 to 2008. These data were combined with the Norwegian Cause of Death Registry and the Norwegian Prescription Database. We performed logistic regression models to examine the association of antidepressant use on risk of having a fatal or nonfatal MI, adjusting for depression, anxiety, diabetes, systolic blood pressure, cholesterol, waist-hip ratio, smoking, age, and sex. Results are presented as odds ratios (ORs) and 95% confidence intervals in parentheses. RESULTS: The results indicated that antidepressant use was associated with a reduced risk of having MI at a later date (OR = 0.49 [0.38-0.64]). Although this association was somewhat stronger for women (OR = 0.46 [0.31-0.68]) compared with men (OR = 0.53 [0.37-0.75]), analysis did not identify a sex-specific association of antidepressant use on MI. Follow-up analyses on different subtypes of antidepressants showed that both selective serotonin reuptake inhibitor and tricyclic antidepressant were associated with a reduced risk of MI. CONCLUSIONS: In this population study, the use of antidepressants was associated with a reduced risk of MI. This association was stronger for women, although we detected no interaction between sex and antidepressant use in terms of reduced risk of MI. Although limitations apply regarding causality, especially concerning a dose-response relationship, the results suggest that antidepressant use might reduce the risk of MI among both men and women.

Toxina botulínica no tratamento da neuralgia pós herpética: um desafio terapêutico / Botulinum toxin in the treatment of postherpetic neuralgia: a therapeutic challenge

A neuralgia pós-herpética (NPH) é a principal complicação do herpes zoster. Caracteriza-se por dor que persiste por mais de três meses após o episódio de reativação do vírus varicela zoster, com impacto importante na qualidade de vida. A terapia de primeira linha da NPH consiste nos antidepressivos tricíclicos, inibidores de recaptação de serotonina e noradrenalina, além dos anticonvulsionantes pregabalina e gabapentina. Nos casos refratários, o uso subcutâneo da toxina botulínica A (TXB-A), é uma possibilidade terapêutica. A TXB-A, além de inibir a exocitose da acetilcolina na fenda sináptica da junção neuromuscular, também diminui a liberação de outros mediadores como glutamato, substância P e peptídeo relacionado à calcitonina, responsáveis pela ativação de nociceptores. Neste estudo, foram analisados os prontuários de seis pacientes com NPH, tratados com TXB-A concomitantemente à terapia padrão, no ambulatório de Dermatologia Geral do Hospital do Servidor Público Municipal de São Paulo, com o objetivo de avaliar se houve melhora da dor, através da comparação dos valores da escala visual de dor (EVA). Palavras-chave: Neuralgia pós herpética. Toxinas Botulínicas Tipo A. Herpes zoster.

Advances in co-opting anti-depressant drugs in glioma therapy.

A study by Chryplewicz et al. demonstrated the efficacy of combining tricyclic antidepressant imipramine and anti-VEGF therapy in treating genetically engineered glioma models. Dual therapy synergistically improved vascular integrity, increased autophagy, and modulated the myeloid and lymphoid compartments in glioma.

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. METHODS: Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. CONCLUSION: This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. ADMINISTRATIVE INFORMATION: Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.

Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.

A lipid nanoparticle platform for mRNA delivery through repurposing of cationic amphiphilic drugs.

Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.

Effect of Epigallocatechin-3-gallate on Stress-Induced Depression in a Mouse Model: Role of Interleukin-1ß and Brain-Derived Neurotrophic Factor.

Epigallocatechin 3-gallate (EGCG) is a natural polyphenolic antioxidant in green tea leaves with well-known health-promoting properties. However, the influence of EGCG on a chronic animal model of depression remains to be fully investigated, and the details of the molecular and cellular changes are still unclear. Therefore, the present study aimed to investigate the antidepressant effect of EGCG in mice subjected to chronic unpredictable mild stress (CUMS). After eight consecutive weeks of CUMS, the mice were treated with EGCG (200 mg/kg b.w.) by oral gavage for two weeks. A forced swimming test (FST) was used to assess depressive symptoms. EGCG administration significantly alleviated CUMS-induced depression-like behavior in mice. EGCG also effectively decreased serum interleukin-1ß (IL-1ß) and increased the mRNA expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampal CA3 region of CUMS mice. Furthermore, electron microscopic examination of CA3 neurons in CUMS mice showed morphological features of apoptosis, loss or disruption of the myelin sheath, and degenerating synapses. These neuronal injuries were diminished with the administration of EGCG. The treatment effect of EGCG in CUMS-induced behavioral alterations was comparable with that of clomipramine hydrochloride (Anafranil), a tricyclic antidepressant drug. In conclusion, our study demonstrates that the antidepressive action of EGCG involves downregulation of serum IL-1ß, upregulation of BDNF mRNA in the hippocampus, and reduction of CA3 neuronal lesions.

Esmolol for intractable ventricular arrhythmias in major amitriptyline toxicity.

A massive tricyclic overdose of 10 g of amitriptyline resulted in cardiovascular collapse with multiple episodes of ventricular tachycardia and ventricular fibrillation despite aggressive attention to current recommended therapy of sodium bicarbonate and hypertonic saline, and correction of electrolytes. Second-line antiarrhythmic therapies failed to reduce the recurrent deterioration to malignant ventricular rhythms. Progression to extracorporeal support was avoided by the use of a titrated esmolol infusion. We discuss the physiological rationale by which esmolol may prevent tachyarrhythmia and fibrillation in severe amitriptyline toxicity.

Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study.

BACKGROUND: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database. METHODS: 6306 patients identified as having CFS during the 2000-2012 period and 6306 controls (with similar distributions of age and sex) were analyzed. RESULT: The patients with CFS were predominantly female and aged 35-64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn's disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group. CONCLUSION: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.