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Background and Objective: Cytisine serves as an affordable smoking cessation aid with acceptable safety profile. However, data comparing its efficacy and safety to standard therapies are limited. We aimed to examine efficacy and safety of cytisine compared to nortriptyline, which is the only approved smoking‐cessation medication in Thailand. Methods: A 12‐month, multicentre, randomized, double‐blinded, placebo‐controlled trial was conducted. Participants aged ≥20 years who smoked ≥10 cigarettes/day were randomly assigned to receive a 25‐day cytisine or a 12‐week nortriptyline treatment course. Brief interventions (BI) for smoking cessation were provided to all participants. The primary outcome was biochemically verified continuous abstinence rate (CAR) at 12 months. Additionally, self‐reported abstinence, verified by exhaled carbon monoxide (CO) ≤ 10 ppm, was collected at 2 weeks, 1, 3, 6 and 12 months to assess both CAR and 7‐day point prevalence abstinence rate (PAR). Results: A total of 1086 participants were recruited and randomized into cytisine (n = 540) and nortriptyline (n = 546) groups. The 12‐month CAR was 12.22% for cytisine and 9.52% for nortriptyline. The relative difference was 0.03 (95% confidence interval [CI]; −0.01 to 0.06) and the relative risk was 1.28 (95% CI; 0.91–1.81). No differences were observed in secondary outcomes between both groups. The incidence of adverse effects from cytisine appeared to be lower than that of nortriptyline. Conclusion: At 12 months, cytisine plus BI was as effective as nortriptyline plus BI for smoking cessation. The adverse events for both cytisine and nortriptyline were minimal and well‐tolerated. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions To evaluate the effectiveness of nortriptyline regimen and migraine dietary/lifestyle modifications on dizziness and stress levels in patients diagnosed with vestibular migraine (VM).A total of 35 patients diagnosed with definite VM based on the International Classification of Headache Disorders were included in this intervention study. Patients self‐selected to receive either nortriptyline regimen alone (10–40 mg daily with biweekly escalation) (group A, n = 17) or migraine dietary/lifestyle modifications alone (group B, n = 18). Main outcome measures were dizziness severity and stress level measured by the visual analog scale (VAS).At 4‐week post‐treatment, dizziness decreased from 6.0 ± 2.5 to 4.2 ± 3.4 (p = 0.069) in group A and from 8.7 ± 1.5 to 3.6 ± 3.0 (p < 0.001) in group B. VAS for stress changed from 5.5 ± 1.3 to 5.4 ± 2.9 (p = 0.93) and from 6.9 ± 3.2 to 5.0 ± 2.7 (p = 0.025) in groups A and B, respectively. The δ values of the VAS score for dizziness were 1.8 ± 3.7 and 5.1 ± 3.1 and the δ values of the VAS score for stress were 0.06 ± 2.9 and 1.9 ± 3.3 in groups A and B, respectively. Quality of life (QOL) improved in 88% patients in group A and 94% patients in group B.Nortriptyline, at a maximum dose of 40 mg, effectively alleviates patient symptoms, while a migraine diet and lifestyle modifications notably reduce vertiginous symptoms and stress levels in VM patients in 4 weeks. Both interventions are equally effective in ameliorating the QOL of patients. The ideal treatment for patients would likely need to include both medication and diet/lifestyle changes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Background: Oral mucositis as a complication of chemotherapy has posed significant challenges to the quality of life in cancer patients. Tricyclic antidepressants, including nortriptyline can control the pain caused by mucositis by inhibiting sodium channels. Since patient compliance and rapid drug effect are the goals of the proposed formulation, it was decided to prepare and evaluate a nortriptyline mouthwash according to the United States Pharmacopeia. Methods: Based on the pharmacopeia, the necessary excipients in the nortriptyline mouthwash were determined, and the amount of each was specified. After validating the UV spectrophotometric technique, drug interaction with the mouthwash container was investigated. In addition to measuring the aqueous activity, necessary microbiological tests were also performed. Results: The UV spectroscopy method validation for nortriptyline was performed at the obtained maximum absorption wavelength (238.5 nm). The findings of the investigation of the interaction of polyethylene terephthalate container with nortriptyline indicate almost no drug adsorption into the internal part of the mouthwash container over 28 days. The results of antibacterial and antifungal/antimycotic tests were within the standard range of the United States Pharmacopeia. The mouthwash's aqueous activity was also found to be 0.81, indicating an unfavorable environment for microbial growth. Conclusion: This study has shown that the prepared nortriptyline mouthwash meets microbiological resistance standards and there is no interaction between the active drug ingredient and the proposed container. Therefore, this formulation can be suggested as a promising candidate for clinical exploration.

Pain is an unfavorable feeling that is generally triggered by endogenous or exogenous harmful stimulation and has a strong emotional impact. The objective of this experimentation was to increase the cutaneous absorption of nortriptyline HCl (NOR) encapsulated in a niosome (norosomes) produced by an ultrasonic approach for the management of antinociceptive and anti-inflammatory disorders. Exploring the implications of the cholesterol:surfactant ratio on norosome compositions, the study revealed that increasing cholesterol significantly enlarged the norosome diameter from 66.84 ± 5.70 to 293.06 ± 36.54 nm (p < 0.05). More research revealed that changes in the cholesterol:surfactant ratio could influence the surface charge (19.27 ± 0.89 to 16.30 ± 0.78 mV) and entrapment efficiency (EE%) (7.90 ± 1.59 to 87.44 ± 2.11%) (p < 0.05). The amorphous nature of NOR in the niosome was shown by solid-state research. The dermal absorption study revealed that NOR was present at larger levels in dermal layers (41.79 ± 2.38%) and the receiver area (28.67 ± 1.33%) for norosome gel than for NOR-Carbopol gel. The norosomal's cell safety was 84%, and the MTT study indicated a reduction in norosome cytotoxicity. The skin irritation analysis conducted on Wistar rats showed that the niosome component used did not cause irritation to the skin. Eventually, in comparison to the control group, norosome formulation demonstrated significant antinociceptive and anti-inflammatory (246.16 ± 53.60 s) actions in the late stage formalin test, tail-flick latency (5.18 ± 0.18 s), and hot plate latency (12.57 ± 1.78 s) (p < 0.05). These findings suggest that niosomes have the potential to enhance the effectiveness of NOR as an antinociceptive and anti-inflammatory agent by improving drug delivery to the targeted site. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy of Duloxetine and Nortriptyline in alleviating the symptoms of severity, anxiety, depression and quality of life in patients with functional dyspepsia (FD). Material and method: We conducted a single-blinded 3-month trial of Duloxetine 20–30  mg daily in 20 patients and Nortriptyline 25  mg daily in 25 FD patients. The primary outcome measure was the severity of FD symptoms by Gastrointestinal symptoms rating scale. Secondary measures included Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Nepean Dyspepsia Index. the patients were measured in 3 stages. Results: 45 patients with FD with a mean age of 37.18  ±  10.62  years participated in the study. The severity of symptoms was significantly lower in the Nortriptyline group than in the Duloxetine group after three months (p =  0.031). The level of anxiety (p =  0.049), depression (p =  0.045) and quality of life (p =  0.046) improved significantly after three months in the Duloxetine group compared to Nortriptyline. Mediation analysis using linear regression revealed a significant mediator role for anxiety. This mediation analysis revealed a 21.13% reduction in anxiety in the Duloxetine group. Conclusion: While both medications demonstrated efficacy, Nortriptyline appeared to be superior in symptom reduction. Duloxetine exhibited more advantages compared to Nortriptyline in addressing anxiety and depression and enhancing the overall quality of life. Also, Duloxetine may have a noteworthy impact, contributing to a 20% reduction in FD symptoms by lowering anxiety levels. [ABSTRACT FROM AUTHOR]

Background/Aims Prokinetic agents and neuromodulators are among the treatment options for functional dyspepsia (FD), but their comparative efficacy is unclear. We aimed to compare the efficacy of mosapride controlled-release (CR) and nortriptyline in patients with FD after 4 weeks of treatment. Methods Participants with FD were randomly assigned (1:1) to receive mosapride CR (mosapride CR 15 mg and nortriptyline placebo) or nortriptyline (mosapride CR placebo and nortriptyline 10 mg) in double-placebo, double-blinded, randomized controlled, parallel clinical study. The primary endpoint was defined as the proportion of patients with overall dyspepsia improvement after 4 weeks treatment. The secondary endpoints were changes in individual symptom scores, anxiety, depression, and quality of life. Results One hundred nine participants were recruited and assessed for eligibility, and 54 in the mosapride CR group and 50 in the nortriptyline group were included in the modified intention-to-treat protocol. The rate of overall dyspepsia improvement was similar between groups (53.7% vs 54.0%, P = 0.976). There was no difference in the efficacy of mosapride CR and nortriptyline in a subgroup analysis by FD subtype (59.3% vs 52.5% in postprandial distress syndrome, P = 0.615; 44.4% vs 40.0% in epigastric pain syndrome, P = > 0.999; 50.0% vs 59.1% in overlap, P = 0.565; respectively). Both treatments significantly improved anxiety, depression, and quality of life from baseline. Conclusion Mosapride CR and nortriptyline showed similar efficacy in patients with FD regardless of the subtype. Both treatments could be equally helpful for improving quality of life and psychological well-being while also relieving dyspepsia. [ABSTRACT FROM AUTHOR]

Background: Treating diabetic peripheral neuropathy (DPN) is a challenging condition with the non-availability of effective therapies for many subjects making pharmacotherapy development vital. Combined use of Nortriptyline and pregabalin can result in complementary and enhancing effects through various mechanisms reducing the disease symptoms. However, existing literature data supporting this combination are limited. Aim: The present study was aimed at assessing the tolerability and safety of a fixed dose combination of Nortriptyline and pregabalin in managing peripheral neuropathy in diabetics. Methods: The study assessed 112 type 2 diabetics with painful diabetic neuropathy for >1 month and NRS pain intensity of >50%. All subjects received a fixed dose combination of 10mg Nortriptyline and 75mg pregabalin once daily in the morning. Efficacy was assessed with mean pain score change on 11-point NRS at 3 visits from baseline (day 1) to 3rd visit (day 28). DSIRS (Daily Sleep Interference Rating Scale) and PGIC (Patient Global Impression of Change) scale were used to assess the efficacy. Safety was assessed with a causal relationship, severity, duration, and nature of all adverse events to study the drug at each visit. Results: PGIC, DSIRS, and NRS at baseline were 4.02, 7.02, and 7.92 which reduced at 2 months and further at the 3rd visit to 1.37, 3.46, and 2.44 respectively. In 5.35% (n=6) subjects, adverse events were reported that were mild in severity and were resolved completely within 24 hours of giving the appropriate and symptomatic medications. Conclusion: The present study concludes that a fixed-dose combination of nortriptyline and pregabalin is a well-tolerated and efficacious modality for the therapeutic management of subjects with diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Tobacco smoking has been a recognized risk factor for cardiovascular diseases (CVD). Smoking is a chronic relapsing disease and pharmacotherapy is a main component of smoking cessation. Obstructive sleep apnea (OSA) and smoking both increase the risk of CVD and are associated with significant morbidity and mortality. There are few existing data examining how pharmacological treatment, such as nicotine replacement therapy (NRT), bupropion, and varenicline, affect smokers suffering with OSA and especially their cardiovascular effects. The aim of this review was to evaluate the effects of smoking cessation pharmacotherapy on OSA with a special emphasis on the cardiovascular system. Results: Only small studies have assessed the effect of NRTs on OSA. Nicotine gum administration showed an improvement in respiratory events but with no permanent results. No specific studies were found on the effect of bupropion on OSA, and a limited number evaluated varenicline's effects on sleep and specifically OSA. Varenicline administration in smokers suffering from OSA reduced the obstructive respiratory events, especially during REM. Studies on second-line medication (nortriptyline, clonidine, cytisine) are even more limited. There are still no studies evaluating the cardiovascular effects of smoking cessation medications on OSA patients. Conclusions: Sleep disturbances are common withdrawal effects during smoking cessation but could be also attributed to pharmacotherapy. Smokers should receive personalized treatment during their quitting attempts according to their individual needs and problems, including OSA. Future studies are needed in order to evaluate the efficacy and safety of smoking cessation medications in OSA patients. [ABSTRACT FROM AUTHOR]

AimTo compare the efficacy of Duloxetine and Nortriptyline in alleviating the symptoms of severity, anxiety, depression and quality of life in patients with functional dyspepsia (FD).Material and methodWe conducted a single-blinded 3-month trial of Duloxetine 20–30 mg daily in 20 patients and Nortriptyline 25 mg daily in 25 FD patients. The primary outcome measure was the severity of FD symptoms by Gastrointestinal symptoms rating scale. Secondary measures included Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Nepean Dyspepsia Index. the patients were measured in 3 stages.Results45 patients with FD with a mean age of 37.18 ± 10.62 years participated in the study. The severity of symptoms was significantly lower in the Nortriptyline group than in the Duloxetine group after three months (p = 0.031). The level of anxiety (p = 0.049), depression (p = 0.045) and quality of life (p = 0.046) improved significantly after three months in the Duloxetine group compared to Nortriptyline. Mediation analysis using linear regression revealed a significant mediator role for anxiety. This mediation analysis revealed a 21.13% reduction in anxiety in the Duloxetine group.ConclusionWhile both medications demonstrated efficacy, Nortriptyline appeared to be superior in symptom reduction. Duloxetine exhibited more advantages compared to Nortriptyline in addressing anxiety and depression and enhancing the overall quality of life. Also, Duloxetine may have a noteworthy impact, contributing to a 20% reduction in FD symptoms by lowering anxiety levels.Clinical trial registrationhttps://en.irct.ir/trial/65512.

Abstract Background Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. Methods We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3 −/− ) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3 −/− mice. Results We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. Conclusion Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. Video Abstract

Objectives/hypothesisTo examine the hearing outcomes of patients with sudden sensorineural hearing loss (SSNHL) treated with oral and intratympanic (IT) steroid only or a combination of steroid and migraine treatment. Our hypothesis was that adjuvant migraine medications may improve outcomes in SSNHL.MethodsA retrospective chart review at a tertiary otology center was conducted to identify patients with SSNHL who received oral steroid and IT dexamethasone injection(s) with or without migraine medications (a combination of nortriptyline and topiramate).ResultsA total of 47 patients received oral steroid and IT dexamethasone injection(s) only, and 46 patients received oral steroid and IT dexamethasone injection(s) as well as migraine lifestyle changes plus a combination of nortriptyline and topiramate. There were no significant differences in demographics and baseline audiometric data between the two groups. Both groups demonstrated improvements in pure tone average (PTA) and hearing thresholds at 250 Hz and 8000 Hz posttreatment. However, compared to steroid-only group, the adjuvant migraine medications group had significantly greater improvements in hearing thresholds at the lower frequencies (250 Hz, 500 Hz, 1000 Hz). Patients in the latter cohort also had greater improvement in PTA (P = .01) and received fewer IT injections (P = .04) PTA improvement of ≥ 10 dB was observed in 36 patients (78%) in the adjuvant migraine medications group and 22 patients (46%) in the control group (P < .001).ConclusionIn multimodal treatment of SSNHL, supplementing oral and IT steroid with migraine medications may result in greater improvements in lower frequency hearing thresholds and PTA. Furthermore, adjuvant migraine treatment can lead to decrease in number of IT injections, thus reducing procedure-related risks and complications.Level of evidence3 Laryngoscope, 131:E283-E288, 2021.

In the liquid state, UV-visible and fluorescence spectroscopy was used to examine the inclusion complexes of nortriptyline (NP) and β-cyclodextrin (β-CD). The degree of inclusion complexation causes NP's absorbance and fluorescence intensity to be significantly increased during interaction with β-CD. The binding constant was determined by UV-VIS and fluorescence spectroscopy, and the results indicated a 1:1 stoichiometry for the inclusion complex at 303 K. Complexation is a spontaneous and exothermic process, as determined by Gibbs's free energy change. To produce solid inclusion complexes (ICs), mixing and co-precipitation were used, which were then characterized using Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), X-ray powder diffraction (XRD), and thermogravimetric analysis/differential scanning calorimetry (TGA/DSC). According to molecular docking studies, the aromatic ring of the NP does not penetrate the secondary hydroxyl rim of the β-CD cavity, but the aliphatic part of the NP trapped in the cavity is more thermodynamically advantageous. NP and NP: β-CD-ICs were screened for in vitro cytotoxicity on Michigan Cancer Foundation-7 (MCF-7) cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and the results showed that the cytotoxicity was not affected by creating an ICs. [ABSTRACT FROM AUTHOR]

ObjectivesTo evaluate the efficacy of a multi-modal migraine prophylaxis therapy for patients with hyperacusis.MethodsIn a prospective cohort, patients with hyperacusis were treated with a multi-modal step-wise migraine prophylactic regimen (nortriptyline, verapamil, topiramate, or a combination thereof) as well as lifestyle and dietary modifications. Pre- and post-treatment average loudness discomfort level (LDL), hyperacusis discomfort level measured by a visual analogue scale (VAS), and scores on the modified Khalfa questionnaire for severity of hyperacusis were compared.ResultsTwenty-two of the 25 patients (88%) reported subjective resolution of their symptoms following treatment. Post-treatment audiograms showed significant improvement in average LDL from 81.3 ± 3.2 dB to 86.4 ± 2.6 dB (P < .001), indicating increased sound tolerability. The VAS discomfort level also showed significant improvement from a pre-treatment average of 7.7 ± 1.1 to 3.7 ± 1.6 post-treatment (P < .001). There was also significant improvement in the average total score on modified Khalfa questionnaire (32.2 ± 3.6 vs 22.0 ± 5.7, P < .001).ConclusionsThe majority of patients with hyperacusis demonstrated symptomatic improvement from migraine prophylaxis therapy, as indicated by self-reported and audiometric measures. Our findings indicate that, for some patients, hyperacusis may share a pathophysiologic basis with migraine disorder and may be successfully managed with multimodal migraine prophylaxis therapy.

Abstract Background Depressive symptoms are common in patients with Parkinson’s disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson’s disease. Methods This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson’s disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson’s disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. Discussion This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson’s disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. Trial registration ClinicalTrials.gov Identifier: NCT03652870 Date of registration – 29th August 2018

Background: Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. Methods: We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3−/−) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3−/− mice. Results: We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. Conclusion: Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. DBhggTBWtuReWsEtfqqAGm Video Abstract [ABSTRACT FROM AUTHOR]

Anticholinerge bijwerkingen van geneesmiddelen kunnen met name voor ouderen schadelijk zijn. Er wordt daarom aangeraden het gebruik van geneesmiddelen met anticholinerge bijwerkingen bij ouderen te beperken. In verscheidene richtlijnen wordt aangeraden om amitriptyline bij ouderen te vervangen door nortriptyline, omdat de anticholinerge werking van nortriptyline minder sterk zou zijn. In hoeverre wordt deze keuze door wetenschappelijk onderzoek onderbouwd? Geeft nortriptyline inderdaad minder anticholinerge bijwerkingen dan amitriptyline en is het verschil in het anticholinerge effect te kwantificeren? [ABSTRACT FROM AUTHOR]

Abstract Background Testicular torsion is a pathological condition which needs emergency surgical intervention. However, after surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. The study was planned to evaluate the efficacy of simultaneous use of Cyclosporine A (CsA) and Nortriptyline (Nort) to repair testicular damages in an experimental torsion/detorsion (T/D) rat model. Methods Male rats (n = 112) were allocated into 7 groups 16 each in; (Group 1); Control group, (Group 2); T/D group, (Group 3–4); CsA 1 and 5 mg/kg, (Group 5–6); Nort 2 and 10 mg/kg and (Group 7); concurrent group, CsA (1 mg/kg) + Nort (2 mg/kg). Right uni-lateral torsion was inducted by twisting testis 720 degrees in the clockwise direction for 1 h. For short-term and mid-term studies, lipid peroxidation, antioxidant enzyme activities, caspase-3 level, histopathological changes and germ cell apoptosis were evaluated. Moreover, in long-term investigation, semen analysis was performed. Results After T/D induction, testis abnormalities both functional and structural were appeared. Pre- and post-treatment with CsA and Nort, separately, reduced MDA and caspase-3 levels, normalized antioxidant levels, ameliorate tissue injury and improved sperm criteria. Conclusion The antioxidant and anti-apoptotic characteristics of CsA and Nort and their protective effects have been shown in our study. Concurrent administration of CsA and Nort in selected low-dose indicated a significant positive effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress in short-term, apoptosis, and histologic changes in mid-term, as well as semen criteria in the long-term appraisal.

Objective:To evaluate the change in quality of life (QOL) of patients with Meniere's disease (MD) after treatment with migraine prophylaxis therapy.Methods:Patients with definite MD were given the Meniere's Disease Outcomes Questionnaire-Retrospective (MDOQ-R) after migraine prophylactic therapy to assess QOL. Changes in physical, emotional, and social parameters affected by MD were calculated, along with a global pre- and posttreatment QOL scores.Results:The MDOQ-R was given to 27 consecutive patients with definite MD. Patients who had at least an 18-month follow-up were included, resulting in 25 questionnaires. The mean change in QOL score was 25 ± 16 (range, -3 to 55), P = .02. Quality of life was improved in 23 (92%) of the respondents in every metric measured, unchanged in 1 (4%), and poorer in 1 (4%) of patients after migraine prophylaxis treatment.Conclusions:Majority of MD patients who had all failed diuretic therapy responded positively to medications used for migraine prophylaxis, as indicated by a significant improvement in QOL. This study may further suggest a correlation between the pathophysiologic basis of disease in MD and vestibular migraine. Patients with MD may be successfully managed with medications intended to treat migraine.

Introduction: Smoking is associated with a higher risk of mortality, especially in smokers with cardiovascular and respiratory diseases. Smoking cessation remains the most effective approach in reducing smoking-related illness risks at all ages. For elderly smokers, smoking cessation has been proved to prolong life expectancy and reduce the risk of stroke and ischemic heart disease. However, a wide selection of smoking cessation medications makes prescribing challenging, especially among elderly smokers. Inability to recommend the best treatment may reduce the smoking cessation success rate in the elderly. Therefore, this study compares the effectiveness of pharmacotherapy available and correlate the effect of ageing on the effectiveness, leading to the recommendation of the best medication for elderly smokers. Method: A systematic searching strategy was performed in three different databases by using predetermined search strings. Results: Overall, this systematic review revealed that varenicline showed the greatest smoking cessation rate among the elderly, followed by bupropion and NRT. Conclusion: It is suggested that varenicline offered the best medical aid for smoking cessation in the elderly. [ABSTRACT FROM AUTHOR]

Aim: In the current clinical trial study, the potency of mirtazapine and nortriptyline was compared in patients with Functional Dyspepsia (FD) who had anxiety or depression. Background: FD usually accompanies other psychosocial disorders. According to previous studies, among these disorders, anxiety and depression have the most correlation. Methods: This randomized clinical trial was organized in Taleghani hospital (Tehran, Iran). In two parallel groups, 42 patients were treated for 12 weeks, with 22 patients receiving 7.5 mg of mirtazapine and 20 patients receiving 25 mg of nortriptyline per day. To gain robust results, the patients with a positive history of antidepressant therapy, organic diseases, alcohol abuse, pregnancy, and major psychiatric disorders were excluded from the study. The subjects were examined by three questionnaires, including Nepean and Hamilton questionnaires. The patients were asked to answer the questions three times during the study: once before the onset of the treatment, second during the treatment, and third at the end of the treatment. Results: Based on Gastrointestinal (GI) manifestations, mirtazapine, in comparison to nortriptyline could significantly suppress the signs and symptoms of FD, including epigastric pains (P=0.02), belching (P=0.004), and bloating (P=0.01). Although the results from the use of mirtazapine compared to the use of nortriptyline (P=0.002) showed a lower mean depression score on the Hamilton questionnaire, no significant differences were found between the effects of these drugs on the anxiety scale of patients (P=0.091). Conclusion: Mirtazapine is more effective for GI symptoms related to gastric emptying. Considering the level of anxiety, mirtazapine, compared to nortriptyline, revealed better outcomes in FD patients suffering from depression. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms are common in patients with Parkinson's disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson's disease. Methods: This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson's disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson's disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. Discussion: This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson's disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. Trial registration: ClinicalTrials.gov Identifier: NCT03652870 Date of registration – 29th August 2018 [ABSTRACT FROM AUTHOR]

In the present study, the effect of nortriptyline (1 and 10 μM), budesonide (10 nM) and their combination on the migration of peripheral blood lymphocytes and monocytes from patients with chronic obstructive pulmonary disease (COPD) towards chemokines CCL5 and CXCL10 was evaluated by flow cytometry. Nortriptyline (10 μM), both alone and in combination with budesonide, inhibited the migration of T helper cells, cytotoxic T lymphocytes, NK cells and B lymphocytes towards CCL5 and CXCL10, as well as enhanced monocyte migration towards these chemokines. The combination of nortriptyline (1 μM) and budesonide suppressed the chemotaxis of lymphocyte subpopulations towards CXCL10, but not towards CCL5, more effectively than budesonide alone. The combination of nortriptyline (10 μM) and budesonide inhibited the migration of lymphocyte subpopulations towards CCL5 and CXCL10 and activated monocyte chemotaxis towards both chemokines more effectively than budesonide alone. The results of this study demonstrate the ability of nortriptyline alone to modulate the migration of peripheral blood lymphocytes and monocytes from patients with COPD and to potentiate the effects of budesonide. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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). Peripheral 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. [ABSTRACT FROM AUTHOR]

Background: Little is known whether cholesterol levels affect depression treatment outcomes. We aimed to study the association between baseline and changes in blood cholesterol levels with drug-specific antidepressant response and long-term prognosis in patients with major depressive disorder (MDD). Methods: From the Danish site of the GENDEP trial, we included patients with MDD randomized to escitalopram or nortriptyline treatment. Total and free cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and depression severity using the Montgomery-Åsberg Depression rating scale (MADRS) were measured at baseline and after 26 weeks of treatment initiation. By linkage with nationwide registers, we analyzed psychiatric and cardiometabolic hospital contacts during the five years after the trial. We assessed the association of cholesterol levels with a) depression severity using linear and mixed effects regression analyses; and b) the register-based outcomes using Cox regression analyses. Results: Among 78 patients (mean age 38 years, 74% women, mean MADRS score 28 [SD=4.5]), baseline cholesterol levels were not correlated with antidepressant response. Among 58 patients with measurements at week 0 and 26, cholesterol levels significantly increased in both treatment groups. Only in patients using escitalopram did the increase in total and free cholesterol and LDL correlate with improved antidepressant response. Baseline or changes in cholesterol were not associated with 5-year outcomes. Limitations: Secondary analyses on a rather small sample. Conclusion: This study provides clinical insight into potential drug-specific associations between increases in cholesterol levels and antidepressant response to escitalopram but not nortriptyline.

ObjectiveTo describe persistent post-stapedotomy vertigo (PSV) and its treatment using migraine prophylaxis.PatientsA retrospective review of all patients with persistent PSV spanning 10 years at a tertiary academic hospital was performed. Patients who experienced persistent vertigo for a minimum of 3 months after surgery were included. Those with possible perilymph fistula, long prosthesis, and benign paroxysmal positional vertigo were excluded.InterventionsAll patients received instructions on migraine dietary and lifestyle changes and Vitamin B2 and magnesium. In addition, prophylactic treatment with nortriptyline, verapamil, or a combination thereof was started.Main outcome measureChanges in vertigo frequency was the main outcome variable. The secondary outcome variables included the time period and medications necessary to achieve symptomatic resolution.ResultsFour women and one man with an average age of 53 years were identified that met criteria for persistent PSV indicating an incidence of 0.9% at our institution. The onset of vertigo symptoms was on average 20 days postoperatively. All five patients had daily vertigo episodes and experienced complete resolution with no vertigo episodes after treatment. Symptomatic resolution was achieved over an average of 9 weeks after initiating treatments.ConclusionsPersistent PSV beyond 3 months is a rare occurrence and its treatment can be challenging when there is no evidence of an underlying pathology. This subset of patients may be suffering from migraine, which was triggered postoperatively. Treatment with migraine prophylaxis in this cohort of patients may result in resolution of vertigo.

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