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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: 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

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]

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.

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.

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The connection between smoking and Obstructive sleep apnea (OSA) is not yet clear. There are studies that have confirmed the effect of smoking on sleep disordered breathing, whereas others did not. Nicotine affects sleep, as smokers have prolonged total sleep and REM latency, reduced sleep efficiency, total sleep time, and slow wave sleep. Smoking cessation has been related with impaired sleep. The health consequences of cigarette smoking are well documented, but the effect of smoking cessation on OSA has not been extensively studied. Smoking cessation should improve OSA as upper airway oedema may reduce, but there is limited data to support this hypothesis. The impact of smoking cessation pharmacotherapy on OSA has been studied, especially for nicotine replacement therapy (NRT). However, there are limited data on other smoking cessation medications as bupropion, varenicline, nortriptyline, clonidine, and cytisine. The aim of this review was to explore the current evidence on the association between smoking and OSA, to evaluate if smoking cessation affects OSA, and to investigate the possible effects of different pharmacologic strategies offered for smoking cessation on OSA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously. [ABSTRACT FROM AUTHOR]

With the thought and strong hope of uniqueness and challenging characteristic highlights and importance of nanofibrous mats (NFMs) along with cyclodextrins (CDs) that having a significant opportunity, chances and handling a vital role in hostile to bacterial activities. For the most part, CDs are utilized to upgrade the antibacterial activity through the improvement of solubility, stability, and etc., to any molecule which can bring inside the CDs cavity via the formation of inclusion complexes. Polymer-mediated electrospun nanofibrous mats (PAN NFMs) are utilized as a nanocarrier for antibacterial activity in this article, utilizing nortriptyline (NP) as a reference molecule. As a result, NP forms an inclusion complex with β-Cyclodextrin (β-CD). As a result, the PAN NFMs are able to absorb it, thereby consolidating the complex NP on the nanofibrous surface. Additionally, the soaking of PAN NFMs in NP solution without β-CD was performed for comparison. To characterize the nanofibrous mats of NP/PAN and NP:β-CD-ICs/PAN NFMs, UV absorption, FTIR, Raman, XRD, and SEM techniques were used. The antibacterial activity of NP and NP:β-CD-ICs have been tried against positive control antibiotics by the disc diffusion method. Thus, the action has been improved for NP:β-CD-ICs/PAN NFMs over NP/PAN NFMs because of the solubility upgraded for the NP by the complexation of β-CD. [ABSTRACT FROM AUTHOR]

Background: Real-world effectiveness of interventions in palliative care need to be systematically quantified to inform patient/clinical decisions. Neuropathic pain is prevalent and difficult to palliate. Tricyclic antidepressants have an established role for some neuropathic pain aetiologies, but this is less clear in palliative care. Aim: To describe the real-world use and outcomes from amitriptyline or nortriptyline for neuropathic pain in palliative care. Design: An international, prospective, consecutive cohort post-marketing/phase IV/pharmacovigilance/quality improvement study of palliative care patients with neuropathic pain where the treating clinician had already made the decision to use a tricyclic antidepressant. Data were entered at set times: baseline, and days 7 and 14. Likert scales graded benefits and harms. Setting/participants: Twenty-one sites (inpatient, outpatient, community) participated in six countries between June 2016 and March 2019. Patients had clinician-diagnosed neuropathic pain. Results: One hundred and fifty patients were prescribed amitriptyline (110) or nortriptyline (40) of whom: 85% had cancer; mean age 73.2 years (SD 12.3); mean 0–4 scores for neuropathic pain at baseline were 1.8 (SD 1.0). By day 14, doses of amitriptyline were 57 mg (SD 21) and nortriptyline (48 mg (SD 21). Fifty-two (34.7%) patients had pain improvement by day 14 (amitriptyline (45/110 (43.3%); nortriptyline (7/40 (18.9%)). Thirty-nine (27.7%) had new harms; (amitriptyline 29/104 (27.9%); nortriptyline 10/37 (27.0%); dizziness (n = 23), dry mouth (n = 20), constipation (n = 14), urinary retention (n = 10)). Benefits without harms occurred (amitriptyline (26/104 (25.0%); nortriptyline (4/37 (10.8%)). Conclusions: Benefits favoured amitriptyline while harms were similar for both medications. [ABSTRACT FROM AUTHOR]

Introduction: Due to the complexity of symptoms in major depressive disorder (MDD), the majority of depression scales fall short of accurately assessing a patient's progress. When selecting the most appropriate antidepressant treatment in MDD, a multidimensional scale such as the Hamilton Depression Rating scale (HAM-D) may provide clinicians with more information especially when coupled with unidimensional analysis of some key factors such as depressed mood, altered sleep, psychic and somatic anxiety and suicidal ideation etc. Methods: HAM-D measurements were carried out in patients with MDD when treated with two different therapeutic interventions. The prespecified primary efficacy variables for the study were changes in score from baseline to the end of the 12 weeks on HAM-D scale (i.e., ≤ 8 or ≥50% response). The study involved three assessment points (baseline, 6 weeks and 12 weeks). Results: Evaluation of both the absolute HAM-D scores and four factors derived from the HAM-D (depressed mood, sleep, psychic and somatic anxiety and suicidal ideation) revealed that the latter showed a greater promise in gauging the anti-depressant responses. Conclusion: The study confirms the assumption that while both drugs may improve several items on the HAM-D scale, the overall protocol may fall short of addressing the symptoms diversity in MDD and thus the analysis of factor (s) in question might be more relevant and meaningful. [ABSTRACT FROM AUTHOR]

Objective: There is limited evidence that adding an antidepressant to electroconvulsive therapy (ECT), compared with ECT monotherapy, improves outcomes. We aimed to determine whether the addition of nortriptyline to ECT enhances its efficacy and prevents post‐ECT relapse. Methods: We conducted a randomized, double‐blind, placebo‐controlled trial (RCT). Patients with major depressive disorder and an indication for ECT received either nortriptyline or placebo during a bilateral ECT course. Outcome measures were mean decrease in Hamilton Rating Scale for Depression (HRSD) score, response, remission, and time to response and remission. Patients who attained remission participated in a 1‐year follow‐up study with open‐label nortriptyline. Outcome measures were relapse and time to relapse. Results: We included 47 patients in the RCT. In the nortriptyline group, 83% showed response, 74% attained remission, and the mean decrease in HRSD score was 21.6 points. In the placebo group these figures were, respectively, 81% (p = 0.945), 73% (p = 0.928) and 20.7 points (p = 0.748). Thirty‐one patients participated in the follow‐up study. In patients who had received nortriptyline during the RCT, 47% relapsed at a mean of 34.2 weeks. Patients who had received placebo showed similar treatment results. In both study phases, no statistically significant differences between the nortriptyline and the placebo group were found. Conclusion: In our sample of severely depressed patients who were often medication resistant and suffering from psychotic depression, the addition of nortriptyline to ECT did not enhance its efficacy or prevent post‐ECT relapse. Encouragingly, even in these patients ECT was highly effective and relapse rates were relatively low. [ABSTRACT FROM AUTHOR]

Background: Diabetic neuropathic pain (DNP) is a common complication of diabetes and has a profound effect on patients quality of life. Therefore. The purpose of the present study was to compare the analgesic effects of duloxetine and nortryptiline in the management of patients with diabetic neuropathy. Methods: This was a randomized, double-blind, parallel-group, placebo-controlled trial in subjects with a proven diagnosis of DM and suffered from neuropathic pain. Patients were recruited in this study from 20 February 2016 (first patient, first visit) to 22 June 2017 (last patient, last visit), including 5 weeks follow-up. A diagnosis of DNP was based on history, clinical examination, Nerve conduction velocity and Diabetic neuropathy symptom score (more than one point). Results: Both drugs reduced pain when compared with placebo. A significant VAS reduction from 6.4 at baseline to 3.75 at endpoint was observed in the duloxetine group. However, there was no significant difference in the efficacy between nortriptyline and duloxetine based on patientchr('39')s visual analogue scale (VAS) (p>0.05). No clinically significant changes or serious adverse events were found among treatment groups including changes in vital signs, laboratory assessments, physical examination or electrocardiograms. The decrease in the mean pain intensity was significantly greater in the duloxetine and nortriptyline group compared to the placebo group both in the primary analysis and in the by-visit analysis (p

Background and Aims: Headache is the most common reason for referring to a physician. Therapeutic approaches of this condition include the treatment of the acute attacks and prevention of future attacks. In this regard, this study aimed to investigate the effect of three medications, namely levetiracetam, sodium valproate, and nortriptyline on the control of migraine headaches in patients with migraine referred to Birjand Neurology Clinic, Birjand, Iran. Materials and Methods: This study was conducted based on a quasi-experimental research method. According to the physician, 120 migraine patients were divided into three groups of levetiracetam (a daily dose of 250 mg), sodium valproate (500 mg), and nortriptyline (25 mg) for four weeks. A questionnaire was used to collect the demographic characteristics of the patient. The data were analyzed using SPSS software (version 16) through the chi-square tets, paired t-test, and ANOVA. Results: The patients (n=120) were divided into three groups of 40 cases per group. The mean age of the patients was 33±11 years, and the majority of the cases (53.3%) were female. In total, 46.7% of the cases had severe headache before taking these medications; however, none of them experienced severe headache after taking the medicine. It should be noted that 77.5% of the patients experienced mild headache. The group taking levetiracetam showed the greatest decrease in headache intensity (P=0.01). Conclusion: According the results, levetiracetam appears to be more effective than the other two medications, especially sodium valproate, in terms of the mitigation of different degrees of headache.

IntroductionDue to the complexity of symptoms in major depressive disorder (MDD), the majority of depression scales fall short of accurately assessing a patient's progress. When selecting the most appropriate antidepressant treatment in MDD, a multidimensional scale such as the Hamilton Depression Rating scale (HAM-D) may provide clinicians with more information especially when coupled with unidimensional analysis of some key factors such as depressed mood, altered sleep, psychic and somatic anxiety and suicidal ideation etc.MethodsHAM-D measurements were carried out in patients with MDD when treated with two different therapeutic interventions. The prespecified primary efficacy variables for the study were changes in score from baseline to the end of the 12 weeks on HAM-D scale (i.e., ≤ 8 or ≥50% response). The study involved three assessment points (baseline, 6 weeks and 12 weeks).ResultsEvaluation of both the absolute HAM-D scores and four factors derived from the HAM-D (depressed mood, sleep, psychic and somatic anxiety and suicidal ideation) revealed that the latter showed a greater promise in gauging the anti-depressant responses.ConclusionThe study confirms the assumption that while both drugs may improve several items on the HAM-D scale, the overall protocol may fall short of addressing the symptoms diversity in MDD and thus the analysis of factor (s) in question might be more relevant and meaningful.

Introduction: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. Methods: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges to exhibit essential roles in the behavior and progression of prolactinomas; in this work, we integrated mRNA- and microRNA (miRNA)-level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. Results: We identified 8 drug candidates through drug repurposing based on mRNA-miRNA-level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven repurposed drugs including 5-fluorocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting. Discussion: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA-level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of the PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments. [ABSTRACT FROM AUTHOR]

• Inflammatory markers correlated differentially with specific depressive symptoms. • 17 of 27 inflammatory markers decreased significantly during antidepressant treatment. • We found no correlation between inflammatory markers and overall response. • Changes in inflammation correlated with response on neurovegetative symptoms. • We found no correlation between inflammatory markers and 10-year prognosis. Inflammation may correlate with a specific subgroup of depression and differential antidepressant response, but no trial has studied changes of many inflammatory markers over several time points and evaluated symptom-specific antidepressant response and long-term prognosis. We performed secondary analyses among 90 outpatients with moderate-severe depression (71% female, mean age 38 years) treated for 26 weeks with escitalopram or nortriptyline. We measured 27 pro- and anti-inflammatory markers at week 0, 8, 12, and 26 and calculated composite inflammation scores. Three depression rating scales were applied and symptom dimensions of depression calculated. Via Danish nationwide registers, 10 years follow-up were included on psychiatric hospital contacts, indicating relapse. Pearson correlation analyses were performed between baseline inflammatory markers and depressive symptom severity, mixed effects models during the 26-week trial, and Cox regression analyses for the register-based outcomes, adjusted for age, sex, BMI, and smoking. Baseline inflammatory markers correlated with differential severity on specific symptom dimensions but not with overall depression severity. A total of 17 of 27 inflammatory markers decreased significantly during treatment. We found no correlation between baseline nor change in inflammatory markers nor composite inflammation scores with differential treatment response on the MADRS, but small correlations between changes in inflammatory markers and differential response on neurovegetative symptoms. Findings were similar among 59 treatment-naïve patients. Inflammatory markers were not associated with differential risks for 10-year relapse. These findings support the importance of studying specific depressive symptoms to further explore the correlation between inflammation with differential antidepressant response in a subgroup of depression. Clinical Trial Registration number: GENDEP is registered at EudraCT2004–001723–38 (http://eudract.emea.europa.eu) and ISRCTN03693000 (www.controlled-trials.com). [ABSTRACT FROM AUTHOR]

It has proven that the presence of different chemicals can affect the succession patterns of necrophagous insects. A comprehensive study was designed on the effects of nortriptyline, diazinon, and aluminum phosphate on arthropod's succession and diversity on cadavers. Sixteen rabbits in two groups were used as a model in this study, 12 of them were treated with the drugs and were placed in two habitats (sun and shade) based on the study design. For each group, one cage was considered as control. Insects were collected twice a day from the cadavers and identified. In total, 549 necrophagous insects from five families, were collected from all the carcasses. Chrysomya albiceps was the dominant insect on all cadavers, expect for one treated with diazinon, in which it was displaced by Dermestes frischii. The highest number of insects were collected on the sixth day for all cadavers. The majority were collected from the shaded cages. Generally, the species diversity was higher for all the cadavers treated with the drugs compared to the control cadavers. The results showed that the presence of diazinon in the cadaver can repel necrophagous insects, on the contrary nortriptyline seems to attract more species/specimen. [ABSTRACT FROM AUTHOR]

Introduction: An antidepressant nortriptyline potentiates glucocorticoid (GC) action with synergistic suppression of inflammatory mediator release, but the precise molecular mechanism is unknown. Materials and methods: Peripheral blood cells from patients with chronic obstructive pulmonary disease (COPD) (n = 21) were incubated with nortriptyline (1 μM or 10 μM), budesonide (10 nM), or their combinations, followed by stimulation with phorbol myristate acetate (PMA) and ionomycin. Cytokine production, glucocorticoid receptor β (GRβ), histone deacetylase 2 (HDAC2) and histone H4 acetylation of K8 (HAT) expression, p65 NF-kB and p38 mitogen- activated protein kinase (p38 MAPK) phosphorylation in NK (CD3-CD56+) and NKT-like (CD3+CD56+) cells were analyzed by flow cytometry. Results: We observed that nortriptyline (10 μM) significantly attenuated the effects of PMA/ionomycin on the synthesis of interferon γ (IFNγ), interleukin 4 (IL-4), and IL-8, expression of GRβ and HAT, as well as p65 NF-kB and p38 MAPK phosphorylation in NK and NKT-like cells, whereas nortriptyline (1 μM) only inhibited IL-4 production by NK and NKT-like cells. Discussion: The combination of nortriptyline (10 μM) and budesonide decreased IFNγ, tumor necrosis factor α, IL-4, IL-8, and GRβ expression, as well as phosphorylated p38 MAPK and p65 NF-κB levels by NK and NKT-like cells above that of budesonide alone. Furthermore, the same association of drugs enhanced HDAC2 expression in NK and NKT-like cells. Conclusion: Collectively, our results show that nortriptyline might enhance GC function through modulation of HAT, HDAC2, GRβ, phospho-p38 MAPK expression. These data provide a strong rationale for combining nortriptyline with budesonide to treat COPD. [ABSTRACT FROM AUTHOR]

You Zhai,1,2 Lihua Wu,1,2 Yunliang Zheng,1,2 Minglan Wu,1,2 Yujie Huang,1,2 Qian Huang,1,2 Jianzhong Shentu,1– 3 Qingwei Zhao,1,2 Jian Liu1,2 1Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Jian LiuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236537Fax +86 571 87214223Email lindaliu87@zju.edu.cnPurpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug.Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs).Results: The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0–t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events.Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.Keywords: bioequivalence, pharmacokinetics, amitriptyline hydrochloride, nortriptyline

Background: Gastric ulcer is among the most serious stomach disorder universally. Several effective drugs are employed in the management of this disease, although there have been adverse effects in some cases. The aim of this study was to investigate the effect of nortriptyline to protect against gastric lesions, induced by indomethacin or cold-stress in rats. Methods: Gastric lesions were induced by oral indomethacin (30 mg/kg) or cold-shock at 2-4°C. Animals were pre-treated with 5, 10 or 20 mg/kg nortriptyline. After 4hr of exposure to indomethacin or cold shock, the stomach was removed for histological examinations and the levels of enzymatic and non-enzymatic oxidative stress markers were determined in the tissue samples. Results: The results showed that nortriptyline at 20 mg/kg significantly restored the activity of the oxidative stress markers, such as Superoxide Dismutase (SOD) and Catalase (CAT) enzymes. It also decreased the tissue Malondialdehyde (MDA) concentration. In addition, nortriptyline at 20 mg/kg, ameliorated the gastric tissue damages caused by indomethacin or the cold shock. Conclusion: The results suggest that improvement in gastric mucosal lesions can be mediated by nortriptyline pretreatment, which is likely due to its antioxidant property.

There has been an increase in the use of antidepressant drugs owing to significant economic challenges across the globe. Consequently, the increase in production of such drugs has impacted pharmaceutical pollution of industrial wastewaters discharged into the environment. Hence, there is a need to develop efficient adsorbents for antidepressant wastewater treatment. The impregnation of silver nanoparticles on biowaste was found to be highly effective in the treatment of oil-polluted water but has not been utilized in the adsorption of drugs. Herein, the dataset associated with the adsorption of antidepressants onto Ananas Comosus Peel (AP) and Silver nanoparticle-loaded Ananas Comosus peel (AgAP) was reported. Batch adsorption methodology was used to study the effect of antidepressant concentration (10–50 mg/L), sonication time (10–120 min), temperature (300–320 K) and adsorbent dosage (0.10–0.18 g). The concentration of antidepressant (Nortriptyline) in solution before and after adsorption was determined by the UV-Spectrophotometer at a maximum wavelength of 239 nm. The isotherm dataset was obtained from the Langmuir, Freundlich, Temkin and Dubinin-Raduskevich models, while kinetic data was evaluated by the pseudo-first order-pseudo-second-order, film diffusion and intraparticle diffusion rate equations. The data on the thermodynamics and adsorbent reusability were also provided. The dataset showed an adsorption capacity of 3.27 mg/g and 4.74 mg/g for AP and AgAP, respectively. The dataset is important to material and environmental scientists and revealed the efficiency of AP and AgAP in the treatment of antidepressant wastewater.

Background and Objectives: - The safety of Pregabalin and Nortriptyline have been proved individually in chronic low backache with radiculopathy. However, there are limited number of studies comparing the tolerability of Pregabalin and Nortriptyline in chronic low backache with radiculopathy. Hence the present study is designed to determine the tolerability of Pregabalin versus Nortriptyline. It is an prospective observational study. Methods: - Patients with chronic low backache with radiculopathy 15-60 years of age without specific cause and significant neurological deficit were included. Patients were followed up at 2 and 4 weeks and their side effect were noted. Results: - There was no statistical difference between pregabalin and nortriptyline groups in terms of visual analogue scale for pain score, from baseline to 2 weeks and from baseline to week 4. The incidence of side effects were statistically less in the nortriptyline group compared to pregabalin group. From the results of the present study it can be concluded that both pregabalin and nortriptyline are effective in the treatment of chronic low backache with radiculopathy with radicular pain but incidence of adverse events are more with the pregabalin compared to nortriptyline. Conclusion: - Anticonvulsants and TCAs are very effective in moderate to severe pain while the other drugs like NSAIDs and opioids are more effective in mild to moderate pain. [ABSTRACT FROM AUTHOR]

Background: Prurigo nodularis (PN) is a chronic dermatologic condition presenting as multiple papulonodular lesions occurring with intense pruritus. Though numerous agents (topical, systemic, phototherapy and biological drugs) have been tried, the outcomes are variable. Objectives: The aim of this study was to assess the role of topical and systemic therapies in primary PN by comparing the Pruritus Grading System (PGS) score at baseline and 1 month post-therapy. Materials and Methods: Of 86 diagnosed cases of PN, 49 cases of primary PN were clinically graded by Pruritus Grading System Score (PGSS), and assessed histopathologically by IHC staining (STAT-1, 3, and 6). Apart from topical agents, oral nortriptyline (mild grade), methotrexate (moderate grade) and thalidomide (severe grade) were administered, whereas doxepin was administered for itching. The PGSS was assessed after 1 month of therapy. Results: Among 49 patients of PN, the majority of patients showed a significant decrease in PGSS (P = <0.001) in 1 mont, which correlated with STAT-6 expression. The combination of different topical and oral agents resulted in a statistically significant change in severity, though individual drugs did not achieve statistically significant results. Conclusion: A combination of selected oral and topical agents can effectively control the severity of PN within one month, and this was found to correlate with STAT 6 expression. [ABSTRACT FROM AUTHOR]

Objective: To determine the effectiveness of nortriptyline and tolerability of side effects in the treatment of neurogenic cough. Secondary goal is to evaluate the association between laryngeal asymmetry and clinical response to nortriptyline. Study Design: Retrospective case series. Materials and Methods: Consecutive patients diagnosed with neurogenic cough at a quaternary care specialty hospital from 2001 to 2020 were identified. Subjects <18 years old, not treated with nortriptyline, did not have a nasolaryngoscopic examination and were lost to follow-up were excluded. Charts were reviewed for demographic information, clinical history, nasolaryngoscopic findings, medication dosage, side effects, and follow-up time. Results: Forty-two patients met inclusion and exclusion criteria, 7 males and 35 females with an average age of 56.5 (±13.1) years. There were 26/36 (72.2%) responders and 10/36 (27.8%) non-responders; 6 patients stopped nortriptyline due to side effects and were not included in the response comparison. Laryngeal asymmetry was present in 36/42 (85.7%) patients. No factors related to laryngeal asymmetry were significantly different between responders and non-responders. Medication tolerance was observed in 3/42 (7.1%) patients. Side effects were reported in 16/42 (38.1%) patients. The most common side effects were sedation 9/42 (21.4%) and xerostomia 3/42 (7.1%). Conclusion: Nortriptyline is effective for treating neurogenic cough with 72% of patients reporting improvement in cough. Evidence of laryngeal asymmetry was not associated with better treatment response. Although 38% experienced side effects, the majority of patients continued nortriptyline despite side effects. Level of Evidence: 4 [ABSTRACT FROM AUTHOR]

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

Psychiatric drugs are among the leading medications prescribed for humans, with their presence in aquatic environments raising concerns relating to potentially harmful effects on non-target organisms. Nortriptyline (NTP) is a selective serotonin-norepinephrine reuptake inhibitor antidepressant, widely used in clinics and found in environmental water matrices. In this study, we evaluated the toxic effects of NTP on zebrafish (Danio rerio) embryos and early larval stages. Developmental and mortality analyses were performed on zebrafish exposed to NTP for 168 h at concentrations ranging from 500 to 46,900 µg/L. Locomotor behaviour and acetylcholinesterase (AChE) activity were evaluated by exposing embryos/larvae to lower NTP concentrations (0.006–500 µg/L). The median lethal NTP concentration after 168 h exposure was 2190 µg/L. Although we did not identify significant developmental changes in the treated groups, lack of equilibrium was already visible in surviving larvae exposed to ≥ 500 µg/L NTP. The behavioural analyses showed that NTP was capable of modifying zebrafish larvae swimming behaviour, even at extremely low (0.006 and 0.088 µg/L) environmentally relevant concentrations. We consistently observed a significant reduction in AChE activity in the animals exposed to 500 µg/L NTP. Our results highlight acute toxic effects of NTP on the early-life stages of zebrafish. Most importantly, exposure to environmentally relevant NTP concentrations may affect zebrafish larvae locomotor behaviour, which in turn could reduce the fitness of the species. More studies involving chronic exposure and sensitive endpoints are warranted to better understand the effect of NTP in a more realistic exposure scenario.

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms. [ABSTRACT FROM AUTHOR]

Background: Narrowband ultraviolet B (NB-UVB) phototherapy has been used as a common treatment for dermatologic diseases such as psoriasis and vitiligo and generally considered a safe form of therapy during pregnancy. Invitro photodegradation of folate after exposure to UVB radiation has been documented but studies on UVB-induced alternation of serum folate level have reported inconsistent results. The aim of this study was to investigate the effect of NB-UVB radiation on serum folate level. Methods: In this study, serum folate levels were evaluated in patients at baseline and after 30 sessions of NB-UVB irradiation. Results: Twenty patients completed the study: 10 psoriasis, 7 vitiligo and 3 mycosis fungoides (patch stage). Mean serum folate level had significantly decreased from 2.76±0.59 ng/ml at baseline to 1.34±0.15 ng/ml after 30 sessions. (Mean NB-UVB cumulative dose 40.35±16.80 j/cm², P=0.001). Conclusion: Serum folate levels may decrease after long-term NB-UVB phototherapy in patients with skin disorders. [ABSTRACT FROM AUTHOR]

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10‐hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50–150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges. [ABSTRACT FROM AUTHOR]

Background: Diabetic neuropathic pain (DNP) is a common complication of diabetes and has a profound effect on patients' quality of life. Therefore. The purpose of the present study was to compare the analgesic effects of duloxetine and nortryptiline in the management of patients with diabetic neuropathy. Methods: This was a randomized, double-blind, parallel-group, placebo-controlled trial in subjects with a proven diagnosis of DM and suffered from neuropathic pain. Patients were recruited in this study from 20 February 2016 (first patient, first visit) to 22 June 2017 (last patient, last visit), including 5 weeks follow-up. A diagnosis of DNP was based on history, clinical examination, Nerve conduction velocity and Diabetic neuropathy symptom score (more than one point). Results: Both drugs reduced pain when compared with placebo. A significant VAS reduction from 6.4 at baseline to 3.75 at endpoint was observed in the duloxetine group. However, there was no significant difference in the efficacy between nortriptyline and duloxetine based on patient's visual analogue scale (VAS) (p>0.05). No clinically significant changes or serious adverse events were found among treatment groups including changes in vital signs, laboratory assessments, physical examination or electrocardiograms. The decrease in the mean pain intensity was significantly greater in the duloxetine and nortriptyline group compared to the placebo group both in the primary analysis and in the by-visit analysis (p<0.003). Conclusion: The present study demonstrates the safety and effectiveness of both duloxetine and nortriptyline in the management of DNP. [ABSTRACT FROM AUTHOR]