Amitriptyline inhibits NLRP3 inflammasome activation via the ASM/CE pathway in a cell model of NAFLD

Background:Nonalcoholic fatty liver disease(NAFLD)is a global health concern with the acid sphingomyelinase(ASM)/ceramide(CE)pathway and the NOD-like receptor family,pyrin domain-containing protein 3(NLRP3)inflammasome identified as pivotal players in lipid disorders and inflammation.This study explores the interaction mechanism between the ASM/CE pathway and NLRP3 in NAFLD cell models,aiming to understand the impact of amitriptyline(Ami),an ASM inhibitor,on lipid deposition and hepatocyte injury by regulating the ASM/CE-NLRP3 pathway.Methods:HepG2 and HL-7702 cells were exposed to free fatty acids(FFAs)to establish the NAFLD model.The cells were divided into 5 groups:control group,model group,Ami group,tumor necrosis factoralpha(TNF-α)group,and Ami+TNF-αgroup.Intracellular lipid droplets were visualized using Oil Red O staining,and Western blot analysis quantified ASM,NLRP3,and caspase 1 protein expression.Enzyme linked immunosorbent assay(ELISA)was measured CE and ASM levels,while qRT-PCR assessed mRNA expression.The apoptotic rate was evaluated by flow cytometry(FCM).Results:Following FFAs incubation,significant increases in ASM and CE levels were observed in HepG2 and HL-7702 cells,accompanied by elevated expression of NLRP3,and caspase 1,and IL-1β.TNF-αtreatment further amplified these indicators.Ami demonstrated a reduction in lipid deposition,suppressed ASM/CE pathway activation,downregulated NLRP3 and caspase 1 expression,and improved apoptosis.Additionally,MCC950,a selective inhibitor of the NLRP3,mitigated NLRP3,caspase 1,and IL-1βexpression,alleviating lipid deposition and apoptosis in the NAFLD cell model.Conclusion:The ASM/CE-NLRP3 pathway in NAFLD cells promotes hepatocyte steatosis,inflammation,and cell damage.Ami emerges as a promising therapeutic agent by inhibiting the ASM/CE-NLRP3 pathway,underscoring its potential as a key target for NAFLD treatment.

Effect of amitriptyline on gastrointestinal function and brain-gut peptides: A double-blind trial

AIM: To study the effects of low-dose amitriptyline (AMT) on gastrointestinal function and brain-gut peptides in healthy Chinese volunteers. METHODS: This was a double-blind, randomised, placebo-controlled, two-period cross-over trial. Twentyeight healthy volunteers were randomised and administered 1-wk treatments of AMT (12.5 mg tid) or placebo. Before and during the final two days of treatment, gastric emptying, proximal gastric accommodation and visceral sensitivity were measured by drinkingultrasonography test; the orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, and fasting blood was collected. Plasma levels of ghrelin, motilin and neuropeptide Y (NPY) were measured by enzyme-linked immunosorbent assay kits.RESULTS: AMT slowed the OCTT (109.2 ± 29.68 min vs 96.61 ± 23.9 min, P = 0.004) but did not affect liquid gastric emptying and had no effect on proximal gastric accommodation. AMT resulted in decreases in the visual analogue scale (VAS) for difficulty in drinking 600 and 800 mL of water (3.57 ± 0.94 vs 2.98 ± 0.85, 5.57 ± 0.82 vs 4.57 ± 0.98, P < 0.01 for both), although it had no significant effect on the VAS for difficulty in drinking 200 mL and 400 mL of water. AMT significantly increased the plasma ghrelin level (442.87 ± 176.79 pg/mL vs 526.87 ± 158.44 pg/mL, P = 0.04) and the neuropeptide-Y level (890.15 ± 131.46 pg/mL vs 965.64 ± 165.63 pg/mL, P = 0.03), whereas it had no effect on the MTL level. CONCLUSION: Low-dose AMT could slow OCTT, make the stomach less sensitive and increase the plasma levels of ghrelin and NPY. Thus, we recommend the use of low-dose AMT for functional gastrointestinal disorders.

Effect of low-dose amitriptyline on globus pharyngeus and its side effects

AIM:To compare the efficacy and side effects of lowdose amitriptyline(AMT)with proton pump inhibitor treatment in patients with globus pharyngeus.METHODS:Thirty-four patients who fulfilled the RomeⅢcriteria for functional esophageal disorders were included in this study.Patients were randomly assigned to receive either 25 mg AMT before bedtime(AMT group)or 40 mg Pantoprazole once daily for 4 wk(conventional group).The main efficacy endpoint was assessed using the Glasgow Edinburgh Throat Scale(GETS).The secondary efficacy endpoints included the Medical Outcomes Study 36-item short form health survey[social functioning(SF)-36]and the Pittsburgh Sleep Quality Index.Treatment response was defined as a>50%reduction in GETS scores.All patients entering this study recorded side effects at days 1,8,15,22 and 29 using a visual analogue scale.RESULTS:Thirty patients completed the study.After 4 wk of treatment,the AMT group had a greater response than the conventional group(75%vs 35.7%,P=0.004).At day 3,the AMT group showed significantly more improvement than the Conventional group in GETS score(3.69±1.14 vs 5.64±1.28,P=0.000).After 4 wk of treatment,the AMT group showed significantly greater improvement in GETS score and sleep quality than the Conventional group(1.25±1.84 vs 3.79±2.33,4.19±2.07 vs 8.5±4.97;P<0.01 for both).Additionally,the AMT group was more likely than the Conventional group to experience improvement in the SF-36,including general health,vitality,social functioning and mental health(P=0.044,0.024,0.049 and 0.005).Dry mouth,sleepiness,dizziness and constipation were the most common side effects.CONCLUSION:Low-dose AMT is well tolerated and can significantly improve patient symptoms,sleep and quality of life.Thus,low-dose AMT may be an effective treatment for globus pharyngeus.

Sitagliptin,sitagliptin and metformin,or sitagliptin and amitriptyline attenuate streptozotocin-nicotinamide induced diabetic neuropathy in rats

Diabetic neuropathies are a family of nerve disorders caused by diabetes. Symptoms of the disease include nerve palsy, mononeuropathy, mononeuropathy multiplex, diabetic amyotrophy, painful polyneuropathy, autonomic neu- ropathy, and thoracoabdominal neuropathy. In this study, type 2 diabetes in rats was induced with nicotinamide- streptozotocin. Drug treatment was initiated on the d 15, with the combination regimen of metformin, pioglitazone and glimipiride or metformin and sitagliptin or sitagliptin, amitriptyline and sitagliptin and led to significantly im- proved glycemic control, increased grip strength and paw jumping response on d 21, 28 and 35 （P 〈 0.001）. Signif- icant increases in blood protein levels and decreases in urinary protein levels were observed in the animals treated with the different regimens on d 21, 28 and 35 （P 〈 0.001）. Combined treatment of streptozotocin and nicotinamide caused marked degeneration of nerve cells, while administration of metformin and sitagliptin showed tissue regen- eration and no body weight gain. In conclusion, treatment with sitagliptin and sitagliptin combined with metformin or amitriptyline results in no body weight gain, but causes an increase in grip strength and pain sensitivity, exhibits neural protection, and reverses the alteration of biochemical parameters in rats with streptozotocin-nicotinamide induced type 2 diabetes.

Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain

AIM:To investigate the efficacy of amitriptyline with proton pump inhibitor(PPI)for the treatment of functional chest pain(FCP).METHODS:This was a randomized,open-label trial investigating the addition of low dose amitriptyline(10 mg at bedtime)to a conventional dose of rabeprazole(20 mg/d)(group A,n = 20)vs a double-dose of rabeprazole(20 mg twice daily)(group B,n = 20)for patients with FCP whose symptoms were refractory to PPI.The primary efficacy endpoints were assessed by global symptom score assessment and the total number of individuals with > 50% improvement in their symptom score.RESULTS:The between-group difference in global symptom scores was statistically significant during the last week of treatment(overall mean difference;3.75 ± 0.31 vs 4.35 ± 0.29,the between-group difference;P < 0.001).Furthermore,70.6% of patients in group A had their symptoms improve by > 50%,whereas only 26.3% of patients in group B had a similar treatment response(70.6% vs 26.3%,P = 0.008).Specifically,patients in group A had a significantly greater improvement in the domains of body pain and general health perception than did patients in group B(52.37 ± 17.00 vs 41.32 ± 12.34,P = 0.031 and 47.95 ± 18.58 vs 31.84 ± 16.84,P = 0.01,respectively).CONCLUSION:Adding amitriptyline to a PPI was more effective than a double-dose of PPI in patients with FCP refractory to a conventional dose of PPI.

THE EFFECTS OF ELECTRO-ACUPUNCTURE VS. AMITRIPTYLINE ON PLATELET 3H-PAROXETINE BINDING SITES IN DEPRESSED PATIENTS

In this study platelet 3H-paroxetine binding site was studied in 16 depressed pa-tients and 16 healthy volunteers. We found that the mean Bmax of 3H-paroxetine binding on theplatelets of depressed patients was significantly lower than that of normal controls. After treated withamitriptyline or electro-acupuncture for 6 weeks, the density of paroxetine binding sites increased to-wards normal in well responded patients. But no significant difference was found between electro-acupuncture and amitriptyline as compared in their effects on 3H-paroxetine binding sites.

Electrocardiograms changes in children with functional gastrointestinal disorders on low dose amitriptyline

AIM: To study the effects of low dose amitriptyline on cardiac conduction in children.

New Approach for the Determination of Tricyclic Antidepressant Amitriptyline Using <i>β</i>-Cyclodextrin-PEG System via Spectrophotomerty

A new and simple procedure for the spectrophotometric determination of the tricyclic antidepressant drug amitriptyline is proposed. The method is based on enhancement of sensitivity of the [AMIYTP]+ β-cyclodextrin and PEG molecules involved in formation of molecules inclusion complex, in presence of polyethylene glycol (PEG) medium. The mole ratio of [AMIYTP]+ β-cyclodextrin and PEG molecules in inclusion complex were determined by the curve fitting method. The value of molar absorptivity of {[AMIYTP: (β CD)] PEG} complex in term of the drug lies in rage of (2.20 - 2.23) × 104 L·mole–1·cm–1 at absorption maximum 242 nm. The slope, intercept and correlation co-efficient were found to be 14.21, 0.0046, and 0.998, respectively. The effect of analytical variables on the determination of the drug and composition of the ion associated complex are discussed in the paper. This method is applicable in the determina-tion of amitriptyline in the pharmaceutical preparations.

Pharmacotherapy in autism spectrum disorders,including promising older drugs warranting trials

Available pharmacotherapies for autism spectrum disorders(ASD)are reviewed based on clinical and research experience,highlighting some older drugs with emerging evidence.Several medications show efficacy in ASD,though controlled studies in ASD are largely lacking.Only risperidone and aripiprazole have Federal Drug Administration approval in the United States.Methylphenidate(MPH)studies showed lower efficacy and tolerability for attention deficit hyperactivity disorder(ADHD)than in the typically developing(TD)population;atomoxetine demonstrated lower efficacy but comparable tolerability to TD outcomes.Guanfacine improved hyperactivity in ASD comparably to TD.Dextroamphetamine promises greater efficacy than MPH in ASD.ADHD medications reduce impulsive aggression in youth,and may also be key for this in adults.Controlled trials of the selective serotonin reuptake inhibitors citalopram and fluoxetine demonstrated poor tolerability and lack of efficacy for repetitive behaviors.Trials of antiseizure medications in ASD remain inconclusive,however clinical trials may be warranted in severely disabled individuals showing bizarre behaviors.No identified drugs treat ASD core symptoms;oxytocin lacked efficacy.Amitriptyline and loxapine however,show promise.Loxapine at 5-10 mg daily resembled an atypical antipsychotic in positron emission tomography studies,but may be weight-sparing.Amitriptyline at approximately 1 mg/kg/day used cautiously,shows efficacy for sleep,anxiety,impulsivity and ADHD,repetitive behaviors,and enuresis.Both drugs have promising neurotrophic properties.

迟发性运动障碍的治疗

迟发性运动障碍的治疗翟金国，郑先振ｌ．ＣＯＭＰＡＲＩＳＯＮＯＦＵＳＩＮＧＴＲＩＭ－ＩＰＲＡＭＩＮＥＡＮＤＡＭＩＴＲＩＰＴＹＬＩＮＥＷＩＴＨＰＥＲＰＨＥＮＡＺＩＮＥＦＯＲＴＨＥＴＲＥＡＴＭＥＮＴＯＦＤＥＬＵＳＩＯＮＡＬＤＥＰＲＥＳＳＩＯＮｂｙＺａｉＪｉ...

Cyclic vomiting syndrome in children: Experience with 181 cases from southern Iran

AIM： To evaluate the clinical presentation, response to prophylactic therapy and outcome of children with cyclic vomiting syndrome （CVS） in Shiraz, Iran. METHODS： During a period of 11 years （March 1994 to March 2005）, 181 consecutive children with a final diagnosis of CVS were evaluated, treated and followed in our center. Patients were randomized to receive either amitriptyline or propranolol as prophylactic treatments. RESULTS： There were 88 boys and 93 girls with mean age of onset of symptoms of 4.9 ± 3.3 years （range, neonatal period to 14 years）, the mean age at final diagnosis was 6.9 years （range, 1.5 to 14）, and the mean duration between the onset of the first attack and the final diagnosis of CVS was 2 ± 1.81 years （range, 1/6 to 8）. The mean duration of each attack was 4.26 days （range, from few hours to 10 d） and the mean interval between the attacks was 1.8 mo （range, 1 wk to 12 too）. The time of onset of the attacks was midnight to early morning in about 70% of cases. Amitriptyline was effective in 46 out of 81 （56%） patients （P 〈 0.001）. Propranolol appeared to have a superior action and was effective in 74 out of 83 （92%） patients （P 〈 0.0001）. CONCLUSION： There is a significant lag time between the onset of clinical symptoms and the final diagnosis of CVS in our area. In patients with typical clinical presentations of CVS, who are examined by an experienced physician, invasive workup is not necessary. Propranolol appears more effective than arnitriptyline for prophylactic use in children with CVS.

Inhibitory Effect of 5-Adenylic Acid on Bitter Taste of Antipsychotic Drugs

The purpose of the present study was to examine the effect of adenylic acid (adenosine 5-monophosphate;AMP), a known nutritional enhancer, on inhibiting the bitterness of antipsychotic medicines administered to patients with mental illnesses, including children. First, we chose four antipsychotic medicines, amitriptyline hydrochloride (AMT), chlorpromazine hydrochloride (CPZ), haloperidol (HPD) and risperidone (RIS) and evaluated the inhibition of their bitterness by AMP through taste sensor measurements. AMP showed a significant bitterness inhibition effect on all drugs. Second, MarvinSketch analysis revealed the potential formation of electrostatic interactions between ionic forms (IV) of AMP and ionic (cationic) forms of each drug, which resulted in bitterness suppression. Third, chemical shift perturbations in 1H-NMR studies suggested an interaction between the phosphate group of AMP and amino group of AMT, CPZ, HPD and RIS. Last, conventional elution experiments of up to 1 min simulating oral cavity conditions were performed for 1 whole AMT tablet, half AMT tablet, crushed half AMT tablet, and crushed AMT tablet containing AMP powder/solution (1, 3 mM potency). The taste sensor output values of the crushed AMT tablet containing AMP powder/solution (1, 3 mM potency) were significantly lower than those of the crushed tablet.

Burning Mouth Syndrome: Patient Profiles, Clinical Symptoms, Affecting Associated Factors, and Treatment Responses

Background: The clinical characteristics of burning mouth syndrome (BMS) are not fully understood. We investigated the profiles of BMS patients, characteristics associated with BMS, and the available treatment methods and their effects. Methods: Seventy-four BMS patients without oral mucosal lesions were enrolled. Their medical history, medications taken, and symptom scores were investigated via questionnaires. Laboratory investigations of parameters potentially associated with BMS were performed. Regarding treatment, 0.01% dexamethasone gargle, amitriptyline, and clonazepam were administered individually or in combination, depending on the degree of symptom improvement. Symptoms were scored from 0 - 10 points;these scores were used to evaluate treatment efficacy and patient satisfaction. Results: Mean age of the patients was 63.6 ± 14.2 years;mean symptom prevalence period was 15.5 ± 24.7 months. BMS was not significantly associated with a history of hypertension, diabetes, or any specific medications. Treatment reduced the symptoms of 85.1% subjects (63/74). Conclusions: Contrary to that in previous studies, we observed significant improvements in BMS patients following combination treatment with dexamethasone gargle, amitriptyline, and clonazepam.

Use of DREAM to assess relative risks of presence of pharmaceuticals and personal care products from a wastewater treatment plant

Concerns related to environmental risks associated with pharmaceuticals and personal care products(PPCPs)have led researchers to seek methods for assessing and monitoring these contaminants in the aquatic environment.Identifying and validating risk assessment tools that can evaluate ecological concerns and risks associated with PPCPs is critical.Herein,the suitability of a dose-related risk and effect assessment model,which estimates predicted environmental concentrations and allowed comparisons with predicted no effect concentrations determined,in combination with in vitro analyses of the whole effluent toxicity,was verified for the characterization of a PPCP hazard.Concentrations of the most utilized PPCPs in Norway were measured in influent and effluent samples and used to parameterize the fate model.Greater than 90%removal was attained for 12 out of 22 detected PPCPs.Removal was not dependent on the class or the concentration of the specific substance and varied between 12%and 100%.The PPCPs detected in the discharged wastewater were utilized to assess individual contributions to the risk of the effluent,and no risk was identified for the targeted 30 PPCP.The simulations provided valuable information regarding the discharge plume distribution over time,which can aid planning of future environmental monitoring investigations.Bioassays(using fish liver cells,PLHC-1)were used for assessing overall effluent toxicity,through cell viability,production of reactive oxygen species,and ethoxyresorufin-O-deethylase(EROD)activities.The present study may allow regulators to use risk-based strategies over removal criteria for monitoring studies and confirms the importance to take PPCP contamination into consideration when establishing environmental regulations.

UV/Chlorine-BAC treatment of antidepressant drug in drinking water:efficacy,process optimization,and microbiological characterization

The environmental pollution caused by psychotropic drugs harms human health and has prompted a stronger emphasis on research into water treatment measures.The UV/Chlorine-biological activated carbon(BAC)combined process was employed in this study to treat amitriptyline(AMT),a typical psychotropic drug,in slightly contaminated drinking water.The removal efficiency of AMT in drinking water by UV/Chlorine and the feasibility of combining it with BAC were determined.The results demonstrated that the removal efficiency of 1μmol/L AMT could reach 98.5%of the 2.0 mg/L chlorine and UV treated for 30 min.A significant removal improvement of AMT was 10%45%compared to UV alone,Chlorine alone,and other oxidants combined,especially the SOUR(Specific Oxygen Uptake Rate),which was 57%-90%compared to other oxidants combined.Secondly,the optimal process parameters for UV/Chlorine-BAC treatment of slightly contaminated drinking water were a combination of UV exposure,chlorine dosage of 2 mg/L,and reaction times of i5 min followed by 30 min of BAC treatment.The AMT degradation,CODMn removal efficiency,and NO_(3)-N production was 88%,65%,and 95%,respectively.There was no significant effect on the number of microorganisms in the BAC medium,ensuring good long-term operation.Furthermore,an investigation was conducted to assess the influence of optimal process operation on the microbial community structure within BAC.This analysis unveiled a positive feedback loop in the colony architecture after implementing ideal process parameters.This study provides significant inspiration for addressing residual antidepressant issues using traditional drinking water treatment processes.