Evaluation of anxiolytic effect of combination of tramadol with gabapentin and pregabalin in Wistar rats

Background: Anxiety is a widespread disorder that approximately 18% of the population experience at some stage in their lives. Pain is a common stimulus that induces anxiety in both animals and human beings. Combination of drugs with good anti-anxiety and analgesic effect can be used for the treatment of chronic pain induced anxiety, post-operative, and procedure-related pain-induced anxiety. Aims and Objectives: The study was conducted to evaluate the anxiolytic activity of combination of gabapentin with tramadol, pregabalin with tramadol compared to standard fluoxetine, in elevated plus maze (EPM) and light-dark arena (LDA) models of anxiety in Wistar albino rats. Materials and Methods: Twenty-four male or female albino Wistar rats from Central Animal House, MRMC, Kalaburagi, were utilized. Fluoxetine 10 mg/kg, gabapentin 30 mg/kg, tramadol 30 mg/kg, and pregabalin 30 mg/kg were used. Eddy’s hot plate method used for inducing anxiety. EPM and LDA models were used to study the effect of drugs in reducing the pain and anxiety. Results: The present study showed that the exposure to hot plate induces pain, creates anxiety, and reduces locomotor and explorative activity among the rats when exposed to hot plate. There was reduction in anxiety after drug administration, in fluoxetine and gabapentin with tramadol groups with >75% increase in entry into the light chamber or open arm at least once or more during the time period of 5 min when compared to hot plate post-exposure readings. Whereas in pregabalin and tramadol group, it was observed that 25% increase in entry of rats into open arm at least once during the time period of 5 min and 25% decrease in entry of rats into light chamber as compared to those rats after exposure to hot plate. Conclusion: Our study has demonstrated that tramadol, pregabalin, and gabapentin have got analgesic as well as anti-anxiety effects in rats when given in combination. All these experimental data, together with the previous experimental studies and the results reported in this work, suggest that combination of these drugs could be more effective in treating anxiety-related disorders such as chronic pain, pain-induced anxiety, post-operative, and procedure-related pain-induced anxiety with minimal side effects. Further dose ranging studies and models might be necessary to better understand the effects of these drugs in combination.

Effect of fluoxetine combined with Shugan Jieyu capsule in the treatment of patients with depression and its impact on heart rate variability / 四川精神卫生

BackgroundDepression is a kind of disease with relatively high suicide risk， which seriously affects the quality of life of patients and their families， and brings a great burden to society. Antidepressants in western medicine are effective， but the improvement of depressive symptoms is relatively limited by single use， and the combination of two antidepressants may increase the risk of adverse reactions in patients. The rational use of Chinese patent medicine and western medicine may play a complementary role， and the safety of Chinese patent medicine is high. ObjectiveTo explore the early clinical efficacy of fluoxetine combined with Shugan Jieyu capsule in the treatment of depression， and to compare the differences in efficacy， safety and influence on heart rate variability between fluoxetine combined with Shugan Jieyu capsule and fluoxetine alone， so as to provide references for clinical medication of depression patients. MethodsFrom December 2015 to June 2016， 64 patients who met the diagnostic criteria of depression in the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） who were hospitalized in the Second Affiliated Hospital of Xinxiang Medical University were selected as the research objects， and were randomly divided into the combined medication group and the fluoxetine group with 32 patients in each group. Patients in both groups were treated with fluoxetine， while patients in the combined medication group were treated with Shugan Jieyu capsule on this basis. Patients in both groups were assessed with Hamilton Depression Scale-24 item （HAMD-24）， Hamilton Anxiety Scale （HAMA） and Heart Rate Variability （HRV） before treatment， and were assessed with HAMD-24 and Treatment Emergent Symptom Scale （TESS） at the end of the 2nd， 4th and 6th week of treatment， and HRV was analyzed again at the end of the 6th week of treatment. ResultsThe study ultimately included 60 patients with depression， with 30 cases in the combination therapy group and 30 cases in the fluoxetine group. At the end of the 2nd， 4th and 6th week of treatment， the HAMD-24 score of the combined drug group was lower than that of the fluoxetine group （t=-2.677， -3.960， -4.432， P<0.05 or 0.01）. Compared with before treatment， the 24-hour mean standard deviation of normal RR intervals （SDNN）， normal low frequency （nLF） and normal high frequency （nHF） in the combined treatment group were higher at the end of the 6th week （t=-73.970， -31.878， -38.721， P<0.01）， but significant lower in LF/HF （t=3.525， P<0.01）. At the end of the 6th week of treatment， the total effective rate of the combined treatment group was higher than that of fluoxetine group， and the difference was statistically significant （86.67% vs. 70.00%， χ2=18.764， P<0.01）. At the 2nd， 4th and 6th week of treatment， there was no significant difference in the number of adverse reactions between the two groups （P>0.05）. ConclusionCompared with fluoxetine alone， Shugan Jieyu capsule combined with fluoxetine may be better in clinical efficacy and improvement of heart rate variability in patients with depression， without increasing adverse reactions.

Governor vessel moxibustion combined with western medication for mild to moderate depression with kidney-yang deficiency: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the therapeutic efficacy of governor vessel moxibustion combined with fluoxetine hydrochloride capsule, simple fluoxetine hydrochloride capsule and placebo moxibustion combined with fluoxetine hydrochloride capsule for mild to moderate depression with kidney-yang deficiency.@*METHODS@#A total of 126 patients with mild to moderate depression with kidney-yang deficiency were randomized into a governor vessel moxibustion group (42 cases, 2 cases dropped off), a western medication group (42 cases, 1 case dropped off) and a placebo moxibustion group (42 cases, 1 case dropped off). The western medication group was given fluoxetine hydrochloride capsule orally, 20 mg a time, once a day. On the basis of the treatment in the western medication group, governor vessel moxibustion was applied from Dazhui (GV 14) to Yaoshu (GV 2) in the governor vessel moxibustion group, once a week; placebo moxibustion was applied in the placebo moxibustion group, once a week. Treatment of 8 weeks was required in the 3 groups. Before and after treatment, the scores of Hamilton depression scale-17 (HAMD-17), Asberg's rating scale for side effects (SERS) and TCM clinical symptom were compared, and the clinical efficacy was evaluated.@*RESULTS@#After treatment, the scores of HAMD-17, SERS and TCM clinical symptom were decreased compared before treatment in the 3 groups (P<0.05), the decrease ranges of above scores in the governor vessel moxibustion group were larger than those in the western medication group and the placebo moxibustion group (P<0.05). The total effective rate was 92.5% (37/40) in the governor vessel moxibustion group, which was higher than 75.6% (31/41) in the western medication group and 80.5% (33/41) in the placebo moxibustion group (P<0.05).@*CONCLUSION@#Governor vessel moxibustion combined with fluoxetine hydrochloride capsule can improve the degree of depression and relieve the clinical symptoms in mild to moderate depression patients with kidney-yang deficiency, the efficacy is superior to simple fluoxetine hydrochloride capsule, and can reduce the fluoxetine hydrochloride capsule-induced adverse effect to a certain extent.

The influence of fluoxetine on orthodontic tooth movement in rats

Abstract This study aimed to evaluate the effects of chronic use of fluoxetine on the amount of orthodontic tooth movement and tissue changes in rats. A total of 192 Wistar rats were divided into 4 groups: S, 0.9% saline solution; F, 20 mg/kg of fluoxetine; SM, 0.9% saline solution with orthodontic movement; and FM, 20 mg/kg of fluoxetine with orthodontic movement. After 30 days of daily saline or fluoxetine administration, an orthodontic device (25cN) was used to mesially displace the first molar in animals of the groups SM and FM. The animals were euthanized 2, 7, 14, and 28 days after placement of the orthodontic appliances and animals of groups S and F were euthanized at the same time. The assessment of tooth movement was made in gypsum castings, the collagen neoformation was assessed by polarization microscopy, the number of osteoclasts and root resorption were evaluated using tartrate-resistant acid phosphatase, and presence of hyalinized areas was assessed by hematoxylin-eosin staining. Fluoxetine did not affect the amount of tooth displacement, percentage of collagen, number of osteoclasts, and presence of hyalinized areas (P>0.05). There was a higher frequency of root resorption areas in the FM group than in the SM group only on the second day (P<0.05). The findings of this study show that chronic use of 20 mg/kg fluoxetine does not affect the amount of tooth movement, collagen neoformation, number of osteoclasts, or hyalinized areas and does not affect root resorption until the last day of orthodontic movement.

Mutagenic Evaluation of Fluoxetine and Fluoxetine-Galactomannan Complex Through the Analysis of Chromosomal Aberrations in Human Peripheral Leukocytes and Salmonella typhimurium/Microssome Assay / Avaliação Mutagênica de Fluoxetina e Complexo Fluoxetina-Galactomanana Através da Análise de Aberrações Cromossômicas em Leucócitos Periféricos Humanos e em Salmonella typhimurium / Ensaio Microssômico

Objectives: The purpose of this study was to evaluate the mutagenic potential of fluoxetine and fluoxetine-galactomannan. Methods: Chromosomal aberration test and Salmonella typhimurium/microsome mutagenicity assay. Results: The results showed that fluoxetine (250 µg/mL) can cause chromosomal breaks of treated leukocytes and increase the frequency of reversion of the tester strains of S. typhimurium / microsome assay only at the highest concentration (5 mg/mL), while fluoxetine encapsulated in galactomannan did not cause these changes (leukocytes and S. typhimuriums strains). Conclusion: In summary, fluoxetine showed a mutagenic effect detectable only at high concentrations in both eukaryotic and prokaryotic models. Furthermore, the fluoxetine/galactomannan complex, in this first moment, prevented the mutagenicity attributed to fluoxetine, emphasizing that the present encapsulation process can be an alternative in preventing these effects in vitro.

Objetivos: avaliar o potencial mutagênico da fluoxetina e da fluoxetina-galactomanana. Métodos: Teste de aberração cromossômica e ensaio de mutagenicidade de Salmonella typhimurium /microssoma. Resultados: a fluoxetina (250 µg/mL) pode causar quebras cromossômicas de leucócitos tratados e aumentar a frequência de reversão das cepas testadoras de S. typhimurium /microssoma apenas na concentração mais alta (5 mg/mL), enquanto a fluoxetina encapsulada em galactomanano não causou essas alterações (leucócitos e cepas de S. typhimurium). Conclusão: a fluoxetina mostrou um efeito mutagênico detectável apenas em altas concentrações em modelos eucarióticos e procarióticos. Além disso, o complexo fluoxetina/galactomanan, neste primeiro momento, evitou a mutagenicidade atribuída à fluoxetina, ressaltando que o presente processo de encapsulamento pode ser uma alternativa na prevenção desses efeitos in vitro.

Olfactory Reference Syndrome: a case report

Olfactory reference syndrome (ORS) is a psychiatric condition characterized by the false belief that an individual emits an offensive or foul odour from their body. It causes lot of embarrassment and social impairment to these patients. Treatment options include antidepressants and antipsychotics. Here we present a case of Olfactory Reference Syndrome who responded to combination of antipsychotics and antidepressant.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats / A serotonina endógena e exógena, mas não o sumatriptano, melhora as convulsões e a neuroinflamação no modelo de convulsão induzida por pentilenotetrazol em ratos

ABSTRACT Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

RESUMO Antecedentes: A epilepsia apresenta comorbidades neuropsiquiátricas como depressão, transtorno bipolar e ansiedade. Os medicamentos que visam o tratamento da epilepsia podem ser úteis para a epilepsia e suas comorbidades neuropsiquiátricas. Objetivo: Investigar os efeitos da modulação serotonérgica em citocinas pró-inflamatórias e as convulsões no modelo de convulsão induzida por pentilenotetrazol (PTZ) em ratos. Métodos: Ratos Wistar machos foram injetados intraperitonealmente com serotonina, inibidor seletivo da recaptação da serotonina fluoxetina, sumatriptano agonista do receptor 5-HT1B / D ou solução salina 30 min antes do tratamento com PTZ. As crises comportamentais foram avaliadas pela escala de Racine. As concentrações de IL-1β, IL-6 e TNF-α no soro e tecido cerebral foram determinadas por ELISA. Resultados: A serotonina e a fluoxetina, mas não o sumatriptano, aliviaram as convulsões induzidas por PTZ ao prolongar os tempos de início das convulsões mioclônicas e tônico-clônicas generalizadas. O efeito anticonvulsivo da fluoxetina foi maior do que o da serotonina. Da mesma forma, a serotonina e a fluoxetina, mas não o sumatriptano, reduziram os aumentos induzidos por PTZ nos níveis de IL-1β e IL-6 no soro e no tecido cerebral. Nenhum dos medicamentos administrados, incluindo PTZ, alterou as concentrações de TNF-α. Conclusões: Nossos achados sugerem que a serotonina endógena e exógena exibe efeitos anticonvulsivantes por suprimir a neuroinflamação. Aparentemente, os receptores 5-HT1B / D não medeiam os efeitos anticonvulsivantes e anti-neuroinflamatórios da serotonina.

Analysis of Adherence to Fluoxetine Treatment through its Plasma Concentration

Abstract Depression plays an important role in non-adherence to medical recommendations. Fluoxetine is a first line of depression treatment. This study aimed to evaluate adherence to drug therapy in fluoxetine users by different methods. A cross-section study was conducted with 53 depressed patients on fluoxetine for at least six months. Drug therapy adherence was assessed by validated questionnaires [Brief Medication Questionnaire (BMQ) and Morisky-Green test (MG)] and by the blood concentration of fluoxetine and its active metabolite norfluoxetine. Blood samples were taken before the daily first dose of fluoxetine. The plasmatic concentration of fluoxetine and norfluoxetine indicated that 58.5% volunteers were within the recommended therapeutic range and thus considered adherent to drug therapy. However, questionnaires indicated a non-adherent majority: 41.5% patients had a high degree of adherence in MG and only 13.2% were adherent to pharmacological treatment in BMQ. Most fluoxetine users showed a plasma concentration of fluoxetine and norfluoxetine within the therapeutic range, despite the low adherence to the drug therapy evaluated by the questionnaires. Thus, we suggest that plasma levels of fluoxetine and norfluoxetine could be used as the main method to check adherence to treatment.

Determination of fluoxetine ，norfluoxetine and sertraline concentration in human placental perfusate and their placental permeability by UFLC-MS/MS / 中国药房

OBJECTIVE To establish t he method for determining the concentrations of fluoxetine ，norfluoxetine and sertraline in human placental perfusate method and their placental permeability. METHODS Using glyburide as internal standard ，the samples were pretreated by protein precipitation method and detected by ultra-fast liquid chromatograph-mass spectrometer/mass spectrometer （UFLC-MS/MS）. The determination was performed on Synergi TM Hydro-RP 80A LC column with mobile phase consisted of water （containing 0.1％ formic acid ）-acetonitrile（containing 0.1％ formic acid ）at the flow rate of 0.70 mL/min，with a gradient elution. The column temperature was set at 40 ℃，and sample size was 5 μL. Detection was performed with electrospray ionization source in multipl e reaction monitoring mode . The ion pairs for quantitative analysis we re m/z 309.9→148.1（fluoxetine），m/z 296.0→134.4 （-167）， （norfluoxetine），m/z 306.1→159.0 （sertraline），m/z 493.9→ No.2018FE001（-207），（internal standard ）. The perfusion model of singal placenta under bidrectional cardiopulmonary bypass was established. Fluoxetine （160 ng/mL），norfluoxetine（160 ng/mL）， sertraline（100 ng/mL）and antipyrine （positive control ，ng/mL）were added into the maternal perfusate. The concen- 65324888 trations of fluoxe tine， norfluoxetine and sertrali ne were measured by above UFLC-MS/MS at 0，10，20，30，45，60，90，120，150 and 180 min of circulation ，and the placental permeability was calculated. RESULTS The linear range of fluoxetine ，norfluoxetine and sertraline were 5.00-500 ng/mL（all r＞ 0.990），and the lower limits of quantification were all 5.00 ng/mL. The RSDs of intra-day and inter-day were all less than 14.0％， and relative error ranged －9.6％ to 14.7％. The relative error of stability test was －4.0％ to 11.0％；the residual effect ，extraction method and matrix effect did not affect the quantitative analysis of the substance to be tested. Totally 31 perfusion model of human placenta under cardiopulmonary bypass were successfully established ，including 15 fluoxetine and norfluoxetine perfusion ，10 sertraline perfusion and 6 antipyrine perfusion. After 3 hours of perfusion ，the average placental permeability of fluoxetine ， norfluoxetine and sertraline were （8.74 ± 1.67）％ ，（10.70 ± 4.81）％ ，（5.90 ± 1.25）％ ，respectively. CONCLUSIONS The established UPLC-MS/MS is simple ，sensitive and accurate. It can be used for determination of fluoxetine ，norfluoxetine and sertraline in human placental perfusate. Fluoxetine ，norfluoxetine and sertraline can pass through the placenta ，but sertraline has a lower placental permeability.

Efficacy of combined fluoxetine and aniracetam tablets in the treatment of senile depression and its effects on serum total bile acid and norepinephrine levels / 中国基层医药

Objective:To investigate the efficacy of combined fluoxetine and aniracetam tablets in the treatment of senile depression and its effects on serum total bile acid (TBA) and norepinephrine (NE) levels.Methods:A total of 100 older adult patients with depression who received treatment in Heze Medical College from January 2019 to December 2019 were included in this study. They were randomly assigned to receive either fluoxetine tablets alone (control group, n = 50) or fluoxetine and aniracetam tablets (study group, n = 50). All patients received two months of treatment. Clinical efficacy, scores of the Hamilton Rating Scale for Anxiety (HAMA) and the Hamilton Rating Scale for Depression (HAMD), adverse reactions, and serum TBA and NE levels were compared between the two groups. Results:Total response rate was significantly higher in the study group than in the control group [96.0% (48/50) vs. 84.0% (42/50), χ2 = 4.00, P = 0.045]. HAMD and HAMA scores post-treatment in the study group were (5.85 ± 1.81) points and (4.81 ± 1.57) points, respectively, which were significantly lower than those in the control group [(11.65 ± 2.65) points, (10.85 ± 2.84) points, t = 10.84, P < 0.001; t = 11.16, P < 0.001). Serum NE level was significantly higher in the study group than in the control group [(138.68 ± 16.35) ng/L vs. (127.17 ± 14.34) ng/L, t = 3.17, P = 0.002]. There were no significant differences in serum TBA level [(5.85 ± 0.63) μmol/L vs. (5.91 ± 0.65) μmol/L] and the incidence of adverse reactions (8.00% vs. 6.00%) between the study and control groups ( t = 0.39, P = 0.692; χ2 = 0.15, P = 0.695). Conclusion:The combined therapy of fluoxetine and aniracetam tablets for the treatment of senile depression is safe and highly effective, does not affect metabolic function and thereby deserves clinical application.

Effects of fluoxetine on lipidomics of hippocampal tissue in chronic unpredictable stress model rats / 中华行为医学与脑科学杂志

Objective:To investigate the effects of fluoxetine (Flx) on lipidomics of hippocampal tissue in chronic unpredictable stress (CUS) model rats.Methods:A total of 30 Sprague-Dawley rats were randomly divided into Sham group, CUS group and CUS+ Flx group, with 10 rats in each group. Rats in the CUS group and CUS+ Flx group were received one or two random stimuli every day for 28 days, and then they were received intraperitoneal injection of normal saline(1 ml/kg) and fluoxetine(10 mg/kg) respectively once a day for 14 days. Rats in the Sham group were maintained in their home cages for 28 days, and then received intraperitoneal injection of saline (1 ml/kg) once a day for 14 days. The sugar water preference experiment was carried out 24 hours after the last injection, and then the rats were killed to separate the rat hippocampus. The levels of lipid composition in hippocampus were detected by high performance liquid chromatography-mass spectrometry. The relative content of lipid was analyzed by Simca-p 14.1 and LipidSearch software version 4.1. SPSS 19.0 was used for statistical analysis. One-way ANOVA or Kruskal-Wallis test was used for comparison among groups, and Bonferroni test was used for post-hoc test. Pearson correlation or Spearman correlation was used to analyze the correlation between behavioral indexes and lipid molecular level in hippocampus.Results:There was significant difference in sugar preference test among the three groups ( F=12.830, P<0.001). The percentage of sucrose intake of rats in CUS group ((43.57±12.38)%) was significantly lower than those in Sham group ((67.09±11.81)%) and CUS+ Flx group ((62.74±8.58)%) (both P<0.05). Ninety five differential lipid molecules were screened among the three groups by lipidomic analysis, mainly distributed in glycerophospholipids and sphingolipids. Among them, levels of PE (34∶1e)+ H( r=-0.477), PE(18∶1p/20∶1)+ H( r=-0.433), PE(18∶1/18∶1)+ Na( r=-0.603), PE(36∶2p)-H( r=-0.382), PE(16∶0/20∶4)-H( r=-0.464), PE(18∶0/18.2)-H( r=-0.482), PE(16∶0e/22∶6)-H( r=-0.514), PE(18∶1/20∶4)-H( r=-0.511) and CerG1 (d18∶2/24∶0+ O)+ H( r=-0.490) were negatively correlated with sucrose preference rate (all P<0.05), whereas levels of PE (42∶6p)+ Na( r=0.379), PE(34∶0p)-H( r=0.397) and SM (d22∶1/16.0)+ HCOO( r=0.388) were positively correlated with sucrose preference rate (all P<0.05). Conclusion:Flx improves the depressive-like behavior of CUS model rats, which may be related to the regulation of hippocampal glycerophospholipid and sphingolipid metabolism.

Brain-derived Neurotropic factor (BDNF) mediates the protective effect of Cucurbita pepo L. on salivary glands of rats exposed to chronic stress evident by structural, biochemical and molecular study

Abstract Acute and chronic stresses affect the salivary glands, representing the source of plasma BDNF during stressful conditions. Pumpkin is a medicinal plant with an evident antioxidant, anti-inflammatory and potential antidepressant effects. Objective To assess the structural and biochemical effects induced by exposure to chronic unpredictable mild stress (CUMS) on salivary glands of albino rats, and to evaluate the role of pumpkin extract (Pump) in ameliorating this effect. Methodology Four groups (n=10 each) of male albino rats were included in this study: the control, CUMS, Fluoxetine-treated and Pump-treated. The corticosterone, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the oxidant/antioxidant profile were all assessed in the serum. The level of BDNF mRNA was measured in the salivary glands using qRT-PCR. Histopathological changes of the salivary glands were also assessed. Results The depressive-like status was confirmed behaviorally and biochemically. Exposure to CUMS significantly up-regulated (p<0.001) the level of serum corticosterone. CUMS induced degenerative changes in the secretory and ductal elements of the salivary glands evident by increased apoptosis. Both Fluoxetine and Pumpkin significantly up-regulated (p<0.001) BDNF expression in the salivary glands and ameliorated the CUMS-induced histopathological and biochemical alterations in the salivary glands. Pumpkin significantly (p<0.001) increased the serum levels of antioxidant enzymes SOD, GPX and CAT, and reduced the serum levels of the pro-inflammatory cytokines TNF-α, IL-6. Conclusion Pumpkin ameliorates the depressive-like status induced in rats following exposure to chronic stress through exerting a promising anti-inflammatory, antioxidant and anti-depressant-like effects. The pumpkin, subsequently, improved stress-induced structural changes in the salivary glands that might be due to up-regulation of BDNF expression in the glands.

Effects of duloxetine, fluoxetine and pregabalin on fentanyl-induced hyperalgesia in rattus novergicus / Efeitos da duloxetina, fluoxetina e pregabalina sobre a hiperalgesia induzida por fentanil em rattus novergicus

ABSTRACT BACKGROUND AND OBJECTIVES: Opioids are drugs used to relieve pain, but may cause increased pain sensitivity, known as opioid-induced hyperalgesia, which adversely affects pain management. This study aimed to check if fentanyl, an opioid widely used in the clinical practice, produces hyperalgesia that can be attenuated by duloxetine, fluoxetine and pregabalin. METHODS: Thirty male Wistar rats were divided into six groups. The animals in group 1 received 1mL of 0.9% saline solution intraperitoneally (IP) and gavage; group 2 received fentanyl at a dose of 100µg.kg-1 IP and 0.9% saline solution per gavage; groups 3, 4 and 5 received fentanyl at the dose of 100µg.kg-1 IP, and gavage with duloxetine, 40mg.kg-1, fluoxetine, 40mg.kg-1 and pregabalin, 40mg.kg-1, respectively. Under general anesthesia with isoflurane, all animals were submitted to plantar surgical incision. The application of Von Frey filaments assessed hyperalgesia at the second hour, one, three, five and seven days after treatment. RESULTS: Two hours after the procedure, no differences were observed between G1 and G2, although G3, G4, and G5 showed less hyperalgesia. On day one and day three, a greater hyperalgesic effect was observed in G2 when compared to G1, G3, G4 and G5. On day five, there was a hyperalgesic effect on G2, and on day seven, there were no differences among the groups. CONCLUSION: The results suggest that fentanyl induces hyperalgesia and the efficacy of duloxetine, fluoxetine, and pregabalin in reducing it.

RESUMO JUSTIFICATIVA E OBJETIVOS: Opioides são fármacos utilizados para o alívio da dor, porém, podem causar aumento da sensibilidade dolorosa, denominada hiperalgesia induzida por opioides, que afeta negativamente o tratamento da dor. O objetivo deste estudo foi avaliar se o fentanil, opioide amplamente utilizado na prática clínica, produz hiperalgesia que pode ser atenuada pela duloxetina, fluoxetina e pregabalina. MÉTODOS: Trinta ratos Wistar machos, foram divididos em 6 grupos. No grupo 1, os animais receberam 1mL de solução fisiológica (SF) a 0,9% por via intraperitoneal (IP) e por gavagem; no grupo 2, fentanil na dose de 100µg.kg-1 IP e SF a 0,9% por gavagem; nos grupos 3, 4 e 5 os animais receberam fentanil na dose de 100µg.kg-1 IP e, por gavagem, receberam respectivamente duloxetina, 40mg.kg-1, fluoxetina, 40mg.kg-1 e pregabalina, 40mg.kg-1. A avaliação da hiperalgesia e sua atenuação foi feita pela aplicação de filamentos de Von Frey, na 2ª hora e nos dias 1, 3, 5 e 7, após o tratamento. RESULTADOS: Na 2ª hora pós-procedimento não foram observadas diferenças entre G1 e G2, entretanto, G3, G4 e G5 se mostraram com menor hiperalgesia. No 1º e 3º dias foi observado maior efeito hiperalgésico em G2 quando comparado com G1, G3, G4 e G5. No 5º dia foi observado efeito hiperalgésico no G2, e no 7º dia não houve diferenças entre os grupos. CONCLUSÃO: Os resultados sugerem que o fentanil induz hiperalgesia e eficácia da duloxetina, fluoxetina e pregabalina na sua redução.

Effect and mechanism of fluoxetine on improving working memory in rats with chronic cerebral ischemia / 中国脑血管病杂志

Objective To observe the protective effects of fluoxetine on working memory impairment induced by chronic cerebral ischemia and further explore its mechanism in rats. Methods The rat model of chronic cerebral ischemia was made by surgical ligation of the bilateral carotid artery. 44 male Sprague Dawley rats were divided into sham group (n = 10) , ischemic model group (ra = 12), ischemic + fluoxetine group (n = 12) , and sham + fluoxetine group (n = 10). Fluoxetine was administered by gavage after 1 week of ischemic surgery and continued for 4 weeks. The sham group and the ischemic model group were given the same volume of 0. 9% saline. The performance of working memory was tested by a modified Morris water maze experiment that lasted for 4 days. The expression of neuronal nuclei (NeuN) , S-100(3, G protein gated inwardly rectifying K channels 1,2, and 3 ( GirKl , 2 , and 3 ) , and sorting nexin 27 ( SNX27 ) in the prefrontal cortex ( PFC) of rats were tested by Western blot, and compare between groups. Results (1) There was no significant difference in swimming speed among the four groups ( P > 0.05 ). In the training experiment, there was no significant difference among the four groups in the escape latency and the swimming distance ( both P > 0.05 ). In the memory retention test, the escape latency of rats in the ischemic model group was significantly increased on 2nd, 3rd and 4th day compared with the sham group (day2: [48.2 ±6. 3] s vs. [27.4±4.0]s, day 3 :[53.9 ±6.4] s vs. [29.4±6.3]s, day4: [41.4± 4. 9] s vs. [23.8 ±3.7] s; all P 0.05). (3) There was no significant difference in the membrane expression of GirKl protein among the four groups (P > 0. 05). Taking the sham group as a reference and the relative grey value of GirK2 and GirK3 is defined as 1, the relative grey values of GirK2 in the ischemia model group and the ischemia + fluoxetine group were 1. 27 ± 0. 07 and 1. 06 ±0.06, the relative grey values of GirK3 in the ischemia model group and the ischemia + fluoxetine group were 1.23 ±0.08 and 1.00 ±0.06. The membrane expression of GirK2 and GirK3 in the ischemic model group was higher than that in the sham group. The membrane expression of GirK2 and GirK3 in the ischemic + fluoxetine group was down-regulated compared with the ischemic model group ( both P < 0. 05). (4) Taking the sham group as a reference and the relative grey value of SNX27 in the sham group is defined as 1, the relative grey values of SNX27 in the ischemia model group, the ischemia + fluoxetine group, and the sham + fluoxetine group were 0. 78 ± 0.09, 0.97 ± 0.04, and 0. 94 ±0.05, respectively. The expression of SNX27 in the ischemic model group was lower than that in the sham group, and the down-regulation of SNX27 expression in the ischemic model group was reversed after fluoxetine treatment (P<0. 05). Conclusion Fluoxetine can ameliorate working memory impairment of rats induced by chronic cerebral ischemia, which may partly reverse the increase of surface expression of GirK2 and GirK3 in the prefrontal cortex through acting on SNX27.

Fluoxetine Induces Apoptotic and Oxidative Neuronal Death Associated with The Influx of Copper Ions in Cultured Neuronal Cells / 전남의대학술지

We examined the effect of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on neuronal viability in mouse cortical near-pure neuronal cultures. Addition of fluoxetine to the media for 24 hours induced neuronal death in a concentration-dependent manner. To delineate the mechanisms of fluoxetine-induced neuronal death, we investigated the effects of trolox, cycloheximide (CHX), BDNF, z-VAD-FMK, and various metal-chelators on fluoxetine-induced neuronal death. Neuronal death was assessed by MTT assay. The addition of 20 µM fluoxetine to the media for 24 hours induced 60–70% neuronal death, which was associated with the hallmarks of apoptosis, chromatin condensation and DNA laddering. Fluoxetine-induced death was significantly attenuated by CHX, BDNF, or z-VAD-FMK. Treatment with antioxidants, trolox and ascorbate, also markedly attenuated fluoxetine-induced death. Interestingly, some divalent cation chelators (EGTA, Ca-EDTA, and Zn-EDTA) also markedly attenuated the neurotoxicity. Fluoxetine-induced reactive oxygen species (ROS) generation was measured using the fluorescent dye 2′,7′-dichlorofluorescin diacetate. Trolox and bathocuproine disulfonic acid (BCPS), a cell membrane impermeable copper ion chelator, markedly attenuated the ROS production and neuronal death. However, deferoxamine, an iron chelator, did not affect ROS generation or neurotoxicity. We examined the changes in intracellular copper concentration using a copper-selective fluorescent dye, Phen Green FL, which is quenched by free copper ions. Fluoxetine quenched the fluorescence in neuronal cells, and the quenching effect of fluoxetine was reversed by co-treatment with BCPS, however, not by deferoxamine. These findings demonstrate that fluoxetine could induce apoptotic and oxidative neuronal death associated with an influx of copper ions.

Which of available selective serotonin reuptake inhibitors (SSRIs) is more effective in treatment of premature ejaculation? A randomized clinical trial

ABSTRACT Purpose: To compare the efficacy and safety of available selective serotonin reuptake inhibitors (SSRIs) in order to find the most effective drug with the least number of side effects in treatment of premature ejaculation (PE). Materials and Methods: This study was a randomized clinical trial. Four hundred and eighty patients with PE in the 4 groups referred to Imam Reza hospital Tehran, Iran from July 2018 to February 2019 were enrolled in the study. The patients received sertraline 50mg, fluoxetine 20mg, paroxetine 20mg and citalopram 20mg, every 12 hours daily. The intravaginal ejaculatory latency time (IELT) before treatment, fourth and eighth weeks after treatment was recorded by the patient's wife with a stopwatch. Results: Mean IELT before, 4 and 8 weeks after treatment in four groups were: sertraline 69.4±54.3, 353.5±190.4, 376.3±143.5; fluoxetine 75.5±64.3, 255.4±168.2, 314.8±190.4; paroxetine 71.5±69.1, 320.7±198.3, 379.9±154.3; citalopram 90.39±79.3, 279.9±192.1, 282.5±171.1 seconds, respectively. The ejaculation time significantly increased in all groups (p <0.05), but there was no significant difference between the groups (P=0.75). Also, there was no significant difference in drugs side effects between groups (p >0.05). The most common side effects were drowsiness and dyspepsia, which were not severe enough to cause discontinuation of the drug. Conclusions: All available SSRIs were effective and usually had no serious complications. In patients who did not respond to any of these drugs, other SSRI drugs could be used as a salvage therapy.

Effect of vitamin D on depression: an experimental study

Background: There is a scarcity of studies regarding antidepressant activity of vitamin D in animals while there are some contradictory reports regarding the same in humans. Therefore the present study was planned to investigate the antidepressant effect of vitamin D and its interaction with standard antidepressant drugs in animals.Methods: Forced swim test (FST) in adult male Wistar rats and tail suspension test (TST) in adult male Swiss albino mice were used to investigate antidepressant activity of vitamin D administered in single dose and multiple doses. Imipramine, a tri-cyclic antidepressant and fluoxetine, a selective serotonin reuptake inhibitor were used as standard antidepressant drugs. For interaction studies, half the therapeutic equivalent dose of vitamin D was combined with sub-effective dose (SED) of imipramine or fluoxetine. Data was expressed as Mean±SD and analyzed by standard statistical tests. P<0.05= significant. Present study was ethically approved.Results: Single dose administration of vitamin D did not show significant antidepressant effect either in FST or TST. Multiple dose administration of vitamin D showed significant antidepressant activity in TST but not in FST. Combination of vitamin D (half dose) with SED of either standard antidepressant drugs did not show any significant antidepressant activity. None of the treatment groups showed any significant difference on locomotor activity.Conclusions: In the present study, multiple dose administration of vitamin D showed some antidepressant activity. Further studies are needed to confirm and elaborate the role of vitamin D in behavioral disorders like depression.

Effects of in vitro amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts

Abstract Objective: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. Methods: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3×10-6M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10-11-3x10-5M, while venlafaxine was added in the range of 10-9-3×10-5M. Then, the antidepressant-induced relaxation responses were recorded isometrically. Results: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. Conclusion: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium.

Effect of Mirtazapine Pre-treatment on Haloperidol, Ergometrine and Fluoxetine Induced Behaviours in Albino Rats.

Background: Central 5-HT and 5-HT serotonergic 2A 2Creceptors are mainly involved in the control ofnigrostriatal and mesolimbic dopaminergic neuronalactivity has been well proved and established. 5-HThas facilitatory effect on stimulated dopamine releaseby stimulating central 5-HT receptors and inhibitory 2Aeffect by stimulating 5-HT receptors. Aim and 2CObjectives: To evaluate 5-HT and 5-HT receptor 2A 2Cblocking activity of Mirtazapine (MIR) and the effectof mirtazapine pre-treatment on Ergometrine (ERG)induced behaviours, Fluoxetine (FLU) induced penileerections and Haloperidol (HAL) induced catalepsy inrats. Material and Methods: Each group wassubdivided into different subgroups consisting 6animals in each. Control group received DimethylSulfoxide (DMSO) and other groups received differentdoses of mirtazapine one hour before ERG/FLU/HAL.Values obtained from control group were comparedwith all remaining groups pre-treatment with differentdoses of MIR. Results: MIR (MIR) at 2.5, 5, 10 and 20mg/kg intraperitoneally (i.p) did not produce any per seeffects. Pre-treatment with 5, 10 and 20 mg/kg i.p. MIRsignificantly antagonised ERG induced behaviours. 5mg/kg i.p. MIR significantly antagonised whereas 10and 20 mg/kg i.p. MIR abolished FLU (10 mg/kg)induced penile erections in rats. MIR 5 and 20 mg/kgi.p. significantly antagonised HAL (1mg/kg) inducedcatalepsy at 1 hr testing time interval while 10 and 20mg/kg MIR significantly antagonised HAL (1 mg/kg)induced catalepsy at 2 hr testing time interval.Conclusion: Our results indicate that MIR at 5, 10 and20 mg/kg possesses 5-HT and 5-HT receptors 2A 2Cblocking activity. At 5, 10 and 20 mg/kg MIR, byblocking central 5-HT receptors predominantly, 2Ccauses release of dopamine from nigrostriataldopaminergic neurons and therefore antagonizes HALinduced catalepsy

Treatment-emergent dhat syndrome in a young male with Obsessive–Compulsive disorder: An alarm for medication nonadherence Highly accessed article

Dhat syndrome refers to a culture-bound syndrome of Southeast Asia, where patients present with anxiety and depressive and somatic symptoms, which they attribute to semen loss. Common presentation of these patients is the passage of semen-like substance in urine. Retrograde ejaculation may cause spermaturia, and patients with firmly held cultural myths related to sexuality may develop features of Dhat syndrome. Here, a patient with obsessive–compulsive disorder on treatment with fluoxetine developed retrograde ejaculation and subsequently features of Dhat syndrome.