Beneficial effects of antidepressant mirtazapine in functional dyspepsia patients with weight loss

AIM: To explore the effects and mechanism of action of antidepressant mirtazapine in functional dyspepsia(FD) patients with weight loss.METHODS: Sixty depressive FD patients with weight loss were randomly divided into a mirtazapine group(MG), a paroxetine group(PG) or a conventional therapy group(CG) for an 8-wk clinical trial. Adverse effects and treatment response were recorded. The Nepean Dyspepsia Index-symptom(NDSI) checklist and the 17-item Hamilton Rating Scale of Depression(HAMD-17) were used to evaluate dyspepsia and depressive symptoms, respectively. The body composition analyzer was used to measure body weight and fat. Serum hormone levels were measured by ELISA.RESULTS:(1) After 2 wk of treatment, NDSI scores were significantly lower for the MG than for the PG and CG;(2) After 4 or 8 wk of treatment, HAMD-17 scores were significantly lower for the MG and PG than for the CG;(3) After 8 wk of treatment, patients in the MG experienced a weight gain of 3.58 ± 1.57 kg, which was significantly higher than that observed for patients in the PG and CG. Body fat increased by 2.77 ± 0.14kg, the body fat ratio rose by 4%, and the visceral fat area increased by 7.56 ± 2.25 cm2; and(4) For the MG, serum hormone levels of ghrelin, neuropeptide Y(NPY), motilin(MTL) and gastrin(GAS) were significantly upregulated; in contrast, those of leptin, 5-hydroxytryptamine(5-HT) and cholecystokinin(CCK) were significantly downregulated. CONCLUSION: Mirtazapine not only alleviates symptoms associated with dyspepsia and depression linked to FD in patients with weight loss but also significantly increases body weight(mainly the visceral fat in body fat). The likely mechanism of mirtazapine action is regulation of brain-gut or gastrointestinal hormone levels.

Rapid improvement in post-infectious gastroparesis symptoms with mirtazapine

We report the case of a 34-year-old woman with severe post-infectious gastroparesis who was transferred from an outside medical facility for a second opinion regarding management. This patient had no prior history of gastrointestinal symptoms. However, in the aftermath of a viral illness, she developed two months of intractable nausea, vomiting, and oral intake intolerance that resulted in numerous hospitalizations for dehydration and electrolyte disturbances. A solid-phase gastric emptying scan had confirmed delayed emptying, confirming gastroparesis. Unfortunately, conventional pro-kinetic agents and numerous anti-emetic drugs provided little or no relief of the patient’s symptoms. At our institution, the patient experienced a cessation of vomiting, reported a significant reduction in nausea, and tolerated oral intake shortly after taking mirtazapine. Based on mirtazapine’s primary action as a serotonin (5-HT) 1a receptor agonist, we infer that this receptor system mediated the clinical improvement through a combination of peripheral and central neural mechanisms. This report highlights the potential utility of 5-HT1a agonists in the management of nausea and vomiting. We conclude that mirtazapine may be effective in treating symptoms associated with non-diabetic gastroparesis that are refractory to conventional therapies.

Determination of Mirtazapine in Human Plasma by HPLC-MS and Bioavailability of Newly Developed Mirtazapine Tablets in Healthy Volunteers

Aim To establish a sensitive and specific liquid chromatography-mass spectrometry method for determination of mirtazapine in human plasma and evaluation of its relative bioavailability. Methods After being alkalized by 25% ammonia, mirtazapine in the plasma was extracted with n-hexane. Desloratadine was used as internal standard (IS). Solu-tes were separated on a C_(18) column with a mobile phase of methanol-ammonium acetate buffer (pH 3.5) (75∶25). The flow rate of the mobile phase was 1 mL·min^(-1). Detection was performed on an electrospray ionization (ESI) mass spectrometer and operated in selected ion monitoring (SIM) and positive-ionization mode using target ionsat m/z 266.2 for mirtazapine and m/z 311.2 for the IS. The fragmentor voltage was 90 V. A randomized cross-over study was performed in 20 healthy volunteers. In the two study periods, twenty healthy Chinese male subjects received a single oral dose of mirtazapine 30 mg. Results The calibration curve was linear over the range of 0.3-200 ng·mL^(-1). The limit of quantitation was 0.1 ng·mL^(-1). The parameters for mirtazapine test tablet and reference tablet were as follows: T_(1/2)(24.7±4.1) and (23.6±4.3) h, T_(max)(1.6±0.8) and (1.5±0.8) h, C_(max)(95.9±29.8) and (91.9±26.7) ng·mL^(-1), respectively. Conclusion The established HPLC-MS method is rapid, sensitive and specific for the determination of mirtazapine in human plasma. The relative bioavailability was 100.0%±10.8%.

Development and Validation of an LC-MS/MS Method for Quantitative Analysis of Mirtazapine in Human Plasma

Mirtazapine (MTZ) is an antidepressant drug, which belongs to the chemical class of piperazinoazepines. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantifica- tion of MTZ in plasma at the concentrations associated with therapy. Diazepam (DZP) was used as internal standard, added to 200 μL of plasma sample prior to a liquid-liquid extraction using hexane. Chroma- tographic separation was achieved on an Agilent? Eclipse XDB C-18 column (100 × 2.1 mm, 3.5 μm) in iso- cratic mode at 40?C. Mobile phase was 10 mM ammonium acetate/acetonitrile/formic acid (60/40/0.1, v/v/v) at a constant flow rate of 0.5 mL?min–1. The injection volume was 10 ?L and the total run time was 3.2 min. The method shows selectivity and linearity. The detection and quantitation limits were established at 0.17 and 0.50 ng?mL–1, respectively. The extraction recoveries for MTZ and DZP were found to be between 84.9 and 93.9%. The intra-day and inter-day precision and accuracy fulfill at the international acceptance criteria. The method shows to be stable for the studied parameters. Therefore, a rapid, specific, and sensitive LC-MS/MS method for quantification of MTZ in human plasma was developed and can be used in therapeu- tic drug monitoring of this drug.

Determination of the antidepressant effect of mirtazapine augmented with caffeine using Swiss-albino mice

Depression is a serious health condition affecting an estimate of 350 million people worldwide.Monotherapy with antidepressants as first line treatment however is found to have limited benefits as compared to augmentation therapy.Psychoactive agents such as caffeine,when added to the antidepressants are found to have positive effects with depression by acting as an antagonist to adenosine receptors.Male Swiss albino mice were grouped into six,first three groups with arbitrary doses of the combination of mirtazapine and caffeine and last three control groups being the untreated,mirtazapine-treated and caffeine-treated groups.

Aqueous Solubility Enhancement of Mirtazapine: Effect of Cosolvent and Surfactant

The poor aqueous solubility of drugs is a challenging problem faced by pharmaceutical scientists in drug formulation. Cosolvency and micellization techniques have been severally used to enhance the solubility of poorly aqueous soluble drugs. Mirtazapine, a tetracyclic antidepressant used for the treatment of moderate to severe depression and anxiety, has very poor aqueous solubility. The objective of the study was to investigate the effect of solubilizing agents (cosolvents and surfactants) on the aqueous solubility of mirtazapine while envisaging that any significant improvement in its aqueous solubility could contribute towards alleviating the withdrawal symptoms often associated with the drug. The solubility of mirtazapine was determined at room temperature in aqueous mixtures of cosolvents (propylene glycol and polyethylene glycol 400) and surfactants (polysorbate 20, polysorbate 80 and sodium lauryl sulfate). An exponential increase in mirtazapine solubility was observed when total drug solubility in water-cosolvent system was plotted against cosolvent fraction volume. Polyethylene glycol 400 gave larger solubilization capacity (σ) when compared to propylene glycol. With the surfactants, linear relationship between the total solubility of the drug in water-surfactant mixtures and surfactant concentration was noted. Sodium lauryl sulfate showed the largest solubilization power (k) when compared to the nonionic surfactants (polysorbate 20 and polysorbate 80 respectively). A linear relationship between standard free energy and partition coefficient was also observed. The result of the study shows that aqueous solubility of mirtazapine is significantly improved by cosolvency and micellization and therefore there exists the possibility of improving the withdrawal symptoms often experienced with the drug. It also suggests that large free energy is required for drugs with high partition coefficients to permeate the biological membrane.

Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice

AIM: To investigate the effects of mirtazapine and fluoxetine, representatives of the noradrenergic and specific serotonergic antidepressant (NaSSA) and se- lective serotonin reuptake inhibitor (SSRI) antidepres- sant respectively, on body weight, ingestive behavior, locomotor activity and tumor growth of human pancre- atic carcinoma xenografts in nude mice. METHODS: A subcutaneous xenograft model of hu- man pancreatic cancer cell line SW1990 was estab- lished in nude mice. The tumor-bearing mice were ran- domly divided into mirtazapine group [10 mg/(kg·d)], fluoxetine group [10 mg/(kg·d)] and control group (an equivalent normal saline solution) (7 mice in each group). Doses of all drugs were administered orally, once a day for 42 d. Tumor volume and body weight were measured biweekly. Food intake was recorded once a week. Locomotor activity was detected weekly using an open field test (OFT). RESULTS: Compared to the fluoxetine, mirtazapine significantly increased food intake from d 14 to 42 and attenuated the rate of weight loss from d 28 to 42 (t = 4.38, P < 0.05). Compared to the control group, food intake was significantly suppressed from d 21 to 42 and weight loss was promoted from d 35 to 42 in the fluoxetine group (t = 2.52, P < 0.05). There was a significant difference in body weight of the mice after removal of tumors among the three groups. The body weight of mice was the heaviest (13.66 ± 1.55 g) in the mirtazapine group and the lightest (11.39 ± 1.45 g) in the fluoxetine group (F(2,12) = 11.43, P < 0.01). The behavioral test on d 7 showed that the horizontal and vertical activities were significantly increased in the mirtazapine group compared with the fluoxetine and control groups (F(2,18) = 10.89, P < 0.01). These effects disappeared in the mirtazapine and fluoxetine groups during 2-6 wk. The grooming activity was higher in the mirtazapine group than in the fluoxetine group (10.1 ± 2.1 vs 7.1 ± 1.9 ) (t = 2.40, P < 0.05) in the second week. There was no significant difference in tumor vol- ume and tumor weight of the three groups. CONCLUSION: Mirtazapine and fluoxetine have no effect on the growth of pancreatic tumor. However, mirtazapine can significantly increase food intake and improve nutrition compared with fluoxetine in a pan- creatic cancer mouse model.

An Efficient Process for Preparing 4-Methyl-2-phenyl Piperazine Hydrochloride and its Derivatives

An improved method for preparation of 4-methyl-2-phenyl piperazine and its derivatives with higher yield and inexpensive reagents was developed, the products were characterized by 1H-NMR and MS.