Meranzin hydrate

J Ethnopharmacol. 2011 Sep 1;137(1):205-13.

Pharmacokinetic study of the prokinetic compounds meranzin hydrate and ferulic acid following oral administration of Chaihu-Shugan-San to patients with functional dyspepsia.[Pubmed: 21605652]

The prokinetic activity of ferulic acid derived from Ligusticum chuanxiong hort in the Chaihu-Shugan-San formula has been shown to be similar to Chaihu-Shugan-San, a popular traditional Chinese medicine for treating functional dyspepsia. The effects of Meranzin hydrate, a compound isolated from Fructus aurantii in the Chaihu-Shugan-San formula, are unclear, as the pharmacokinetics have never been studied in patients with functional dyspepsia. This study aimed to describe the pharmacokinetics of ferulic acid and merazin hydrate by evaluating the prokinetics induced by Chaihu-Shugan-San and Meranzin hydrate.
METHODS AND RESULTS:
Gastric emptying and intestinal transit were measured after oral administration of a single dose of Chaihu-Shugan-San or Meranzin hydrate in rats. The tone of rat ileum was selected as direct evidence of the prokinetic activity of Meranzin hydrate. Patients with functional dyspepsia were recruited, and Meranzin hydrate and ferulic acid were identified by ultra performance liquid chromatography with tandem mass spectrometry in the plasma of patients following a single oral administration of Chaihu-Shugan-San. The resulting pharmacokinetic properties were determined by ultra performance liquid chromatography coupled to photo diode array. RESULTS: In rats, single doses of Chaihu-Shugan-San (20 g/kg) and Meranzin hydrate (28 mg/kg) significantly accelerated gastric emptying and intestinal transit (Chaihu-Shugan-San: 68.9 ± 5.6% and 72.3 ± 4.7%, Meranzin hydrate: 72.9 ± 3.8% and 75.2 ± 3.1%) compared with the control (55.45 ± 3.7% and 63.51 ± 5.1%, P<0.05), showing similar results as cisapride (69.6 ± 4.8% and 71.6 ± 6.3%). Meranzin hydrate (30, 100 μmol/L) directly increased the amplitude of rat ileum compared with the control (P<0.01). The pharmacokinetics profiles of Meranzin hydrate and ferulic acid in patient plasma was fitted with a two-compartment model detected by a simple, rapid and accurate UPLC method. Time to reach peak concentration of Meranzin hydrate (0.371 mg/L) and ferulic acid (0.199 mg/L) was 23.57 min and 27.50 min, respectively. The elimination half-life and area under the concentration-time curve from t=0 to the last time of Meranzin hydrate and ferulic acid were 139.53 min and 31.445 μg min/mL and 131.27 min and 14.835 μg min/mL, respectively. The absorption constant and volume of distribution of Meranzin hydrate and ferulic acid were 0.185 ± 0.065 min(-1) and 3782.89 ± 2686.72 L/kg and 0.524 ± 0.157 min(-1) and 11713 ± 7618.68 L/kg, respectively. The experimental results of the pharmacokinetic parameters of Meranzin hydrate and ferulic acid indicate that they were absorbed and distributed rapidly.
CONCLUSIONS:
The pharmacodynamics and pharmacokinetics of prokinetic Chaihu-Shugan-San and its compounds are useful for monitoring Chaihu-Shugan-San formulas in clinical practice and for understanding therapeutic mechanisms.

Exp Ther Med. 2013 Oct;6(4):913-918.

Comparison between the pharmacokinetics of meranzin hydrate in a rat model of chronic depression and in controls following the oral administration of Chaihu-Shugan-San.[Pubmed: 24137289]

Previous studies have shown that Meranzin hydrate (MH) may be beneficial in depressive disorders. However, to the best of our knowledge, the pharmacokinetic characteristics of MH in depression have not previously been investigated. Chronic mild stress (CMS) in rats is used as a model of depression. The present study was designed to evaluate and compare the pharmacokinetics of MH in CMS and control rats following the oral administration of Chaihu-Shugan-San (CSS).
METHODS AND RESULTS:
Rats were randomly divided into CMS and control groups and blood samples were obtained following the oral administration of CSS. The quantification of Meranzin hydrate levels in the plasma for pharmacokinetic study was achieved using a simple and rapid ultra-performance liquid chromatography with photodiode array (UPLC-PDA) method. Following the oral administration of CSS to CMS rats and controls, the maximum plasma concentration (Cmax) of Meranzin hydrate was 58.66±6.64 and 57.54±12.67 ng/ml at 108.00±26.83 and 54.00±8.22 min, respectively. Compared with the value of the area under the concentration-time curve (AUC)0-1440 in control rats (19,896.76±1,041.95 μg·min/l), the AUC0-1440 value was reduced in CMS rats (18,401.32±4332.65 μg·min/l). There were no significant differences in the majority of the pharmacokinetic parameters of Meranzin hydrate, including the values for Cmax, AUC0-1440, clearance rate (CL/F) and mean residence time (MRT0-1440), between the CMS rats and the controls.
CONCLUSIONS:
However, the pharmacokinetic parameters showed that CMS accelerated the absorption of Meranzin hydrate in rats following the oral administration of CSS.

Amino Acids. 2013 Feb;44(2):413-22.

The involvement of AMPA-ERK1/2-BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate.[Pubmed: 22782214]

It was recently discovered that ketamine can relieve depression in a matter of hours through an action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This is much more rapid than the several weeks required for the available antidepressants to show therapeutic efficacy. However, ketamine has negative side effects. The aim of this study was to determine whether the natural prokinetic drug Meranzin hydrate (MH) has a fast-acting antidepressant effect mediated by AMPA receptors.
METHODS AND RESULTS:
By means of in vivo and in vitro experiments, we found that (1) treatment of rats with Meranzin hydrate at 9 mg/kg decreased immobility time in a forced swimming test (FST), as did the popular antidepressant fluoxetine and the AMPA receptor positive modulator aniracetam. Pretreatment of rats with NBQX (10 mg/kg), an antagonist of AMPA receptors, blocked this effect of Meranzin hydrate. (2) Meranzin hydrate increased number of crossings of forced swimming rats in the open field test. (3) FST enhanced hippocampal ERK1/2, p-ERK1/2 and BDNF expression levels. Meranzin hydrate (9 mg/kg) treatment further up-regulated hippocampal p-ERK1/2 and BDNF expression levels, and this effect was prevented by NBQX. (4) Meranzin hydrate-increased BDNF expression corresponded with MH-decreased immobility time in the FST. (5) In vitro experiments, we found that incubation of rats hippocampus slices with Meranzin hydrate (10, 20 μM respectively) increased concentrations of BDNF and p-ERK1/2. This effect of MH (20 μM) were prevented by NBQX.
CONCLUSIONS:
In conclusion, in animals subjected to acute stress, the natural prokinetic drug Meranzin hydrate produced a rapid effect mediated by AMPA receptors and involving BDNF modulation through the ERK1/2 pathway.

Neuropharmacology. 2013 Apr;67:318-25.

Meranzin hydrate exhibits anti-depressive and prokinetic-like effects through regulation of the shared α2-adrenoceptor in the brain-gut axis of rats in the forced swimming test.[Pubmed: 23063894]

In recent years, the brain-gut axis theory has received increasing attention in studies of depression. However, most studies separately address potential antidepressant and prokinetic treatments. Investigations of drugs that could potentially treat comorbid depression and gastrointestinal (GI) dysfunction via a common mechanism of action have not yet been performed in detail. To find a common mechanism of action of our patented drug, Meranzin hydrate (MH), in the antidepressant and prokinetic treatment.
METHODS AND RESULTS:
The forced swimming test (FST) model of depression, plasma ghrelin measurement, and in vivo and in vitro measurements of GI motility were used. 1. Administration of MH (9 mg/kg) decreased the immobility time during the FST after acute treatment; this effect was inhibited by the alpha 2-adrenoceptor antagonist, yohimbine, but not by the alpha 1-adrenoceptor antagonist, prazosin. 2. After chronic treatment, the immobility time of rats during the FST was decreased significantly by Meranzin hydrate (2.25 mg/kg). 3. MH (9 mg/kg) increased plasma ghrelin levels in rats subjected to the FST; this increase was enhanced by the ghrelin receptor agonist, GHRP-6. 4. Meranzin hydrate (9 mg/kg) also promoted gastric emptying and intestinal transit in rats with or without FST. 5. In vitro, Meranzin hydrate (10 μM) increased jejunal contractions in rats subjected to the FST; this effect was inhibited by yohimbine. Furthermore, the inhibitory effect of yohimbine was partly reversed by the ghrelin receptor agonist, GHRP-6.
CONCLUSIONS:
Our study revealed that Meranzin hydrate from natural resources exhibits antidepressive and prokinetic-like effects through the regulation of the common mediator, the alpha 2-adrenoceptor.

J Gastrointest Surg. 2011 Jan;15(1):87-96.

Meranzin hydrate induces similar effect to Fructus Aurantii on intestinal motility through activation of H1 histamine receptors.[Pubmed: 21061180]

This experiment studied the potential effect of Meranzin hydrate (MH) and decoction of herb Fructus Aurantii (FA) on rat gut motility. It also investigated the prokinetic mechanism of Meranzin hydrate.
METHODS AND RESULTS:
Experiments were performed on male Sprague–Dawley rats (200–220 g). The study included: (1) qualitation of Meranzin hydrate and four other known compounds in FA and jejunum after oral administration of FA decoction to rats; (2) in vitro experiment of Meranzin hydrate on rat jejunum contractions; (3) in vivo experiment of FA and Meranzin hydrate in rats. Dose-dependently, Meranzin hydrate (1–100 μM) increased amplitude in longitudinal and circular jejunum muscles. Pretreatment of jejunum longitudinal strips with benzhydramine (1 μM) remarkably inhibited the contractions induced by histamine (1 μM) and Meranzin hydrate (10 or 30 μM). Pretreatment of jejunum longitudinal strips with atropine (1 μM) reduced the contractions induced by acetylcholine (1 μM) but did not influence the contractions induced by Meranzin hydrate (10 or 30 μM). Interestingly, the antagonism of benzhydramine to Meranzin hydrate was also verified in vivo. Meranzin hydrate can be absorbed into the jejunum following oral administration of FA decoction. In healthy rats, Meranzin hydrate (7, 14, and 28 mg/kg) and FA (3.3, 10, and 20 g/kg) both promoted intestinal transit and gastric emptying in a dose-dependent manner when gavaged acutely. In cisplatin model rats, Meranzin hydrate (14 and 28 mg/kg) significantly reversed cisplatin-induced delay in gastric emptying.
CONCLUSIONS:
Meranzin hydrate can induce similar effect to Fructus Aurantii on intestinal motility and it was, at least in part, mediated by stimulation of H1 histamine receptors.