[Multiple Gastrointestinal Stromal Tumor with Neurofibromatosis Type â :Report of One Case].

Gastrointestinal stromal tumors(GISTs)in the stomach,duodenum,and rectum have low occurrence,and the coexistence GISTs in three parts with neurofibromatosis type Ⅰ(NF-Ⅰ)is even rare.This paper reports a case of GISTs with a family history of NF-Ⅰ.There were multiple nodular masses of different sizes on the patient's face,trunk,and limbs.The patient was admitted due to chest tightness for 5 days and black stools for 1 day.Enhanced CT examination of the abdomen suggested multiple space-occupying lesions in the upper abdomen with multiple small nodules under the abdominal wall,and neurofibromatosis and intestinal stromal tumor cannot be excluded.Finally,surgical pathology confirmed that the multiple tumors in the abdominal cavity were GISTs.The case was confirmed as wild-type GISTs by genetic testing,and the patient recovered well nearly one year after the operation.

In vitro and in vivo drug-drug interaction of losartan and glimepiride in rats and its possible mechanism.

BACKGROUND: Losartan and glimepiride are commonly used drugs to treat chronic diseases of hypertension and diabetes; they are both substrates of CYP2C9. The aim of the present study was to investigate the possible interaction of losartan and glimepiride both in vitro (rat liver microsomes) and in vivo (healthy Sprague-Dawley rats). METHODS: In rat liver microsomes, 1-10 µmol/l losartan and glimepiride were coincubated, and the inhibitory effect was analyzed. In the subsequent pharmacokinetic study, 15 healthy Sprague-Dawley rats received administrations of 5 mg/kg losartan or 1 mg/kg glimepiride or a coadministration. RESULTS: In the rat liver microsome system, glimepiride showed a slight inhibition of losartan at concentrations of 1-10 µmol/l, whereas losartan exhibited no inhibitory effect on glimepiride. In vivo, glimepiride did not modify the plasma concentration of losartan and its metabolite E-3174. The alteration of an increased AUC and Cmax was observed in the pharmacokinetic parameters of glimepiride and hydroxy glimepiride. CONCLUSIONS: Glimepiride did not affect losartan pharmacokinetics in rats, while losartan potently altered glimepiride metabolism; this result was inconsistent with the in vitro outcome. The mechanism requires further investigation. In clinical settings, attention should be paid to the interaction of these two drugs in the human body as well as the possible adverse reactions of glimepiride.

[Advance in studies on natural antidepressant drugs and cytochrome P450].

In the fast pace of modern life and under the heavy work pressure, the prevalence of depression has increased year by year. Meanwhile, the demands for antidepressant drugs have also grown, especially the high-efficiency and low-toxicity natural antidepressant drugs, mainly including polyphenols, flavonoids, organic acids, alkaloids and terpenoids. Cytochrome P450 (CYP450) is a type of enzymes involving oxidative metabolism of drugs in vivo, and can change the pharmacokinetics and efficacy of drugs. Therefore, it is of important significant to define the effect of natural antidepressant drugs on CYP450 in human bodies, in order to improve the rational clinical medication, avoid drug interactions and reduce adverse reactions.

Drug-drug interaction of losartan and glimepiride metabolism by recombinant microsome CYP2C9*1, 2C9*3, 2C9*13, and 2C9*16 in vitro.

OBJECTIVE: Co-administration of anti-hypertension and anti-diabetic drugs is common in clinical settings. METHODS: In this study, we characterized the drug-drug interactions of losartan (LOS) and glimepiride (GLP) using recombinant cytochrome P450 (CYP) 2C9 enzymes (CYP2C9*1, CYP2C9*3, CYP2C9*13, and CYP2C9*16). RESULTS: Metabolism of losartan by recombinant CYP2C9* 1, CYP2C9*3, CYP2C9*13, and CYP2C9* 16 was inhibited by glimepiride competitively with IC50 values of 0.669 ± 0.055 µM, 0.424 ± 0.032 µM, 2.557 ± 0.058 µM, and 0.667 ± 0.039 µM, respectively. The inhibitory effect of glimepiride on losartan metabolism by CYP2C9*13 was marginal. The apparent Ki value of glimepiride with CYP2C9*3 (0.0416 ± 0.0059 µM) was significantly lower than with CYP2C9*1 (0.1476 ± 0.0219 µM) and CYP2C9*16 (0.2671 ± 0.0456 µM). On the other hand, losartan weakly inhibited the hydroxylation of glimepiride by P450 2C9 enzymes competitively. The potencies for inhibition of glimepiride hydroxylation were determined to be CYP2C9*1~CYP2C9*3~CYP2C9*16 > CYP2C9*13 by 4 µM losartan. No significant inhibition was observed when 0.5 µM losartan was used. CONCLUSIONS: Given these results, the potential inhibition of losartan metabolism by CYP2C9*3, CYP2C9*13, and CYP2C9*16 in vivo by glimepiride deserves further investigation. These results may provide valuable information for optimizing the anti-hypertension efficacy of losartan when glimepiride is co-administered to patients.

[Analgesic effect of ferulic acid on CCI mice: behavior and neurobiological analysis].

To study the analgesic effect of chronic administration with ferulic acid, and preliminarily discuss its mechanism. Thermal hyperalgesia and mechanical allodynia tests were conducted to observe the analgesic effect of chronic administration with ferulic acid on CCI mice. The neurochemical detection method was applied to observe the effect chronic administration with ferulic acid on monoamine neurotransmitter and monoamine oxidase activity. Compared with the normal group, CCI mice showed notable reduction in heat sensation and nociceptive threshold in and mechanical allodynia. Ferulic acid (10, 20, 40 and 80 mg x kg(-1), po) could significantly reverse the situations. In an in-depth study, we found that the reason for these results was that ferulic acid was dose-dependent in increasing 5-HT and NE levels in hippocampus, frontal cortex and amygdale and could inhibit MAO-A activity in mouse brains. These results showed that ferulic acid has the analgesic effect. Its mechanism may be related to the inhibition of monoamine oxidase activity and the increase in monoamine neurotransmitter in mouse brains.

High level nitrosamines in rat faeces with colorectal cancer determined by a sensitive GC-MS method.

N-nitrosamines (NAs) are common toxic substances that have a strong correlation with many human diseases, such as liver damage and cancer. However, there is a lack of studies on methods involving the detection of NAs in biological samples, possibly owing to the interference of complex biological matrices and the influence of endogenous NAs. In this work, solid-phase extraction with mixed solid phases and adsorption sedimentation were used to successfully establish a gas chromatography-mass spectrometry (GC-MS) method for detecting eight NAs in rat faeces. Chromatographic separation of analytes was performed with Agilent VF-WAXms (30 m × 0.25 mm, 0.25 µm) GC columns. The LLOQs of eight NAs were set to the concentration of 0.5 ng/g and the obtained standard curves were linear, and correlation coefficients (r) were ≥ 0.99 for samples with concentration ranges of 0.5-500 ng/g. The inter and intra-assay precisions were< 15% for all analytes in the quality control samples, and the accuracies ranged from 88.67% to 108.33%. The extraction recoveries were above 78.56% for seven NAs, and a significant matrix effect was not observed. The application of this method revealed that the levels of NAS in the faeces of rats with colorectal cancer were higher than those of normal rats. Additionally, the effect of a high nitrite diet on NAs in faeces was analysed; the results confirmed that a high nitrite diet might contribute to an abnormal increase in NAs. Our work provides an analytical method for further in vivo study of NAs. Furthermore, a pilot study on the relationship between NAs and colorectal cancer was completed.

Silibinin affects the pharmacokinetics of methadone in rats.

The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: control group, single dose of 100 mg/kg group, multiple doses of 100 mg/kg group, and multiple doses of 30 mg/kg group. A single dose of 6 mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Compared with the control group (without silibinin), both 30 and 100 mg/kg silibinin significantly increased the Cmax of methadone, but only 100 mg/kg silibinin significantly increased the AUC(0-t) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30 mg/kg silibinin; its Tmax was decreased by 100 mg/kg silibinin and the Cmax was increased by single dose of 100 mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant.

Glucocorticoid-induced leucine zipper may play an important role in icariin by suppressing osteogenesis inhibition induced by glucocorticoids in osteoblasts.

BACKGROUND AND PURPOSE: Icariin is a potent stimulator of osteogenic differentiation; however, the mechanism underlying its osteogenic effect remains unclear. The osteogenic effect of icariin is related to the upstream glucocorticoid-induced leucine zipper (GILZ) signaling pathway, and antagonism with dexamethasone-induced osteoblast inhibition was noted. METHODS: MC3T3-E1 cells were cultured in induced medium treated with icariin with or without dexamethasone. After short interfering RNA (siRNA) were used to silence GILZ expression, the degree of mineralization, proliferation, and GILZ expression as well as the levels of osteogenic (OPG, RANKL, ALP, OC and RUNX2) markers were tested. RESULTS: Dexamethasone inhibited, while icariin increased, osteogenic activity, as indicated by ALP activity and calcium nodules. Meanwhile, dexamethasone dose-dependently (10-6M-10-4M) increased GILZ and RANKL expression and reduced ALP, OPG and OC, but the pattern of mRNA expression was reversed when icariin was added. Furthermore, GILZ (dexamethasone-induced) inhibition caused by icariin or moderately silenced by GILZ siRNA abolished the osteogenesis inhibition effect of dexamethasone, as indicated by the changes in the GILZ, ALP, OPG and RANKL expression levels; ALP activity; and calcium nodule. CONCLUSIONS: These results indicate that the GILZ-mediated osteogenic signal pathway is involved in the osteogenic effect induced by icariin.