Simplified LC-MS/MS method for quantification of IG-105, a novel tubulin ligand, and its application to the pharmacokinetic study in rats at the anticancer effective dose.

IG-105, N-(2, 6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel carbazole sulfonamide, shows a potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In the present study, a rapid and convenient liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and applied to the pharmacokinetic study of IG-105 in rats. Chromatographic separation was accomplished on a C18 column using an isocratic mobile phase of acetonitrile-water-acetic acid (56:44:0.2, v/v/v). The ion transitions of IG-105 and combretastatin A4 (internal standard) in selected reaction monitoring mode were m/z 398→154 and m/z 317→286, respectively. The assay exhibited good linearity over the range of 2-512 ng/mL. Intra- and inter-day precisions were within 8.2 %, and the accuracies ranged from -6.0 to 3.7 %. The extraction recoveries were higher than 90 %, and the matrix effects were negligible. All quality control samples were stable at different storage conditions. The validated LC-MS/MS method was successfully applied to a preclinical pharmacokinetic study of IG-105 in rats after a single oral dose of 100, 250, or 1000 mg/kg which showed tumor growth inhibition activity. The absorption of IG-105 was proved to be rapid but saturated to a certain extent into the blood circulation, from where it was distributed and eliminated gradually.

[Characteristics of neuromyelitis optica spectrum disorder associated with the area postrema].

Objective: To evaluate the clinical characteristics and the corresponding MRI and laboratory findings in patients with neuromyelitis optica spectrum disorder (NMOSD) associated with area postrema (AP). Methods: The study was a retrospective analysis of data from 120 NMOSD patients, and 18 cases were with AP out of these patients, The clinical presentation, MRI changes, serological markers and treatment outcome were reported. Results: AP occurred in 18 patients (15%, 18/120). AP was the onset symptom in 14 (14/18) patients and 3 days to 7 months (median 40 days) later, optic neuritis or myelitis was involved. One patient presented AP after optic neuritis. Three patients (3/18) had AP and myelitis or optic neuritis simultaneously. AP symptom presented as intractable nausea and vomiting, hiccups. Compared to the patients without AP (n=102), the patients with AP (n=18) had shorter duration and fewer numbers of optic neuritis(P<0.05). There was no statistical difference in sex, onset age, course of disease (relapsing or monophasic) and EDSS scores (P>0.05). The MRI revealed flake or linear lesions in medulla. Twelve patients had cervical cord lesions extending to medulla lesions (12/18). Eleven patients had long cord lesions extending more than 3 spinal cords. The AQP4-antibody did not differ in patients with or without AP (14/18 vs 75/102). The symptom of AP was successfully relieved with methylprednisolone. Conclusion: AP symptoms/signs are common in patients with NMOSD. Vomiting and hiccups can be the first symptoms. The medulla lesions and the lesions extending to upper cervical cord are unique to NMOSD. Awareness of AP presentations is helpful for early diagnosis and proper treatment to prevent further disability.

[MRI features of ventricular system tuberculosis].

OBJECTIVE: To study the MRI features of ventricular system tuberculosis. METHODS: Nineteen patients with ventricular system tuberculosis in our hospital from Mar. 2009 to Sep. 2014 were retrospectively identified. Their clinical features and cranial MRI characteristics were reviewed. RESULTS: There were 13 males and 6 females, aged from 15-81 years(mean 37±16). Eight patients had intraventricular tuberculosis, with 5 long striped or irregular shaped intraventricular tuberculosis and 3 with ventricular tuberculoma. Six patients had tubercular ependymitis and 5 had intraventricular tuberculosis along with tubercular ependymitis. The lesions of 14 patients were in the lateral ventricle; 13 in occipital or temporal horn of lateral ventricle, 9 complicated by tubercular meningitis, and 10 complicated by brain tuberculoma. The lesion of 5 patients were in the fourth ventricle, 5 in the postmedian of the fourth ventricle, 5 complicated by tubercular meningitis and 4 complicated by hydrocephalus. There were 4 cases with ring-enhancement and 15 with heterogeneous enhancement. Ten cases were complicated by peripheral edema. CONCLUSIONS: The diagnosis of ventricle system tuberculosis is difficult due to its low incidence. The site, cranial MRI characteristics, the patterns of enhancement and complications have certain specificity and are useful in the diagnosis of ventricular system tuberculosis.

Preclinical pharmacokinetic analysis of SNX-2112, a novel Hsp90 inhibitor, in rats.

SNX-2112 is a novel Hsp90 inhibitor. The aim of this study was to investigate the pharmacokinetics, tissue distribution, plasma protein binding and excretion profiles of SNX-2112 in Sprague-Dawley rats after a single intravenous injection. The pharmacokinetic properties of SNX-2112 were examined after a single i.v. injection of 2.5, 5, and 10mg/kg to rats, respectively. The tissue distribution and urinary, fecal, and biliary excretion patterns of SNX-2112 were investigated following a single i.v. injection of 10mg/kg. The results suggested that the pharmacokinetic properties of SNX-2112 fitted well into a two-compartment open model with t(1/2ß) values of 9.96±4.32, 10.43±4.06, 10.41±4.38h and area under the curve values of 7.62±1.03, 8.10±0.77, 15.80±1.00(µg/mL) h according to the single doses of 2.5, 5, and 10mg/kg, respectively. Approximately 0.13±0.09% and 3.62±0.77% of SNX-2112 were excreted via the urine and feces within 72h, respectively; 2.59±0.67% was excreted into the bile up to 24h after a single i.v. injection of 10mg/kg. The major elimination route was therefore through excretion in the feces. The binding rate of SNX-2112 with plasma protein was found to be concentration-dependent. In conclusion, this study first provided the full pharmacokinetic characteristics and tissue distribution of SNX-2112, which would be helpful for its clinical regiment design.

Pilot study on the relationship between male stomach and liver cancer death and mutagenicity of drinking water in the Huangpu River area.

A quasi-historical cohort study method was used to collect the data of male stomach and liver cancer death from 1984 to 1988 in male residents (> or = 30 years old) of three tap-water-drinking communities at the upper, middle and lower reaches of the Huangpu River. Total person-years observed are 184,645. The result shows that the world standard population standardized cut-off mortalities (> or = 30 years old) of male stomach and liver cancer increase gradually from the upper to lower reaches. The mortalities from the upper to the lower reaches are 62.7, 86.2 and 146.0/100,000 person-years for male stomach cancer and 56.9, 67.7 and 81.3/100,000 person-years for male liver cancer, respectively. This trend is consistent with the change of the rate of positive Ames Test results of drinking water from the upper to lower reaches (0, 70, 100%). It suggests that a causal correlation may exist between the two. The distribution of other possible risk factors in the three communities is also described.

Effects of drinking water from the lower reaches of the Huangpu River on the risk of male stomach and liver cancer death.

A quasi-historical cohort study method was used to collect the data of male stomach and liver cancer death and the data of exposure to relevant risk factors from 1984 to 1988 in male tap-water- and raw-water-drinking cohorts (> or = 30 years old) at both the upper and lower reaches of the Huangpu River. Total person-years observed are 172,448. The Odds Ratios of drinking water from the lower reaches for male stomach cancer and liver cancer death are 2.021 (p < 0.01) and 1.851 (p < 0.01), respectively, in unconditional logistic regression analysis after controlling possible confounding factors. The result shows that drinking water from the lower reaches of the Huangpu River is one of the important risk factors for male stomach and liver cancer death in local areas.