To study the related substances in nicergoline, electrospray positive ionization high resolution TOF/MS was used for the determination of the accurate mass and elemental composition of the related substances. Triple quadrupoles tandem MS/MS was employed for the determination of the fragmentations of the parent ions. 16 related substances were detected and identified to be eight synthetic by-products and eight degradation products, by using impurity references matching, product mass spectra fragmentations elucidation, and verified further according to synthetic processes and stress testing results. The results obtained are valuable for nicergoline manufacturing process control and quality assurance.
Chromatography, High Pressure Liquid ; Nicergoline ; chemical synthesis ; chemistry ; Quality Control ; Tandem Mass Spectrometry

This study aimed to identify the related substances of phloroglucinol injection by two-dimensional liquid chromatography quadrupole time-of-flight mass spectrometry (2D-LC-Q-TOF/MS). The first-dimensional separation was carried out on an HSS T3 (250 mm × 4.6 mm, 5 μm) column by gradient elution using 1.36 g·L^-1 potassium dihydrogen phosphate buffer solution (pH adjusted to 3.0 with diluted phosphoric acid) and acetonitrile as the mobile phases. The separated components were then trapped in switch valve tube lines respectively and delivered to the second-dimensional desalting gradient elution which was performed with a BDS C18 (100 mm × 4.6 mm, 2.4 μm) column using 0.1% formic acid and methanol as the mobile phases. After rapid desalting, electrospray-ionization quadrupole time-of-flight high resolution mass spectrometry was used for determining the accurate masses and elemental compositions of the parents and their product ions for both phloroglucinol and its related substance. Structures of the related substances were then figured out by mass spectrometry elucidation, organic reaction mechanism analysis, and/or comparison with reference substances. Under the established analytical conditions, phloroglucinol and its related substances were adequately separated, 17 main related substances were detected and identified in the injection and its stressed samples for the first time. The identification results can provide reference for the quality control of phloroglucinol injection.

The study aims to identify the related substances in fasudil hydrochloride by hyphenated techniques. A WondaSil C18 (250 mm x 4.6 mm, 5 microm) column was used for the separation of the related substances with a mixture of methanol and ammonium acetate buffer solution as the mobile phase by gradient elution. The structures of the related substances were speculated by electrospray positive ionization LC-TOF/MS accurate ion mass and MS/MS determination and elucidation, and verified further through synthesis and spectroscopic analysis. Fasudil hydrochloride and the related substances were separated under the established HPLC condition. Three related substances in fasudil hydrochloride were characterized by hyphenated techniques. The hyphenated LC-MS method is useful for the identification of related substances in fasudil hydrochloride and the results obtained are valuable for its manufacturing process and quality control.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; chemistry ; Calcium Channel Blockers ; chemistry ; Chromatography, Liquid ; Drug Contamination ; Quality Control ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry ; Vasodilator Agents ; chemistry

UNLABELLEDTo establish a sensitive and accurate method to study the pharmacokinetics of (-)-clausenamide [(-)-clau] and its major metabolite 6-hydroxyl-clausenamide (6-OH-clau) in the plasma of the Beagle dog.

METHODS(-)-Clau was orally administered to six Beagle dogs at the dose of 30 mg x kg(-1), venous blood from front leg was sampled and plasma was separated for analysis. After extraction with ethyl acetate, the plasma samples were analyzed by HPLC/MS and the mobile phase was a mixture of methanol-water-acetic acid (60: 40: 0. 8) at the flow rate of 1.0 mL x min(-1). The API-ES positive ion SIM detection was carried out for the detection of both (-)-clau ([M + H] (+), m/z 298 ) and 6-OH-clau ([M + H - H2 O](+), m/z 296) with glipzide (glip) ([M + H](+), m/z 446) as internal standard. The pharmacokinetic parameters were calculated by 3P97 software.

RESULTSThere was good linear relationship ( r > 0. 999) between the SIM responses and the concentrations for (-)-clau and 6-OH-clau at the range from 1.0 to 200 ng x mL(-1) and 0.2 to 40.0 ng x mL(-1), respectively. The absolute recovery was greater than 85%. The plasma concentration-time curves of (-)-clau and 6-OH-clau were both best fitted to a two-compartment model. The C(max) of (-)-clau and 6-OH-clau were (21 +/- 10) ng x mL(-1) and (3.9 +/- 2.2) ng x mL(-1), T(max) were (0.8 +/- 0.5) h and (1.3 +/- 0.5) h, T 1/2 alpha were (0.9 +/- 0.6) hand (1.4 +/- 0.6) h, T 1/2 beta were (19 +/- 23) hand (13 +/- 12) h, AUC(0-24 h) were (69 +/- 14) h x ng x mL(-1) and (12 +/- 7) h x ng x mL(-1) respectively.

CONCLUSIONThe established HPLC/MS method was sensitive and specific for the determination of (-)-clau. It was shown that the absorption and first phase elimination of (-)-clau were very quick in Beagle dogs, but the terminal elimination was very slow. The plasma concentration profile of its major metabolite 6-OH-clau was similar to (-)-clau and the AUC was relatively small in comparison with (-)-clau.

Administration, Oral ; Animals ; Area Under Curve ; Chromatography, High Pressure Liquid ; methods ; Dogs ; Female ; Lactams ; blood ; chemistry ; isolation & purification ; metabolism ; pharmacokinetics ; Lignans ; blood ; chemistry ; isolation & purification ; metabolism ; pharmacokinetics ; Male ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; Rutaceae ; chemistry ; Spectrometry, Mass, Electrospray Ionization ; methods ; Stereoisomerism

To investigate the principal metabolites of 1-(1-(6-methoxyl-2-naphthyl) ethyl)-2-(4-nitrobenzyl)-6,7-dimethoxyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (code designation: P91024) in rats after ig administration by LC-MS/MS, the phase I metabolites were discovered by comparing the fullscan and SIM chromatograms of the test samples with the corresponding blanks. The structures of phase I metabolites were identified by ESI-MS spectra and the product spectra of the corresponding adduct ions. The phase II metabolites were identified in the test samples after the phase I metabolites were completely removed with solvent extraction and then treated with glucuronidase for enzymolysis of phase II glucuronide conjugates and the hydrolysates. Two phase I metabolites of P91024 were identified in rat feces, one phase I and five phase II in bile, one phase I and three phase II in urine, and four phase I and one phase II in plasma. Their structures were elucidated, separately. P91024 was extensively metabolized in rat. The metabolites can be easily screened and identified by LC-MS/MS method.
Animals ; Bile ; metabolism ; Chromatography, Liquid ; Female ; Fibrinolytic Agents ; blood ; metabolism ; pharmacokinetics ; urine ; Male ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization ; Tetrahydroisoquinolines ; blood ; metabolism ; pharmacokinetics ; urine

To study the photo-degradation products of 1-[1-(6-methoxy-2-naphthyl) ethyl]-2-(4-nitrobenzyl)-6,7-dimethoxyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (code designation: P91024). The chemical structures of the major photo-degradation products of P91024 were identified by HPLC-MS and spectroscopic methods, and their reference substances were also synthesized for confirmation. The three major photo-degradation products were identified to be N-(4-nitrobenzyl)-6,7-dimethoxyl-3, 4-dihydroisoquinoline bromide, 1-[1-(6-methoxyl-2-naphthyl) ethyl]-6, 7-dimethoxyl-1, 2, 3, 4-tetrahydroisoquinoline and 2-isopropyl-6-methoxyl-naphthalene, respectively.
Chromatography, High Pressure Liquid ; methods ; Fibrinolytic Agents ; chemistry ; Molecular Structure ; Photolysis ; Quality Control ; Spectrometry, Mass, Electrospray Ionization ; methods ; Tandem Mass Spectrometry ; methods ; Tetrahydroisoquinolines ; chemistry

The pharmacokinetics of the main components of protocatechualdehyde, salvianolic acid B, tanshinone II(A), cryptotanshinone, and the hydrophilic or lipophilic extracts of Salvia Miltiorrhiza Bge., in rat plasma were studied after oral administration separately to explore the interactions between them. Some components in the hydrophilic extract depress the absorption of the protocatechualdehyde, on the contrary, enhance the absorption of the salvianolic acid B and depress its elimination rate. The concomitant components in the lipophilic extract might enhance the absorption of cryptotanshinone and its distribution from the centre compartment to the peripheral compartment, and the metabolism to tanshinone II(A). The 'concomitant components' in the extract of Chinese material medica had significant effect on the pharmacokinetics of its 'marker components'. It can not only be rival, synergic, but also have the effects on metabolism. Therefore the traditional Chinese medicine was a complicated system, It should be taken a scientific and dialectic view in the research and development processes.
Animals ; Area Under Curve ; Benzaldehydes ; blood ; chemistry ; pharmacokinetics ; Benzofurans ; blood ; chemistry ; pharmacokinetics ; Catechols ; blood ; chemistry ; pharmacokinetics ; Diterpenes, Abietane ; Drug Interactions ; Female ; Male ; Metabolic Clearance Rate ; Molecular Structure ; Phenanthrenes ; blood ; chemistry ; pharmacokinetics ; Plant Extracts ; blood ; chemistry ; pharmacokinetics ; Plants, Medicinal ; chemistry ; Rats ; Rats, Sprague-Dawley ; Salvia miltiorrhiza ; chemistry

After oral administration of Salvia miltiorrhiza (Danshen in Chinese), Panax notoginseng (Sanqi in Chinese) and Danshen Sanqi combination suspensions to Beagle dogs, the plasma concentration-time profiles of danshensu, tanshinone II(A), cryptotanshinone, notoginsenoside R1, ginsenoside Rg1 and Rb1 were analyzed by LC-MS/MS. Pharmacokinetic parameters were calculated and analyzed with BAPP 2.0 software. The results showed that the Cmax and AUC of danshensu, notoginsenoside R1, ginsenoside Rg1 and Rb1 in Danshen Sanqi combination group all decreased in comparison with those of Danshen or Sanqi given alone, while the CLz/F and Vz/F increased to some extent. No significant differences of the pharmacokinetics of tanshinone II(A) and cryptotanshinone were observed between groups.
Administration, Oral ; Animals ; Area Under Curve ; Diterpenes, Abietane ; blood ; pharmacokinetics ; Dogs ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacokinetics ; Female ; Ginsenosides ; blood ; pharmacokinetics ; Lactates ; blood ; pharmacokinetics ; Male ; Panax notoginseng ; chemistry ; Phenanthrenes ; blood ; pharmacokinetics ; Plants, Medicinal ; chemistry ; Salvia miltiorrhiza ; chemistry

OBJECTIVE: The purpose of this study was to review the incidence, types, chemotherapy regimens, operation methods, pregnancy rate and propiosis of the ov#arian malignancy under the age of twenty years old. METHODS: Retrospective reviews of the medical recordings for 22 patients with ovarian malignancy under the age of twenty years old in the Department of Obstetrics and Gynecology, Hanyang University from 1986 to 1997 were done. RESULTS: Gerin cell tumor accounts for the majority of cases (77%), whereas 5 patients(23%) belong to the common epithelial poup which were all mucinous type. Our experiences with 22 cases are as followings: 5 mucinous cystadenocarcinoma, 8 immature teratoma, 4 endodermal sinus tumor, 3 dysgernma and 2 mixed germ cell tumor. The incidence of this group was 8.2% (22/266) in all ovarian malignancy. Fourteen of them are stage I, each one is, stage II and IV, and six patients are stage III. The average age was 14.9 years old in germ cell tumor and 18.4 yems old in mucinous cystadenoearcinoma. Malignant ovarian cancer under the age of twenty can be treated with conservative surgery, followed by adjuvant chemotherapy. Commonly used chemotherapeutic regimens were VAC(Vincristine, Actinomycin-D; Cyclophosphamide), VBP(Vinblastine, Bleomycin, Cisplatin) and BEP(Bleomycin, Etoposide, Cisplatin). Second look operations were done in 11 patienth and histologic positive findings were detected in 4 of them. The length of follow-up ranged ftom 3 months to 137 months and median value was 44 rnonths. CONCLUSIONS: It is concluded that for young women who wish to preserve child-bearing capacity, regardless of the stage of the tumor, fertility preserving surgery with complete surgical staging, if necessary followed by combination chemotherapy is an appropriate treatment.
Bleomycin ; Chemotherapy, Adjuvant ; Cystadenocarcinoma, Mucinous ; Drug Therapy ; Drug Therapy, Combination ; Endodermal Sinus Tumor ; Etoposide ; Female ; Fertility ; Follow-Up Studies ; Gynecology ; Humans ; Incidence ; Medical Records ; Mucins ; Neoplasms, Germ Cell and Embryonal ; Obstetrics ; Ovarian Neoplasms ; Pregnancy Rate ; Retrospective Studies ; Teratoma

To investigate the effects of allicin on rats by NMR-based metabonomic method, the changes of endogenous metabolites in normal rat urine and the influences on metabolism were analyzed with bio-nuclear magnetic resonance (NMR) method and partial least-squares discriminant analysis (PLS-DA) after intraperitoneal administration of allicin solution. The identified biochemical effects associated with allicin dosing included elevated then gradually recovered urinary levels of Kreb's cycle intermediates, such as citrate, alpha-ketoglutarate and succinate and increased concentrations of ketones. Meanwhile, decreased urinary concentrations of glucose, lactate, alanine, hippurate and trimethylamine oxide were observed. The PLS-DA revealed that the metabonomic profiles of allicin treated groups were obviously different from those of the control group. Allicin may change metabolism significantly in normal rats. The study of the pharmacologic mechanism of allicin by metabonomic method is practicable and it could be explored further.
Animals ; Magnetic Resonance Spectroscopy ; Male ; Metabolomics ; Rats ; Rats, Sprague-Dawley ; Sulfinic Acids ; metabolism ; urine