共查询到20条相似文献,搜索用时 15 毫秒
1.
Sungkyoon Kim Leonard B. Collins Gunnar BoysenAvram Gold Louise M. BallBlair U. Bradford Ivan Rusyn 《Toxicology》2009
Trichloroethylene (TCE, CAS 79-01-6) is a widely used industrial chemical, and a common environmental pollutant. TCE is a well-known carcinogen in rodents and is classified as “probably carcinogenic to humans”. Several analytical methods have been proposed for detection of TCE metabolites in biological media utilizing derivatization-free techniques; however, none of them is suitable for simultaneous detection of both oxidative metabolites and glutathione conjugates of TCE in small volume biological samples. Here, we report a new combination of methods for assessment of major TCE metabolites: dichloroacetic acid (DCA), trichloroacetic acid (TCA), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG). First, DCA and TCA were extracted with ether. Second, the remaining aqueous fraction underwent solid phase extraction for DCVC and DCVG. Then, DCA and TCA were measured by hydrophilic interaction liquid chromatography ion exchange negative electrospray ionization tandem mass spectrometry, while DCVC and DCVG were measured by reverse phase positive electrospray ionization tandem mass spectrometry. This method was applied successfully to measure all 4 TCE metabolites in as little as 50 μl of serum from mice orally exposed to TCE (2100 mg/kg, 2 h). Serum concentrations (mean ± standard deviation) of the TCE metabolites obtained with this method are comparable or equivalent to those previously reported in the literature: DCA, 0.122 ± 0.014 nmol/ml (limit of detection: 0.01 nmol/ml); TCA, 256 ± 30 nmol/ml (0.4 nmol/ml); DCVG, 0.037 ± 0.015 nmol/ml (0.001 nmol/ml); DCVC, 0.0024 ± 0.0009 nmol/ml (0.001 nmol/ml). This method opens new opportunities to increase throughput and decrease number of animals required for mechanistic studies on TCE in rodents. 相似文献
2.
The present study was carried out to investigate the species differences in the nephrotoxic response to S-(1,2-dichlorovinyl)glutathione (DCVG) using rats, hamsters and guinea-pigs. DCVG was given intraperitoneally in physiological saline to groups of 5 animals at doses 0, 165 and 330
. Urine was collected for 24 h and the animals were then sacrificed. Significantly increased levels of urinary glucose, N-acetyl-β-d-glucosaminidase, γ-glutamyl transpeptidase, proteins and blood urea nitrogen were observed in rats at both dose levels of DCVG. An increase, but not of similar magnitude, of these biochemical parameters was noted in hamsters only at the higher dose of DCVG. Guinea-pigs showed significant increases in these biochemical parameters at the lower dose, but not at the higher dose. Light-microscopic studies showed increasing proximal tubular necrosis (PTN) in rats with increasing dose of DCVG, but PTN involving straight tubules only was observed at the higher dose in hamsters. PTN was again observed in guinea-pigs at the lower dose, but not at the higher dose of DCVG. 相似文献
3.
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats but not humans. Rat FDVE nephrotoxicity is attributed to FDVE glutathione conjugation and bioactivation of subsequent FDVE-cysteine S-conjugates, in part by renal beta-lyase. Although FDVE conjugation and metabolism occur in both rats and humans, the mechanism for selective toxicity in rats and lack of effect in humans is incompletely elucidated. This investigation measured FDVE S-conjugate cytotoxicity in cultured human proximal tubular HK-2 cells, and compared this with known cytotoxic S-conjugates. HK-2 cells were incubated with FDVE and its GSH, cysteine S-mercapturic acid, cysteine S-sulfoxide, and mercapturic acid sulfoxide conjugates (0.1-2.7 mM) for 24 h. Cytotoxicity was determined by lactate dehydrogenase (LDH) release, total LDH, and the ability of viable cells to reduce a tetrazolium-based compound (MTT). FDVE was cytotoxic only at concentrations >/=0.9 mM. No increase in LDH release was observed with either FDVE-GSH conjugate. The FDVE-cysteine conjugates S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine (DFEC) and (Z)-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-FFVC) caused significant differences in LDH release and MTT reduction only at 2.7 mM; (Z)-FFVC was slightly more cytotoxic. Both S-(1,1-difluoro-2-fluoromethoxy-2-(trifluoromethyl) ethyl)-L-cysteine sulfoxide (DFEC-SO) and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine sulfoxide ((Z)-N-Ac-FFVC-SO) caused slightly greater changes in LDH release or total LDH than the corresponding equimolar DFEC and (Z)-N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl) vinyl)-L-cysteine ((Z)-N-Ac-FFVC) conjugates. In contrast to FDVE S-conjugates, S-(1,2-dichlorovinyl)-L-cysteine was markedly cytotoxic, at concentrations as low as 0.1 mM. These results show that human proximal tubular cells are relatively resistant to FDVE and FDVE S-conjugate cytotoxicity. This may partially explain the lack of FDVE nephrotoxicity in humans. 相似文献
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Sungkyoon Kim David Kim Leonard B. Collins 《Toxicology and applied pharmacology》2009,238(1):90-10358
Trichloroethylene (TCE) is a well-known carcinogen in rodents and concerns exist regarding its potential carcinogenicity in humans. Oxidative metabolites of TCE, such as dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are thought to be hepatotoxic and carcinogenic in mice. The reactive products of glutathione conjugation, such as S-(1,2-dichlorovinyl)-l-cysteine (DCVC), and S-(1,2-dichlorovinyl) glutathione (DCVG), are associated with renal toxicity in rats. Recently, we developed a new analytical method for simultaneous assessment of these TCE metabolites in small-volume biological samples. Since important gaps remain in our understanding of the pharmacokinetics of TCE and its metabolites, we studied a time-course of DCA, TCA, DCVG and DCVG formation and elimination after a single oral dose of 2100 mg/kg TCE in male B6C3F1 mice. Based on systemic concentration-time data, we constructed multi-compartment models to explore the kinetic properties of the formation and disposition of TCE metabolites, as well as the source of DCA formation. We conclude that TCE-oxide is the most likely source of DCA. According to the best-fit model, bioavailability of oral TCE was ∼ 74%, and the half-life and clearance of each metabolite in the mouse were as follows: DCA: 0.6 h, 0.081 ml/h; TCA: 12 h, 3.80 ml/h; DCVG: 1.4 h, 16.8 ml/h; DCVC: 1.2 h, 176 ml/h. In B6C3F1 mice, oxidative metabolites are formed in much greater quantities (∼ 3600 fold difference) than glutathione-conjugative metabolites. In addition, DCA is produced to a very limited extent relative to TCA, while most of DCVG is converted into DCVC. These pharmacokinetic studies provide insight into the kinetic properties of four key biomarkers of TCE toxicity in the mouse, representing novel information that can be used in risk assessment. 相似文献
6.
Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate beta-lyases to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate beta-lyases are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. 相似文献
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8.
cis-6-(2-Acetylvinylthio)purine (cAVTP) and trans-6-(2-acetylvinylthio)guanine (tAVTG) are thiopurine prodrugs provisionally inactivated by an α,β-unsaturated substituent on the sulfur of the parental thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). The active thiopurines are liberated intracellularly by glutathione (GSH) in reactions catalyzed by glutathione transferases (GSTs) (EC 2.5.1.18). Catalytic activities of 13 human GSTs representing seven distinct classes of soluble GSTs have been determined. The bioactivation of cAVTP and tAVTG occurs via a transient addition of GSH to the activated double bond of the S-substituent of the prodrug, followed by elimination of the thiopurine. The first of these consecutive reactions is rate-limiting for thiopurine release, but GST-activation of this first addition is shifting the rate limitation to the subsequent elimination. Highly active GSTs reveal the transient intermediate, which is detectable by UV spectroscopy and HPLC analysis. LC/MS analysis of the reaction products demonstrates that the primary GSH conjugate, 4-glutathionylbuten-2-one, can react with a second GSH molecule to form the 4-(bis-glutathionyl)butan-2-one. GST M1-1 and GST A4-4 were the most efficient enzymes with tAVTG, and GST M1-1 and GST M2-2 had highest activity with cAVTP. The highly efficient GST M1-1 is polymorphic and is absent in approximately half of the human population. GST P1-1, which is overexpressed in many cancer cells, had no detectable activity with cAVTP and only minor activity with tAVTG. Other GST-activated prodrugs have targeted GST P1-1-expressing cancer cells. Tumors expressing high levels of GST M1-1 or GST A4-4 can be predicted to be particularly vulnerable to chemotherapy with cAVTP or tAVTG. 相似文献
9.
酞丁安对映体合成及其抗单纯疱疹病毒活性评价 总被引:1,自引:0,他引:1
酞丁安(3-酞酰亚胺-2-氧-正丁醛双缩氨硫脲,TDA)是药物研究所创制的抗病毒新药。为了研究其对映异构体(R),(S)-TDA对病毒活性及毒性是否有差异,并与消旋酞丁安(RS)-TDA的抗病毒活性及毒性进行比较,本文分别用已知构型的(R)-与(S)-丙氨酸为原料,通过缩合等6步反应,得到光学活性的(R)-,(S)-TDA,并与外消旋酞丁安比较其抗病毒活性及毒性。三者的抗单纯疱疹病毒活性与对细胞的毒性差别不大,说明消旋酞丁安临床使用是安全有效的。 相似文献
10.
Mahipal SV Subhashini J Reddy MC Reddy MM Anilkumar K Roy KR Reddy GV Reddanna P 《Biochemical pharmacology》2007,74(2):202-214
Growth inhibitory effects of 15-lipoxygenase-1 [13-(S)-HPODE and 13-(S)-HODE] and 15-lipoxygenase-2 [15-(S)-HPETE and 15-(S)-HETE] (15-LOX-1 and LOX-2) metabolites and the underlying mechanisms were studied on chronic myeloid leukemia cell line (K-562). The hydroperoxy metabolites, 15-(S)-HPETE and 13-(S)-HPODE rapidly inhibited the growth of K-562 cells by 3h with IC(50) values, 10 and 15microM, respectively. In contrast, the hydroxy metabolite of 15-LOX-2, 15-(S)-HETE, showed 50% inhibition only at 40microM by 6h and 13-(S)-HODE, hydroxy metabolite of 15-LOX-1, showed no significant effect up to 160microM. The cells exposed to 10microM of 15-(S)-HPETE and 40microM of 15-(S)-HETE showed typical apoptotic features like release of cytochrome c, caspase-3 activation and PARP-1 (poly(ADP) ribose polymerase-1) cleavage. A flow cytometry based DCFH-DA analysis and inhibitory studies with DPI, a pharmacological inhibitor of NADPH oxidase, NAC (N-acetyl cysteine) and GSH revealed that NADPH oxidase-mediated generation of ROS is responsible for caspase-3 activation and subsequent induction of apoptosis in the K-562 cell line. 相似文献
11.
In vivo metabolism, nephrotoxicity and covalent binding to proteins were evaluated in male Fischer 344 rats that received [2,3-14C]-N-(3,5-dichlorophenyl)succinimide (14C-NDPS). Some animals were pretreated with the enzyme inducer phenobarbital (PB, 80 mg/kg per day, for 3 days, i.p. in saline) prior to receiving a non-nephrotoxic dose of 14C-NDPS (0.2 mmol/kg, i.p. in corn oil). Other rats were pretreated with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT, 100 mg/kg, 1 h prior to NDPS, i.p. in saline) before administration of a non-toxic or a toxic dose (0.2 or 0.6 mmol/kg, respectively, i.p. in corn oil) of 14C-NDPS. Non-pretreated animals received either dose of 14C-NDPS, but did not receive PB or ABT. All rats were sacrificed 6 h after administration of 14C-NDPS. Nephrotoxicity was monitored by measuring urine volume, urine protein concentrations, blood urea nitrogen levels, and kidney weights. The NDPS metabolic profile in tissue, blood, and urine was analyzed by HPLC. Covalent binding of 14C-NDPS-derived radioactivity to tissue proteins was also measured. Compared with non-pretreated rats, PB-pretreatment potentiated the toxicity of the non-toxic dose of 14C-NDPS. In contrast, ABT-pretreatment protected the rats against NDPS nephrotoxicity. The amount of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA), an oxidative, nephrotoxic metabolite of NDPS, was elevated in kidney homogenates and urine by PB-pretreatment (0.2 mmol/mg NDPS). ABT pretreatment inhibited NDPS metabolism at both doses. Covalent binding of 14C-NDPS (0.2 mmol/kg)-derived radioactivity to renal and plasma proteins was higher in the PB-pretreated rats than in the non-pretreated animals. In contrast, ABT-pretreatment partially inhibited covalent binding at both doses of 14C-NDPS. Our results suggest that there is a relationship between oxidative metabolism of NDPS, covalent binding of an NDPS metabolite to renal proteins, and NDPS-induced nephrotoxicity in rats. 相似文献
12.
Vaidya VS Shankar K Lock EA Bucci TJ Mehendale HM 《Toxicology and applied pharmacology》2003,188(2):110-121
S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a metabolite of a common environmental contaminant, trichloroethylene, is a selective proximal tubular nephrotoxicant. The objective of our study was to examine the dose-response relationship of renal injury and repair following DCVC administration. Male Swiss-Webster mice were injected with DCVC [15, 30, or 75 mg/kg ip in distilled water (10 ml/kg)] and the extent of nephrotoxicity and tissue repair was assessed over a 14-day period. The renal injury due to the low and medium doses of DCVC peaked at 36 and 72 h after dosing, respectively, and then regressed over time due to a timely and adequate tissue repair response. At the highest dose tissue repair was inhibited, thereby causing progression of renal injury, which led to acute renal failure and death of the mice. The possibility that compromised tissue repair was a result of the extensive nephrotoxic injury attendant to the high dose of DCVC was investigated via an equinephrotoxicity study in which separate groups of mice received 40 (LD40) and 75 (LD90) mg DCVC/kg, respectively. Bioactivation-based renal proximal tubular injury measured in these two groups over a time course was identical but there was a marked difference in mortality due to an early and robust tissue repair in the first group relative to the second group. These results support the concept that quantitative evaluation of renal tissue repair in parallel with injury is useful in the assessment of the likely toxic outcome associated with exposure to nephrotoxic drugs and toxicants. 相似文献
13.
Donald F. Smee Robert W. Sidwell Scott M. Clark Bill B. Barnett Rex S. Spendlove 《Antiviral research》1981,1(5):315-323
The antiviral effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin), 3-deazaguanine (3-DG), 3-deazauridine (3-DU) and 9-(S)-(2,3-dihydroxypropyl)adenine ([S]-DHPA) on reovirus types 1, 2 and 3 replication and host cell functions are described. Inhibition of cytopathic effect (CPE) and of immunofluorescent cell counts (IFCC) were determined to assess antiviral activity in Madin-Darby bovine kidney (MDBK) cells. Ribavirin showed the strongest inhibitory effects with inhibition at 3.2 μg/ml. 3-DG and 3-DU had moderate activity and (S)-DHPA exhibited only weak effects. There was little difference in the degree of inhibition among reovirus serotypes. Antiviral effects were reversed by guanosine (for ribavirin and 3-DG), uridine (for 3-DU) and adenosine (for [S]-DHPA). Comparative studies with reovirus type 3 indicated both CPE and IFCC inhibition to be approximately equally sensitive parameters. In radiolabel uptake studies, each compound moderately inhibited uptake of radioactive precursor molecules at dosage levels where viral inhibition was observed, suggesting a lack of specific reovirus inhibitory effects. 相似文献
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15.
Raymond P. Baumann Kimiko Ishiguro Philip G. Penketh Krishnamurthy Shyam Rui Zhu Alan C. Sartorelli 《Biochemical pharmacology》2011,(10):1201
To most effectively treat cancer it may be necessary to preferentially destroy tumor tissue while sparing normal tissues. One strategy to accomplish this is to selectively cripple the involved tumor resistance mechanisms, thereby allowing the affected anticancer drugs to gain therapeutic efficacy. Such an approach is exemplified by our design and synthesis of the intracellular hypoxic cell activated methylating agent, 1,2-bis(methylsulfonyl)-1-methyl-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS900) that targets the O-6 position of guanine in DNA. KS900 is markedly more cytotoxic in clonogenic experiments under conditions of oxygen deficiency than the non-intracellularly activated agents KS90, and 90M, when tested in O6-alkylguanine-DNA alkyltransferase (AGT) non-expressing cells (EMT6 mouse mammary carcinoma, CHO/AA8 hamster ovary, and U251 human glioma), and than temozolomide when tested in AGT expressing cells (DU145 human prostate carcinoma). Furthermore, KS900 more efficiently ablates AGT in HL-60 human leukemia and DU145 cells than the spontaneous globally activated methylating agent KS90, with an IC50 value over 9-fold lower than KS90. Finally, KS900 under oxygen-deficient conditions selectively sensitizes DU145 cells to the chloroethylating agent, onrigin, through the ablation of the resistance protein AGT. Thus, under hypoxia, KS900 is more cytotoxic at substantially lower concentrations than methylating agents such as temozolomide that are not preferentially activated in neoplastic cells by intracellular reductase catalysts. The necessity for intracellular activation of KS900 permits substantially greater cytotoxic activity against cells containing the resistance protein O6-alkylguanine-DNA alkyltransferase (AGT) than agents such as temozolomide. Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue. 相似文献
16.
Four stereoisomers of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid were prepared by reaction of L- and D-cysteine with fumaric acid. The absolute configuration of the diastereoisomer of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid from Amanita pantherina were assigned as (2R, 1'R) and (2R, 1'S) by analysis of the optical properties. Pharmacological tests showed that all of the four stereoisomers inhibited the depolarization of NMDA on spinal motorneurones in newborn rats, The inhibition intensity of L-A,D-A and D-B were higher than that of L-B. 相似文献
17.
目的建立毛细管电泳法测定(S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯中R异构体的方法。方法采用毛细管电泳法。以磺酸-β-环糊精(S-β-CD)为选择剂;25 mmol/L硼酸盐缓冲液(pH 8.9,含S-β-CD 1.8%)为运行缓冲液;运行电压为25 kV;柱温为15℃;检测波长:214 nm;3.4 kPa压力进样10 s。结果 (S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯与R异构体的分离度为2.9。R异构体在2~30μg/m L与峰面积线性关系良好(r=0.999 5),平均回收率为96.6%,RSD值为4.9%(n=6)。结论建立的毛细管电泳法操作简便,结果准确可靠,可用于(S)-2-(6-羟基-2,3-二氢苯并呋喃-3-基)乙酸甲酯中R异构体的控制。 相似文献
18.
Objective of the present study was to test the importance of tissue repair in the final outcome of S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced nephrotoxicity using colchicine (CLC) intervention. Male Swiss Webster (SW) mice were administered a normally nonlethal dose of DCVC (30 mg/kg, i.p.) on day 0 and CLC (2 mg/kg, i.p.) at 42 and 66 h after administration of DCVC. The mice were observed for mortality and various renal injury and repair parameters were studied during a time course of 0-14 days. Administration of 30 mg DCVC/kg led to loss of renal architecture by day 1, which sustained until day 5, and regressed thereafter to reach normal architecture by day 10 resulting in 100% survival. Renal dysfunction as assessed by increases in plasma BUN and creatinine levels was concordant during this time course. Urinary volume increased significantly between days 10 and 14 with significant increases in urinary glucose concentrations on days 1-4. Calpain leakage increased from day 1 and remained so until day 5 before declining at later time points. In contrast, CLC intervention led to marked inhibition of S-phase DNA synthesis and 100% mortality by 120 h. H&E sections of kidneys revealed loss of renal architecture on day 1 which progressively worsened from day 2 to 4. Polyuria and glycosuria were evident during the first 2 and 3 days, respectively. Calpain immunohistochemistry revealed progressive leakage of calpain in the extracellular space during 2-4 days which lead to increased renal injury as evident from significant increases in calpain specific breakdown products (CSBPs) of alpha-fodrin during the same period of time. The group of mice receiving 2 mg CLC/kg alone showed a significant increase in urinary creatinine concentration on day 5. Neither the expression nor localization of aquaporin 1 was altered in any of the treatment groups. These results show that antimitotic intervention after DCVC-initiated renal injury leads to expansion and progression of that injury, which appears to be due to proteolytic destruction of neighboring cells mediated by calpain leaking out of necrosed renal tubular epithelial cells. 相似文献
19.
P.K. Dutta D. Gillespie K. Hammons M.A. Haney 《Journal of pharmaceutical and biomedical analysis》1991,9(10-12):865-870
The properties of polybenzyl glutamate, a well known polyamino acid vary considerably with molecular weight in both solid state and in solution. Therefore, accurate determinations of the molecular weights of these polyamino acids is essential. The dual viscometer/refractometer when used as detector system for size exclusion chromatography provides a way of determining accurate molecular weights. An indirect method of determining the molecular weight distribution (MWD) and the radius of gyration distribution (RgD) of polybenzyl glutamate is described. The MWD is calculated from the measured value of intrinsic viscosity (IV) and the known IV-to-MW relationship, at every SEC retention volume slice. Such a technique of determining MWD requires no calibration and is more precisely measurable than conventional SEC methods. 相似文献
20.
虎刺楤木中氨基酸及微量元素的测定 总被引:4,自引:0,他引:4
托吡卡胺纸柄服药膜,是在眼药膜基础上的一次革新。本文介绍了其制备工艺、质量控制、刺激试验和散瞳试验,证明本品安全、有效、且散瞳效果优于滴眼液。 相似文献