维铁缓释片的质控方法及临床应用的研究

目的介绍维铁缓释片的质控方法及临床应用。方法建立质量控制方法。临床应用于治疗缺铁性贫血,并建立对照组相比较。结果处方中Fe、维生素C、烟酰胺、维生素B1、维生素B2、维生素B6均具有良好的线性范围,r均大于0.9990,平均回收率结果良好。药物治疗组HB＇RBC上升高于对照组2,副作用明显小于对照组1。结论该质控方法的研究有效控制了维铁缓释片的质量。维铁缓释片治疗缺铁性贫血疗效好,副作用小,是安全有效的治疗缺铁性贫血的药物。     

细胞因子类制品的无菌检查法

目的针对不同剂型细胞因子类制品建立适宜的无菌检查方法。方法依据《中国药典》2005年版三部要求,将细胞因子类制品按照不同的品种和剂型,分别采取直接接种法和薄膜过滤法进行无菌检查。结果与结论细胞因子类制品不同的品种和剂型可以采用不同的无菌检查法,并对新建立的无菌检查法进行方法学验证。     

Dietary Acrylamide Exposure and Hemoglobin Adducts – National Health and Nutrition Examination Survey (2003–04)

The objective of this study is to evaluate the relationship between dietary AA and hemoglobin adducts using the National Health and Nutrition Examination Survey (NHANES, 2003–04). Measured acrylamide (AA–Hb) and glycidamide (Gly–Hb) hemoglobin adducts for over 7000 participants >3 years, 24-h dietary recall, food frequency questionnaire (FFQ), lifestyle and demographic data, and anthropometric measurements are available from NHANES (2003–04). The 24-h dietary recall and FFQ data were combined with AA concentration data in food from the US FDA to estimate “usual” AA dietary exposure. The associations between dietary AA and AA–Hb and Gly–Hb were evaluated using linear regression models with smoking, age, gender, energy and macronutrient intake, body surface area, and activity level as covariates. Dietary AA positively correlates with AA–Hb and Gly–Hb (p < 0.05) but the correlation is small (R-Squared < 3.5%). Relative to the background adduct levels, the incremental increase in AA–Hb and Gly–Hb from average dietary AA is small (7% and 9% for AA–Hb and Gly–Hb, respectively). Non-dietary sources of exposure, measurement errors associated with the use of the FFQ, and uncertainty in the data on AA levels in foods are possible explanations for the observed lack of association between dietary AA and AA–Hb and Gly–Hb.     

The effect of early auditory deprivation on the age-dependent expression pattern of NR2B mRNA in rat auditory cortex

NMDA receptors have been well shown to be involved in neuronal plasticity. In order to understand the role of NR2B subtype NMDA receptors in auditory function development, the present study investigated the effect of early auditory deprivation on the expression of NR2B mRNA in rat auditory cortex (AC) during postnatal development. For normal rats, the NR2B mRNA expression was highest at birth (postnatal day 1 [P1]) and declined rapidly to low level during adulthood. However, during the critical period of rat auditory development (two to three weeks after birth), there was a transient NR2B expression peak on postnatal day 21 (P21). For the auditory-deprived rats, the general declining trend of NR2B mRNA expression from birth to adult was similar to that observed in the normal group, whereas the expression level from P15 to P27 was significantly lower than normal and the transient peak on P21 disappeared. In both groups, the distribution pattern of NR2B mRNA-positive neurons was also examined in various layers and dorsal, medial and ventral subdistricts of AC. There is no significant effect on the spatial expression of the NR2B mRNA in the AC between normal and deprived group. Our results indicated that the early auditory deprivation decreased the expression levels of NR2B mRNA in AC during the critical period of rat auditory development, suggesting that NR2B plays an important role in the developmental plasticity of auditory function in rats.     

Effects of estrogen,age, and calpain on MAP kinase and NMDA receptors in female rat brain

17-beta-Estradiol (E2), by activating Src and ERK/MAP kinases, enhances NMDA receptor phosphorylation and function. NR2 subunits of NMDA receptors are truncated by calpain, an effect prevented by tyrosine phosphorylation of the subunits. The present study investigated whether E2-mediated activation of ERK and NR2 subunits phosphorylation were altered in 24-month-old female rats. Ovariectomy reduced ERK2 phosphorylation in brains from 3- but not 24-month-old female rats. In ovariectomized rats, restoration of estrogen levels increased ERK2 and NR2 phosphorylation in young but not aged animals. Calcium treatment of frozen-thawed brain sections decreased NR2 levels in both young and aged female rats. This effect was absent in E2-treated young ovariectomized female rats, but was not modified in aged ovariectomized female rats. These results indicate that E2 activation of ERK2 and NR2 phosphorylation is markedly reduced in aged female rats, whereas calpain-mediated truncation of NR2 subunits is not different in young and aged rats. They suggest that several key elements of the mechanisms involved in estrogen-mediated regulation of synaptic plasticity are altered in aged animals.     

浅论当前中药饮片处方应付存在的问题与改进措施

分析中药处方应付中存在的品种应付不规范、炮制品应付不规范、并开名称应付不规范、医生书写处方不规范等常见问题,提出可通过规范中药饮片名称、制定统一的中药饮片处方应付标准、建立相对统一的中药饮片炮制规范、加强对医生和药师的管理与培训、强化行政管理部门的监管职能等途径来确保处方应付的正确性,以最大限度发挥中药饮片疗效和保障患者用药安全.     

Development of a Human Antibody Tolerant Mouse Model to Assess the Immunogenicity Risk Due to Aggregated Biotherapeutics

We describe a novel human immunoglobulin G₂ (IgG₂)-tolerant and immune-competent heterozygous mouse model (Xeno-het) developed by crossbreeding a human Ig-tolerized XenoMouse® with a C57BL/6J wild-type mouse. The Xeno-het mouse expresses both mouse and human immunoglobulin G (IgG) genes, resulting in B-cells expressing human and mouse IgG, and secretion of human and mouse Ig into serum. This model was utilized to evaluate the immunogenicity risk of aggregated and chemically modified human antibodies. The mice were tested for their ability to break tolerance to self-tolerant monomeric antibodies. Aggregates made by mechanical stirring elicited an anti-drug antibody (ADA) response, but did not induce a robust and long-term memory B and T-cell response. Chemically modified antibodies made by oxidation were only weak and transient inducers of an immune response, as measured by a lack of both an ADA response and a B-cell antigen-specific response. Aggregate size was an important characteristic, as specific-sized protein-coated beads were able to elicit an immune response. We propose the use of this model to identify risk factors such as aggregation during manufacturing at early development for an increased potential immunogenicity risk. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3545–3555, 2013     

Fenobam sulfate inhibits cocaine-taking and cocaine-seeking behavior in rats: implications for addiction treatment in humans

Rationale

The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be critically involved in drug reward and addiction. Because the mGluR5 negative allosteric modulators (NAMs) 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) significantly inhibit addictivelike behaviors of cocaine and other drugs of abuse in experimental animals, it has been suggested that mGluR5 NAMs may have translational potential for treatment of addiction in humans. However, neither MPEP nor MTEP have been evaluated in humans due to their off-target actions and rapid metabolism.

Objectives

Herein, we evaluate a potential candidate for translational addiction research: a new sulfate salt formulation of fenobam, a selective mGluR5 NAM that has been investigated in humans.

Results

In rats, fenobam sulfate had superior pharmacokinetics compared to the free base, with improved maximal plasma concentration (C _max) and longer half life. Oral (p.o.) administration of fenobam sulfate (30 or 60 mg/kg) inhibited intravenous (i.v.) cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior, and cocaine-associated cue-induced cocaine-seeking behavior in rats. Fenobam sulfate also inhibited p.o. sucrose self-administration and sucrose-induced reinstatement of sucrose-seeking behavior, but had no effect on locomotion.

Conclusions

This study provides additional support for the role of mGluR5 signaling in cocaine addiction and suggests that fenobam sulfate may have translational potential in medication development for the treatment of cocaine addiction in humans.     

Preclinical factors affecting the pharmacokinetic behaviour of tanshinone IIA,an investigational new drug isolated from Salvia miltiorrhiza for the treatment of ischaemic heart diseases

Tanshinone IIA (TSIIA) is a major active triterpenoid isolated from Salvia miltiorrhiza. The purposes of this study were to investigate various preclinical factors that determined the pharmacokinetics of TSIIA. After oral dosing at 6.7, 20, and 60 mg kg^?1, TSIIA was detected mainly as glucuronidated conjugate (TSIIAG) with only small amounts of the unchanged in the plasma. TSIIA was predominantly excreted into the bile and faeces as TSIIAG, and urine to a minor extent. The C_max and AUC_0?t of TSIIAG after i.p. administration were significantly lower than those after intragastric administration. The plasma concentration–time profiles of TSIIA following oral dosing of TSIIA showed multiple peaks. The C_max and AUC_0?t of TSIIA and its glucuronides in rats with intact bile duct were significantly lower than those of rats with bile duct cannulation. Studies from the linked-rat model and intraduodenal injection of bile containing TSIIA and its metabolites indicate that TSIIA glucuronides underwent hydrolysis and the aglycone was reabsorbed from the gut and excreted into the bile as conjugates. TSIIA had a wide tissue distribution, with a very high accumulation in the lung, but very limited penetration into the brain and testes. TSIIA was metabolized by rat CYP2C, 3A and 2D, as ticlopidine, ketoconazole and quinidine all inhibited TSIIA metabolism in rat liver microsomes. Taken collectively, these findings indicate that multiple factors play important roles in determining the pharmacokinetics of TSIIA.