Transdermal delivery of venlafaxine hydrochloride: the effects of enhancers on permeation across pig ear skin

Venlafaxine representing a new class of antidepressants is a potent serotonin/ norepinephrine reuptake inhibitor. Transdermal delivery of venlafaxine hydrochloride (VHCl) may result in proper patient compliance by reducing the incidence of the undesirable GI problems generally associated with its plural oral dosing. The present study is an attempt to investigate the improvement of the transdermal flux of the hydrophilic VHCl by certain permeation enhancers viz. glycerin, urea, propylene glycol and mixture of propylene glycol and ethanol across pig ear skin. The cumulative drug release was the highest from the formulation F5 consisting of the mixture of propylene glycol and ethanol in sodium alginate gel with a load of 25% w/w VHCl with 96% permeation enhancement. The steady state flux observed with F5 was 0.203 mg cm(-2) hr and an area of 15.27 cm(2) would suffice to arrive at a required therapeutic concentration of VHCl in the blood.     

Acridine derivatives as anti-BVDV agents

Twenty-six 9-aminoacridine derivatives were evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. While seven compounds (9, 10, 14, 19, 21, 22, 24) did not affect any virus and two (6, 11) were moderately active against CVB-5 or Reo-1, 17 compounds exhibited a marked specific activity against BVDV, prototype of pestiviruses which are responsible for severe diseases of livestock. Most anti-BVDV agents showed EC₅₀ values in the range 0.1-8 μM, thus comparing favorably with the reference drugs ribavirine and NM 108. Some compounds, particularly those bearing a quinolizidinylalkyl side chain, displayed pronounced cytotoxicity. Further studies are warranted in order to achieve still better anti-BVDV agents, and to explore the potential antiproliferative activity of this kind of compounds.     

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome

BACKGROUND:

Ezatiostat is a glutathione analog prodrug glutathione S‐transferase P1‐1 (GSTP1‐1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate‐1 risk myelodysplastic syndrome (MDS).

METHODS:

Patients were randomized by 1 stratification factor—baseline cytopenia (anemia only vs anemia with additional cytopenias)—to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria.

RESULTS:

Overall, 11 of 38 (29%) red blood cell (RBC) transfusion‐dependent patients had HI‐Erythroid (HI‐E) response. The median duration of HI‐E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI‐E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI‐E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat‐related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%).

CONCLUSIONS:

Ezatiostat is the first GSTP1‐1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS. Cancer 2012. © 2011 American Cancer Society.     

Effects of Treatment for Tobacco Dependence on Resting Cerebral Glucose Metabolism

While bupropion HCl and practical group counseling (PGC) are commonly used treatments for tobacco dependence, the effects of these treatments on brain function are not well established. For this study, 54 tobacco-dependent cigarette smokers underwent resting ¹⁸F-fluorodeoxyglucose–positron emission tomography (FDG–PET) scanning before and after 8 weeks of treatment with bupropion HCl, PGC, or pill placebo. Using Statistical Parametric Mapping (SPM 2), changes in cerebral glucose metabolism from before to after treatment were compared between treatment groups and correlations were determined between amount of daily cigarette usage and cerebral glucose metabolism. Compared with placebo, the two active treatments (bupropion HCl and PGC) had reductions in glucose metabolism in the posterior cingulate gyrus. Further analysis suggested that PGC had a greater effect than bupropion HCl on glucose metabolism in this region. We also found positive correlations between daily cigarette use and glucose metabolism in the left occipital gyrus and parietal–temporal junction. There were no significant negative correlations between daily cigarette use and glucose metabolism. Our findings suggest that bupropion HCl and PGC reduce neural activity much as the performance of a goal-oriented task does in the default mode network of the brain, including the posterior cingulate gyrus. Thus, this study supports the theory that active treatments for tobacco dependence move the brain into a more goal-oriented state.     

HPLC法测定复方聚甲酚磺醛软膏中盐酸辛可卡因的含量

目的 建立以HPLC法测定复方聚甲酚磺醛软膏中盐酸辛可卡因的含量.方法 色谱柱为Agilent TC-C18(250mm×4.6mm,5μm);流动相为乙腈-0.02mol·L-1磷酸二氢钾溶液(用0.1mol·L-1氢氧化钾溶液调节pH值至4.6)(40∶60);检测波长为230nm,流速为1.0mL·min-1.结果 盐酸辛可卡因在2.1333μg·mL-1～21.3332μg·mL-1检测范围内线性关系良好(r=0.99996,n=6),平均回收率为100.50%(n=9,RSD=0.8%).结论 本法操作简便、灵敏度高、重现性好.     

阿糖胞苷5’-缬氨酸酯前体药物的小肠吸收机制

目的 研究阿糖胞苷的5’-缬氨酸酯前药在大鼠小肠内的吸收情况。方法 运用单向灌流模型研究药物在小肠内的吸收机制，利用高效液相色谱法测定药物和酚红在灌流液中的浓度。结果 阿糖胞苷 5’-缬氨酸酯前药的小肠渗透率是母药阿糖胞苷的10.6倍，在小肠内的吸收存在浓度依赖性，能够被小肠寡肽转运蛋白的专属底物头孢氨苄明显抑制。结论 阿糖胞苷 5’-缬氨酸酯前药是小肠寡肽转运蛋白的底物，在大鼠小肠内的吸收是由小肠寡肽转运蛋白介导的主动转运过程。     

Characteristics of new composite- and classical potentiometric sensors for the determination of pioglitazone in some pharmaceutical formulations

The construction and electrochemical response characteristics of poly(vinyl chloride) membrane sensors for pioglitazone HCl (PG) are described. The sensing membranes incorporate ion association complexes of pioglitazone cation and sodium tetraphenylborate (NaTPB) (sensor 1) or phosphomolybdic acid (PMA) (sensor 2) or phosphotungstic acid (PTA) (sensor 3) as electroactive materials. The sensors display a fast, stable and near-Nernstian response over a relative wide pioglitazone concentration range (1x10(-2) to 10(-6)M), with cationic slopes of 55.0+/-0.5, 58.0+/-0.5 and 53.0+/-0.5mV per concentration decade over a pH range of 1.0-5.0. The sensors show good discrimination of pioglitazone from several inorganic and organic compounds. The direct determination of 2.5-3900.0mug/ml of pioglitazone show an average recovery of 98.5, 99.0 and 98.4% and a mean relative standard deviation of 1.6, 1.5 and 1.7% at 100.0mug/ml for sensors 1, 2 and 3, respectively. The proposed sensors have been applied for direct determination of pioglitazone in some pharmaceutical preparations. The results obtained by determination of pioglitazone in tablets using the proposed sensors are comparable favorably with those obtained using the HPLC method. The sensors have been used as indicator electrodes for potentiometric titration of pioglitazone.     

抗组胺药物应用进展

抗组胺药物治疗过敏性疾病已广泛地应用于临床。由于第 1代抗组胺药物嗜睡的不良反应而影响了它的临床应用 ,2 0世纪 80年代后生产的第 2代抗组胺药物具有H1受体选择性高、无镇静作用与组胺作用分离等特点 ,称非镇静抗组胺药 (NSA)。但第 2代抗组胺药仍有一些不良反应 ,尤以心脏的毒性作用 ,这与抗组胺药物相互作用、药动学、以及药物的分子结构有关。 1997年新型抗组胺药物———非索非那定 (fexofenadine)问世 ,它是作用快、疗效高、相对安全低毒的抗组胺药。非索非那定的开发 ,为寻找既无中枢镇静作用 ,也无心脏毒性的抗组胺药物开辟了新的途径     

Degradation of glyceraldehyde-3-phosphate dehydrogenase induced by acetylleucine chloromethyl ketone in U937 cells

We examined whether any changes were induced in cellular proteins by an inhibitor of acylpeptide hydrolase (ACPH) (EC 3.4.19.1), acetylleucine chloromethyl ketone (ALCK), which was shown in our previous report to induce apoptosis of human U937 cells. Extract prepared from U937 cells in 0.05% Triton X-100-PBS was incubated with ALCK at 37 degrees, and then analyzed using SDS-PAGE. A 36kDa protein in the cell extract was decreased markedly during the incubation period. This protein was purified and identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) by its specific enzyme activity, N-terminal amino acid sequence, and Western blotting. Incubation of purified GAPDH with ALCK resulted in a decrease of GAPDH activity, but not in a decrease in the amount of GAPDH. The ALCK-induced GAPDH decrease in the cell extract was abrogated by co-incubation with a serine protease inhibitor, diisopropyl fluorophosphate, suggesting that GAPDH was first inactivated by ALCK, and subsequently degraded by a serine protease(s). GAPDH degradation was also observed in U937 cell cultures in the presence of ALCK. The significance of GAPDH inhibition in the apoptotic process is discussed.     

Trigonella foenum graecum seed extract protects kidney function and morphology in diabetic rats via its antioxidant activity

Oxidative stress is involved in the development and progression of diabetic nephropathy (DN). Because Trigonella foenum graecum has been reported to have antidiabetic and antioxidative effects, we hypothesized that T foenum graecum seed aqueous extract (TE) restores the kidney function of diabetic rats via its antioxidant activity. Rats were fed diets enriched with sucrose (50%, wt/wt), lard (30%, wt/wt), and cholesterol (2.5%, wt/wt) for 8 weeks to induce insulin resistance. After a DN model was induced by streptozotocin, the rats were administered a low (440 mg/kg), medium (870 mg/kg), or high (1740 mg/kg) dose of TE by oral intragastric intubation for 6 weeks. In TE-treated DN rats, blood glucose, kidney/body weight ratio, serum creatinine, blood urea nitrogen, 24-hour content of urinary protein, and creatinine clearance were significantly decreased compared with nontreated DN rats. Diabetic rats showed decreased activities of superoxide dismutase and catalase, increased concentrations of malondialdehyde in the serum and kidney, and increased levels of 8-hydroxy-2′-deoxyguanosine in urine and renal cortex DNA. Treatment with TE restored the altered parameters in a dose-dependent manner. Furthermore, all of the ultramorphologic abnormalities in the kidney of diabetic rats, including the uneven thickening of the glomerular base membrane, were markedly ameliorated by TE treatment. We conclude that TE confers protection against functional and morphologic injuries in the kidneys of diabetic rats by increasing activities of antioxidants and inhibiting accumulation of oxidized DNA in the kidney, suggesting a potential drug for the prevention and therapy of DN.