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Objective:To study the kinetics of transdermal absorption of volatile oil from Angelica slinesis in fetal skin and investi-gate the mechanism of penetration enhancement in terms of morphology. Methods: Franz diffusion cells were used to investigate the transdermal characteristics in vitro. The content of ligustilide was determined by HPLC, and the cumulative permeation amount per unit area and rate constant of ligustilide were calculated. The effects of volatile oil from Angelica slinesis on skin ultrastructure was observed by a scanning electron microscope and a transmission electron microscope. Results:The kinetics of volatile oil at different concentra-tions was all in accordance with Higuchi equations. The ultrastucture changes of fetal skin under the scanning electron microscope were as follows:the wrinkles on skin surface increased, some areas of stratum corneum peeled off and turnovered like worn-out cotton pad-ding, the follicular orifice was enlarged, and the cuticles of the hair shaft dropped off and became thinner. The changes of fetal skin ul-trastucture under the transmission electron microscope were as follows:stratum corneum cells peeled off, the cell junction in basal lam-ina and stratum spinosum were broken, and the intercellular space was enlarged. Conclusion: The volatile oil from Angelica slinesis has good transdermal permeability. Its enhancement mechanism of transdermal drug absorption is closely related with the effects on skin ultrastructure, which can change the structure of stratum corneum to increase the cell gaps resulting in enhancing drug penetration.
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Objective: To establish a high performance liquid chromatography-tandem mass spectrometric method ( HPLC-MS/MS) method for the determination of PA-824 in the plasma of Beagle dogs, and study the pharmacokinetics of PA-824 in Beagle dogs. Methods:Carbamazepine was used as the internal standard, and the plasma samples were pretreated with ethyl acetate for the liquid-liquid extraction of PA-824. An Eclipse Plus C18 column (100 mm × 2. 1 mm, 3. 5 μm) was used with the mobile phase consisting of methanol-water (90 :10). The flow rate was 0. 6 ml·min-1 and the column temperature was 30 ℃. The injection volume was 5 μl and the sample analysis time was 5 min. The determination was performed with an electrospray ionization ( ESI) source in the positive multiple reaction monitoring (MRM) mode. The ion pairs were m/z 360. 1→m/z 175. 0 (collision energy of 35, solution cluster volt-age of 65) for PA-824 and m/z 237. 2→m/z 194. 0 (collision energy of 28, solution cluster voltage of 83) for carbamazepine. After the oral administration, PA-824 in plasma was measured at different time points, and then the pharmacokinetic parameters were calcu-lated by DAS 2. 0 software. Results: PA-824 showed a good linear relationship within the range of 50-10000 ng · ml-1 ( r =0. 9991). The recovery was 97. 7%-105. 1%, and the RSDs of intra-day and inter-day were less than 5. 0%. At three different dosa-ges (100, 200 and 500 mg) of PA-824, AUC0-twere (5735. 18 ± 1918. 76),(11548. 47 ± 1838. 04) and (21987. 88 ± 4587. 58) ng·min·ml-1,t1/2 were(14.17 ±5.97),(11.11 ±4.39) and (13.13 ±5.46)h,and Cmaxwere(626.66 ±188.48),(2399.13 ± 516.51) and (4861.33 ±2253.61)ng·ml-1, respectively. Conclusion:The method is simple, accurate, rapid and reproducible, and suitable for the pharmacokinetic study of PA-824 in the plasma of Beagle dogs.
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Objective To study the absorption characteristics of promethazine hydrochloride in different parts of rat intestine, provide evidence for the development of new preparation. Methods Rat single-pass intestinal perfusion model was established. By using high performance liquid chromatography (HPLC), 25, 50, 100 μgmL-1 promethazine hydrochloride concentration changing in different parts of the intestine was detected. Through the relevant calculation, the absorption rate constant ( Ka ) , and the apparent absorption coefficient ( Papp ) were obtained. Results With the concentration increase of promethazine hydrochloride in duodenal and ileal segments, the Ka and Papp increased significantly in the same part. Ka was (28.00±0.02)×10-2min-1 and Papp was (9.64±0.22) in the jejunum were the highest when the promethazine hydrochloride concentration was 50 μgmL-1 . As the concentration increased in colon, there were no significant changes in Ka and Papp . Conclusion Promethazine hydrochloride is absorbed in various intestinal segments, most obviously in duodenum and ileum, the absorption order is duodenum>ileum>jejunum>colon. Promethazine hydrochloride is absorbed most in the small intestine, in line with the intestinal absorption characteristics.
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Objective To study the absorption characteristics of promethazine hydrochloride in different parts of rat intestine, provide evidence for the development of new preparation. Methods Rat single-pass intestinal perfusion model was established. By using high performance liquid chromatography (HPLC), 25, 50, 100 μgmL-1 promethazine hydrochloride concentration changing in different parts of the intestine was detected. Through the relevant calculation, the absorption rate constant ( Ka ) , and the apparent absorption coefficient ( Papp ) were obtained. Results With the concentration increase of promethazine hydrochloride in duodenal and ileal segments, the Ka and Papp increased significantly in the same part. Ka was (28.00±0.02)×10-2min-1 and Papp was (9.64±0.22) in the jejunum were the highest when the promethazine hydrochloride concentration was 50 μgmL-1 . As the concentration increased in colon, there were no significant changes in Ka and Papp . Conclusion Promethazine hydrochloride is absorbed in various intestinal segments, most obviously in duodenum and ileum, the absorption order is duodenum>ileum>jejunum>colon. Promethazine hydrochloride is absorbed most in the small intestine, in line with the intestinal absorption characteristics.
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<p><b>OBJECTIVE</b>To observe if VIR576, an 20-mer peptide derived from the C-proximal subfragment of a1-antitrypsin (a1-AT) which inhibits human immunodeficiency virus type 1 (HIV-1) entry into the target cells by interacting with fusion peptide (FP), can also directly inhibit CD4(+) T cell activation in vitro.</p><p><b>METHODS</b>Splenocytes isolated from DO11.10 OVA Tg mice were stimulated with ovalbumin or concanavalin A to test the effects of VIR576 on antigen-specific or non-antigen-specific T cell activation. Both primary CD4(+)CD25(-) T cells from DO11.10 mice and CD4(+) T cell line A2b were activated with specific antigens to evaluate the effects of VIR576.</p><p><b>RESULTS</b>VIR576 inhibited antigen-specific splenocyte activation but had no significant effect on non-antigen-specific T-cell activation, which bypassed the crosstalk between the CD3-signaling complex and TCR. We furthermore observed that VIR576 could also down-regulate antigen-specific CD4(+) T-cell activation.</p><p><b>CONCLUSIONS</b>Given the high susceptibility of activated CD4(+) T cells in the mucosa to HIV-1 infection, the inhibitory effects of VIR576 on both HIV entry into the target cells and CD4(+) T-cell activation suggest the potential of VIR576 as a microbicide for prevention of sexual transmission of HIV.</p>
Subject(s)
Animals , Mice , CD3 Complex , CD4-Positive T-Lymphocytes , HIV Fusion Inhibitors , Pharmacology , HIV-1 , Lymphocyte Activation , Mice, Transgenic , Ovalbumin , Peptide Fragments , Pharmacology , alpha 1-Antitrypsin , PharmacologyABSTRACT
Background and purpose: The metastasis-associated in colon cancer-1 (MACC1) is highly expressed in different cancers and has an effect on the proliferation and apoptosis of tumor cells through the regulation of extracellular signal-regulated kinase (ERK)1/2 pathway. However, the role of MACC1 in ovarian cancer has been rarely studied. The study was aimed to suppress MACC1 gene expression by siRNA and explore the relationship between MACC1 expression and chemosensitivity to cisplatin in ovarian cancer cell line SKOV3/DDP. Methods:Empty plasmid p-super-EGFP-1 (negative control group) and p-super-EGFP-MACC1 shRNA (experimental group) were transfected into ovarian cancer cell SKOV3/DDP respectively. SKOV3/DDP cells without transfection were used as blank group. Then, MACC1 mRNA and protein levels were measured by RT-PCR and Western blot, respectively. Cell proliferation and IC50 of cisplatin was determined by methyl thiazolyl tetrazolium test (MTT). Apoptosis rate was determined by lfow cytometer (FCM). ERK1/2 and p-ERK1/2 protein levels were determined by Western blot. Results:Compared with those in blank and negative control groups, MACC1 mRNA and protein levels deceased in experimental group. The IC50 of cisplatin in experimental group was lower than that in the other groups (26.094 vs 47.501/47.089μmol/L, P<0.05). There was a lower expression of p-ERK1/2 in experimental group (0.3979 vs 00.6712/0.6681, P<0.05). Apoptosis rate was significantly higher in the experimental group before and after treatment of cisplatin (1.32%vs 0.66%/0.48%, P<0.05;36.70%vs 18.53%/16.60%, P=0.000). Conclusion:MACC1 gene may be involved in cisplatin resistance phenomenon in SKOV3/DDP cells through ERK1/2 pathway.
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OBJECTIVE:To observe the effect of different concentration of borneol nasal drops on the vasopermeability of nasal mucosa and the cerebral vessels.METHODS:Guinea pigs were divided into5groups,i.e.borneol group in3different concentrations(0.5%,1.0%and2.0%),histamine group and liquid paraffin group.Guinea pigs were injected i.v with2%evans blue(EB)after administration with nasal drops,which were then put to death10min later;the nasal mucosa and brain tissue of which were obtained and the EB contents in which were determined.RESULTS:Compared with the liquid paraffin group,the EB contents in the nasal mucosa and brain tissue in the borneol groups were higher(P
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Objective To optimize the proportion of three transdermal penetration enhancers on transdermal absorption of ligustrazine hydrochloride.Methods Permeation tests in vitro through BALB/c nude mouse skin in two compartment diffusion cells were performed to study the effect of synthetic borneol,menthol,and Azone on trandermal absorption of ligustrazine hydrochloride by changing their concentrations,and uniform design method was used to determine the penetration coefficient of ligustrazine hydrochloride and optimize the proportion of three transdermal penetration enhancers.ResultsThe optimal proportion and contents of synthetic borneol,menthol,and Azone were 1.5%∶1.5%∶1.5%(15 mg/mL∶15 mg/mL∶15 mg/mL),the real penetration coefficient of ligustrazine hydrochloride was 69.575 ?g/(h?cm2),while the theoretical penetration coefficient was 69.749 ?g/(h?cm2).Conclusion Uniform design method is an effective way to optimize the proportion of three transdermal penetration enhancers on trandermal absorption of ligustrazine hydrochloride.