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ABSTRACT: RNA interference (RNAi), as a new technology of gene therapy, has been used in the studies of many diseases in vitro, however, targeting delivery of small interference RNA (siRNA) is still a bottleneck for clinical therapy of siRNA agents. Aptamer is a group of oligonucleotides with high affinity and targeting, and is becoming another important means of delivery for siRNA. In this review, we summarized siRNA delivery obstacles in vivo and recent attractive developments increatively using cell-internalizing aptamers to deliver siRNAs to target cells.
Yao xue xue bao = Acta pharmaceutica Sinica 07/2012; 47(7):850-5.
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Hai-yan Du,
Li-hou Dong,
Bi-jun Zhao,
Jie Fu,
Qing-qing Wang,
Fang Chen,
Lun Ou,
Na Li,
Xiao Sun,
Zhong-ming Tang, Hai-feng Song
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ABSTRACT: DNAs containing unmethylated CpG motifs can stimulate innate and adaptive immunity. The aim of this study was to investigate the immunostimulatory and anti-neoplasm effects of a novel CpG oligodeoxynucleotide, ODN10, in tumor-bearing mice.
B16 melanoma-bearing C57BL/6 mice were administered ip or sc with ODN10 or conventional CpG ODN1826 on the indicated days post inoculation. The animal survival rate and the inhibitory effect on tumor growth were observed in vivo. B and T lymphocyte proliferation, natural killing cell cytotoxicity and the phagocytic ability of peritoneal macrophages from the animals were determined using [(3)H]-thymidine incorporation assay, 4-h (51)Cr release assay and neutral red chromometry method, respectively. The serum levels of IL-12, IL-4 and IgE were quantified using ELISA assays. Histological examination of tumor tissues was performed after HE staining, and the expression of PCNA, CD63, and CD80 in tumor tissues was analyzed with immunohistochemistry.
ODN10 (1, 5 and 25 mg/kg) significantly inhibited the growth and metastasis of the tumor, and significantly prolonged the survival of tumor-bearing mice, as compared with ODN1826. The immune status was suppressed in tumor-bearing mice. Both ODN10 and ODN1826 significantly reversed the suppressed immunoactivities in tumor-bearing mice, which included promoting B and T lymphocyte proliferation, enhancing NK cell and peritoneal macrophage activities, inducing IL-12 secretion and inhibiting IL-4 and IgE secretion. Further, CpG ODNs decreased PCNA and CD63 expression while induced expression of CD80. ODN10 presented more potent activity, and displayed the most prominent immunostimulatory potential.
ODN10 produces prominent immunomodulatory effects on cellular immunity in tumor-bearing mice, which might help reverse the established Th2-type responses to the Th1-type responses, thus may be used as a potent anti-tumor immunotherapy agent or adjuvant.
Acta Pharmacologica Sinica 06/2012; 33(8):1047-54. · 1.95 Impact Factor
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ABSTRACT: To study the pharmacokinetics of cantide, an antisense oligonucleotide, and its metabolites after iv gtt administration in rhesus monkeys, a dual solid phase extraction pretreatment method coupling with non-gel sieving capillary electrophoresis analysis method was used for determination of cantide and its metabolites in plasma and their pharmacokinetic parameters were calculated. The pharmacokinetic behavior of cantide and its metabolites (M1 and M2) after iv gtt administration (8, 16 and 24 mg kg(-1)) in rhesus monkeys were investigated. After iv gtt administration of cantide to rhesus monkeys, cantide in plasma was eliminated rapidly and the terminal elimination half-life (t1/2) was 57.91-77.97 min, the correlation coefficients (r) to the dose of Cmax AUC(o-inf) and AUC(0-t) of the prototype was 0.9918, 0.9568 and 0.9773, respectively. The metabolites of cantide reached the Cmax following cantide immediately and the Cmax of metabolites were lower than that of the prototype. The CL(S) of cantide and its metabolites (M1 and M2) were 1.60-2.19, 5.92-8.58 and 6.07-8.78 mL min(-1) kg(-1), respectively. So, it is concluded that the Cmax of cantide and its metabolites increased with the dose, which is the same as their AUC(0-inf) and AUC(0-t). The CL(S) of metabolites were higher than that of the prototype. The MRT and t1/2 of metabolites in the high dose group increased obviously.
Yao xue xue bao = Acta pharmaceutica Sinica 11/2011; 46(11):1370-3.
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ABSTRACT: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS).
Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method.
The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively.
Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.
Acta Pharmacologica Sinica 11/2010; 31(11):1500-7. · 1.95 Impact Factor
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ABSTRACT: Aim: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS).
Acta Pharmacologica Sinica 10/2010; 31(11):1500-1507. · 1.95 Impact Factor
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ABSTRACT: To evaluate and compare the efficacy and clinical results of cervical expansive open door laminoplasty (EOLP) with different hinge position.
From February 2006 to February 2007, a total of 102 cases with cervical spondylotic myelopathy were assessed in this randomized controlled trial. Fifty-seven patients underwent EOLP with the hinge located at the inner margin of the lateral mass classified as wide-open group. Forty-five cases who underwent EOLP with the hinge positioned at the lamina margin served as narrow-open group. The clinical results and radiological examinations of both groups were evaluated 24 months after surgery.
There were no significant differences in operation time, bleeding quantity and recovery rate of Japanese Orthopaedic Association (JOA) scores. The incidence of C(5) palsy and severity of axial symptoms in the wide-open group were significantly lower than those in the narrow-open group (P < 0.05). There were no significant differences in cervical curvature index and range of motion between the two groups.
Well-suited and appropriated inwardly shift the hinge could promote clinical outcomes after EOLP, especially decrease the incidence of the C(5) palsy and the severity of axial symptom, but it is contraindication for patients with ossification of posterior longitudinal ligament, ossification of ligament flavum and fluorosis cervical stenosis.
Zhonghua wai ke za zhi [Chinese journal of surgery] 08/2010; 48(16):1229-33.
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ABSTRACT: An improved liquid chromatographic method with on-line solid phase extraction (SPE) and tandem mass spectrometric detection was optimised for quantification of the anti-HIV peptide Sifuvirtide in human plasma. The SPE sorbents, loading buffer composition and other aspects of the on-line SPE column were investigated in detail for efficiently extracting the interesting peptides and simultaneously discarding the large amount of proteins. The gradient elution program was optimised on the analysis column to decrease the matrix effect and obtain excellent selectivity. The multiple charge ion at m/z 946.4 of Sifuvirtide was quantified by a linear ion trap mass spectrometer, operating in the positive mode, and selective reaction monitoring (SRM) acquisition. Method validation results demonstrated that the linear calibration curve covered a range of 6.1-6250 ng/mL, and the correlation coefficients (r(2)) were above 0.992. The lower limit of detection (LLOD) with a signal-to-noise (S/N) ratio higher than 10 was 6.1 ng/mL. The accuracy ranged from -7.6 to 10.6%, and the intra- and inter-batch precisions were less than 8.7% and 5.5%, respectively. Finally, more than nine hundred of samples from a clinical trial was completely analyzed using this on-line SPE coupled HPLC-MS/MS system in one single week, due to the rapid run-time of individual sample (6.5 min).
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 07/2010; 878(21):1893-8. · 2.78 Impact Factor
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ABSTRACT: To investigate the association between Trp2 allele polymorphism with degenerative disc disease (DDD) in a Chinese Han population.
A total of 125 DDD patients (58 males and 67 females, 51.8 +/- 7.6 years old), and 125 controls matched in sex and age (63 males and 62 females, 45.3 +/- 8.3 years old) were recruited in the case-control study. Their peripheral blood samples were collected for DNA isolation. Based on NCBI genebank, the corresponding single nucleotide polymorphisms (snp)-SNP1 (rs7533552) and SNP2 (rs2077871) were identified. Hardy-Weinberg equilibrium was analyzed both in case and control groups. Then the case group was classified into different clinical phenotypes according to severity of degeneration, sole or multi-disc degeneration and different affected discs. Genotyping of all selected SNPs was performed by SNP stream technology. The association analysis between phenotypes and SNPs was conducted. Pairwise linkage disequilibrium was calculated in control population using Haploview 4.0 software.
SNP1 (rs7533552), SNP2 (rs2077871) and corresponding SNP of Trp2 allele were gentyped and both polymorphisms distributed in line with Hardy-Weinberg equilibrium in case and control groups. Allelic frequency of SNP1A, SNP1G, SNP2C and SNP2T (42%, 47%, 88% and 90% respectively) of case group were not significantly different from those of control group (48%, 53%, 88% and 10% respectively, all P > 0.05). Genotypic frequencies of SNP1AA, SNP1AG, SNP1GG, SNP2CC, SNP2CT and SNP2TT in case group were not significantly different from those of control group (all P > 0.05). However there was an association with genotypic frequencies of SNP2 and severity of disc degeneration (chi(2) = 6.920, P = 0.031).
Trp2 allele is one of risk factors for the development and severity of DDD in a Chinese Han population.
Zhonghua yi xue za zhi 01/2010; 90(3):148-52.
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ABSTRACT: To build a 3D finite element model of whole lumbar spine and verify its efficiency and analyze the biomechanical change of L3-4 motion segment.
L1-L5 segment data were obtained from computed tomography (CT) scans of the lumbar spine of a 40-year-old man with no abnormal findings. A three-dimensional finite element model of the human whole lumbar spine was built in the Mimics and the ABAQUS software. The model was composed of bony vertebrae, articulating facets, intervertebral disc and associated ligaments. The basic stress analysis of L3-4 motion segment was made under the considerations of different material properties of bone, ligaments and facet joints contacting frictional property. The stress on annulus fiber, nucleus pulposus, endplate and facet joints under axial pressure (0.3 MPa, 0.5 MPa, 1.0 MPa, 2.0 MPa & 4.0 MPa) were analyzed.
A three-dimensional finite element model of human L3-L4 motion segment has 272, 619 elements, the stresses were higher in the posterior of annulus fiber, the Max pressure stress (S33) distributed in nucleus pulposus and the center of endplate. The stresses increased as axial pressure rose.
3D finite element model of whole lumbar spine and L3-4 motion segment were established successfully and the stress analyses were feasible and reliable.
Zhonghua yi xue za zhi 05/2009; 89(17):1162-5.
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ABSTRACT: Optimal design of antiviral short-interfering RNA (siRNA) targeting highly divergent hepatitis B virus (HBV) was validated by quantitative structure activity relationship (QSAR) analysis.
The potency of 23 synthetic siRNAs targeting 23 sites throughout HBV pregenomic RNA were evaluated at 10 nmol/L by determining the inhibition on the expression of S/P/pregenomic mRNA and hepatitis B surface antigen (HBsAg) quantitatively in HepG2.2.15 cells. Genotype homology within HBV genomes was identified through plentiful computational analysis and the multiple linear regression analysis was made to validate the relationship between the functional siRNAs and primary characteristics. Based on the preliminary results, relationships between different determined endpoints [S/P mRNA, HBsAg, C/P mRNA, hepatitis B e antigen (HBeAg) and viral DNA load] and siRNA efficacy evaluation were investigated.
Genotype homology, open reading frame (ORF) S/P, X and C had tight correlation with the ability of siRNAs on inhibiting the expression of S/P/Pregenomic mRNA and HBsAg (P<0.01), of which, ORF C was negatively correlated with the siRNA potency (P<0.05). Further study showed that siRNA potency evaluation was influenced by different determined endpoints. P-target siRNAs showed significant inhibition on the S mRNA and HBsAg expression. S-target siRNAs inhibited the expression of S mRNA and HBsAg strongly. X-target siRNAs played active roles in inhibiting all 5 determined endpoints. C-target siRNAs blocked the expression of C mRNA, HBeAg and viral DNA load significantly.
The antiviral potency of siRNA was relevant to its primary characteristics and determined endpoints were important for siRNA efficacy evaluation for complex genome with overlapping ORF, which was helpful for siRNA optimal design.
Acta Pharmacologica Sinica 01/2009; 29(12):1522-8. · 1.95 Impact Factor
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ABSTRACT: To investigate the association of polymorphisms of PAX1 gene with congenital scoliosis (CS) in Chinese Han population and the relationship between the PAX1 gene polymorphisms and the clinical phenotypes of CS.
Peripheral blood samples were collected from 127 CS patients, 55 male and 72 female, aged (12.9 +/- 4.3) (2 - 23), and 127 sex- and age-matched controls. Based on genotype data from the International HapMap project, the tagging single nucleotide polymorphisms (tSNPs) were selected using Haploview 4.0 software. Hardy-Weinberg equilibrium was analyzed both in the control and case groups. The case group was classified into different clinical phenotypes according to vertebral defect type, location of deformity, extent of developmental disruption, combined rib malformations, and neural canal deformity. Genotyping of all selected SNPs was done by SNPstream technology. The association between phenotypes and SNP was analyzed. Pairwise linkage disequilibrium was calculated in the control population using Haploview 4.0 software.
The sites: SNP1 (rs17861031) and SNP2 (rs6047590), of PAX1 gene were genotyped and both polymorphisms were distributed in line with the Hardy-Weinberg equilibrium in these 2 groups. There was no linkage disequilibrium between these 2 SNPs. The genotype frequencies of SNP1AA, SNP1AG, SNP1GG, SNP2AA, SNP2AT, and SNP2TT of the case group were 2%, 26%, 72%, 2%, 19%, and 80% respectively, all not significantly different from those of the control group (2%, 26%, 72%, 2%, 26%, and 82% respectively, all P > 0.05). The allele frequencies of SNP1A, SNP1G, SNP2A, and SNP2T of the case group were 15%, 85%, 11%, and 89% respectively, all not significantly different from those of the control group (15%, 85%, 10%, and 90% respectively, all P > 0.05). No positive sites were found in different clinical phenotypes.
The genetic variants of PAX1 gene may not be associated with the susceptibility to CS and different clinical phenotypes of CS in Chinese Han population.
Zhonghua yi xue za zhi 10/2008; 88(37):2597-602.
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ABSTRACT: To analyze and compare the Imaging findings of adult idiopathic scoliosis and degenerative scoliosis which were the most common adult scoliosis, and evaluate imaging characteristics.
The radiological and clinical data of 98 case, among them, 41 cases of adult idiopathic scoliosis and 57 cases of degenerative scoliosis, were analyzed retrospectively.
There were differences at presence age, sex ratio, anatomic area of scoliosis and apex between two types of adult scoliosis. The analyses and comparison between the two groups revealed significant change in the Cobb angle, involved segment and convex side orientation (all P < 0.05).
Adult idiopathic scoliosis and degenerative scoliosis show distinctive imaging characteristics. These characteristics combining clinical data are decisive in diagnosis.
Zhonghua yi xue za zhi 07/2008; 88(23):1630-3.
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Hai-Yan Du,
Shao-You Xia, Hai-Feng Song,
Na Li,
Ming-Mei Shang,
Jia Zou,
Qing-Qing Wang,
Lun Ou,
Xiao Sun,
Ai-Guo Ji,
Zhong-Ming Tang
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ABSTRACT: To study the relationship between primary structures of oligodeoxynucleotides (ODN) containing unmethylated deoxycytidyldeoxyguanosine (CpG) dinucleotide motifs and their immunostimulatory activities in mouse spleen cells.
A series of CpG ODN with different primary structures were synthesized. Their capabilities to stimulate mouse spleen cell proliferation were determined by [3H]thymidine incorporation assay. Cytokine (interleukin [IL]-6, IL-12, and IFN-alpha) secretion spectra induced by CpG ODN were assessed by ELISA. The ability of CpG ODN to activate natural killer cells was evaluated by standard 4 h (51)Cr-release assay. Flow cytometry was utilized to examine the expressions of various lymphocyte surface molecules on diverse immunocytes. An effective CpG ODN for murine, ODN1826, was set as the template of modification and the positive control.
The immunostimulatory activities of CpG ODN with different sequences and compositions varied markedly, both in character and in extent. It was useless for improving the immunostimulatory activity of ODN1826 by simply increasing the functional hexameric CpG motif number, modifying the site of CpG motifs, or changing the distance between multi-CpG motifs. However, an addition of a self-complementary palindrome structure at the 3'-end, but not the 5'-end of CpG ODN, aroused marked improvement in its activity. Several designed ODN had superior comprehensive immunostimulatory properties compared to ODN1826.
The immunostimulatory activity of a CpG ODN was relevant to its primary structure. It was useless for promoting immunostimulatory activity to simply change CpG motif number, space, or distance. The 3'-end palindrome structure of CpG ODN is associated with enhanced immunostimulatory activity.
Acta Pharmacologica Sinica 11/2007; 28(10):1637-44. · 1.95 Impact Factor
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ABSTRACT: To study the relationship between the structure of dermatan sulfate (DS) derivatives and their anti-thrombotic activities, DS-derived oligosaccharides (with different structures and relative molecular weight (M(r))) were prepared, and the effects of the DS-derived oligosaccharides on the activities of heparin cofactor II (HCII), activated protein C (APC), blood platelet, and vascular endothelial cells were studied. The major disaccharides of DS and polysulfated dermatan sulfate (PSDS) were IdoA-1-->3-GalNAc-4-OSO(3) and IdoA-2OSO(3)-1-->3-GalNAc4, 6-diOSO(3), respectively. The results showed that the consequence of the thrombotic inhibitory effects of DS and its derivatives were as follows: PSDS>low molecular weight polysulfated dermatan sulfate (LPSDS)>DS. Both DS and PSDS inhibited platelet aggregation in the concentration-dependent manner, and the IC(50) value of DS and PSDS is 12.7+/-1.3 and 28.6+/-0.9 mg/mL, respectively. DS oligosaccharides (DSOSs) and PSDS oligosaccharides (PSDSOSs) both significantly inhibited P-selectin expression on platelet surface (P<0.01), while DSOSs have no different effect compared with PSDSOSs. DSOSs and PSDSOSs significantly enhanced the activity of HCII in inhibiting thrombin in the plasma. The most active PSDSOS was PSDSOS(1) with M(r) of 4959, which enhanced the HCII activity by 91% (P<0.01). The experiments on APC activity showed that DS and its derivatives enhanced APC activity. The most active PSDSOS was PSDSOS(3) with M(r) of 2749, which enhanced the APC activity to 331+/-27% (P<0.01). DSOSs and PSDSOSs enhanced tissue plasminogen activator (t-PA) activity and reduced the plasminogen activator inhibitor (PAI) activity from cultured human umbilical vein endothelial cells (HUVEC), resulting in the ratio of t-PA/PAI going up. PSDSOSs which have the same M(r) as DSOSs produced more active effects in above assays, except for platelet aggregation.
Thrombosis Research 02/2007; 119(3):377-84. · 2.44 Impact Factor
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ABSTRACT: To explore the feasibility and mechanism of recombinant adenovirus Ad-pl4ARF in cancer gene therapy.
The proliferation of different liver cancer cells was assessed by morphology and trypan blue assay. Cell apoptosis was confirmed by detecting phosphatidylserine (PS) externalization with Annexin V/PI double staining. The expression of related proteins was analyzed by Western bloting. Nude mouse model bearing subcutaneous transplanted BEL7402 tumor was established to study the therapeutic ability of Ad-pl4ARF.
Ad-pl4ARF suppressed cell growth and proliferation, and promoted cell apoptosis of cancer cell lines with different genetic background. Ad-pl4ARF inhibited growth of liver cancer cells ( HepG2, BEL7402) in a dose-dependent manner. Ad-pl4ARF lead to overexpression of Bax and p21, the downstream regulating genes of p53. In the experimental therapy on nude mice bearing subcutaneous transplanted BEL7402 tumor, Ad-pl4ARF suppressed tumor growth significantly.
pl4ARF is a short gene and with powerful function, which are consistent with the requirements for tumor suppressor genes used in gene therapy. It may play an important role in gene therapy against malignancies in the future.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 10/2006; 28(9):641-5.
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ABSTRACT: To investigate the inhibitory effect of antisense oligodeoxynucleotides targeting HER-2 mRNA on growth of breast cancer.
Human breast cancer cells of the line SK-BR-3 that overexpresses HER-2 were injected subcutaneously into BALB/c nude mice. Seven to ten days after tumors were collected and made into homogenate. Antisense oligodeoxynucleotide HA6722 targeting HER-2 mRNA and its control sequence Scramble were synthesized. Forty-nine BALB/c nude mice were injected with homogenate of SK-BR-3 cells and then randomly divided into 7 equal groups: Group 1, injected intravenously with docetaxel (TXT) 7.5 mg.kg(-1).d(-1) once a week twice; Group 2, injected intravenously with TXT 15 mg.kg(-1).d(-1) once a week twice; Group 3, injected intravenously with TXT 7.5 mg.kg(-1).d(-1) once a week twice + HA6722 5 mg.kg(-1).d(-1) for 12 days; Group 4, injected intravenously with HA6722 5 mg.kg(-1).d(-1) for 12 days; Group 5, injected intravenously with TXT 7.5 mg.kg(-1).d(-1) once a week twice + Scramble6722 5 mg.kg(-1).d(-1) for 12 days; and Group 7, injected with normal saline. After the drug administration the mice were observed for additional 3-4 weeks to measure the size of tumor every other day. Then the mice were killed and the tumors were taken out to be examined. The inhibition rate was calculated.
The inhibition rate of tumor in Group 3 was 88.3%, not significantly different from that in Group 2 (88.7%, P > 0.05). The inhibition rate in Group 4 was 76.3%. The inhibition rates of tumor of Groups 2, 3, and 4 were all significantly higher than that in Group 7. However, the inhibition rate of tumor of Group 6 was not significantly different from that in Group 7.
Antisense oligodeoxynucleotides targeting HER-2 mRNA inhibits the growth of breast cancer in a sequence specific and dose-dependent manner.
Zhonghua yi xue za zhi 03/2006; 86(8):540-3.
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ABSTRACT: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion.
Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPE-LC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. A four-(127)I iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC(50)) of sifuvirtide on cell fusion was determined by co-cultivation assay.
The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88-5000 microg/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10 626+/-2886 microg/L and 528+/-191 microg/L, and the terminal elimination half-lives (T(1/2)) were 6.3+/-0.9 h and 5.5+/-1.0 h, respectively. After sc, T(max) was 0.25-2 h, and the absolute bioavailability was 49%+/-13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC(50) of 0.33 microg/L.
An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T(1/2) of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC(50) in vitro.
Acta Pharmacologica Sinica 11/2005; 26(10):1274-80. · 1.95 Impact Factor
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ABSTRACT: Aim: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion.
Acta Pharmacologica Sinica 09/2005; 26(10):1274-1280. · 1.95 Impact Factor
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ABSTRACT: Aim: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion.Methods: Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPE-LC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. Afour-127I iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC50) of sifuvirtide on cell fusion was determined by co-cultivation assay.Results: The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88–5000 μg/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10 626±2 886 μg/L and 528±191 μg/L, and the terminal elimination half-lives (T1/2) were 6.3±0.9 h and 5.5±1.0 h, respectively. After sc, Tmax was 0.25–2 h, and the absolute bioavailability was 49%±13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC50 of 0.33 μg/L.Conclusion: An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T1/2 of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC50in vitro.
Acta Pharmacologica Sinica 09/2005; 26(10):1274 - 1280. · 1.95 Impact Factor
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ABSTRACT: To study the pharmacokinetics and accumulation of an Escherichia coli expressed His-tag fused recombinant human endostatin (rh-endostatin) in Rhesus monkeys.
Rh-endostatin was iv or sc injected in Rhesus monkeys, and the rh-endostatin concentration in serum samples was determined by an enzyme immunoassay (EIA) method. The serum drug concentration-time data were analyzed by compartmental analysis using the practical pharmacokinetic program 3p97.
Following iv administration at a dose rate of 1.5, 4.5, and 13.5 mg/kg in rhesus monkeys, the concentration-time curves of rh-endostatin were best fitted to a three-compartment open model. AUC(0-infinity) linearly increased with dose, while Cls exhibited no significant difference among different dose groups. The terminal half-lives (lambda3) were 8+/-8, 3.1+/-1.4, and 20+/-14 h, respectively. After sc administration at a dose rate of 1.5 mg/kg, the concentration-time curve was best fitted to a two-compartment open model, with a terminal half-life (T(1/2beta)) of 8+/-3 h. Bioavailability following sc injection was approximately 70%+/-3%. After consecutive iv injection of rh-endostatin at a dose rate of 1.5 mg.kg(-1).d(-1) for 7 d, the AUC(0-24 h) substantially increased from 22+/-13 mg.h.L(-1) (d 1) to 50+/-29 mg.h.L(-1) (d 7), with an accumulation factor of 2.3+/-0.6 (P < 0.05).
The pharmacokinetic behavior of rh-endostatin in Rhesus monkeys complies with linear kinetics within the examined dose range. It tends to be accumulated in bodies after repeated administration at a dose level of 1.5 mg.kg(-1).d(-1) for more than 7 consecutive days.
Acta Pharmacologica Sinica 02/2005; 26(1):124-8. · 1.95 Impact Factor
