Biomedical subjects

B Wang

Publications and source records attributed to B Wang.

At least 397 records · Page 22Linked to original sources

PubMed1999

Synthesis and evaluation of the physicochemical properties of esterase-sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers.

In an attempt to improve the membrane permeabilities of opioid peptides, we have synthesized cyclic prodrugs of [Leu5]-enkephalin and DADLE using a coumarinic acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid- and phenylpropionic acid-based cyclic prodrugs followed similar strategies. Key intermediates were the compounds with the C-terminal amino acids of opioid peptides (L-Leu, [Leu5]-enkephalin; D-Leu, DADLE) attached to the phenol hydroxyl group and the remaining amino acids of the peptide linked via the N-terminal amino acid (L-Tyr) attached to the carboxylic acid groups of the prodrug moieties (coumarinic acid or propionic acid). Cyclization of these linear precursors gave the cyclic prodrugs in 30-50% yields. These cyclic prodrugs exhibited excellent transcellular permeation characteristics across Caco-2 cell monolayers, an in vitro model of the intestinal mucosa. To correlate the cellular permeabilities of these cyclic prodrugs with their physicochemical properties, we calculated their Stokes-Einstein molecular radii from their diffusion coefficients which were determined by NMR and we determined their membrane interaction potentials using immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs exhibited molecular radii similar to those of the parent compounds, [Leu5]-enkephalin and DADLE. However, these cyclic prodrugs were shown to have much higher membrane interaction potentials than their corresponding opioid peptides. Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently due to the alteration of their lipophilicity and hydrogen bonding potential, but not their molecular sizes.

Amino Acid Sequence↗

PubMed1999

The effect of conformation on the membrane permeation of coumarinic acid- and phenylpropionic acid-based cyclic prodrugs of opioid peptides.

In an earlier study using Caco-2 cells, an in vitro cell culture model of the intestinal mucosa, we have shown that the coumarinic-based (3 and 4) and the phenylpropionic acid-based (5 and 6) cyclic prodrugs were more able to permeate the cell monolayers than were the corresponding opioid peptides, [Leu5]-enkephalin (1, H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (2, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). In an attempt to explain the increased permeation of the cyclic prodrugs, we have determined the possible conformations of these cyclic prodrugs in solution, using spectroscopic techniques (2D-NMR, CD) and molecular dynamics simulations. Spectroscopic as well as molecular dynamic studies indicate that cyclic prodrug 4 exhibits two major conformers (A and B) in solution. Conformer A exhibited a type I beta-turn at Tyr1-D-Ala2-Gly3-Phe4. The presence of a turn was supported by ROE cross-peaks between the NH of D-Ala2 and the NH of Gly3 and between the NH of Gly3 and the NH of Phe4. Conformer B of cyclic prodrug 4 consisted of type II beta-turns at the same positions. The type II turn was stabilized by hydrogen bonding, thus forming a more compact structure, whereas the type I turn did not exhibit similar intramolecular hydrogen bonding. Spectroscopic data for compounds 3, 5 and 6 are consistent with the conclusion that these cyclic prodrugs have solution structures similar to those observed with cyclic prodrug 4. The increased lipophilicity and well-defined secondary structures in cyclic prodrugs 3-6, but not in the linear peptides 1 and 2, could both contribute to the enhanced ability of these prodrugs to permeate membranes.

Cell Membrane Permeability↗

PubMed1999

Development of an ELISA for paraquat; improvement of antibody characteristics by reversed affinity chromatography.

An enzyme-linked immunosorbent assay (ELISA) for paraquat is described. The microtitration plate-based assay has a limit of detection of 10 pg per well, and was specific for paraquat and monoquat. Reversed affinity chromatography was used to refine the polyclonal antibody preparation and eliminate interfering antibodies. There were consequent and significant improvements in assay sensitivity and performance. The potential for application of the assay to a variety of matrices is discussed.

Animals↗

PubMed1999

Functional analysis of the 5'-flanking region of FTA for expression of rat GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase.

The tissue-specific and species-specific expression of the ABH antigens is well known among vertebrate species and it is regulated by the alpha(1,2)fucosyltransferase that forms the H antigen, a precursor of the A and B antigens. To investigate the mechanisms governing the tissue-specific and species-specific expression of this alpha(1,2)fucosyltransferase, we characterized the gene structure, including the promoter region, of FTA, a rat orthologous homolog of human FUT1 that encodes the H alpha(1, 2)fucosyltransferase and is responsible for the expression of the ABH antigens on human red blood cells. Northern blot and 5'-RACE analyses suggested that at least two forms of FTA mRNA (2.9 and 2.6 kb), which use alternative transcription start sites, are present in the cancer cell lines RCN-9 (rat colon cancer) and PC12 (rat pheochromocytoma), whereas only the 2.6 kb form was detected in normal colon, stomach and pancreas. Transcriptional activity of the 5'-flanking sequence, which contains three putative Sp1-binding sites, but lacks both TATA and CAAT boxes, was examined. Transient transfection experiments of promoter-reporter gene constructs showed high promoter activity in RCN-9, PC12 and human colon cancer (WiDr) cell lines, weak activity in human vascular endothelial (ECV304) cells and no activity in human erythroleukemia (HEL) cells. The results suggest that the 5'-flanking region of FTA contains a tissue-specific promoter. Deletional analysis of the 5'-flanking sequence revealed regions containing cell-type-specific positive acting element(s) and negative regulatory element(s), which are related to the promoter activity.

5' Untranslated Regions↗

PubMed1999

An extreme-sib-pair genome scan for genes regulating blood pressure.

Hypertension, a risk factor for many cardiovascular, cerebrovascular, and renal diseases, affects one in four Americans, at an annual cost of>$30 billion. Although genetic mutations have been identified in rare forms of hypertension, including Liddle syndrome and glucocorticoid-remediable aldosteronism, the abundance of plausible candidate genes and potential environmental risk factors has complicated the genetic dissection of more prevalent essential hypertension. To search systematically for chromosomal regions containing genes that regulate blood pressure, we scanned the entire autosomal genome by using 367 polymorphic markers. Our study population, selected from a blood-pressure screen of >200,000 Chinese adults, comprises rare but highly efficient extreme sib pairs (207 discordant, 258 high concordant, and 99 low concordant) and all but a single parent of these sibs. By virtue of the sampling design, the number of sib pairs, and the availability of genotyped parents, this study represents one of the most powerful of its kind. Although no regions achieved a 5% genomewide significance level, maximum LOD-score values were >2.0 (unadjusted P<.001) for regions containing five markers (D3S2387, D11S2019, D15S657, D16S3396, and D17S1303), in our primary analysis. Other promising regions identified through secondary analyses include loci near D4S3248, D7S2195, D10S1423, D20S470, D20S482, D21S2052, PAH, and AGT.

Adolescent↗

PubMed1999

Cooperation between transcription factor AP-1 and NF-kappaB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia.

The expression of interleukin-8 (IL-8) has been shown to play an important role in the growth and metastasis of human pancreatic cancer. In the present study, we investigated the regulation of IL-8 gene expression by hypoxic environments. Exposure of the human pancreatic cancer cells COLO357 and FG to hypoxia in culture resulted in a time-dependent increase in steady-state levels of IL-8 mRNA and IL-8 protein secretion. The induction of IL-8 expression was correlated with transcriptional activation of the IL-8 gene. Deletion and point mutation analyses of the IL-8 promoter revealed that both AP-1 and NF-kappaB binding sites were necessary for IL-8 induction by hypoxia. Consistently, hypoxia induced both AP-1 and NF-kappaB activity. These data suggest that hypoxic environments upregulate the IL-8 gene via cooperation of NF-kappaB and AP-1 and contribute to the progression and metastasis of human pancreatic cancer.

Adenocarcinoma↗

PubMed1999

Generation of antigen-specific cytotoxic T lymphocytes and regulation of cytokine production takes place in the absence of CD3zeta.

The TCR-associated protein CD3zeta plays a major role in regulating the state of responsiveness to peptide-MHC complexes on the surface of antigen-presenting cells. In this paper the requirement of CD3zeta in the generation of cytotoxic T cells was compared with its requirement in cytokine gene activation in two mutant mice: ZKO mice with a disrupted CD3zeta gene and ZTG mice in which a truncated CD3zeta segment was expressed as a transgene on the ZKO background. Upon infection of ZTG mice with lymphocytic choriomeningitis virus (LCMV), antigen-specific cytotoxic T lymphocyte (CTL) responses were detected, identical to responses in wild-type mice. In addition, antigen-specific CTL responses to allogeneic class I and class II MHC in ZTG animals were indistinguishable from those in wild-type animals. However, CTL responses to the same major antigens were not detectable in ZKO mice. We conclude that the signal transduction pathways leading to CTL development and cytokine production can be triggered through TCR in the absence of functional CD3zeta, provided the remainder of the TCR-CD3 complex is expressed at high levels on the cell surface. Surprisingly, IFN-gamma production in response to LCMV followed the same kinetics in ZKO, ZTG and wild-type mice. However, in vitro studies showed that cytokine production in general was abnormally regulated in T lymphocytes from ZKO mice, in contrast to ZTG T cells. Taken together, these studies support the hypothesis that development of CTL can take place in the absence of functional CD3zeta. However, CTL development requires stronger TCR-initiated signal transduction events than induction of cytokine genes.

Abatacept↗

PubMed1999

Comparison of the sedation and recovery profiles of Ro 48-6791, a new benzodiazepine, and midazolam in combination with meperidine for outpatient endoscopic procedures.

UNLABELLED: In this randomized, double-blinded study, we compared the onset and recovery characteristics of an investigational benzodiazepine, Ro 48-6791 (when administered alone or combined with meperidine), a midazolam-meperidine combination for sedation during gastrointestinal (GI) endoscopic procedures. Ninety consenting outpatients scheduled for upper or lower GI procedures were randomly assigned as follows: Group I received midazolam 1 mg IV and meperidine 50 mg; Group II received Ro 48-6791 0.5 mg IV and meperidine 50 mg; or Group III received Ro 48-6791 1.0 mg IV alone. If the level of sedation did not achieve an Observer's Assessment of Alertness/Sedation (OAA/S) score of 4 (where 5 = awake/alert to 1 = asleep) in < or = 2 min, a second bolus dose, equal to half of the original dose of midazolam or Ro 48-6791, was administered. The onset time was defined as the time to achieve an OAA/S score of 4. During the procedure, a bolus dose equal to half of the total induction dose was given to maintain an OAA/S score of 4. The induction and maintenance dosages, as well as recovery times to an OAA/S score of 5, were recorded. A heel-toe line walk (HTLW) test used to determine the time to "fitness for discharge." Although the onset times were similar in all three groups, the induction dosages were significantly reduced in Group II compared with Groups I and III. There were significantly more patients requiring supplemental sedative boluses and "rescue" analgesia with Ro 48-6791 than with midazolam. The Ro 48-6791 groups also experienced more dizziness after the procedures. Ro 48-6791 was associated with a higher incidence of inadequate sedation (18% vs 3%) without the opioid. The time for the HTLW test to return to baseline values after the procedure was similar among the three groups. However, the Ro 48-6791 groups had significantly reduced times to return to an OAA/S score of 5 and to achieve the baseline HTLW value after the last dose of the benzodiazepine. In conclusion, compared with midazolam, Ro 48-6791 is more potent and may be associated with a more rapid early recovery after endoscopic GI procedures. However, sedation with Ro 48-6791 required more supplemental bolus doses and "rescue" analgesic medication and was associated with a higher incidence of dizziness. IMPLICATIONS: The investigational water-soluble benzodiazepine, Ro 48-6791, is a more potent sedative than midazolam, which appears to have a slightly shorter duration of action. Unfortunately, use of Ro 48-6791 increased the requirement for supplemental doses of the sedative medication and the need for "rescue" analgesics during the procedure and was associated with more dizziness after the procedure.

Adjuvants, Anesthesia↗

PubMed1999

Immediate breast reconstruction with the TRAM flap after neoadjuvant therapy.

Neoadjuvant therapy is a relatively new weapon in the chemotherapeutic arsenal against breast carcinoma. However, there has been concern that preoperative chemotherapy might lead to an increased incidence of complications and delays in postoperative treatment. A retrospective study was performed at M.D. Anderson Cancer Center of all patients with locally advanced breast cancer who had undergone neoadjuvant therapy followed by mastectomy and immediate reconstruction with the transverse rectus abdominis musculocutaneous (TRAM) flap. Patients were evaluated for the incidence of complications and any delays in resumption of postoperative chemotherapy. Thirty-one patients underwent immediate reconstruction with the TRAM flap. Twenty-two patients were reconstructed with free TRAM flaps whereas 9 patients were reconstructed with pedicled TRAM flaps. Seventeen patients (55%) had complications postoperatively, but only 2 patients (6%) had a delay in the resumption of chemotherapy. Seven patients were smokers, five (71%) of whom had complications, which was not a significant difference from the rate in nonsmokers (50%). Although delays in postoperative chemotherapy occurred in smokers (29%, vs. 0% in nonsmokers), the number of patients was too small to attain statistical significance. Based on this study it is felt that immediate reconstruction with the TRAM flap can be performed safely in patients on a neoadjuvant protocol. Although not contraindicated, immediate reconstruction with the TRAM flap in smokers in this setting may be associated with higher morbidity.

Breast Neoplasms↗

PubMed1999

Influence of radiation on late complications in patients with free fibular flaps for mandibular reconstruction.

Carcinoma of the mandible is a disease that evokes images of devastating functional and cosmetic outcomes. Most of these malignancies require treatment with surgical resection and perioperative irradiation (XRT). To minimize the incidence of postoperative complications, the timing of perioperative XRT has been questioned. This study reviewed 140 patients at M.D. Anderson Cancer Center over a 7-year period who underwent mandibular resection and reconstruction with a free fibular flap. The patients were divided into the following four groups: (1) preoperative XRT followed by immediate reconstruction, (2) preoperative XRT followed by delayed reconstruction, (3) postoperative XRT, and (4) no XRT. The complications studied included exposure of bone and hardware, orocutaneous fistula, osteoradionecrosis, partial and complete flap loss, and severe cervical contractures. Of the 140 patients studied, 59 (42%) had at least one complication. Complications per group were the following: group 1, 45%; group 2, 46%; group 3, 47%; and group 4, 28%. The results show that the incidence of complications is relatively equal between groups that received preoperative vs. postoperative XRT.

Combined Modality Therapy↗

PubMed1999

Induction of apoptosis by beta radiation from tritium compounds in mouse embryonic brain cells.

Induction of apoptosis by tritium exposure was investigated in both cultured embryonic mid brain cells and brain sections of embryos and of newborns in mice. In the cultures of mid brain cells, addition of methyl-3H-thymidine (3H-TdR) (21 kBq mL(-1)) and tritiated water (5.616 MBq mL(-1)) induced late appearances and low percentages of apoptosis when compared to x-irradiation at the ID50 dose, the inhibitory dose that reduced cellular differentiation by 50% of the control. A significant increase in p53 protein was detected about 2 h before the marked appearance of apoptosis. The pregnant mice were given an intraperitoneal injection of tritiated water at the concentration of 481.8 kBq g(-1) of body weight on gestation day 12.5, by which treatment behavioral changes in the offspring occurred. Increased apoptotic cells were observed in the neural tube of embryos from 1 d after the injection to 1 wk postnatal age. Apoptosis induced by x-rays appeared 2 h after irradiation, with a peak at 4 h. Increase of apoptotic cells was also found in the brain cortexes of newborns. The percentage of apoptosis in the brain was higher in the prenatal tritiated water exposed mice than in the prenatal x-irradiated mice. Possible mechanisms on apoptosis and its relation to the higher relative biological effectiveness value of tritium beta-rays are discussed.

Animals↗

PubMed1999

Diffusion-weighted MR imaging: diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset.

PURPOSE: To evaluate the diagnostic accuracy of diffusion-weighted magnetic resonance (MR) imaging performed within 6 hours of the onset of stroke symptoms. MATERIALS AND METHODS: The authors reviewed the patient records and images from all patients hospitalized in a 10-month period in whom diffusion-weighted imaging was performed within 6 hours of the onset of strokelike symptoms (n = 22). Analyses included comparison of the initial interpretation of the diffusion-weighted images with the final clinical diagnosis; blinded reviews of computed tomographic (CT) scans and conventional and diffusion-weighted images; and determination of lesion contrast-to-noise ratios (CNRs). RESULTS: Diffusion-weighted images indicated stroke in 14 patients, all of whom had a final diagnosis of acute stroke. Diffusion-weighted images were negative in eight patients, all of whom had a final clinical diagnosis other than stroke (100% sensitivity, 100% specificity, chi 2 = 23.00, P < .0001). Blinded reviews yielded 100% sensitivity and 86% specificity for diffusion-weighted MR imaging (chi 2 = 15.43, P < .0005); 18% sensitivity and 100% specificity for conventional MR imaging (chi 2 = 2.85, P > .2); and 45% sensitivity and 100% specificity for CT (chi 2 = 4.40, P > .10). Lesion percentage CNRs were 77% for diffusion-weighted imaging, 5.5% for CT, 9.8% for T2-weighted MR imaging, and 3.1% for proton-density-weighted MR imaging (P < .002 for diffusion-weighted imaging vs others). CONCLUSION: Diffusion-weighted MR imaging is highly accurate for diagnosing stroke within 6 hours of symptom onset and is superior to CT and conventional MR imaging.

Aged↗

PubMed1999

Absence of the derived allele at the DYS199 locus in 3 NE Chinese populations.

The allelic states of DYS199 locus were studied by allele-specific PCR. We found that all of the 107 samples chosen from three populations of northeast China had DYS199 C alleles. The result excluded the possibility that this mutation first identified in native American populations came from the three populations of northeast China.

Alleles↗

PubMed1999

Angiotensinogen gene polymorphisms M235T/T174M: no excess transmission to hypertensive Chinese.

The gene encoding angiotensinogen (AGT) has been widely studied as a candidate gene for hypertension. Most studies to date have relied on case-control analysis to test for an excess of AGT variants among hypertensive cases compared with normotensive controls. However, with this design, nothing guarantees that a positive finding is due to actual allelic association as opposed to an inappropriate control population. To avoid this difficulty in our study of essential hypertension in Anqing, China, we tested AGT variants using the transmission/disequilibrium test, a procedure that bypasses the need for a control sample by testing for excessive transmission of a genetic variant from parents heterozygous for that variant. We analyzed two AGT polymorphisms, M235T and T174M, which have been associated with essential hypertension in whites and Japanese, using data on 335 hypertensive subjects from 315 nuclear families and their parents. Except in the group of subjects younger than 25 years, M235 and T174 were the more frequently transmitted alleles. We found that 194 parents heterozygous for M235T transmitted M235 106 times (P=0.22) and that 102 parents heterozygous for T174M transmitted T174 60 times (P=0.09). Stratifying offspring by gender, M235 and T174 were transmitted 60 of 106 times (P=0.21) and 44 of 75 times (P=0.17), respectively, in men, and 46 of 88 times (P=0.75) and 16 of 27 times (P=0.44), respectively, in women. Our results were also negative in all age groups and for the affected offspring with blood pressure values >/=160/95 mm Hg. Thus, this study provides no evidence that either allele of M235T or T174M contributes to hypertension in this Chinese population.

Adult↗

PubMed1999

Familial aggregation of pulmonary function in a rural Chinese community.

We investigated familial aggregation of pulmonary function among asthma index families and randomly selected nuclear families in a rural community in China. Measurements of pulmonary function and related risk factors were obtained from each family member. A generalized estimation equation model was used to explore the independent relation of pulmonary function among family members, with adjustment for sex, age, height, weight, education, smoking, and asthma status. There was a significant parent-child and sib-sib correlation of pulmonary function. The parent-child correlation of pulmonary function was similar for the first and second children. The correlation was greatest between sib-sibs, followed by mother-child, and less pronounced between father-child among asthma families. The rate of reduced pulmonary function in a subsequent sibling was lowest (4.0%) when both of the parents and the first sibling were in the high-pulmonary-function tertile (high-high group) and was highest (18.4%) when both the parents and the first sibling were in the low-pulmonary-function tertile (low-low group). The rates were intermediate if only the parents (7.0%, low-high group) or only the first sibling (11.5%, high-low group) was in the reduced-pulmonary-function tertile. Our data indicate a strong familial aggregation of pulmonary function in both asthma and random families in this population.

Adolescent↗

PubMed1999

The IL-1 receptor and Rho directly associate to drive cell activation in inflammation.

IL-1-stimulated mesenchymal cells model molecular mechanisms of inflammation. Binding of IL-1 to the type I IL-1 receptor (IL-1R) clusters a multi-subunit signaling complex at focal adhesion complexes. Since Rho family GTPases coordinately organize actin cytoskeleton and signaling to regulate cell phenotype, we hypothesized that the IL-1R signaling complex contained these G proteins. IL-1 stimulated actin stress fiber formation in serum-starved HeLa cells in a Rho-dependent manner and rapidly activated nucleotide exchange on RhoA. Glutathione S-transferase (GST) fusion proteins, containing either the full-length IL-1R cytosolic domain (GST-IL-1Rcd) or the terminal 68 amino acids of IL-1R required for IL-1-dependent signal transduction, specifically coprecipitated both RhoA and Rac-1, but not p21(ras), from Triton-soluble HeLa cell extracts. In whole cells, a small-molecular-weight G protein coimmunoprecipitated by anti-IL-1R antibody was a substrate for C3 transferase, which specifically ADP-ribosylates Rho GTPases. Constitutively activated RhoA, loaded with [gamma-32P]GTP, directly interacted with GST-IL-1Rcd in a filter-binding assay. The IL-1Rcd-RhoA interaction was functionally important, since a dominant inhibitory mutant of RhoA prevented IL-1Rcd-directed transcriptional activation of the IL-6 gene. Consistent with our previous data demonstrating that IL-1R-associated myelin basic protein (MBP) kinases are necessary for IL-1-directed gene expression, cellular incorporation of C3 transferase inhibited IL-1R-associated MBP kinase activity both in solution and in gel kinase assays. In summary, IL-1 activated RhoA, which was physically associated with IL-1Rcd and necessary for activation of cytosolic nuclear signaling pathways. These findings suggest that IL-1-stimulated, Rho-dependent cytoskeletal reorganization may cluster signaling molecules in specific architectures that are necessary for persistent cell activation in chronic inflammatory disease.

ADP Ribose Transferases↗

PubMed1999

Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia.

PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase. PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing. RESULTS: The percentage of patients with undetectable (< 0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5 days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70 micromol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003). CONCLUSION: CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.

Adolescent↗

PubMed1999

Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.

Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.

Caco-2 Cells↗