Biomedical subjects
D J Yang
Publications and source records attributed to D J Yang.
Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia.
PURPOSE: To develop a hydrophilic ligand to image tumor hypoxia at positron emission tomography (PET). MATERIALS AND METHODS: Biodistribution of fluorine-18-labeled fluoroerythronitroimidazole (FETNIM) and F-18-labeled fluoromisonidazole (FMISO) was determined at PET and autoradiography in three mammary-tumor-bearing rats. The partition coefficient of FETNIM, FMISO, and misonidazole was determined. RESULTS: Biodistribution of F-18-labeled FETNIM at 1, 2, and 4 hours showed tumor-to-blood ratios of 2.29 +/- 0.599, 2.41 +/- 0.567 and 8.02 +/- 2.420, respectively, and tumor-to-muscle ratios of 0.66 +/- 0.267, 2.11 +/- 0.347, and 5.92 +/- 2.240, respectively. The tumor-to-blood count density ratio with F-18-labeled FETNIM at 4 hours after injection was significantly higher than with F-18-labeled FMISO. Autoradiographs indicated that both agents could help differentiate hypoxic versus necrotic region in the tumor. CONCLUSION: F-18-labeled FETNIM can help detect tumor hypoxia and is easier to prepare, less costly, and more hydrophilic than F-18-labeled FMISO.
Pyripyropenes, Novel ACAT inhibitors produced by Aspergillus fumigatus. III. Structure elucidation of pyripyropenes E to L.
Eight new pyripyropenes, E to L, were isolated from the culture broth of Aspergillus fumigatus FO-1289-2501 selected as a higher producer by NTG mutation. Structural elucidation indicated that all the pyripyropenes have the same pyridino-alpha-pyrone sesquiterpene core as pyripyropenes A to D. Among them, pyripyropene L showed the most potent inhibition against acyl-CoA: cholesterol acyltransferase (ACAT) activity with an IC50 value of 0.27 microM in rat liver microsomes.
Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. II. Structure elucidation of terpendoles A, B, C and D.
Structures of terpendoles A, B, C and D, novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors, were determined by spectroscopic studies. All terpendoles consist of diterpene and indole moieties in common. Terpendoles A, C and D possess an additional isoprenyl unit via oxygen atom(s) of their diterpene moieties. The relative stereochemistries of terpendoles C and D were confirmed by NOE experiments and X-ray crystallographic analysis.
Isochromophilones III-VI, inhibitors of acyl-CoA:cholesterol acyltransferase produced by Penicillium multicolor FO-3216.
New azaphilones named isochromophilones III-VI were isolated from the culture broth of Penicillium multicolor FO-3216 as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). Their structures were elucidated by NMR and other spectroscopic analyses. The IC50 values of isochromophilones III, IV, V and VI for ACAT activity in an enzyme assay using rat liver microsomes were calculated to be 110, 50, 50 and 120 microM, respectively.
Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. III. Production, isolation and structure elucidation of new components.
Eight new components of terpendoles E to L were isolated and characterized from the culture broth of Albophoma yamanashiensis using a different production medium. All the structures were elucidated by spectroscopic analyses including various NMR experiments, indicating that all the terpendoles have the same indoloditerpene core as terpendoles A to D. Terpendoles J, K and L showed the moderate inhibition against acyl-CoA: cholesterol acyltransferase (ACAT) activity with IC50 values of 38.8, 38.0 and 32.4 microM in rat liver microsomes, respectively. But terpendoles E-I showed weak activities (IC50 145-388 microM).
Detecting recurrent or residual lung cancer with FDG-PET.
UNLABELLED: We investigated the diagnostic accuracy of FDG-PET in the detection of recurrent lung cancer. METHODS: Thirty-nine lesions in 38 patients with clinically suspected recurrent or residual lung cancer were studied with PET. All PET images were visually interpreted in conjunction with thoracic CT or MRI. Semiquantitative analysis using standardized uptake values (SUVs) was also performed in 25 lesions. FDG-PET diagnoses were correlated with pathological diagnoses and clinical outcome. RESULTS: The sensitivity and specificity of FDG-PET for detecting recurrent tumors were 100% (26/26) and 61.5% (8/13), respectively. The difference in mean SUV between recurrent tumors and noncancerous lesions was statistically significant [11.2 +/- 5.7 (n = 16) vs. 3.5 +/- 1.8 (n = 9), p < 0.0001]. False-positive results showed relatively lower SUVs than true-positives and also demonstrated increased uptake in a curvilinear rather than nodular shape. CONCLUSION: FDG-PET is useful for detecting recurrent lung cancer after treatment. False-positive diagnoses might be reduced by analysis of uptake shape and serial changes in SUV, but further study is needed.
Total hip arthroplasty in patients with ankylosing spondylitis: longterm followup.
OBJECTIVE: To evaluate the longterm functional effects of total hip arthroplasty (THA) on 46 patients. METHODS: Clinical and radiographic examinations were performed on 46 patients (74 THA) with ankylosing spondylitis (AS). The mean followup period was 100 months (range 37-174 months); 32 hips were followed for more than 10 years. RESULTS: Significant benefit was obtained in pain control (all but 2) and function (mean improvement in range of motion 128 degrees) in the early stage so that patients could be gainfully employed. An average 100 months after THA, the overall functional results were rated excellent in 21 hips, good in 28, fair in 7, and poor in 18. Only 6 hips (8%) in our series developed clinically significant (Class III or IV) heterotopic ossification. Seventeen hips needed a 2nd operation because of loosening (11 hips), deep infection (3), malposition of acetabular component (2), and prosthetic failure (1). Another 6 hips showed definite loosening on radiographs and needed to be revised. The total incidence of failure was 31% (23 hips). The average time from the index operation to loosening was 9.5 years (range 4-13 years). Factors contributing to component loosening were young age, short stature, and decreased postoperative range of motion. CONCLUSION: Total hip arthroplasty can be very important and beneficial to patients with AS, but the patients, being young and active, and with their rigid spines, do not treat their prostheses gently and are very dependent upon their mobility. They must be kept under supervision long after THA, probably for the rest of their lives, to identify possible longterm complications.
In vivo and electron microscopic studies of rat liver after intravenous injection of polyamino acid microspheres.
In vivo and electron microscopy were used to study the hepatocellular responses of rat livers to intravenously injected polymeric microspheres. Two microsphere preparations with different surface characteristics and degradability were used in this study. In vivo microscopy revealed that both poly(benzyl L-glutamate) (PBLG) and poly(hydroxypropyl L-glutamine) (PHPG) microspheres caused disturbance in the microcirculation of rat liver up to 2 months after injection. The observed changes included stagnant flow and adherence of white blood cells to the endothelial lining of venules an sinusoids. Kupffer cell (KC) activation following phagocytosis of microspheres was evidenced by the enlargement of KCs and increased number of KCs taking up fluorescent latex particles. Electron microscopy of rat livers revealed a wide range of hepatocellular injury associated with the administration of PBLG and PHPG microspheres. These results indicate that a small amount of remaining microspheres is sufficient to induce continuous disturbance to hepatic microcirculation and that particulate drug carriers should be designed to be rapidly degraded so that the return to normal liver function is possible.
Diagnostic and therapeutic potential of poly(benzyl L-glutamate).
Poly(benzyl L-glutamate) (PBLG) microcapsules, prepared by a solvent evaporation technique for intravenous injection, are evaluated for their potential use in diagnostic computed tomographic enhancement of liver images. The smaller microcapsules, < 3 microns, loaded with a radiopaque contrast material, ethyl iopanoate (IOPAE), produced prolonged opacification of the liver when delivered intravenously. In vivo tissue distribution studies of PBLG-131I-IOPAE (5 microCi/rat, iv) showed that liver had the highest uptake (percent of injected dose/g of tissue) among other organs 24 h postinjection. An in vitro estrogen receptor assay in pig uteri indicated that PBLG conjugated with estrone did not interfere with estrogen receptor affinity, suggesting the estrogen therapy potential of PBLG-estrone.
Imaging, biodistribution and therapy potential of halogenated tamoxifen analogues.
Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.
Rapid synthesis of 3-[18F]fluoro-1-(2'-nitro-1'-imidazolyl)-2-propanol ([18F]fluoromisonidazole).
Explore the source record for details and available documents.
Formation and characterization of cisplatin-loaded poly(benzyl l-glutamate) microspheres for chemoembolization.
Chemoembolization using microspheres of 100- to 200-microns is a useful way to treat primary and secondary hepatic tumors. In a search for a better embolic material, we described in detail the preparation and characterization of a poly(benzyl l-glutamate) (PBLG) microspheres containing cisplatin (CDDP). We determined the optimal experimental conditions to produce spherical free-flowing microspheres that were able to release drug content (44% [w/w] CDDP) in a sustained manner. We found that solvent viscosity played a key role in determining the resulting microsphere characteristics. Microscopic studies showed that increasing the polymer concentration (to 10% [w/v]) and the viscosity of the organic phase produced microspheres with uniform drug distribution. Increasing polymer concentration also markedly improved drug incorporation efficiency. In vitro release studies revealed that the release of CDDP was a function of drug loading; microspheres with a higher amount of entrapped CDDP had a slower release rate. This observation and the fact that CDDP/PBLG microspheres did not show "burst effect" at higher loading is ascribed to the formation of uniformly distributed drug crystal networks within the polymer matrix. The favorable properties of the CDDP/PBLG system warrants its further evaluation on experimental animal models for the treatment of hepatic tumors.
Computed tomographic liver enhancement with poly(d,1-lactide)-microencapsulated contrast media.
Explore the source record for details and available documents.
Preparation, characterization, and evaluation of ioxilan carbonate particles for computed tomography contrast enhancement of liver.
RATIONALE AND OBJECTIVES: To prepare and characterize a new particulate contrast medium, cyclic carbonate of ioxilan (IX-C) particles, as a macrophage imaging agent for computed tomography (CT) enhancement of the liver. METHODS: Cyclic carbonate of ioxilan was synthesized from ioxilan, a nonionic water-soluble contrast agent. The IX-C particles prepared by a solvent extraction-evaporation method were characterized by size distribution, degradability, suspension stability, and median lethal dose. Pharmacokinetics of IX-C particles and their effectiveness in enhancing liver attenuation and in detecting hepatic tumors were evaluated using normal and VX2-tumor-bearing rabbits. RESULTS: The IX-C particles were biodegradable, with ioxilan and carbon dioxide as the degradation products. The particles had an average size of 1 to 2 microns and were stable in saline suspension. The median lethal dose determined for IX-C particles was 2.6 and 3.1 g/kg body weight for female and male rabbits, respectively. A dose of 200 mg iodine/kg body weight caused an increase of 38 Hounsfield units in liver attenuation. In rabbit, hepatic clearance of the contrast medium occurred in 2 days. A tumor barely visible in precontrast scans could be detected after contrast injection. CONCLUSIONS: Development of particulate contrast medium from nonionic contrast agents represents a new approach. Ioxilan carbonate particles have suitable physicochemical properties that warrant further studies before clinical evaluation.
[Chemical constituents of Hydrangea macrophylla (Thunb.) Ser].
Explore the source record for details and available documents.
Halogenated analogues of tamoxifen: synthesis, receptor assay, and inhibition of MCF7 cells.
This study was conducted to develop a ligand for imaging estrogen-receptor-positive breast tumors by positron emission tomography or single photon emission computed tomography. We synthesized fluoro and iodo analogues of tamoxifen, and these halogenated analogues produced greater affinity for binding to the receptor than tamoxifen. Values of the inhibition affinity constants were as follows: tamoxifen, 15,000 nM; fluoromethyl-N,N-diethyltamoxifen, 2500 nM for the cis isomer and 500 nM for the trans isomer; and iodomethyl-N,N-diethyltamoxifen, 1500 nM for the cis isomer and 1000 nM for the trans isomer. In studies of human MCF7 breast tumor cell growth, concentrations that inhibited tumor growth in 50% of the cases were as follows: tamoxifen, 11 microM; fluoromethyl-N,N-diethyltamoxifen, 4.5 and 11.8 microM for the cis and trans isomers, respectively; and iodomethyl-N,N-diethyltamoxifen, 2.4 and 6.3 microM for the cis and trans isomers, respectively. These studies suggest that both fluoro and iodo analogues of tamoxifen may be useful diagnostic compounds for predicting the response of estrogen-receptor-positive breast tumors to tamoxifen analogues used in chemotherapy.
Differentiation of residual or recurrent tumors from post-treatment changes with F-18 FDG PET.
Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) was used to differentiate recurrent or residual malignant disease from the effects of cancer treatment. Transaxial images were obtained after injection of 5-10 mCi (185-370 MBq) of F-18 FDG in 68 patients (including 33 with brain tumors) whose posttreatment computed tomographic (CT) or magnetic resonance (MR) imaging findings had been suggestive of malignant disease. PET findings were correlated with surgical results in 18 patients and with the outcomes of CT, MR imaging, clinical, and laboratory 9-month follow-up studies in 50 patients. There was good agreement between F-18 FDG uptake and presence or absence of malignant disease except in four cases of brain tumors in which histologic findings could not be correlated with biologic behavior. The putative sensitivity and specificity in the 33 cases of brain tumors were 80% and 94%, respectively. The authors conclude that PET with F-18 FDG is useful in detection of previously treated metabolically active tumors but is limited in diagnosis of recurrent microscopic or metabolically inactive tumors.