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Biomedical subjects

S W Schwendner

Publications and source records attributed to S W Schwendner.

At least 19 recordsLinked to original sources
PubMed1997

Apolipoprotein E2 transgenic rabbits. Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis.

Transgenic rabbits were produced that expressed high plasma levels (30-70 mg/dl) of human apolipoprotein (apo) E2(Cys-158), an apoE variant associated with the human genetic disorder type III hyperlipoproteinemia (HLP). Male transgenic rabbits fed normal chow had up to 8-fold (289 +/- 148 mg/dl) and 15-fold (697 +/- 452 mg/dl) increases in plasma total cholesterol and triglycerides, respectively, compared with nontransgenic males. Female transgenic rabbits had only a modest hyperlipidemia (total cholesterol, 140 +/- 46 mg/dl; total triglycerides, 174 +/- 66 mg/dl). Both sexes displayed the hallmarks fo type III HLP: beta-migrating very low density lipoproteins (beta-VLDL) (intestinal and hepatic remnant lipoproteins) and significantly increased VLDL and intermediate density lipoproteins. Apolipoprotein E2-containing VLDL particles were cleared from teh circulation more slowly and were more resistant to lipoprotein lipase-mediated lipolysis than normal VLDL. Only females had increased high density lipoproteins (HDL) (40%), which were shifted from typical small HDL to larger HDL1. Plasma apoE2 was predominantly associated with beta-VLDL in males and with HDL in females. To ascertain reasons for the phenotypic gender difference, we treated male transgenic rabbits with 17alpha-ethinyl estradiol. Estrogen treatment for 10 days dramatically decreased total cholesterol (73%) and triglycerides (89%) and converted beta-VLDL to pre-beta-migrating VLDL. Concomitantly, lipoprotein lipase and hepatic lipase activities increased by 90%, low density lipoprotein receptor activity was stimulated significantly, apoE2 was redistributed to HDL, and HDL were converted to HDL1. Conversely, ovariectomy in female transgenic rabbits significantly increased total cholesterol (75%), triglycerides (117%), and beta-VLDL, while decreasing lipoprotein lipase and hepatic lipase activities by 35% and redistributing apoE2 to the beta-VLDL. Thus, estrogen status appears to be responsible for much of the gender difference of the lipoprotein phenotype, mainly by modulating both lipase and low density lipoprotein receptor activities. Furthermore, transgenic rabbits fed normal chow for 11 months developed fatty streaks, and some had more advanced atherosclerotic lesions, especially around the aortic arch and proximal abdominal aorta. The lesions were more extensive in males, roughly correlating with the magnitude of the hyperlipidemia. Therefore, high plasma levels of human apoE2 in transgenic rabbits result in a type III HLP phenotype, in which males have both more severe hyperlipidemia and more extensive atherosclerosis than females.

Animals↗
PubMed1996

Hypolipidemic and hyperlipidemic phenotypes in transgenic mice expressing human apolipoprotein E2.

Transgenic mice were produced that expressed different plasma levels (3-60 mg/dl) of human apolipoprotein (apo) E2(Arg158 --> Cys), which is associated with the recessive form of human type III hyperlipoproteinemia (HLP). In transgenic mice fed a normal chow diet, low levels of apoE2 (<10 mg/dl) did not significantly alter the lipid phenotype. Mice expressing intermediate levels of apoE2 (10-30 mg/dl) had a 50-60% decrease in total cholesterol compared with nontransgenic mice. The decrease was almost entirely due to a reduction in high density lipoprotein (HDL) cholesterol. These hypolipidemic apoE2 transgenic mice were cross-bred with human apoB transgenic mice, which have increased total cholesterol and low density lipoprotein (LDL) levels. The apoE2/apoB double transgenics revealed that expression of apoE2 on the background of human apoB overexpression resulted in a substantial decrease in LDL and HDL cholesterol and a corresponding accumulation of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL). Thus, the double transgenics had a lipid phenotype resembling human type III HLP. In contrast to the hypolipidemic mice, mice expressing high levels of apoE2 (>50 mg/dl) were hyperlipidemic. The VLDL and IDL in these mice were significantly increased and cholesterol-enriched and had other characteristics of remnant lipoproteins. Upon agarose gel electrophoresis, the VLDL and IDL from both intermediate and high expressers migrated more slowly toward the beta position compared with the pre-beta-mobility of nontransgenic mouse VLDL and IDL. Thus, depending on plasma apoE2 levels, the expression of human apoE2 in the transgenic mice leads to either a hypolipidemic or hyperlipidemic phenotype. This animal model provides the opportunity to study the factors that cause hypolipidemia and those that precipitate the hyperlipidemia of type III HLP.

Animals↗
PubMed1996

Computed tomography scanning of Morris hepatomas with liver-specific polyiodinated triglycerides.

RATIONALE AND OBJECTIVES: We compared the computed tomography (CT) scanning characteristics of a polyiodinated triglyceride analog with those of a urographic agent to distinguish Morris-7777 hepatoma (MH) cells from normal hepatocytes in rats. METHODS: Eighteen Buffalo rats were laparotomized and MH cells injected directly into the hepatic parenchyma or introduced via the portal vein to produce, respectively, focal or diffuse lesions in the liver. Baseline CT scans were obtained 21 days after implantation and prior to intravenous administration of either the polyiodinated triglyceride (45-100 mg I/kg) or the nonionic contrast agent, iohexol (560 mg I/kg). Images were obtained at 0-3 hr and 24 hr. Gross pathologic inspection was performed to validate the imaging results. RESULTS: Hepatomas were nearly isodense with normal liver parenchyma in many of the animals, rendering lesion detection difficult with no contrast agent. The bolus administration of iohexol improved lesion detection in many cases. Lesion conspicuity, however, was significantly improved with the polyiodinated triglyceride at less than one eighth the dose of iohexol. CONCLUSION: Because of their biochemical nature, polyiodinated triglyceride analogs are specifically cleared by the liver. Consequently, they offer several advantages over nonspecific urographic agents in their ability to enhance lesion conspicuity in this hepatoma model.

Animals↗
PubMed1995

Polyiodinated triglyceride analogs as potential computed tomography imaging agents for the liver.

A series of glyceryl 2-oleoyl 1,3-bis[omega-(3-amino-2,4,6-triiodophenyl)] alkanoates was synthesized, radioiodinated with iodine-125, emulsified, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic agents in computed tomography. All seven analogs displayed rapid liver uptake wherein between 65 and 78% of the injected dose accumulated in the liver by 30 min. Liver values ranged from 46 to 93% 3 h after injection which corresponded to liver to blood ratios ranging from 21 to 450. Moreover, subsequent elimination of radioactivity from the liver was nearly linear with respect to alkyl chain length. Analogs with longer alkyl chain length were eliminated from the liver more rapidly than their shorter chain counterparts. Because of their biochemical similarities to naturally occurring triglycerides, these novel analogs may prove useful not only for high-resolution anatomic imaging of focal liver lesions, but also for evaluating a variety of diffuse diseases known to affect hepatic function and biochemistry.

Animals↗
PubMed1992

Potential organ or tumor imaging agents. 32. A triglyceride ester of p-iodophenyl pentadecanoic acid as a potential hepatic imaging agent.

A triglyceride analog, glycerol-2-palmitoyl-1,3-di-15-(p-iodophenyl)pentadecanoate (DPPG) was synthesized and radiolabeled for evaluation as a potential functional liver scintigraphic agent. Uptake of DPPG was compared in normal, diabetic, tumor-bearing and heparin pretreated rats, revealing differences in uptake and clearance of radioactivity, correlating with hepatic lipase activity of these groups. Similar results were observed by gamma-camera scintigraphy. Comparing the uptake of DPPG with that of its fatty acid component, 15-(p-iodophenyl)pentadecanoic acid (IPPA), revealed that the peak uptake of IPPA in the liver was about half that of DPPG. Based upon these findings, DPPG warrants further study as a hepatic radiodiagnostic agent.

Animals↗
PubMed1990

Tumor visualization with a radioiodinated phospholipid ether.

The known ability of phospholipid ethers to accumulate in certain tumors prompted the synthesis and evaluation of a radioiodinated phospholipid ether analog as a potential tumor imaging agent. Tissue distribution studies with [125I]-rac-1-0-[12-(m-iodophenyl)dodecyl-2-0-methylglycero-3- phosphocholine in rats bearing the Walker 256 carcinosarcoma showed the tumor to contain the highest concentration of radioactivity at 24 hr (15% of the dose) and a tumor-to-blood ratio of 13. Scintigraphic images taken at 24 hr compared favorably with those obtained with (67Ga)-citrate. In contrast with the latter, however, the phospholipid ether showed little propensity to accumulate in an inflammatory lesion in the rat. Tumor visualization was also accomplished in a rabbit bearing the V x 2 adenocarcinoma. We conclude that phospholipid ethers may represent a new class of carrier molecules for the transport of radionuclides to tumors.

Adenocarcinoma↗
PubMed1989

Potential tumor or organ imaging agents--31. Radioiodinated sterol benzoates and carbamates.

A series of radioiodinated benzoate and carbamate esters of cholesterol and pregnenolone wherein the acyl moiety served as the carrier for radioiodine was synthesized and evaluated as potential imaging agents for the adrenal cortex. 2,6-Dimethyl-3-iodobenzoyl and N-(4-iodophenyl) carbamoyl groups were chosen as the acyl functionality in an attempt to provide esters resistant to in vivo hydrolysis. Tissue disposition studies in rats revealed that their biodistribution was determined by the attached sterol carrier-the cholesterol esters demonstrated significant uptake at 24 h in the adrenal whereas the corresponding pregnenolone derivatives showed only slight affinity for steroid-secreting tissues at this time.

Adrenal Cortex↗
PubMed1989

Potential tumor- or organ-imaging agents. 29. Radioiodinated esters and amides of 20-hydroxy- and 20-aminopregn-5-en-3 beta-ols.

Radioiodinated benzoyl esters and amides of epimeric 20-hydroxy- and 20-aminopregn-5-en-3 beta-ols were synthesized in an effort to find an agent that would be rapidly and selectively taken up by adrenal cortical tissue. Achievement of such a goal would provide a basis for the development of adrenal imaging agents superior to those currently available for clinical use. The iodobenzoyl derivatives were obtained by treating the appropriate epimer with 2-iodobenzoic acid in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine. The resulting esters and amides were readily labeled with radioiodine by isotope exchange with sodium iodide-125 in pivalic acid. Tissue distribution studies in female rats revealed that only the esters displayed appreciable adrenal specificity, and the ester having the same configuration at C-20 as cholesterol was significantly better than the corresponding C-20 epimer.

Adrenal Cortex↗
PubMed1989

Potential tumor or organ-imaging agents. 30. Radioiodinated phospholipid ethers.

A radioiodinated analogue of a naturally occurring alkyl lysophospholipid (ALP) was synthesized for evaluation as a potential tumor-localizing imaging agent. rac-1-[12-(m-Iodophenyl)dodecyl]-2-methylglycero-3-phosphocholine (ET-12IP-OMe, 14) was radiolabeled with iodine-125 via an isotope-exchange procedure. Tissue distribution studies with [125I]ET-12IP-OMe in tumor-bearing rats revealed an immediate tumor uptake of radioactivity. Although radioactivity was also present in nontarget tissues at this time, clearance of tracer from the tumor was much slower and thus provided a suitable tumor to nontarget tissue ratio at 24 h. As a result of this selective accumulation, it was possible to clearly delineate the tumor with gamma-camera scintigraphy.

Animals↗
PubMed1989

Noninvasive assessment of lipid disposition in treated and untreated atherosclerotic rabbits.

In an effort to visualize whole body cholesteryl ester (CE) deposition using the nuclear medicine imaging technique of gamma camera scintigraphy, 125I-cholesteryl iopanoate (125I-CI), a nonhydrolyzable CE analogue, was used as a marker for CE deposition in atherosclerotic New Zealand white rabbits. Groups of animals were fed either a cholesterol-enriched diet (2%, w/w) or the same diet supplemented with the hypolipidemic drugs colestipol (1%, w/w) and/or clofibrate (0.3%, w/w). Injections of 125I-CI were administered biweekly. At the end of 15 weeks, animals were scintigraphically scanned and sacrificed for tissue analysis. The results demonstrated that while drug treatment had no significant effect on plasma lipid levels, it substantially lessened atherosclerotic involvement in the thoracic-abdominal aorta. These differences in aortic lipid accumulation were reflected in the whole-body scans which showed a reduction in tissue accumulation of 125I-CI in the drug-treated groups. Gamma camera scintigraphy thus represents a rapid means of visualizing tissue CE accumulation which could facilitate the evaluation of lipid-lowering drug efficacy and possible antiatherosclerotic effect.

Animals↗
PubMed1989

Lipoprotein incorporation enhances radioiodinated cholesteryl ester uptake into steroid hormone-secreting tissues.

This study was undertaken to determine whether incorporation of radioiodinated cholesterol derivatives into plasma lipoproteins prior to administration to animals could lead to improvements in adrenal localization of radioactivity. Rat high density lipoproteins (HDL) were labeled with [125I]cholesteryl iopanoate, a nonhydrolyzable ester of cholesterol. No enhancement in adrenal uptake of radioactivity was noted at 30 min following administration of the HDL preparation to control rats when compared with [125I]NP-59. However, when animals were made hypolipidemic by treatment with either 4-APP or ethinyl estradiol, the adrenal radioactivity after i.v. administration of the HDL preparation was found to be over 15 times greater than that achieved with [125I]NP-59. Scans of hypolipidemic rats taken at 30 min correlated well with the tissue distribution results.

Adrenal Cortex↗
PubMed1988

Iodine-125 cholesteryl iopanoate for measuring extent of atherosclerosis in rabbits.

Rabbits rendered atherosclerotic by mechanical aortic de-endothelialization and 6 wk of cholesterol feeding were administered estradiol-17 beta-cypionate, an anti-atherogenic agent in rabbits. These animals were compared to a similar, untreated group and control animals fed a regular non-atherogenic diet. Iodine-125 cholesteryl iopanoate ([125I]Cl), a nonhydrolyzable cholesteryl ester derivative, was administered intravenously at regular intervals throughout the study. Six days after the last dose of [125I]Cl, the animals were scanned with a gamma camera. After animals were killed, tissue distribution of the 125I radioactivity showed a significant decrease of [125I]CI accumulation in the aorta of estrogen-treated as compared to untreated, cholesterol-fed animals. However, the accumulation of [125I]CI in the aortas was insufficient to accurately define the presence of atheroma by gamma camera scintigraphy.

Animals↗
PubMed1987

Potential tumor- or organ-imaging agents. 28. Radioiodinated esters of cholesterol and pregnenolone.

Previous studies had shown radioiodinated esters of cholesterol and pregnenolone to accumulate in steroid-secreting tissues of the rat. This was particularly true for radioiodinated iopanoate esters. The present study was undertaken to examine the effect of the iopanoyl amino group on the tissue distribution of these esters. While the tissue distribution profiles for cholesteryl iopanoate and the desamino analog (III) were somewhat comparable, such was not the case for the corresponding esters of pregnenolone. Moreover, this subtle structural change of removing the amino group was observed to affect the in vivo stability of the esters to hydrolysis. This conclusion is in accordance with the observation that the tissue distribution profiles for the free acids I and II are not significantly different from each other. These studies serve to demonstrate that relatively minor modifications of the acyl moiety have a profound effect on both the uptake and distribution of these sterol esters in various tissues.

Animals↗
PubMed1986

Potential tumor- or organ-imaging agents. 26. Polyiodinated 2-substituted triacylglycerols as hepatographic agents.

A series of omega-(3-amino-2,4,6-triiodophenyl)alkanoic acids and the corresponding 1,3-dipalmitoylglycerol 2-[omega-(3-amino-2,4,6-triiodophenyl)alkanoates] were synthesized, radioiodinated with iodine-125, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic imaging agents. Acid analogues 1d and 1e afforded relatively high levels of radioactivity in the liver (45 and 49% injected dose) 5 min after intravenous administration to rats. These acids displayed a marked propensity to become bound to plasma albumin. In contrast, triacylglycerol analogues 10a and 10c did not become immediately associated with plasma albumin but instead rapidly became associated with plasma lipoproteins and showed a different tissue distribution profile than free acids 1a and 1c. Although long-chain triacylglycerol analogues 10d and 10e exhibited some capacity to accumulate in the liver at 5 and 30 min, respectively, analysis of the plasma revealed significant in vivo ester hydrolysis. It would thus appear that liver radioactivity following administration of 10d and 10e was due to uptake of the free acid and not the intact triacylglycerol. Triacylglycerol analogues 10a and 10c, on the other hand, were taken up intact and showed liver accumulations of 25 and 35% of the administered dose at 30 min.

Animals↗
PubMed1986

Potential tumor- or organ-imaging agents. 27. Polyiodinated 1,3-disubstituted and 1,2,3-trisubstituted triacylglycerols.

A series of glyceryl 1,3-bis- and 1,2,3-tris[omega-(3-amino-2,4,6-triiodophenyl)alkanoates] were synthesized, radioiodinated with iodine-125, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic imaging agents. Of the nine target compounds synthesized and evaluated in rats, glyceryl 1,2,3-tris[3-(3-amino-2,4,6-triiodophenyl)propionate] (5b) displayed rapid and sustained liver specificity. This agent was found to accumulate in the liver in concentrations of 60, 75, and 86% of the administered dose at 5 min, 30 min, and 24 h, respectively. Moreover, the 24-h liver-to-blood ratio of 235 justifies further studies in higher animal species.

Animals↗
PubMed1984

Potential tumor or organ-imaging agents, 24. Radioiodinated pregnenolone esters.

A series of radioiodinated pregnenolone esters was prepared in an effort to find an agent that would be rapidly and selectively taken up by adrenal cortical tissue. Achievement of such a goal would provide the basis for the development of an adrenal imaging agent having several advantages over those agents currently available for clinical use. The radioiodinated esters for this study were readily prepared by treating pregnenolone with the appropriate iodobenzoic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino-pyridine (DMAP). The resulting esters were readily labeled with radioiodine by isotope exchange with sodium iodide-125 in pivalic acid. Subsequent tissue distribution studies in rats revealed that those esters displaying the most stability towards hydrolysis achieved the highest concentration in adrenal cortical tissue. For example, the 2,3,5-triiodobenzoate (6) showed an adrenal uptake of 23% of administered dose per gram of tissue at 0.5 hours. The achievement of high levels of radioactivity in the adrenal with this agent at early time periods warrants further evaluation of this agent in other animals.

Adrenal Cortex↗