Complexes of Ga(III) and In(III) radionuclides are widely used in diagnostic imaging. In this study, the following ligands of denticities 4, 5, and 6 respectively were prepared: N,N'-bis-(2,2-dimethyl-2-mercaptoethyl) ethylenediamine (4SS), 1-carboxy-N-N'-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine (5SS), and N,N'-bis(2,2- dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS). Syntheses of the two new ligands, 5SS and 6SS, are described. Equilibrium constants for their In(III) and Ga(III) complexes were determined by both direct and ligand-competitive potentiometric methods. The formation constant (KML = [ML]/[M][L]) of In(III)--6SS in 0.100 M KNO3 at 25.0 degrees C is 10(39.8), and its pM at physiological pH (7.4 with 100% excess of the ligand) is 30.9. These values are higher than those of any other previous reported ligand for In(III). The stability constants of the complexes of 4SS, 5SS, 6SS, and the analogous ligand EDDASS, N,N'-bis(2-mercaptoethyl) ethylenediamine-N,N'-diacetic acid, which does not contain gem-dimethyl groups, are compared. The thermodynamic stabilities of the In(III) complexes of all ligands except 6SS are greater than those of the corresponding Ga(III) complexes. The presence of the geminal dimethyl groups in 6SS increased the stability of the Ga(III) and In(III) complexes over those of EDDASS. The effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling. The serum stabilities and biodistributions out to 1 h postinjection of 67/68Ga and 111In chelates of 4SS, 5SS, and 6SS were measured and compared with those of EDDASS. The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo. The biodistributions of the 67/68Ga- and 111In-ligand complexes exhibited distinct trends. None of the 67/68Ga- and 111In-chelates demonstrated significant heart or brain uptake. The majority of uptake for all compounds was in the liver and kidney. The degree of clearance through the liver corresponded to the thermodynamic stability of the complex. Correlations between in vivo behavior, molecular modeling data, and thermodynamic stability of the complexes are discussed.
Octreotide, an analogue of the hormone somatostatin, has applications as a therapeutic and imaging agent for somatostatin-positive tumors. We have developed a generally applicable, convenient stepwise solid-phase synthetic protocol for octreotide (D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-threoninol). [Cys(Acm)2,D-Trp(Boc)4,Lys(Boc)5,Thr(fBu)6,Cys(Acm)7,des(threoninol)]octreotide was assembled by Fmoc solid-phase synthesis and the intramolecular disulfide bond formed by treatment of the resin-bound peptide with thallium trifluoroacetate [TKTfajg]. Sidechain protection of Trp by the Boc group was found to preserve Trp integrity during Tl(Tfa)a treatment. The protected peptide was cleaved from the resin by aminolysis with threoninol and purified by semipreparative RP-HPLC. Isolated [D-Trp(Boc)4,Lys(Boc)5,Thr(fBu)6]octreotide had the correct molecular mass ([ + H]+ = 1275 Da) and sequence and was obtained in 14% yield at >98% purity. [D-Trp(Boc)4,Lys(Boc)5,Thr(fBu)6]octreotide was utilized for the solutionphase synthesis of CPTA-D-Phe^octreotide, where CPTAis 4-[(l,4,8,ll-tetraazacyclotetradecl-yl)methyl]benzoic acid. Cyclic dianhydride of diethylenetriaminepentaacetic acid (DTPA) was coupled to a portion of the protected peptide-resin following disulfide bond formation. The DTPA-conjugated, side-chain-protected peptide was cleaved from the resin by aminolysis with threoninol, side-chain deprotected with trifluoroacetic acid, and purified by semipreparative RP-HPLC. The isolated DTPA-o-Phe1-octreotide had the correct molecular mass ([M + H]+ = 1395 Da) and was obtained in 5% yield at >90% purity. The efficiency of aminolysis was partially dependent upon the linkage between 4-(hydroxymethyl)phenoxy (HMP) handles and the resin and/or resin particle size. The somatostatin receptor binding affinities of synthetic DTPA-D-PheLoctreotide and CPTA-D-Phe^octreotide to AtT-20 mouse pituitary carcinoma cell membranes were examined by labeling with mIn and 64Cu, respectively, and performing Scatchard analyses. The dissociation constant ( &) for our synthetic [111In]DTPA-D-Phe1octreotide was 4.31 nM, which is comparable to a K¿ = 5.57 nM obtained with commercially available DTPA-D-Phe1-octreotide. The K¿ for [64Cu]CPTA-D-Phe1-octreotide was 78.5 pM. On the basis of the criteria of molecular mass, RP-HPLC elution time, sequence analysis, and somatostatin receptor binding affinity, our synthetic octreotide is identical to commercially available octreotide. The aminolysis protocol used here has distinct advantages over either reductive cleavage or preformed linker methods described previously for the preparation of octreotide.
Summary:The use of blood and/or bone marrow stem cell transplantation (SCT) grew extensively in the last decade as technological advances led to improved outcomes and wider availability. The first study of SCT costs, however, was not published until 1989. This paper summarizes current knowledge about costs and cost-effectiveness of allogeneic and autologous SCT for leukemias and lymphoma. Methodological issues in cost studies such as types of costs, methods of data collection, and time horizons are discussed, and studies are evaluated with regard to these issues. Considerations specific to economic analyses of SCT are considered, including the potential impact of technological changes, learning curve effects, and inter-institutional differences. Keywords: cost-effectiveness, economics, stem cell transplantation The field of blood and bone marrow transplantation (stem cell transplantation, SCT) has changed dramatically over the past 10 years. Major advances in SCT technology has led to improved outcomes and wider availability. Numbers of SCT have increased from less than 5000 to more than 40 000 annually, and hundreds of papers related to SCT have been published.1 Yet relatively few studies have addressed the costs and cost-effectiveness of this complex technology, although perceived high costs contribute to the controversy over its use.The first comprehensive study of the costs of SCT was reported in 1989 and indicated that, while allogeneic bone marrow transplantation for patients with acute myelogenous leukemia (AML) was very costly, it was more cost-effective than chemotherapy.2 In the past 3 years, with physicians facing increased economic pressures in the United States and abroad, many more studies have included economic analyses. These studies report markedly lower costs of SCT than in 1989 and even more favorable cost-effectiveness profiles for persons with hematological malignancies. In this paper, we provide an overview of economic analyses in general and subsequently summarize studies of costs of SCTs for leukemia and lymphoma.Because the studies we review were conducted utilizing various methodologies and make numerous, differing assumptions regarding cost and clinical parameters, we begin our paper with a proposed framework for reviewing cost analyses (Section 1). We then review some of the 'issues' that our framework highlights, based on the work of others in the field (Section 2).3-8 Section 3 begins with a table summarizing the current literature on costs of SCT using the framework developed in Section 1. Section 3 also discusses the more current, well-designed/presented studies, highlighting the authors' conclusions. Section 4 presents some additional issues to be considered in cost analyses of SCT. A framework for comparing cost studiesThere is growing attention to the costs and cost-effectiveness of medical interventions. Review of the sizable body of literature devoted to the topic reveals conflicting definitions of cost as well as discrepant methods for conducting and reporting studies. The w...
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