Influence of a TcN core on the biological and physicochemical behavior of Tc complexes of L,L-EC and L,L-ECD

^99mTc-nitrido complexes of L,L-ethylene dicysteine (^99mTcN-L,L-EC) and ^99mTcN-L,L-ethylene dicysteine diethylester (^99mTcN-L,L-ECD) were prepared and their characteristics compared to those of the respective ^99mTc-oxo complexes. ^99mTcN-L,L-EC and ^99mTcO-L,L-EC migrate to similar extents during electrophoresis at pH 12, but, at pH 6, ^99mTcN-L,L-EC migrates further than ^99mTcO-L,L-EC. Renal excretion of ^99mTcN-L,L-EC is inferior to that of ^99mTcO-L,L-EC, indicating that the TcN-glycine sequence has lower affinity for the renal tubular system. Both ^99mTcO-L,L-ECD and ^99mTcN-L,L-ECD are neutral, but ^99mTcN-L,L-ECD is hydrophilic and shows minimal brain uptake in both mice and the baboon.     

Multicenter Randomized Comparison of the Efficacy and Safety of Xenon and Isoflurane in Patients Undergoing Elective Surgery

Background: All general anesthetics used are known to have a negative inotropic side effect. Since xenon does not have a negative inotropic effect, it could be an interesting future general anesthetic. The aim of this clinical multicenter trial was to test the hypothesis of whether recovery after xenon anesthesia is faster compared with an accepted, standardized anesthetic regimen and that it is as effective and safe.

Method: A total of 224 patients in six centers were included in the protocol. They were randomly assigned to receive either xenon (60 +/- 5%) in oxygen or isoflurane (end-tidal concentration, 0.5%) combined with nitrous oxide (60 +/- 5%). Sufentanil (10 [mu]g) was intravenously injected if indicated by defined criteria. Hemodynamic, respiratory, and recovery parameters, the amount of sufentanil, and side effects were assessed.

Results: The recovery parameters demonstrated a statistically significant faster recovery from xenon anesthesia when compared with isoflurane-nitrous oxide. The additional amount of sufentanil did not differ between both anesthesia regimens. Hemodynamics and respiratory parameters remained stable throughout administration of both anesthesia regimens, with advantages for the xenon group. Side effects occurred to the same extent with xenon in oxygen and isoflurane-nitrous oxide.     

Characteristics and biological behaviour of 99mTc-labelled hydroxyacetyltriglycine, a potential alternative to 99mTc-MAG3

Substitution of the oxidation-sensitive thiol function of mercaptoacetyltriglycine (MAG3) by a hydroxyl group yields a tetraligand (hydroxyacetyltriglycine or HAG3) which is almost insensitive to oxidation and has the advantage over MAG3 that it can be stored safely without protection of the alcohol function. We found that deprotected HAG3 could be directly labelled at alkaline pH (pH≥11.5) and room temperature in high yield (>95%). Results of electrophoresis experiments suggested a comparable structure for ^99mTc-HAG3 and ^99mTc-MAG3, namely binding of an oxotechnetium(V)core via three deprotonated amides and a deprotonated hydroxyl group. Biodistribution studies in mice at 10 min and 30 min p.i. showed a slightly higher urinary excretion, a faster renal transit and a significantly lower hepatobiliary handling for ^99mTc-HAG3 than for ^99mTc-MAG3. In a baboon, the 1-h plasma clearance of ^99mTc-HAG3 was clearly higher than that of ^99mTc-MAG3. Its plasma protein binding was in the same order as that of Hippuran and much lower than that of ^99mTc-MAG3. Evaluation in a human volunteer confirmed the favourable biological characteristics of ^99mTc-HAG3, namely a rapid renal excretion, a high 1-h plasma clearance and a negligible hepatobiliary handling. The results indicate that ^99mTc-HAG3 may be an easy-to-prepare and practical substitute for ^99mTc-MAG3 with improved renal excretion characteristics. Received 1 May and in revised form 18 July 1997     

Synthesis of 18F-fluoroalkyl-beta-D-glucosides and their evaluation as tracers for sodium-dependent glucose transporters.

Three omega-(18)F-fluoro-n-alkyl-beta-D-glucosides (alkyl = ethyl (5a)), n-butyl (5b), and n-octyl (5c)) were synthesized and evaluated as potential substrates for the sodium/D-glucose cotransporter SGLT1. METHODS: The ligands were prepared by (18)F-fluoride displacement of the corresponding tetraacetyl-protected tosylate alkylglucoside precursors in CH(3)CN, followed by hydrolysis of the protective acetate esters with NaOMe/MeOH. Transport of the nonradioactive analogs 5a, 5b, and 5c by the human sodium-D-glucose cotransporter hSGLT1 was characterized in vitro in oocytes of Xenopus laevis that expressed hSGLT1. The biodistribution of the tracers was determined in mice and the presence of metabolites in the blood was investigated. Compound 5a was also evaluated in mice pretreated with phlorizin. The intrarenal distribution of 5a in mice kidney was visualized using autoradiography. RESULTS: The radiochemical yield of 5a, 5b, and 5c was in the range of 8%-15% (end of bombardment) with a total synthesis time of 90 min. The in vitro evaluation after expression of the hSGLT1 showed that 2'-fluoroethyl-beta-D-glucoside (5a) was transported with similar Michaelis-Menten K(m) and V(max) (maximum velocity) values as compared with methyl-alpha-D-glucopyranoside (alpha MDG). The more lipophilic compounds 5b and 5c were not transported but inhibited transport of alpha MDG. In vivo tissue distribution in mice revealed that 5a, 5b, and 5c were cleared mainly by the renal pathway and that 5a showed a significantly higher accumulation in the kidneys and a slower renal excretion as compared with 5b and 5c. Compound 5a was retained mainly in the renal outer medulla containing S3 segments of proximal tubules and the accumulation could be blocked by phlorizin pretreatment. Compound 5c passed the blood-brain barrier to some extent. CONCLUSION: The data indicate that 2'-(18)F-fluoroethyl-beta-D-glucoside (5a) is a specific tracer of Na(+)-dependent glucose transport that may be used to visualize this transport activity in the S3 segments of renal proximal tubules.     

Continuously elevated cardiac troponin I in two patients with multiple myeloma and fatal cardiac amyloidosis

Myeloma-associated systemic amyloidosis (AL) with cardiac involvementhas a poor prognosis, with a median survival of <1year [1]. Standard therapy with oral melphalan and prednisoloneis unsatisfactory, with an overall response rate for AL of 20%.The diagnosis of cardiac amyloidosis in patients with multiplemyeloma is most commonly based on     

Characterisation of tremor-associated local field potentials in the subthalamic nucleus in Parkinson's disease

We simultaneously recorded local field potentials (LFPs) in the subthalamic nucleus (STN) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm in eight patients with idiopathic tremor-dominant Parkinson's disease (resting tremor) during the bilateral implantation of deep brain stimulation electrodes. Recordings were made at different heights (in 0.5- to 2.0-mm steps beginning outside the STN) using up to five concentrically configured macroelectrodes (2 mm apart). The patients were instructed to relax their contralateral forearm (rest condition). We analysed the coherence between tremor EMGs and STN LFPs, which showed significant tremor-associated coupling at single tremor and double tremor frequencies. Moreover, the EMG–LFP coherences were characterised by differences between antagonistic muscles (flexor, extensor) and by the spatial distribution of LFPs within the STN. Coherence at single and double tremor frequencies occurred significantly more frequently within STN than above STN (in the zona incerta). In this study, we were able to show that, within STN, tremor-associated LFP activity varied with spatial distribution and with the contralateral antagonistic forearm muscles. These findings suggest the existence of distribution- and muscle-specific tremor-associated LFP activity at different tremor frequencies and an organisation of tremor-related subloops within the STN.     

Generation and sustained expansion of mouse spleen invariant NKT cell lines with preserved cytokine releasing capacity

Invariant Natural Killer T (iNKT) cells are CD1d restricted innate lymphoid cells with an invariant T cell receptor (TCR) alpha chain gene rearrangement (Valpha24-Jalpha18 in human and Valpha14-Jalpha18 in mouse). iNKT cells play a pivotal role in anti-tumor immune responses via cytokine mediated transactivation of various cells which mediate innate and adaptive immune responses. Here we describe, to our knowledge for the first time, the generation of long-term mouse spleen derived iNKT cell lines. We found that dendritic cells (DC) derived from the D1 line, but not Mf4/4 macrophages, loaded with the artificial iNKT cell ligand alpha-Galactosylceramide (alphaGalCer) could be employed to expand iNKT cells in vitro. Furthermore, exogenously added IL-7, but not IL-2 or IL-15 had a pronounced additive effect on iNKT cell expansion. Using this method up to 10(8) iNKT cells could be obtained from one spleen within 12 to 14 weeks, and cell lines could be continued for up to 24 months. Importantly, the iNKT cell lines had retained the capacity to swiftly secrete substantial amounts of both T helper (Th) 1 and Th2 cytokines upon activation. In conclusion we have generated iNKT cell lines with high yields that can be maintained for up to 24 months, by repeated stimulation using alpha-GalCer loaded D1.DC and IL-7. These in vitro expanded iNKT cells preserved the capacity to swiftly produce both Th1 and Th2 type cytokines and are currently being utilized in pre-clinical adoptive transfer models to identify and optimize the characteristics of therapeutically effective iNKT cells in an anti-tumor setting.