Louis J. Theodore

The use of metalloids (-SiMe3,-SnR3) as protected carbanions : Selective activation and new cyclization processes

Abstract Two aspects of organosilicon and -tin chemistry will be dealt with in this paper: the reactivity of allylmetalloids and the potential of the C-MR3 function as a protected carbanion which can be unmasked to provide synthetically useful carbon nucleophiles with the primary focus on the latter.

The pharmacokinetics and pharmacodynamics of d- and dl-verapamil in rabbits

Summary: The pharmacokinetics and pharmacodynamics of d- and dl-verapamil were studied in conscious rabbits in randomized cross-over fashion. Following a single intravenous dose, there was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic properties of the compounds. The mean (±SD) clearances of d- and dl-verapamil were 0.13 ± 0.03 and 0.12 ± 0.05 L/min/kg, respectively. The mean (±SD) steady-state volume of distribution was 9.7 ± 5.2 L/kg for d-verapamil and 8.1 ± 4.1 L/kg for dl-verapamil. No difference was observed between the compounds in their binding to plasma proteins. The mean (±SD) half-life in plasma was 98.7 ± 63.8 min for d-verapamil and 96.3 ± 38.0 min for dl-verapamil. In contrast to the lack of stereoselective differences in the pharmacokinetic properties of verapamil, there were marked differences in the pharmacodynamics of d- and dl-verapamil. dl-Verapamil appeared to prolong the PR interval to a greater degree than did d-verapamil, consistent with the more potent calcium channel effects of the l-enantiomer. Similarly, dl-verapamil had more potent hypotensive effects compared with the d-enantiomer, which produced no effects on systemic arterial pressure. Chronotropic effects, judged to be caused by autonomic reflexes in response to the hypotensive effects of the compound, were also statistically greater for dl-verapamil than for d-verapamil. These results demonstrate stereoselective pharmacodynamic effects in vivo of verapamil.

Comparison of pretargeted and conventional CC49 radioimmunotherapy using 149Pm, 166Ho, and 177Lu.

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.