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Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d- and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in(More)
We present the case of a 51-year-old female who had a four-year history of Parkinson's disease with severe “on-off ” and disabling progression of symptoms on chronic levodopa therapy. After obtaining FDA approval, we implanted a Medtronic deep brain stimulation lead stereotactically into the right anterior pallidum contralateral to her most Symptomatologic(More)
BACKGROUND This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. METHODS Patients had adenocarcinoma of the colon or rectum with progression within(More)
AIM To evaluate the tolerability, pharmacokinetics and tumour response of first-line trebananib plus paclitaxel and carboplatin followed by trebananib maintenance in high-risk or advanced ovarian cancer. METHODS In this open-label phase 1b study, patients received intravenous (IV) trebananib 15 mg/kg administered weekly (QW) plus paclitaxel 175 mg/m(2)(More)
Carbonyl reductase (CR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of several carbonyls. Anthracyclines used to treat cancer are reduced by CR at the C13 carbonyl and the resulting metabolites are implicated in the cardiotoxicity associated with anthracycline therapy. CR also is believed to have a role in(More)
An enantiocontrolled route to aziridinomitosenes had been developed from l-serine methyl ester hydrochloride. The tetracyclic target ring system was assembled by an internal azomethine ylide cycloaddition reaction based on silver ion-assisted intramolecular oxazole alkylation and cyanide-induced ylide generation via a labile oxazoline intermediate (62 to(More)
OBJECTIVE To evaluate the utility of a modified calculation of the alveolar dead space fraction (Vd/Vt), combined with plasma D-dimers, to aid in the exclusion of acute pulmonary embolism (PE). METHODS A prospective comparison of screening modalities was performed in a metropolitan teaching ED. Ambulatory patients evaluated for PE underwent simultaneous(More)
The aziridinomitosene derivative (1S,2S)-6-desmethyl(methylaziridino)mitosene (4) was shown to alkylate plasmid DNA at pH 7.4 in the absence of a reducing agent [Vedejs, E., Naidu, B. N., Klapars, A., Warner, D. L., Li, V. -s., Na, Y., and Kohn, H. (2003) J. Am. Chem. Soc. 125, 15796-15806], an activity not found in the parent mitomycins. We sought to(More)
A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl(More)
BACKGROUND AND PURPOSE The sensitivity to the intoxicating effects of alcohol as well as its adverse medical consequences differ markedly among individuals, which reflects in part differences in alcohol's absorption, distribution, metabolism, and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol's brain(More)