Shapiro, Theresa - Johns Hopkins University

个人简介

Dr. Theresa Shapiro is a Professor of Medicine (Division of Clinical Pharmacology) and of Pharmacology and Molecular Sciences. Her interest is in the preclinical and clinical pharmacology of new drugs for sleeping sickness and malaria. Current studies include applying dynamically changing drug concentrations to parasites in vitro, to probe their pharmacokinetic governance. Dr. Shapiro received a medical degree and PhD from the Johns Hopkins University before joining the faculty. She has served on expert committees for the World Health Organization, the U.S. Food and Drug Administration, the National Institutes of Health and the U.S. Pharmacopeia.

研究领域

The central theme of our research is antiparasitic chemotherapy. On a molecular basis, we are interested in understanding the mechanism of action for existing antiparasitic agents, and in identifying vulnerable metabolic targets for much-needed, new, antiparasitic chemotherapy. Clinical studies are directed toward an evaluation, in humans, of the efficacy, pharmacokinetics, metabolism, and safety, of experimental antiparasitic drugs. The following are examples of ongoing work. The topoisomerases, "magicians of the cell", catalyze alterations in the topological state of DNA. These reactions are essential for the orderly synthesis of nucleic acids and for cell survival. A number of clinically important antitumor and antibacterial drugs have as their mechanism of action the inhibition of topoisomerase activity. We have found that topoisomerase inhibitors, or gene silencing by means of RNA interference, cause dramatic alterations in the structure and replication of nuclear and mitochondrial DNA in African trypanosomes (the organisms that cause sleeping sickness). We have also found that several of the classical antitrypanosomal drugs inhibit trypanosome topoisomerase activity in vivo. Of considerable importance, the severity of the molecular lesions attributable to enzyme inhibition correlates closely with trypanosome killing. The advent and rapid spread of chloroquine-resistant falciparum malaria is widely regarded as a public health crisis. Safe new antimalarial drugs are urgently needed. Atovaquone, a broad-spectrum antiprotozoal agent, is almost unique in its dual action against both tissue and bloodstream stages of the malaria parasite. We conducted a prospective, double-blind, placebo-controlled clinical trial which demonstrated that atovaquone can protect healthy volunteers against Plasmodium falciparum. The study used a highly sensitive polymerase chain reaction assay to detect subclinical parasitemia and to distinguish between the two possible mechanisms for prophylaxis.

近期论文

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Shapiro TA, Ranasinha CD, Kumar N, and Barditch-Crovo P (1999) Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J. Trop. Med. Hyg. 60: 831-836. View on Pubmed Ye L, Dinkova-Kostova AT, Wade KL, Zhang Y, Shapiro TA, Talalay P (2002) Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta. Feb 316(1-2):43-53. Erratum in Clin Chim Acta 2002 Jul: 321 (1-2) 127-9 View on Pubmed Bodley AL, Chakraborty AK, Xie S, Burri C, Shapiro TA. (2003) An unusual type IB topoisomerase from African trypanosomes. Proc Natl Acad Sci USA. Jun 24; 100 (13) 7539-7544. View on Pubmed Nenortas E, Kulikowicz T, Burri C, Shapiro TA. (2003) Antitrypanosomal activities of fluoroquinolones with pyrrolidinyl substitutions. Antimicrob Agents Chemother Sep; 47 (9): 3015-3017. View on Pubmed Arav-Boger R, Shapiro TA. (2004) Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annu Rev Pharmacol Toxicol Oct 07 (Epub ahead of print) View on Pubmed Posner GH, McRiner AJ, Paik JH, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B. (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimmers in rodents. J Med Chem Feb 26: 47(5): 1299-301. View on Pubmed