A practical approach to assess the hazardous exposure potential of investigational drugs.

PURPOSE: A method to evaluate the hazardous exposure potential of investigational drugs was developed in order to comply with hazardous drug handling standards. SUMMARY: New nationwide standards require health-system pharmacies to recognize potential occupational risks and protect employees from any hazardous exposure. United States Pharmacopeia general chapter 800 (USP<800>) provides recommendations on handling precautions for commercial hazardous drugs. Recommendations for investigational drugs are less clear, with USP<800> suggesting more widespread protections when information is deemed insufficient to assess the risk. The investigational drug services pharmacy at a freestanding pediatric hospital developed a method to evaluate the hazardous potential of investigational drugs in order to determine the likelihood that a drug held an occupational handling risk. The goal of the project was to ensure compliance with hazardous drug handling standards and provide adequate employee protection while minimizing the financial burden on the health-system pharmacy. CONCLUSION: Investigational drugs that meet any of 4 defined criteria should be subject to hazardous drug handling precautions until adequate safety data are available.

Mutations in Caenorhabditis briggsae identify new genes important for limiting the response to EGF signaling during vulval development.

Studies of vulval development in the nematode C. elegans have identified many genes that are involved in cell division and differentiation processes. Some of these encode components of conserved signal transduction pathways mediated by EGF, Notch, and Wnt. To understand how developmental mechanisms change during evolution, we are doing a comparative analysis of vulva formation in C. briggsae, a species that is closely related to C. elegans. Here, we report 14 mutations in 7 Multivulva (Muv) genes in C. briggsae that inhibit inappropriate division of vulval precursors. We have developed a new efficient and cost-effective gene mapping method to localize Muv mutations to small genetic intervals on chromosomes, thus facilitating cloning and functional studies. We demonstrate the utility of our method by determining molecular identities of three of the Muv genes that include orthologs of Cel-lin-1 (ETS) and Cel-lin-31 (Winged-Helix) of the EGF-Ras pathway and Cel-pry-1 (Axin), of the Wnt pathway. The remaining four genes reside in regions that lack orthologs of known C. elegans Muv genes. Inhibitor studies demonstrate that the Muv phenotype of all four new genes is dependent on the activity of the EGF pathway kinase, MEK. One of these, Cbr-lin(gu167), shows modest increase in the expression of Cbr-lin-3/EGF compared to wild type. These results argue that while Cbr-lin(gu167) may act upstream of Cbr-lin-3/EGF, the other three genes influence the EGF pathway downstream or in parallel to Cbr-lin-3. Overall, our findings demonstrate that the genetic program underlying a conserved developmental process includes both conserved and divergent functional contributions.