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One of the most critical drivers of innovation in the drug delivery field is commercialization potential, which is facilitated by intellectual property (IP) protection primarily in the form of patents. This chapter provides a detailed overview of the evolution of the global IP landscape around drug delivery over the past 30 years, paying particular attention to the three most widely used drug delivery systems: oral, topical, and parenteral. Emerging areas of IP growth including targeted, nanoscale, and immunoconjugate drug delivery systems are highlighted, as is the importance and core requirements of a program to proactively monitor the dynamic IP landscape.

External cues, including familiar music, can release Parkinson's disease patients from catalepsy but the neural basis of the effect is not well understood. In the present study, posturography, the study of posture and its allied reflexes, was used to develop an animal model that could be used to investigate the underlying neural mechanisms of this sound-induced behavioral activation. In the rat, akinetic catalepsy induced by a dopamine D2 receptor antagonist (haloperidol 5 mg/kg) can model human catalepsy. Using this model, two experiments examined whether novel versus familiar sound stimuli could interrupt haloperidol-induced catalepsy in the rat. Rats were placed on a variably inclined grid and novel or familiar auditory cues (single key jingle or multiple key jingles) were presented. The dependent variable was movement by the rats to regain equilibrium as assessed with a movement notation score. The sound cues enhanced movements used to regain postural stability and familiar sound stimuli were more effective than unfamiliar sound stimuli. The results are discussed in relation to the idea that nonlemniscal and lemniscal auditory pathways differentially contribute to behavioral activation versus tonotopic processing of sound.

Extremely low-frequency electromagnetic fields (ELF-EMF) have been reported to induce lesions in DNA and to enhance the mutagenicity of ionising radiation. However, the significance of these findings is uncertain because the determination of the carcinogenic potential of EMFs has largely been based on investigations of large chromosomal aberrations. Using a more sensitive method of detecting DNA damage involving microsatellite sequences, we observed that exposure of UVW human glioma cells to ELF-EMF alone at a field strength of 1 mT (50 Hz) for 12 h gave rise to 0.011 mutations/locus/cell. This was equivalent to a 3.75-fold increase in mutation induction compared with unexposed controls. Furthermore, ELF-EMF increased the mutagenic capacity of 0.3 and 3 Gy gamma-irradiation by factors of 2.6 and 2.75, respectively. These results suggest not only that ELF-EMF is mutagenic as a single agent but also that it can potentiate the mutagenicity of ionising radiation. Treatment with 0.3 Gy induced more than 10 times more mutations per unit dose than irradiation with 3 Gy, indicating hypermutability at low dose.

Purpose: Both [131I]meta-iodobenzylguanidine ([131I]MIBG) and the topoisomerase I inhibitor topotecan are effective as single-agent treatments of neuroblastoma. The aim of this study was to investigate the efficacy of [131I]MIBG in combination with topotecan in vitro and in vivo. Experimental Design: The cell lines used were SK-N-BE(2c) (human neuroblastoma) and UVW/NAT (glioma cell line transfected with the noradrenaline transporter gene). Three different treatment schedules were assessed: topotecan given before (schedule 1), after (schedule 2), or simultaneously (schedule 3) with [131I]MIBG. DNA strand breakage was evaluated by comet assay, and cytotoxicity was determined by clonogenic survival. Efficacy was also measured by growth delay of tumor xenografts in nude mice. Results: Combination schedules 2 and 3 caused more cytotoxicity than schedule 1. Similarly, significant DNA damage was observed following treatment schedules 2 and 3 (P < 0.005) but not schedule 1. The mean number of days for a doubling in volume of SK-N-BE(2c) tumors and a 10-fold increase in volume of UVW/NAT tumors were 10.4 and 18.6 (untreated), 19.7 and 25.3 (topotecan alone), 22.8 and 31.9 ([131I]MIBG alone), 26.3 and 37.1 (combination schedule 1), 34.3 and 49.7 (combination schedule 2), and 53.2 and >71 (combination schedule 3), respectively. The highest rate of cure of both xenografts was observed following treatment with combination schedule 3. Conclusions: The combination of topotecan and [131I]MIBG compared with either treatment alone gave rise to greater than additive DNA damage, clonogenic cell kill, and tumor growth delay. These effects were dependent on the scheduling of the two agents.

This article provides an overview of the factors that may contribute to the effective term of protection for a pharmaceutical product in the USA––by patent and by FDA market exclusivities, identifies public and commercial sources for collecting relevant patent term and exclusivity data, and provides a strategy for ensuring that the effective term of protection has been calculated accurately.

Background We describe an in vitro tumour model for targeted radiotherapy and gene therapy that incorporates cell population heterogeneity. Materials and methods Transfectant mosaic spheroids (TMS) and transfected mosaic monolayers (TMM) are composed of two cell populations derived from a single cell line. The cells of one population were transfected with the noradrenaline transporter gene (NAT), allowing active uptake of a radiolabelled targeting agent meta-[131I]iodobenzylguanidine ([131I]MIBG); the other population of cells was derived from the same parent line and transfected with a marker gene – green fluorescent protein (GFP). After treatment with [131I]MIBG, cell kill was determined in TMM by clonogenic assay and in TMS by clonogenic assay and spheroid growth delay. Results We have used the TMS model to assess the ‘radiological bystander effect’ (radiation cross-fire) conferred by the β-emitting radiopharmaceutical [131I] MIBG whose cellular uptake is facilitated by the transfected gene encoding NAT. We show that cell killing by [131I]MIBG in both TMS and TMM cultures increased in direct proportion to the fraction of NAT-transfected cells and that the degree of cell killing against fraction transfected was greater in TMS, suggestive of a greater bystander effect in the three-dimensional culture system. Conclusions TMS provide a useful model for assessment of the effectiveness of targeted radiotherapy in combination with gene therapy when less than 100% of the target cell population is expressing the NAT transgene. Further, this novel model offers the unique opportunity to investigate radiation-induced bystander effects and their contribution to cell cytotoxicity in radiotherapy and other gene therapy applications. Copyright © 2002 John Wiley & Sons, Ltd.

The myeloid transforming gene Evi-1 encodes a protein with two zinc finger domains, designated ZF1 and ZF2, with distinct DNA binding specificities. For the first time we demonstrate that Evi-1 has transcriptional repressor activity which is directly proportional to the amount of Evi-1 protein in cells. Repression has been observed with two distinct promoters: the minimal HSV-1 tk promoter and a VP16 inducible adenovirus E1b minimal promoter. Optimal repression is DNA binding dependent and is mediated by either ZF1 or a heterologous GAL4 DNA binding domain (GAL4DBD) but is significantly less efficient through the ZF2 binding site. Both GAL4DBD/Evi-1 fusion and non-fusion proteins have been used to map the repressor activity to a proline-rich region located within amino acids 514-724 between the ZF1 and ZF2 domains. Constitutive expression of mutant proteins lacking the repressor domain are defective for transformation of Rat1 fibroblasts demonstrating that this region is required for the oncogenic activity of the Evi-1 protein. These studies show that the Evi-1 gene encodes a transcriptional repressor and has important implications for the mechanism of action of the Evi-1 protein both in development and in the progression of some myeloid leukaemias.