Search

Late preterm newborns often require treatment with potent drugs. Drug disposition is inadequately studied in this population, but when studied it is usually immature compared with that of term newborns. This immaturity reflects biologic immaturity and can be analyzed systematically according to the principal steps in pharmacokinetics: absorption, distribution, metabolism, and elimination. When studied developmentally, drug disposition often does not mature linearly with age, nor necessarily in predictable or generalizable patterns. Instead, more detailed study of specific pathways of drug disposition is needed in the late preterm newborn to support safe and effective drug therapy. Copyright © 2006 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Introduction: The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs.Methods: Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts.Results: ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L- and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts.Conclusions: Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients. [ABSTRACT FROM AUTHOR]

Pharmacologic study is needed in the extremely immature newborns who currently survive. Study is needed of both the drug treatment previously established in more mature neonates and of novel drug therapy. Carefully controlled studies are needed to identify accurately both beneficial and harmful drug therapy and the mechanisms of that toxicity. Careful pharmacologic study of drug disposition and its mechanisms might lead to dosing paradigms or patient selection that minimize toxicity and maximize efficacy. In vivo, translational models of neonatal diseases are limited, but can be used to identify novel treatments and study mechanisms of established, successful therapy. Findings from such studies can generate hypotheses for study in humans leading to a continuing scientific interchange from bedside to bench to bedside. Similarly, clinical observations can generate hypotheses for study in translational models where more invasive analyses are possible. Specific areas of drug treatment should focus on neonatal disorders with long-term, adverse outcomes, such as chronic lung disease, that is amenable to translational study with animal models. National data show a progressive decrease in the clinician-scientist pool entering biomedical research. The future of neonatal pharmacology studies requires an increase in training programs for the physician-scientist whose clinical education in neonatology can be complemented by rigorous basic-science training. Success as a clinician-scientist will require collaboration with full-time basic scientists who can continue studies during periods of clinical work and provide critical study methodology to the overall study design. Such a work environment must be supported by academic institutions and may require more flexibility in the promotion and tenure schedule and process, such as the nature of what it rewards. To complement this, the NIH could modify its grant reporting process to identify co-investigators in studies who may provide unique input to the study concepts and design, such as clinical correlations or clinical investigations.Journal of Perinatology (2006) 26, S8-S12. doi:10.1038/sj.jp.7211423. [ABSTRACT FROM AUTHOR]

Medical educational opportunities and resources are considerably limited in the developing world. The expansion of computing and Internet access means that there exists a potential to provide education to students through distance learning programmes. This study investigated the feasibility of providing distance learning course in surgery in Malawi. The study investigated the user requirements, technical requirements and Internet connections in two teaching hospitals in Malawi. In addition the appropriateness of current course material from the Edinburgh Surgical Sciences Qualification to Malawi trainees was assessed. The study found a high degree of interest from Malawian trainees in distance learning. The provision of basic science modules such as anatomy and physiology and the ability to access journals were considered highly desirable. The current ESSQ course would require extensive re-modelling to make it suitable to an African trainee's requirements. Internet speeds remain slow and access is currently expensive. There is considerable interest in distance learning programmes in Malawi but access to them is limited partly because of slow and expensive Internet access. Understanding the needs of trainees in countries such as Malawi will allow better direction of educational aid and resources to support surgical training. [ABSTRACT FROM AUTHOR]