Piloting Your Nanovehicle to Overcome Biological Barriers.

Designing an effective nanoparticle for selective drug transport requires careful consideration of the complex biological barriers encountered in transit to the desired target. Here, we review several of these barriers, and provide possible methods for formulating liposomal nanoparticles to overcome them. The methods include the biotinylation of an antibody, and subsequent conjugation to a PEGylated cationic lipid nanoparticle. Additionally, the incorporation of drug, and other relevant characteristics of the nanoparticle are also discussed.

Water for Warfighters in Iraq and Afghanistan: A Summary of Lessons Learned.

The Army is the Department of Defense executive agent for land-based field water supplies. The Army Corps of Engineers, Army Quartermaster Corps, and Army Medical Department coordinate to provide the necessary support to obtain, treat, disinfect, certify, distribute, and monitor drinking water during deployments. This collaboration is necessary to ensure that an adequate quantity of acceptable quality drinking water is available for deployed personnel at all base camps and in all operations. Important lessons were learned from the beginning of operations in Iraq in 2003 continuing throughout 2 wars. These included lessons about the employment and management of bottled water during deployments, the quality and potential usefulness of "wastewater" from the reverse osmosis water purifiers, the usefulness and acceptability of military packaged water, and our lack of preparedness to readily address the drinking water needs of small squad and platoon-sized operations lasting more than a few days. The lessons we learned have and will continue to enhance our ability to readily meet Warfighters' requirements for that most critical of supplies--sustaining a supply of safe, aesthetically pleasing drinking water.

US veterinary support to standardization of food and water safety and animal care and use within NATO.

NATO requires all standardization agreements and Al-lied Medical Publications to be reviewed at least once every 3 years to ensure they reflect current technologies and national military policies and procedures. This is particularly applicable with regard to veterinary medi-cine and food and water safety where advances in scientific knowledge and practices may result in documents quickly becoming obsolete. Such is the case with the 8 standardization agreements for which the FWSVS has responsibility; all are currently undergoing major revisions. With each revision, national representatives, including US veterinary and preventive medicine personnel, must review the documents to ensure there are no significant issues which would prevent ratification and implementation. This improves standardization and enhances interoperability between NATO partners to minimize duplication. This is accomplished by leveraging other national military capabilities, while maintaining confidence that the food, water, and veterinary support provided to their Warriors, support personnel, and animals in the field is safe and high in quality. Adherence to such standards is a major factor in maintaining the operational readiness of all alliance armed forces.

Discovery of XL413, a potent and selective CDC7 inhibitor.

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

Discovery and characterization of an inhibitor of glucosylceramide synthase.

Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.

Discovery of a new class of glucosylceramide synthase inhibitors.

A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.

Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

Synthesis and activity of novel bile-acid conjugated glucocorticoid receptor antagonists.

A series of potent steroidal glucocorticoid receptor antagonists has been discovered. After conjugation to cholic acid, the compounds retained an affinity for GR in vitro and had modest in vivo efficacy.

Discovery of potent and selective inhibitors of 11beta-HSD1 for the treatment of metabolic syndrome.

High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.

What should non-US behavioral health systems learn from the USA?: US behavior health services trends in the 1980s and 1990s.

Several countries, such as the USA, inadvertently created a different behavioral health payment system from the rest of medicine through the introduction of diagnostic-related group exemptions for psychiatric care. This led to isolation in the administration and delivery of care for patients with mental health and substance abuse disorders from other medical services with significant, yet unintended, consequences. To insure an efficient and effective health-care system, it is necessary to recognize the problems introduced by segregating behavioral health from the rest of medical care. In this review, the authors assess trends in behavioral health services during the last two decades in the USA, a period in which independently managed behavioral health care has dominated administrative practices. During this time, behavioral health has been an easy target for aggressive cost cutting measures. There have been no clinically significant improvements in the number of adults receiving minimally adequate treatment or in the percentage of the population with behavior health problems receiving psychiatric care with the possible exception of depression. While decreased spending for behavioral health services has been well documented during this period, these savings are offset by costs shifted to greater medical service use with a net increase in the total cost of health care. Targeting behavioral health for reduction in health-care spending through independent management, starting with diagnostic procedure code or diagnostic-related group exemption may not be the wisest approach in addressing the increasing fiscal burden that medical care is placing on the national economy.

The effectiveness of an interactive small group diabetes intervention in improving knowledge, feeling of control, and behavior.

The objective of this study is to evaluate the effectiveness of a small group intervention in improving knowledge, feeling of control, and behaviors related to self-management of diabetes. The intervention includes educational content on diabetes self-management as well as discussion of attitudes, feelings, and motivations about living with diabetes. The authors randomized volunteers into an intervention group that participated in the small-group learning activity and a control group that received a diabetes self-care book. A survey was conducted by telephone before and after each intervention and the difference in change over time between the groups was assessed for each outcome. Compared to the control group, participants in the small-group activity reported significant changes on all three outcomes adjusting for demographic differences between the groups. Because facilitating the learning session does not require clinically trained personnel, this type of intervention could broaden the resources available to people with diabetes.