Perspectives on the knowledge of asbestos disease in the United States - what was known, by whom, and when.

Historical research on asbestos disease can be traced back to the early twentieth Century. The majority, if not all of the early research was conducted outside the United States. There are a number of historical time-lines published that chronical these studies. However, what these time-lines do not address is how widespread this information was, who had access to it, and who may have been furthering this research here in the United States. To address these questions, we can look to the writings of early pioneers in occupational medicine like Alice Hamilton and Carey P. McCord from that era to determine the extent that asbestos disease was mentioned or being discussed. Based on the works of Dr. Hamilton and Dr. McCord, the dissemination and penetration of knowledge about asbestos within the medical and industrial hygiene communities during the first half of the twentieth Century in the United States were very limited or non-existent.

Characterizing and Communicating Risk with Exposure Reconstruction and Bayesian Analysis: Historical Locomotive Maintenance/Repair Associated with Asbestos Woven Tape Pipe Lagging.

Our reconstructed historical work scenarios incorporating a vintage 1950s locomotive can assist in better understanding the historical asbestos exposures associated with past maintenance and repairs and fill a literature data gap. Air sampling data collected during the exposure scenarios and analyzed by NIOSH 7400 (PCM) and 7402 (PCME) methodologies show personal breathing zone asbestiform fiber exposures were below the current OSHA exposure limits for the eight-hour TWA permissible exposure limit (PEL) of 0.1 f/cc (range <0.007-0.064 PCME f/cc) and the 30-minute short-term excursion limit (EL) of 1.0 f/cc (range <0.045-0.32 PCME f/cc) and orders of magnitude below historic OSHA PEL and ACGIH TLVs. Bayesian decision analysis (BDA) results demonstrate that the 95th percentile point estimate falls into an AIHA exposure category 3 or 4 as compared to the current PEL and category 1 when compared to the historic PEL. BDA results demonstrate that bystander exposures would be classified as category 0. Our findings were also significantly below the published calcium magnesium insulations exposure range of 2.5 to 7.5 f/cc reported for historic work activities of pipefitters, mechanics, and boilermakers. Diesel-electric locomotive pipe systems were typically insulated with a woven tape lagging that may have been chrysotile asbestos and handled, removed, and reinstalled during repair and maintenance activities. We reconstructed historical work scenarios containing asbestos woven tape pipe lagging that have not been characterized in the published literature. The historical work scenarios were conducted by a retired railroad pipefitter with 37 years of experience working with materials and locomotives.

Rating locomotive crew diesel emission exposure profiles using statistics and Bayesian Decision Analysis.

For more than 20 years CSX Transportation (CSXT) has collected exposure measurements from locomotive engineers and conductors who are potentially exposed to diesel emissions. The database included measurements for elemental and total carbon, polycyclic aromatic hydrocarbons, aromatics, aldehydes, carbon monoxide, and nitrogen dioxide. This database was statistically analyzed and summarized, and the resulting statistics and exposure profiles were compared to relevant occupational exposure limits (OELs) using both parametric and non-parametric descriptive and compliance statistics. Exposure ratings, using the American Industrial Health Association (AIHA) exposure categorization scheme, were determined using both the compliance statistics and Bayesian Decision Analysis (BDA). The statistical analysis of the elemental carbon data (a marker for diesel particulate) strongly suggests that the majority of levels in the cabs of the lead locomotives (n = 156) were less than the California guideline of 0.020 mg/m(3). The sample 95th percentile was roughly half the guideline; resulting in an AIHA exposure rating of category 2/3 (determined using BDA). The elemental carbon (EC) levels in the trailing locomotives tended to be greater than those in the lead locomotive; however, locomotive crews rarely ride in the trailing locomotive. Lead locomotive EC levels were similar to those reported by other investigators studying locomotive crew exposures and to levels measured in urban areas. Lastly, both the EC sample mean and 95%UCL were less than the Environmental Protection Agency (EPA) reference concentration of 0.005 mg/m(3). With the exception of nitrogen dioxide, the overwhelming majority of the measurements for total carbon, polycyclic aromatic hydrocarbons, aromatics, aldehydes, and combustion gases in the cabs of CSXT locomotives were either non-detects or considerably less than the working OELs for the years represented in the database. When compared to the previous American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) of 3 ppm the nitrogen dioxide exposure profile merits an exposure rating of AIHA exposure category 1. However, using the newly adopted TLV of 0.2 ppm the exposure profile receives an exposure rating of category 4. Further evaluation is recommended to determine the current status of nitrogen dioxide exposures. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: additional text on OELs, methods, results, and additional figures and tables.].

Addressing the medicinal chemistry bottleneck: a lean approach to centralized purification.

The use of standardized lean manufacturing principles to improve drug discovery productivity is often thought to be at odds with fostering innovation. This manuscript describes how selective implementation of a lean optimized process, in this case centralized purification for medicinal chemistry, can improve operational productivity and increase scientist time available for innovation. A description of the centralized purification process is provided along with both operational and impact (productivity) metrics, which indicate lower cost, higher output, and presumably more free time for innovation as a result of the process changes described.

Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.

The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.

PDE-10A inhibitors as insulin secretagogues.

Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.

Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR alpha/gamma/delta pan agonists: synthesis, structure-activity relationship, and in vivo efficacy.

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.

Indanylacetic acid derivatives carrying aryl-pyridyl and aryl-pyrimidinyl tail groups--new classes of PPAR gamma/delta and PPAR alpha/gamma/delta agonists.

Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.

Substituted indanylacetic acids as PPAR-alpha-gamma activators.

A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.

In vitro SAR of (5-(2H)-isoxazolonyl) ureas, potent inhibitors of hormone-sensitive lipase.

A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.

Prospects for kinase activity modulators in the treatment of diabetes and diabetic complications.

The worldwide population afflicted with diabetes is growing at an epidemic rate. There are almost five times the number of people suffering from this disease today as compared to 10 years ago and the worldwide diabetic population is expected to exceed 300 million by the year 2028. This trend appears to be driven by the world's adoption of a "western lifestyle" comprising a combination of unhealthy dietary habits and a sedentary daily routine. Today, diabetes is the sixth leading cause of death in the United States and the death rates associated with diabetes have increased by 30% over the last decade. While medications are available to reduce blood glucose, approximately one third of the patients on oral medications will eventually fail to respond and require insulin injections. Consequently, there is a tremendous medical need for improved medications to manage this disease that demonstrate superior efficacy. Emerging knowledge regarding the underlying mechanisms that impair glucose-stimulated insulin secretion and the action of insulin on its target tissues has grown tremendously over the last two decades. During that same period of time, an understanding of the important role that phosphorylation state plays in signal transduction has drawn attention to several kinases as attractive approaches for the treatment of diabetes. Recent advances include the discovery of a"small molecule" allosteric binding site on the insulin receptor, inhibitors of glycogen synthase kinase-3(GSK-3) which improve insulin sensitivity in diabetic animal models and inhibitors of protein kinase C- beta that are presently being evaluated in clinical trials for diabetic retinopathy. This review will detail these recent discoveries and highlight emerging biological targets that hold potential to normalize blood glucose and prevent the progression of diabetes related complications.