Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions

[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone (GDC-0973) is a potent and highly selective inhibitor of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase (ERK) 1/2 (MEK1/2), a MAPK kinase that activates ERK1/2. The objectives of these studies were to characterize the disposition of GDC-0973 in preclinical species and to determine the relationship of GDC-0973 plasma concentrations to efficacy in Colo205 mouse xenograft models. The clearance (CL) of GDC-0973 was moderate in mouse (33.5 ml · min(-1) · kg(-1)), rat (37.9 ± 7.2 ml · min(-1) · kg(-1)), and monkey (29.6 ± 8.5 ml · min(-1) · kg(-1)). CL in dog was low (5.5 ± 0.3 ml · min(-1) · kg(-1)). The volume of distribution across species was large, 6-fold to 15-fold body water; half-lives ranged from 4 to 13 h. Protein binding in mouse, rat, dog, monkey, and human was high, with percentage unbound, 1 to 6%. GDC-0973-related radioactivity was rapidly and extensively distributed to tissues; however, low concentrations were observed in the brain. In rats and dogs, [(14)C]GDC-0973 was well absorbed (fraction absorbed, 70-80%). The majority of [(14)C]GDC-0973-related radioactivity was recovered in the bile of rat (74-81%) and dog (65%). The CL and volume of distribution of GDC-0973 in human, predicted by allometry, was 2.9 ml · min(-1) · kg(-1) and 9.9 l/kg, respectively. The predicted half-life was 39 h. To characterize the relationship between plasma concentration of GDC-0973 and tumor growth inhibition, pharmacokinetic-pharmacodynamic modeling was applied using an indirect response model. The KC(50) value for tumor growth inhibition in Colo205 xenografts was estimated to be 0.389 μM, and the predicted clinical efficacious dose was ～10 mg. Taken together, these data are useful in assessing the disposition of GDC-0973, and where available, comparisons with human data were made.     

Neurocognitive outcomes in young adults with early-onset type 1 diabetes: a prospective follow-up study

OBJECTIVE

The aim of this study was to reexamine the neurocognitive function of a cohort of young adults with early-onset type 1 diabetes and compare their cognitive function to a matched control group. We also examined whether cognitive function was related to prospectively obtained severe hypoglycemia history, long-term glycemic control, or severe diabetic ketoacidosis.

RESEARCH DESIGN AND METHODS

Testing included Wechsler Intelligence Scale for Children and Adults, Wechsler Memory Scale, Cattell Culture Fair Intelligence Test (CCFIT), Wisconsin Card Sorting Test (WCST), youth and adult self-report, and Beck Depression Inventory. We tested 34 control subjects (mean ± SE, age 19.5 ± 0.5 years) and 33 type 1 diabetic subjects (age 19.3 ± 0.5 years, age at type 1 diabetes onset 3.3 ± 0.3 years, A1C from diagnosis 8.7 ± 0.1%, and diabetes duration 16.0 ± 0.5 years).

RESULTS

There was no difference in full-scale IQ scores in type 1 diabetic and control subjects (100.7 ± 2.0 vs. 102.5 ± 1.4). There was no difference between groups in memory subtests or in reporting of emotional and behavioral difficulties. The type 1 diabetes group scored lower on the CCFIT for fluid intelligence compared with control subjects (P = 0.028) and also scored lower on WCST with more perseverative errors (P = 0.002) and fewer categories completed (P = 0.022).

CONCLUSIONS

These data suggest no difference in general intellectual ability, memory, and emotional difficulties in our cohort of young adults with early-onset type 1 diabetes compared with control subjects and no deterioration over time. There were, however, findings to suggest subtle changes leading to poorer performance on complex tasks of executive function.The impact of type 1 diabetes on the developing brain remains controversial. Earlier age of diabetes onset has long been identified as one of the strongest risk factors associated with cognitive dysfunction, ranging from poorer performance on general intellectual testing (1,2) to specific deficits with visuospatial tasks, attention, and psychomotor efficiency. The effect of early-onset diabetes, however, is confounded by the impact of recurrent severe hypoglycemia. Repeated severe hypoglycemia has been reported to adversely affect various cognitive domains, in particular long-term memory, attention, and verbal IQ, although this has not been consistent across studies (3,4). Moreover, many of these studies are limited by their retrospective collection of hypoglycemia history.We previously reported neurocognitive outcomes in 84 children with early-onset diagnosis of type 1 diabetes defined as type 1 diabetes onset before 6 years of age (4). In that initial study, we compared those subjects who had a history of early severe hypoglycemia with those who had a history of late severe hypoglycemia and also compared those who had experienced severe hypoglycemia with peers who had no history of seizures. Surprisingly, there were no group differences revealed on intellectual, memory, or behavioral measures. Furthermore, there was no evidence that episodes of seizure or coma, even those occurring in early childhood, resulted in broad cognitive dysfunction, nor was there evidence of specific memory difficulties at the time of testing.In this study, we reevaluate the neurocognitive function of the cohort—with onset of type 1 diabetes before age 6 years—now that they are young adults. This early-onset type 1 diabetes cohort is unique in that all subjects were initially recruited from a population-based cohort and have been prospectively followed from diagnosis with documentation of hypoglycemia rates and other key clinical data, including A1C, at regular 3-month clinic visits.Our aims were, first, to determine whether there had been any deterioration in neurocognitive function in this population-based cohort of young adults with early-onset type 1 diabetes over the 10 years since they were previously tested. Second, we sought for the first time to compare the neurocognitive outcomes of this cohort to a group of age- and sex-matched healthy young adults. Finally, we aimed to determine whether cognitive function in this cohort of patients with early-onset type 1 diabetes was related to their severe hypoglycemia history, long-term glycemic control, or history of severe diabetic ketoacidosis.     

"Spice" girls: synthetic cannabinoid intoxication

Background

“Spice” refers to various synthetic cannabinoid-containing products that seem to have rapidly become popular recreational drugs of abuse. Very little medical literature currently exists detailing the adverse effects and emergency department (ED) presentations associated with “spice” use.

Objectives

To describe the presentation of 2 patients who recreationally used a “spice” product and to briefly summarize what is known about “spice” and synthetic cannabinoids.

Case Report

Two patients presented to the ED with, predominantly, anxiety after recreationally using a “spice” product that we subsequently confirmed to contain the synthetic cannabinoids, JWH-018 and JWH-073.

Conclusion

We suspect that use of “spice” products may increase. Although anxiety was a prominent presentation in both of the patients described here, undoubtedly, future studies will describe the manifestations of intoxication and toxicity with the various synthetic cannabinoids.     

Knowledge of Cardiovascular Health Among Chinese, Korean and Vietnamese Immigrants to the US

Cardiovascular disease (CVD) is the leading cause of death among Asian Americans, the majority of whom are foreign-born. However, CVD and risk factor data is sparse for specific Asian immigrant populations. To assess knowledge and understanding of CVD and risk factors within Chinese, Korean and Vietnamese immigrant populations, we conducted eight focus groups of 77 participants between 36 and 84?years old. Participants correctly identified signs and symptoms for heart attacks while knowledge about stroke was incomplete. While poor diet, lack of exercise, older age, and high cholesterol were frequently discussed as risk factors, mechanisms perceived as contributing to heart disease were influenced primarily by non-Western paradigms. Non-Western remedies were discussed in detail among Chinese and Vietnamese participants. All participants desired more information, and identified barriers to effective communication with healthcare providers. A deeper understanding of beliefs and barriers faced by Asian immigrants can help guide health promotion efforts.     

Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring

Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effects of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Female rats were placed on a control or folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, female pups from each maternal diet group were randomized to the control or supplemented diet and mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At necropsy, mammary tumor parameters, genomic DNA methylation, and DNA methyltransferase activity were determined in the offspring. Both maternal and postweaning folic acid supplementation significantly increased the risk of mammary adenocarcinomas in the offspring (OR = 2.1, 95% CI 1.2-3.8, P = 0.008 and OR = 1.9, 95% CI 1.1-3.3, P = 0.03, respectively). Maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance (P = 0.002) and increased the multiplicity of mammary adenocarcinomas (P = 0.008) in the offspring. Maternal, but not postweaning, folic acid supplementation significantly reduced global DNA methylation (P = 0.03), whereas postweaning, but not maternal, folic acid supplementation significantly decreased DNA methyltransferase activity (P = 0.05) in nonneoplastic mammary glands of the offspring. Our findings suggest that a high intrauterine and postweaning dietary exposure to folic acid may increase the risk of mammary tumors in the offspring. Further, they suggest that this tumor-promoting effect may be mediated in part by altered DNA methylation and DNMT activity.     

Special Scientific Session of the International Skeletal Society, San Diego, California, September 2011

Abstracts

Special Scientific Session of the International Skeletal Society, San Diego, California, September 2011     

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

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Gender relations and sexual communication among female students in the Mekong River Delta of Vietnam

Young women's ability to pursue a safer-sex life in line with their wishes is crucial to their sexual health. Although some previous observations have suggested that young women's lack of ability to negotiate safer sex is due to gender power imbalances in the culture of Vietnam, studies that have tested this hypothesis explicitly and quantitatively are few and far between. The present study aimed to test the association between perceived gender relations and perceived self-efficacy in communicating sexual matters among undergraduate female students in the Mekong River Delta of Vietnam. The analysis involved secondary data from 260 subjects from a larger survey regarding gender equity. Structural equation modeling was used to examine the study's hypothesis. Results showed that adherence to traditional gender roles and norms was significantly associated with female students' reduced self-efficacy to communicate on safer-sex matters, such as refusing unwanted sex or requesting condom use. This association remained invariant in the cross-validation process between partnered and unpartnered groups. Programmes that aim to promote safer-sex negotiation and practices for this population may need to address the influence of gender relations and power.     

Both Fidaxomicin and Vancomycin Inhibit Outgrowth of Clostridium difficile Spores

Fidaxomicin (FDX) is approved to treat Clostridium difficile-associated diarrhea and is superior to vancomycin in providing a sustained clinical response (cure without recurrence in the subsequent 25 days). The mechanism(s) behind the low recurrence rate of FDX-treated patients could be multifactorial. Here, we tested effects of FDX, its metabolite OP-1118, and vancomycin on spore germination and determined that none affected the initiation of spore germination but all inhibited outgrowth of vegetative cells from germinated spores.