Utility of Gastric-Retained Alginate Gels to Modulate Pharmacokinetic Profiles in Rats

A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague–Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting.     

The effects of liver impairment on the pharmacokinetics of brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases

Purpose

Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.

Methods

Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses).

Results

Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration–time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history.

Conclusions

Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.     

Ovarian Cancer: Deaf and Hearing Women’s Knowledge Before and After an Educational Video

Members of the Deaf community report language and cultural barriers to accessing health information and care. This study evaluated whether an ovarian cancer education video in American Sign Language with English captioning and voice-over could close the anticipated knowledge gap between Deaf and hearing women’s cancer knowledge. Consented Deaf (n?=?55) and hearing (n?=?52) women’s General, Ovarian, and Total Cancer Knowledge were assessed before and after viewing the video. At baseline, hearing women demonstrated significantly higher General, Ovarian, and Total Cancer Knowledge scores than Deaf women. By the post-test, all of Deaf women’s knowledge scores had increased, closing the baseline gap. However, hearing women’s post-video knowledge had also increased, thereby creating a new knowledge gap. The ovarian cancer education video offers an effective method to increase ovarian and general cancer knowledge for Deaf and hearing women.     

Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate

Given that 1.3 million new cases of breast cancer are universally registered among women and approximately 36 % of the patients die annually, the revelation of new predictive markers for treatment efficiency is of vital importance. Recently, our group has depicted that KLK4, KLK5, and KLK14 are differentially expressed in breast carcinoma. The objective of this study was to determine and investigate the expression pattern of the KLK4, KLK5, and KLK14 genes in breast cancer cells after treatment with established chemotherapeutic agents. We evaluated these genes’ expression after treatment of the BT-20 cells with epirubicin, docetaxel and methotrexate, determining their cytotoxic effect by MTT and trypan blue assays. The relative quantification of genes’ mRNA levels was performed by using the SYBR Green® chemistry, and the HPRT1 served as an endogenous control gene. The drugs triggered apoptosis in treated cells and induced deregulations in the expression of the above KLKs. The most significant alterations were a 12-fold and tenfold increase of KLK5 in docetaxel and methotrexate-treated cells, respectively, while the KLK4 levels decreased by ten-fold in epirubicin, five-fold in docetaxel and twenty-fold in methotrexate treated-cells, compared to the untreated ones. In the case of KLK14 levels, a twofold increase in epirubicin and threefold decrease in methotrexate-treated cells were observed. Present significant alterations in the expression pattern of KLK4, KLK5, and KLK14 could comprise an initial stage for predicting chemotherapy response in breast cancer and should be further investigated as predictive markers in the future.     

Malrotation of the intestine and chronic volvulus as a cause of protein-losing enteropathy in infancy

Protein-losing enteropathy in children is caused by intestinal metabolic, inflammatory, or infectious processes, or by lymphatic obstruction (intestinal lymphangiectasia). In this report, a 17-month-old child is presented with protein-losing enteropathy due to intestinal malrotation and chronic midgut volvulus causing lymphatic obstruction and spillage of lymph in the intestine and the peritoneum. This report should alert the pediatrician that intestinal malrotation should be added to the wide list of possible causes of protein-losing enteropathy in children.     

Imported Klebsiella pneumoniae carbapenemase-producing K. pneumoniae clones in a Greek hospital: impact of infection control measures for restraining their dissemination

The recent emergence of carbapenemase-producing Enterobacteriaceae strains represents a major threat for hospitalized patients. We document the dissemination and control of carbapenemase-producing Klebsiella pneumoniae clones in a Greek hospital. During a 3-year study period (January 2009 to December 2011), carbapenemase-producing K. pneumoniae strains were isolated from clinical samples from 73 individual patients. Phenotyping and molecular testing confirmed that 52 patients were infected with K. pneumoniae carbapenemase 2 (KPC-2) producers, 12 were infected with VIM-1 producers, and the remaining 9 were infected with isolates producing both KPC-2 and VIM-1 enzymes. Twenty-eight of these clinical cases were characterized as imported health care associated, and 23 of these were attributed to KPC producers and 5 were attributed to KPC and VIM producers. The remaining 45 cases were deemed hospital acquired. In the second year of the study, intensified infection control intervention was implemented, followed by active surveillance and carrier isolation in the third year. The incidence of carbapenemase-producing K. pneumoniae patient cases decreased from 0.52/1,000 patient days in 2009 to 0.32/1,000 patient days in 2010 (P = 0.075). Following these additional infection control measures, the incidence fell to 0.21/1,000 patient days in 2011 and differed significantly from that in 2009 (P = 0.0028). Despite the fact that the imported cases of carbapenemase-producing K. pneumoniae were equally distributed over this 3-year period, the incidence of hospital-acquired cases decreased from 0.36/1,000 patient days in 2009 to 0.19/1,000 patient days in 2010 (P = 0.058) and to 0.1/1,000 patient days in 2011 (P = 0.0012). Our findings suggest that rigorous infection control measures and active surveillance can effectively reduce the incidence of secondary transmission due to KPC-producing pathogens.     

Functional effects of genetic polymorphism in inflammatory genes in subjective memory complainers

A number of genetic risk factors have been identified for Alzheimer's disease (AD) including genes involved in the inflammatory response (interleukin 1A, [IL-1α (-889)], interleukin 1B (IL-1β [+3953]), and tumor necrosis factor (TNF [-308 and -850]). We investigated the prevalence and functional consequences (baseline cognitive performance, plasma cytokine levels) of possession of these putative genetic risk factors within a group of subjective memory complainers (SMC, n = 226) and age and sex matched noncomplainers (NMC, n = 167). We observed no effect of any of the genetic factors investigated on cognitive performance. Further, there was no difference in the frequency of the disease-associated alleles, or cytokine levels between subjective memory complainers and noncomplainer participants. There was no relationship between TNF polymorphisms and TNF levels. There was a significant increase in plasma IL-1β levels in those homozygous for the disease-associated allele (i.e., IL-1β +3953 TT). Follow-up longitudinal assessments on this cohort will provide insight as to how these polymorphisms may affect the risk of cognitive decline over time.     

FGF-1 and proteolytically mediated cleavage site presentation influence three-dimensional fibroblast invasion in biomimetic PEGDA hydrogels

Controlled scaffold degradation is a critical design criterion for the clinical success of tissue-engineered constructs. Here, we exploited a biomimetic poly(ethylene glycol) diacrylate (PEGDA) hydrogel system immobilized with tethered YRGDS as the cell adhesion ligand and with either single (SSite) or multiple (MSite) collagenase-sensitive domains between crosslinks, to systematically study the effect of proteolytic cleavage site presentation on hydrogel degradation rate and three-dimensional (3-D) fibroblast invasion in vitro. Through the incorporation of multiple collagenase-sensitive domains between cross-links, hydrogel degradation rate was controlled and enhanced independent of alterations in compressive modulus. As compared to SSite hydrogels, MSite hydrogels resulted in increased 3-D fibroblast invasion in vitro, which occurred over a wider range of compressive moduli. Furthermore, encapsulated soluble acidic fibroblast growth factor (FGF-1), a potent mitogen during processes such as vascularization and wound healing, was incorporated into SSite and MSite PEGDA scaffolds to determine its in vitro potential on fibroblast cell invasion. Hydrogels containing soluble FGF-1 significantly enhanced 3-D fibroblast invasion in a dose-dependent manner within the different types of PEG matrices investigated over a period of 15 days. The methodology presented provides flexibility in designing PEG scaffolds with desired mechanical properties, but with increased susceptibility to proteolytically mediated degradation. These results indicate that effective tuning of initial matrix stiffness and hydrogel degradation kinetics plays a critical role in effectively designing PEG scaffolds that promote controlled 3-D cellular behavior and in situ tissue regeneration.