Probing Covalent Interactions at a Silicone Adhesive/Nylon Interface.

Covalent bonding is one of the most robust forms of intramolecular interaction between adhesives and substrates. In contrast to most noncovalent interactions, covalent bonds can significantly enhance both the interfacial strength and durability. To utilize the advantages of covalent bonding, specific chemical reactions are designed to occur at interfaces. However, interfacial reactions are difficult to probe in situ, particularly at the buried interfaces found in well-bonded adhesive joints. In this work, sum frequency generational (SFG) vibrational spectroscopy was used to directly examine and analyze the interfacial chemical reactions and related molecular changes at buried nylon/silicone elastomer interfaces. For self-priming elastomeric silicone adhesives, silane coupling agents have been extensively used as adhesion promoters. Here with SFG, the interfacial chemical reactions between nylon and two alkoxysilane adhesion promoters with varied functionalities (maleic anhydride (MAH) and epoxy) formulated into the silicone were observed and investigated. Evidence of reactions between the organofunctional group of each silane and reactive groups on the polyamide was found at the buried interface between the cured silicone elastomer and nylon. The adhesion strength at the nylon/cured silicone interfaces was substantially enhanced with both silane additives. SFG results elucidated the mechanisms of organo-silane adhesion promotion for silicone at the molecular level. The ability to probe and analyze detailed interfacial reactions at buried nylon/silicone interfaces demonstrated that SFG is a powerful analytical technique to aid the design and optimization of materials with desired interfacial properties.

Collective Rayleigh-Plateau Instability: A Mimic of Droplet Breakup in High Internal Phase Emulsion.

Using a microfluidic multi-inlet coflow system, we show the Rayleigh-Plateau instability of adjacent, closely spaced fluid threads to be collective. Although droplet size distributions and breakup frequencies are unaffected by cooperativity when fluid threads are identical, breakup frequencies and wavelengths between mismatched fluid threads become locked due to this collective instability. Locking narrows the size distribution of drops that are produced from dissimilar threads, and thus the polydispersity of the emulsion. These observations motivate a hypothesized two-step mechanism for high internal phase emulsification, wherein coarse emulsion drops are elongated into close-packed fluid threads, which break into smaller droplets via a collective Rayleigh Plateau instability. Our results suggest that these elongated fluid threads break cooperatively, whereupon wavelength-locking reduces the ultimate droplet polydispersity of high-internal phase emulsions, consistent with experimental observations.

The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

PURPOSE: Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. METHODS: Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). RESULTS: Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. CONCLUSIONS: Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

Inhibition by erlotinib of primary lung adenocarcinoma at an early stage in male mice.

PURPOSE: Erlotinib, a small molecule inhibitor of the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR), increases survival of advanced non-small cell lung cancer patients who failed standard chemotherapy (Phase III study). We evaluated whether erlotinib is also effective at an early stage of primary lung tumorigenesis in a carcinogen-induced lung tumor model in mice. METHODS: Sixteen weeks after carcinogen (urethane) injection, when small self-contained adenomas are evident, male and female A/J mice were treated IP with 10 mg/kg erlotinib or Captisol vehicle daily over 3.5 weeks (15 mice per group). The efficacy, metabolism and mechanism of action of erlotinib were evaluated. RESULTS: Erlotinib reduced tumor burden in males by twofold compared to vehicle (12.7 +/- 1.2 vs 26.2 +/- 2.5 mg, respectively; p < 0.0001), while tumor burden in erlotinib-treated females slightly increased compared to vehicle by 21% (15.1 +/- 1.2 vs 11.9 +/- 0.9 mg, respectively; p < 0.05). Tumor multiplicity, in contrast, was unaffected by erlotinib. The levels of erlotinib that accumulated in plasma, lung tumor tissue and adjacent uninvolved (UI) lung were comparable in males and females. Males, however, accumulated more OSI-420, an active and pharmacologically equipotent metabolite of erlotinib, than females in plasma, lung tumors, and UI lung. In both genders, 80% of tumors contained Kras mutations at codon 61, but no EGFR mutations were detected. The cellular distribution and concentration of EGFR were also similar between genders. In control mice, however, phosphorylated EGFR (pEGFR) levels were nearly 2.5-fold higher in males compared to females in UI lungs and sevenfold higher in lung tumors. Further, erlotinib decreased the contents of pEGFR in UI lungs and lung tumors, particularly in males. CONCLUSIONS: Adenomas from male mice in this early lung cancer model are responsive to erlotinib treatment, possibly because of a greater dependence of male tumor growth on the EGFR pathway compared to females. Importantly, these results indicate that small lung adenomas from male mice that utilize EGFR signaling but also harbor Kras mutations shrink in response to erlotinib, suggesting that erlotinib may be beneficial for some patients very early during lung cancer progression.

A phase II trial of erlotinib monotherapy in advanced pancreatic cancer as a first- or second-line agent.

INTRODUCTION: Pancreatic adenocarcinoma carries a grim prognosis. In 2007, gemcitabine with erlotinib emerged as an appropriate treatment option for patients with advanced inoperable or metastatic disease (APC). In this phase II trial we sought to evaluate the efficacy of erlotinib monotherapy in patients with APC who had disease refractory to or ineligibility for gemcitabine-based therapy. METHODS: Eligible patients who had received 0 or 1 non-EGFR inhibitor containing gemcitabine-based chemotherapy for APC were recruited prospectively and treated with erlotinib 150 mg orally daily until unacceptable toxicity or disease progression. Primary endpoint was progression-free survival (PFS). Correlations of clinical response with smoking, rash, steady-state concentration of erlotinib and its metabolite (OSI-420) as well as the nicotine metabolite cotinine were performed. RESULTS: The trial was terminated early for futility. Eighteen of the 34 planned subjects were recruited. Median PFS and OS were 42 and 95 days, respectively. Best response was stable disease (21%). There was a trend for improved PFS and OS in never smokers compared to current and past smokers (128.5, 39, 42 days and 173, 100, 88 days, respectively). Past/current smokers had lower steady-state concentrations of erlotinib and OSI-420 compared to never smokers. There was evidence of recent smoking exposure in 30% of patients self-identified as past smokers. Rash was infrequent, with no cases of grade III/IV rash and it was not related to treatment outcomes. CONCLUSIONS: Overall, erlotinib monotherapy failed to improve outcomes compared to historical controls in patients with APC after 0-1 prior systemic therapies. There was a trend for improved PFS and OS in never smokers.

A sampling of factors relative to the epidemiology of gastrointestinal nematode parasites of cattle in the United States.

Gastrointestinal nematodosis of cattle is a parasitic condition resulting from an immense and seemingly forever-expanding array of factors. Countless determinants influence the incidence and severity of the species-specific infections that occur in cattle, determinants that affect the free-living or environmental stages of the parasites and the parasitic stages. The vast majority of animals have a subclinical or economic level of parasitism undetectable to the eye but quantified more accurately by treatment-induced improved performance (e.g., feed efficiency, nitrogen balance, weight gain, milk production). Unfortunately, the results of treatment (effectiveness and improved animal performance) sometimes can be as varied as the parasitisms that are being treated.

Current Status of Parasite Control at the Feed Yard.

Fly and louse infestations are readily discerned and remedied in feedlot cattle. Tapeworm and fluke infections are accepted as probable but, given the lack of anthelmintics with realistic efficacy against these infections, these helminths are allowed to persist without treatment. Nematode infections are considered ubiquitous with cattle coming from pasture and are targeted with a macrocyclic lactone, usually in combination with a benzimidazole. Populations of nematodes seem to be effectively controlled by a combination of anthelmintic treatment, animal resistance and resilience, lack of reinfection, and diet.

A phase IIa randomized, double-blind trial of erlotinib in inhibiting epidermal growth factor receptor signaling in aberrant crypt foci of the colorectum.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use.

Field evaluation of moxidectin/praziquantel oral gel in horses.

The safety and efficacy of 2% moxidectin/12.5% praziquantel oral gel administered at a rate of 0.4 mg moxidectin and 2.5 mg praziquantel/kg was studied in client-owned horses under field use conditions. Four hundred horses (300 treated with moxidectin/praziquantel oral gel and 100 treated with vehicle) were enrolled, feces were collected, and eggs were counted. Investigators as well as horse owners were masked to treatment assignment. No adverse reactions to treatment were observed in any horses. Moxidectin/praziquantel gel reduced Anoplocephala spp by more than 99% and provided a significant (P <.05) reduction (> 98%) in the strongyle egg count of treated horses.

Using BCMA software to improve patient safety in Veterans Administration Medical Centers.

Bar Code Medication Administration (BCMA) software, as developed by the Veterans Health Administration, is an innovative, automated system that uses wireless, point-of-care technology with an integrated bar code scanner. The system can dramatically reduce medication administration errors by letting clinicians verify a patient's identity and validate medications against active orders.

Pickering-Emulsion-Templated Encapsulation of a Hydrophilic Amine and Its Enhanced Stability Using Poly(allyl amine).

Efficient encapsulation of tetraethylenepentamine (TEPA), as an example aliphatic amine, was achieved by an emulsion-templated, in situ polymerization. Hydrophobically modified clay nanoplatelets were employed as emulsifiers to obtain water-in-oil (W/O) dispersions followed by interfacial polymerization between a portion of the TEPA cargo and polymethylene polyphenylene isocyanate (PMPPI). The resultant capsules exhibit spherical shape, desirable thermal stability, modest barrier properties, and shear-induced release in an epoxide monomer mixture. Most importantly, a significant gain in capsule barrier properties was realized by introducing poly(allyl amine) (pAAm) as an interface-selective reactive additive in the Pickering emulsions. In addition to the fundamental interest of pAAm localization and interface-selective reactivity, this microencapsulation system for aliphatic amines has technological potential in coating, self-healing, and drug-delivery applications.

HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation.

Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

Effect of intermittent dosing regimens of erlotinib on methylnitrosourea-induced mammary carcinogenesis.

EGF receptor (EGFR) inhibitors are used in the therapy of lung and pancreatic cancers and effectively prevent cancers in multiple animal models. Although daily dosing with erlotinib is effective, weekly dosing may reduce toxicity and have advantages, particularly for prevention. We tested alternative dosing regimens for preventive/therapeutic efficacy in a rat mammary cancer model. For prevention, erlotinib was administered by gavage beginning 5 days after methylnitrosourea (MNU). For therapy and biomarker studies, rats with palpable mammary cancers were treated for six weeks or for six days, respectively. Experiment A, erlotinib (6 mg/kg body weight/day, intragastric): daily (7 times/week); one day on/one day off; and two days on/two days off. All regimens decreased tumor incidence, increased tumor latency, and decreased cancer multiplicity versus controls (P < 0.01). However, intermittent dosing was less effective than daily dosing (P < 0.05). Experiment B, erlotinib (6 mg/kg body weight/day) daily or two days on/two days off or one time per week at 42 mg/kg body weight. All regimens reduced cancer incidence and multiplicity versus controls (P < 0.01). Interestingly, daily and weekly dosing were equally effective (P > 0.5). Experiment C, erlotinib administered at 42 or 21 mg/kg body weight 1 time per week, decreased tumor incidence and multiplicity (P < 0.01). Erlotinib had a serum half-life of ≤ 8 hours and weekly treatment yielded effective serum levels for ≤ 48 hours. Daily or weekly treatment of cancer bearing rats reduced mammary tumor size 25% to 35%, whereas control cancers increased >250%. Levels of phosphorylated extracellular signal-regulated kinase (ERK) were strongly decreased in rats treated daily/weekly with erlotinib. Thus, altering the dose of erlotinib retained most of its preventive and therapeutic efficacy, and based on prior clinical studies, is likely to reduce its toxicity.

Phase IIA trial testing erlotinib as an intervention against intraductal pancreatic mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMN) are a distinct type of precursor lesions that cause about 5% of pancreatic adenocarcinoma (1, 2). Four-year survival rates of 40% to 75% are reported (3-7). There is currently no chemotherapy specifically approved for treating IPMNs. The number of IPMN cases has significantly increased over the last decade (8).

Quality-monitoring program for bar-code-assisted medication administration.

PURPOSE: The implementation of a quality-monitoring program that identifies and corrects problems associated with using a bar-code-assisted medication administration (BCMA) system is described. SUMMARY: In November 2004, the Bar Code Resource Office assembled a work group to develop a quality program to improve machine-readable, bar-coded medications. The project scope involved the development of a pharmacy-based quality program for unit-dose packaging and bar-code labeling to improve the scanning success rate of bar-coded medications at the point-of-care. Data were collected from facility-based BCMA coordinators at each medical center regarding specific reasons for bedside scanning circumvention, as well as successful scan rates in the pharmacy and at the bedside. The pharmacy and bedside scanning data were aggregated and the baseline of successful scans was determined to be 95%. The reported reasons for scanning circumvention were grouped into six categories: bar-code labeling, missing doses, labels not scanning, error messages, mispackaged medications, and mislabeled medications. The work group developed strategies to mitigate problems in each of the areas. As a result of this effort, the Department of Veterans Affairs created a directive that outlined the best practices for unit-dose packaging and labeling, as well as requirements for ongoing data collection and reporting. CONCLUSION: A quality-monitoring program that identified and provided best-practice recommendations corrected problems associated with using a BCMA system and improved bar-code labeling processes.