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1.  Mimicking the Impact of Infant Tongue Peristalsis on Behavior of Solid Oral Dosage Forms Administered During Breastfeeding 
Journal of Pharmaceutical Sciences  2017;106(1):193-199.
An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.
doi:10.1016/j.xphs.2016.08.006
PMCID: PMC5157687  PMID: 27686681
in vitro models; oral drug delivery; pediatric; physical characterization; drug delivery systems; API, active pharmaceutical ingredient; NSDS, nipple shield delivery system; PEEK, polyetheretherketone; SB, sulforhodamine B; TM, tongue mimic; TMS, tongue mimic system
2.  Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability 
The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1α endonuclease activity that bound to the kinase site on the enzyme. Structure–activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.
doi:10.1021/ml500315b
PMCID: PMC4291719  PMID: 25589933
Unfolded protein response; IRE1α; kinase; inhibitor
3.  Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody 
Molecular cancer therapeutics  2010;9(10):2641-2651.
AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings. Mol Cancer Ther; 9(10); 2641–51.
doi:10.1158/1535-7163.MCT-10-0213
PMCID: PMC4430860  PMID: 20937592
4.  AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues 
Background
The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and –B expression and kinase activity is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models.
Methods
In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours.
Results
Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ≤0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues.
Conclusion
Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0307-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0307-x
PMCID: PMC4221688  PMID: 25367255
Histone H3; Mitosis; Pharmacodynamics; Cytometry; Tumor biopsies
5.  IGF1R blockade with ganitumab results in systemic effects on the GH–IGF axis in mice 
The Journal of endocrinology  2014;221(1):145-155.
Ganitumab is a fully human MAB to the human type 1 IGF receptor (IGF1R). Binding assays showed that ganitumab recognized murine IGF1R with sub-nanomolar affinity (KD=0.22 nM) and inhibited the interaction of murine IGF1R with IGF1 and IGF2. Ganitumab inhibited IGF1-induced activation of IGF1R in murine lungs and CT26 murine colon carcinoma cells and tumors. Addition of ganitumab to 5-fluorouracil resulted in enhanced inhibition of tumor growth in the CT26 model. Pharmacological intervention with ganitumab in naïve nude mice resulted in a number of physiological changes described previously in animals with targeted deletions of Igf1 and Igf1r, including inhibition of weight gain, reduced glucose tolerance and significant increase in serum levels of GH, IGF1 and IGFBP3. Flow cytometric analysis identified GR1/CD11b-positive cells as the highest IGF1R-expressing cells in murine peripheral blood. Administration of ganitumab led to a dose-dependent, reversible decrease in the number of peripheral neutrophils with no effect on erythrocytes or platelets. These findings indicate that acute IGF availability for its receptor plays a critical role in physiological growth, glucose metabolism and neutrophil physiology and support the presence of a pituitary IGF1R-driven negative feedback loop that tightly regulates serum IGF1 levels through Gh signaling.
doi:10.1530/JOE-13-0306
PMCID: PMC4160154  PMID: 24492468
ganitumab; GF1R; IGFBP3; receptor pituitary; human; murine
6.  Detection of soft tissue foreign bodies by nurse practitioner-performed ultrasound 
Background
This study aimed to evaluate the accuracy of emergency nurse practitioner (NP)-performed point-of-care ultrasound (POCUS) for the detection of soft tissue foreign bodies (FBs).
Methods
Following a 2-h training session, ten NPs were assessed on their ability to detect various FBs in an experimental model. FBs (wood, metal and plastic) were inserted randomly into eight experimental models (uncooked chicken thighs) by an independent observer. Control experimental models had no FB inserted, but all had a 1-cm incision made on their surface. NPs, blinded to the type of model, were then assessed on their ability to detect the FBs by ultrasound examination using high-frequency linear transducers (Toshiba Nemio). Models were also scanned by two experienced emergency physicians (EPs) as a further control.
Results
Overall, NP-performed POCUS detected 47 of the 60 foreign bodies with a sensitivity, specificity, positive predictive value and negative predictive value of 78.3%, 50%, 82% and 43%, respectively, compared with 83.3%, 75%, 90.9% and 60% for EPs. Sensitivity for detecting specific types of FB was 95%, 85% and 50% for wood, metal and plastic, respectively, for NP-performed POCUS, compared with 100%, 100% and 50% in the EP group.
Conclusions
NPs with no previous ultrasound experience can detect soft tissue FBs with accuracy comparable to that of EPs in an experimental model. Test sensitivity was high for wood and metal foreign bodies. Specificity was generally low.
doi:10.1186/2036-7902-6-2
PMCID: PMC3922659  PMID: 24476553
Nurse practitioners; Point-of-care ultrasound; Wound care; Foreign bodies; Diagnosis
7.  Epitope-Specific Mechanisms of IGF1R Inhibition by Ganitumab 
PLoS ONE  2013;8(2):e55135.
Background
Therapeutic antibodies targeting the IGF1R have shown diverse efficacy and safety signals in oncology clinical trials. The success of these agents as future human therapeutics depends on understanding the specific mechanisms by which these antibodies target IGF1R signaling.
Methodology/Principal Findings
A panel of well-characterized assays was used to investigate the mechanisms by which ganitumab, a fully human anti-IGF1R antibody undergoing clinical testing, inhibits IGF1R activity. Epitope mapping using IGF1R subdomains localized the ganitumab binding site to the L2 domain. Binding of ganitumab inhibited the high-affinity interaction of IGF-1 and IGF-2 required to activate IGF1R in cells engineered for IGF1R hypersensitivity and in human cancer cell lines, resulting in complete blockade of ligand-induced cellular proliferation. Inhibition of IGF1R activity by ganitumab did not depend on endosomal sequestration, since efficient ligand blockade was obtained without evidence of receptor internalization and degradation. Clinically relevant concentrations of ganitumab also inhibited the activation of hybrid receptors by IGF-1 and IGF-2. Ganitumab was not an agonist of homodimeric IGF1R or hybrid receptors in MCF-7 and COLO 205 cells, but low-level IGF1R activation was detected in cells engineered for IGF1R hypersensitivity. This activation seems biologically irrelevant since ganitumab completely inhibited ligand-driven proliferation. The in vivo efficacy profile of ganitumab was equivalent or better than CR and FnIII-1 domain-specific antibodies, alone or in combination with irinotecan. CR domain-specific antibodies only blocked IGF-1 binding to IGF1R but were more potent than ganitumab at inducing homodimer and hybrid receptor downregulation in vitro, however this difference was less obvious in vivo. No inhibition of hybrid receptors was observed with the FnIII-1 domain antibodies, which were relatively strong homodimer and hybrid agonists.
Conclusions/Significance
The safety and efficacy profile of ganitumab and other anti-IGF1R antibodies may be explained by the distinct molecular mechanisms by which they inhibit receptor signaling.
doi:10.1371/journal.pone.0055135
PMCID: PMC3562316  PMID: 23383308
8.  The WISTAH hand study: A prospective cohort study of distal upper extremity musculoskeletal disorders 
Background
Few prospective cohort studies of distal upper extremity musculoskeletal disorders have been performed. Past studies have provided somewhat conflicting evidence for occupational risk factors and have largely reported data without adjustments for many personal and psychosocial factors.
Methods/design
A multi-center prospective cohort study was incepted to quantify risk factors for distal upper extremity musculoskeletal disorders and potentially develop improved methods for analyzing jobs. Disorders to analyze included carpal tunnel syndrome, lateral epicondylalgia, medial epicondylalgia, trigger digit, deQuervain’s stenosing tenosynovitis and other tendinoses. Workers have thus far been enrolled from 17 different employment settings in 3 diverse US states and performed widely varying work. At baseline, workers undergo laptop administered questionnaires, structured interviews, two standardized physical examinations and nerve conduction studies to ascertain demographic, medical history, psychosocial factors and current musculoskeletal disorders. All workers’ jobs are individually measured for physical factors and are videotaped. Workers are followed monthly for the development of musculoskeletal disorders. Repeat nerve conduction studies are performed for those with symptoms of tingling and numbness in the prior six months. Changes in jobs necessitate re-measure and re-videotaping of job physical factors. Case definitions have been established. Point prevalence of carpal tunnel syndrome is a combination of paraesthesias in at least two median nerve-served digits plus an abnormal nerve conduction study at baseline. The lifetime cumulative incidence of carpal tunnel syndrome will also include those with a past history of carpal tunnel syndrome. Incident cases will exclude those with either a past history or prevalent cases at baseline. Statistical methods planned include survival analyses and logistic regression.
Discussion
A prospective cohort study of distal upper extremity musculoskeletal disorders is underway and has successfully enrolled over 1,000 workers to date.
doi:10.1186/1471-2474-13-90
PMCID: PMC3476983  PMID: 22672216
Epidemiology; Ergonomics; Cohort; Carpal tunnel syndrome; Strain index; TLV for HAL

Results 1-8 (8)