Cherry Valley, IL, United States
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A system and method for facilitating the maintenance of an industrial heat treating furnace are disclosed.


Atienzar F.A.,UCB BioPharma SPRL | Blomme E.A.,AbbVie | Chen M.,U.S. Food and Drug Administration | Hewitt P.,Merck KGaA | And 10 more authors.
BioMed Research International | Year: 2016

Drug-induced liver injury (Dili) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in Dili prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic Dili has improved, identifying compounds with a risk for idiosyncratic Dili (iDili) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical Dili models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed. © 2016 Franck A. Atienzar et al.


PubMed | National Institute of Clinical Neurosciences, Medical University of Warsaw, Albert Ludwigs University of Freiburg, Innsbruck Medical University and 11 more.
Type: Journal Article | Journal: Movement disorders : official journal of the Movement Disorder Society | Year: 2016

Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA.The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia.This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N=369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores.At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P<.0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events.Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. 2016 International Parkinson and Movement Disorder Society.


Wu J.,University of Pennsylvania | Ruiz-Rodriguez J.,ETH Zurich | Comstock J.M.,Ipsen Inc. | Dong J.Z.,Ipsen Inc. | Bode J.W.,ETH Zurich
Chemical Science | Year: 2011

The synthesis of the bioactive form of human glucagon-like peptide, GLP-1 (7-36), by the chemoselective ligation of two unprotected fragments, a C-terminal peptide α-ketoacid with an N-terminal peptide hydroxylamine, is reported. No reagents are required for the ligation and no byproducts are produced. Unprotected glutamic acid, histidine, arginine, lysine, serine, and tyrosine residues do not interfere with the ligation; no side products arising from undesired reactions of the side chains are detected. This synthesis is the first reported example of the application of the α-ketoacid-hydroxylamine amide ligation to the synthesis of a complex, unprotected peptide. Its success underscores the potential broad utility of this amide ligation for the synthesis of complex peptides and related targets. © The Royal Society of Chemistry 2011.


Natale J.J.,5150 Center Avenue | Spinelli T.,Helsinn Healthcare SA | Calcagnile S.,Helsinn Healthcare SA | Lanzarotti C.,Helsinn Healthcare SA | And 3 more authors.
Journal of Oncology Pharmacy Practice | Year: 2015

Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU) - a new NK1 RA - and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug-drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates. © The Author(s) 2015.


PubMed | Saint Antoine Hospital, Ipsen, Paris-Sorbonne University and Ipsen Inc.
Type: Journal Article | Journal: Histopathology | Year: 2016

To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC).Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with real-time polymerase chain reaction (PCR) and manual and automated immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues. SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3 and SSTR5 transcripts were expressed in ~25% of HCCs, but not in adjacent non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and 32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected. Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority of HCCs and adjacent non-tumour liver tissues, but membrane staining was <20% of that in HCCs. The results obtained with the two IHC methods were highly correlated (P < 0.0001). Statistical analyses also showed a positive correlation between SSTR2 membrane staining and cytokeratin 19 expression (P = 0.04), serum -fetoprotein level (P = 0.002), and poor differentiation (P = 0.05).Membrane SSTR2 is detected reliably in HCCs by IHC, and is a potential therapeutic target, as it is coexpressed with markers of poor prognosis.


Mordin M.,RTI Health Solutions | Masaquel C.,RTI Health Solutions | Abbott C.,Ipsen Inc. | Copley-Merriman C.,RTI Health Solutions
BMJ open | Year: 2014

OBJECTIVE: To describe the health-related quality of life (HRQOL) burden of cervical dystonia (CD) and report on the HRQOL and patient perception of treatment benefits of abobotulinumtoxinA (Dysport).DESIGN: The safety and efficacy of a single injection of abobotulinumtoxinA for CD treatment were evaluated in a previously reported international, multicenter, double-blind, randomised trial. HRQOL measures were assessed in the trial and have not been previously reported.SETTING: Movement disorder clinics in the USA and Russia.PARTICIPANTS: Patients had to have a diagnosis of CD with symptoms for at least 18 months, as well as a total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score of at least 30; a Severity domain score of at least 15; and a Disability domain score of at least 3. Key exclusion criteria included treatment with botulinum toxin type A (BoNT-A) or botulinum toxin type B (BoNT-B) within 16 weeks of enrolment.INTERVENTIONS: Patients were randomised to receive either 500 U abobotulinumtoxinA (n=55) or placebo (n=61).PRIMARY AND SECONDARY OUTCOME MEASURES: Efficacy assessments included TWSTRS total (primary end point) and subscale scores at weeks 0, 4, 8, 12; a pain visual analogue scale at weeks 0 and 4; and HRQOL assessed by the SF-36 Health Survey (SF-36; secondary end point) at weeks 0 and 8.RESULTS: Patients with CD reported significantly greater impairment for all SF-36 domains relative to US norms. Patients treated with abobotulinumtoxinA reported significantly greater improvements in Physical Functioning, Role Physical, Bodily Pain, General Health and Role Emotional domains than placebo patients (p≤0.03 for all). The TWSTRS was significantly correlated with Physical Functioning, Role Physical and Bodily Pain scores, for those on active treatment.CONCLUSIONS: CD has a marked impact on HRQOL. Treatment with a single abobotulinumtoxinA injection results in significant improvement in patients' HRQOL.TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov, numbers NCT00257660 and NCT00288509. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.


To describe the health-related quality of life (HRQOL) burden of cervical dystonia (CD) and report on the HRQOL and patient perception of treatment benefits of abobotulinumtoxinA (Dysport).The safety and efficacy of a single injection of abobotulinumtoxinA for CD treatment were evaluated in a previously reported international, multicenter, double-blind, randomised trial. HRQOL measures were assessed in the trial and have not been previously reported.Movement disorder clinics in the USA and Russia.Patients had to have a diagnosis of CD with symptoms for at least 18months, as well as a total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score of at least 30; a Severity domain score of at least 15; and a Disability domain score of at least 3. Key exclusion criteria included treatment with botulinum toxin type A (BoNT-A) or botulinum toxin type B (BoNT-B) within 16weeks of enrolment.Patients were randomised to receive either 500 U abobotulinumtoxinA (n=55) or placebo (n=61).Efficacy assessments included TWSTRS total (primary end point) and subscale scores at weeks 0, 4, 8, 12; a pain visual analogue scale at weeks 0 and 4; and HRQOL assessed by the SF-36 Health Survey (SF-36; secondary end point) at weeks 0 and 8.Patients with CD reported significantly greater impairment for all SF-36 domains relative to US norms. Patients treated with abobotulinumtoxinA reported significantly greater improvements in Physical Functioning, Role Physical, Bodily Pain, General Health and Role Emotional domains than placebo patients (p0.03 for all). The TWSTRS was significantly correlated with Physical Functioning, Role Physical and Bodily Pain scores, for those on active treatment.CD has a marked impact on HRQOL. Treatment with a single abobotulinumtoxinA injection results in significant improvement in patients HRQOL.The trial is registered at ClinicalTrials.gov, numbers NCT00257660 and NCT00288509.


The article examines why defining gas quenching in bar pressure no longer applies, why a new definition is needed, and how this definition enables a better understanding of which steel and what cross section can be hardened via gas quenching. The result is a totally nonuniform heat transfer rate on various surfaces of different parts, which depends on a number of variables and factors. This uneven transitory step creates huge temperature differentials, and is the major factor in distortion when quenching in these media. Gas quenching is a pure, convective type single-phase quench. Gas species, pressure, and velocity are the main controlling factors. A procedure developed by Ipsen to predict the hardness and structure after gas quenching makes use of the necessary cooling rate in the temperature region of the pearlite and ferrite formation.

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