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Martin K.J.,Saint Louis University | Pickthorn K.,Amgen | Huang S.,Amgen | Block G.A.,Denver CO | And 5 more authors.
Kidney International | Year: 2014

AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, lowers plasma parathyroid hormone in preclinical uremic animal models and in normal healthy individuals. Here, we studied its efficacy in hemodialysis patients suffering from secondary hyperparathyroidism. Major inclusion criteria were hemodialysis for at least 3 months, serum parathyroid hormone over 300 pg/ml, a corrected serum calcium of 9.0 mg/dl or more, and stable doses of vitamin D analogs for at least 3 weeks prior to screening. Twenty-eight patients were enrolled in one of five cohorts (5, 10, 20, 40, 60 mg). Cohorts 1-3 (four patients each) were treated in a two-period crossover design, while cohorts 4 and 5 (eight patients each) were randomized 1:1 to AMG 416 or placebo. Patients were admitted to a clinical research unit following hemodialysis and studied for 3 days prior to discharge for hemodialysis. Single intravenous doses of AMG 416 from 5 to 60 mg were well tolerated, and plasma levels increased in a dose-related manner. AMG 416 treatment was associated with significant, dose-dependent reductions in serum parathyroid hormone and fibroblast growth factor 23. Compared with placebo, all dose groups of 10 mg or more were associated with attenuation in the rise in serum phosphate during the interdialytic period. Dose-dependent reductions in serum calcium were observed and were well tolerated. Thus, AMG 416 represents a novel therapeutic approach for the treatment of secondary hyperparathyroidism in hemodialysis patients © 2013 International Society of Nephrology.


WILMINGTON, Mass.--(BUSINESS WIRE)--Charles River Laboratories International, Inc. (NYSE: CRL) today reported its results for the fourth-quarter and full-year 2016 and provided guidance for 2017. For the quarter, revenue from continuing operations was $466.8 million, an increase of 31.9% from $353.9 million in the fourth quarter of 2015. Revenue growth was driven primarily by the Discovery and Safety Assessment and Manufacturing Support segments. Research Models and Services revenue also increased. The acquisitions of WIL Research, Agilux Laboratories, Blue Stream Laboratories, and Oncotest contributed 20.9% to consolidated fourth-quarter revenue growth, both on a reported basis and in constant currency. The addition of a 53rd week at the end of 2016, which is periodically required to align to a December 31st calendar year end, contributed approximately 5.1% to reported fourth-quarter revenue growth. The impact of foreign currency translation reduced reported revenue growth by 2.4%. Excluding the effect of these items, organic revenue growth was 8.3%. On a GAAP basis, net income from continuing operations attributable to common shareholders was $44.7 million for the fourth quarter of 2016, an increase of 36.4% from $32.8 million for the same period in 2015. Fourth-quarter diluted earnings per share on a GAAP basis were $0.93, an increase of 34.8% from $0.69 for the fourth quarter of 2015. On a non-GAAP basis, net income from continuing operations was $58.3 million for the fourth quarter of 2016, an increase of 23.3% from $47.3 million for the same period in 2015. Fourth-quarter diluted earnings per share on a non-GAAP basis were $1.21, an increase of 21.0% from $1.00 per share for the fourth quarter of 2015. Both the GAAP and non-GAAP earnings per share increases were driven primarily by the acquisition of new businesses, notably WIL Research, as well as higher revenue for legacy operations. A gain from the Company’s venture capital investments contributed $0.02 per share in the fourth quarter of 2016, compared to a negligible impact for the same period in 2015. James C. Foster, Chairman, President and Chief Executive Officer, said, “Our fourth-quarter results provided a strong finish to an exceptional year in which we met our long-term revenue goals for all of our businesses except Discovery, and our long-term operating margin targets for the three business segments. We were very pleased that three of our businesses, Safety Assessment, Microbial Solutions, and Biologics Testing Solutions, reported low-double-digit organic revenue growth for the full year. Client demand for our unique portfolio of essential products and services remained strong across each of our client segments, particularly for our biotechnology clients, who were the primary driver of our revenue growth in 2016.” “Our continued investments to broaden our early-stage portfolio, the scientific expertise of our staff, our focus on productivity and efficiency initiatives, and our ability to offer flexible partnership structures are the primary reasons that we are the partner of choice for many of our clients. Based on our view of the opportunities in 2017, we believe we will again deliver high single-digit organic revenue growth and earnings per share growth at a faster rate than revenue,” Mr. Foster concluded. Revenue for the RMS segment was $124.7 million in the fourth quarter of 2016, an increase of 9.5% from $113.8 million in the fourth quarter of 2015. Organic revenue growth was 5.7%. Revenue growth was driven primarily by higher sales of research model services, and sales of research models also increased. In the fourth quarter of 2016, the RMS segment’s GAAP operating margin increased to 26.7% from 24.1% in the fourth quarter of 2015. On a non-GAAP basis, the operating margin increased to 27.3% from 25.4% in the fourth quarter of 2015. Both the GAAP and non-GAAP operating margin increases were due primarily to higher sales volume and the benefit of efficiency initiatives. Revenue from continuing operations for the DSA segment was $241.7 million in the fourth quarter of 2016, an increase of 50.6% from $160.5 million in the fourth quarter of 2015. Growth was driven primarily by the acquisitions of WIL Research, Agilux Laboratories, and Oncotest, which contributed 41.6% to DSA revenue growth. Organic revenue growth was 7.9%. Low-double-digit growth in the legacy Safety Assessment business was partially offset by lower revenue for the legacy Discovery Services business, which declined due primarily to softer demand from global clients for Early Discovery services. Robust demand from biotechnology clients continued to drive revenue growth in the DSA segment. In the fourth quarter of 2016, the DSA segment’s GAAP operating margin declined to 18.1% from 23.1% in the fourth quarter of 2015. The margin decline was due to costs associated with the evaluation and integration of acquisitions, including amortization of intangible assets, as well as the benefit from a tax law change in Quebec in the fourth quarter of 2015. On a non-GAAP basis, the operating margin decreased to 23.8% from 27.1% in the fourth quarter of 2015, due primarily to the tax law change in Quebec, which benefited both the GAAP and non-GAAP DSA operating margin by approximately 230 basis points in the fourth quarter of 2015. The acquisition of WIL reduced the fourth-quarter operating margin by approximately 100 basis points, and foreign exchange benefited the DSA operating margin by approximately 80 basis points due primarily to a weaker British pound. Revenue for the Manufacturing segment was $100.3 million in the fourth quarter of 2016, an increase of 26.2% from $79.5 million in the fourth quarter of 2015. The acquisitions of Blue Stream Laboratories and WIL Research’s contract development and manufacturing (CDMO) services contributed 9.2% to Manufacturing revenue growth in the fourth quarter of 2016. Organic revenue growth was 12.9%, primarily driven by robust growth in the Microbial Solutions and Biologics Testing Solutions businesses. In the fourth quarter of 2016, the Manufacturing segment’s GAAP operating margin increased to 31.0% from 23.7% in the fourth quarter of 2015. The GAAP operating margin increase was primarily driven by lower acquisition costs related to Celsis, as well as leverage from higher revenue in the Microbial Solutions business. On a non-GAAP basis, the operating margin increased to 34.2% from 33.8% in the fourth quarter of 2015, driven by operating margin improvement in the Microbial Solutions business as a result of higher revenue and the benefit of efficiency initiatives. For 2016, revenue increased by 23.3% to $1.68 billion from $1.36 billion in 2015. Organic revenue growth was 7.7%. On a GAAP basis, net income from continuing operations attributable to common shareholders was $154.5 million in 2016, an increase of 2.8% from $150.3 million in 2015. Diluted earnings per share on a GAAP basis in 2016 were $3.22, an increase of 2.2% from $3.15 in 2015. On a non-GAAP basis, net income from continuing operations was $218.9 million in 2016, an increase of 22.1% from $179.3 million in 2015. Diluted earnings per share on a non-GAAP basis in 2016 were $4.56, an increase of 21.3% from $3.76 in 2015. For 2016, RMS revenue was $494.0 million, an increase of 5.0% from $470.4 million in 2015. Organic revenue growth was 4.1%. On a GAAP basis, the RMS segment operating margin increased to 27.6% in 2016 from 25.7% in 2015. On a non-GAAP basis, the operating margin increased to 28.4% in 2016 from 27.1% in 2015. For 2016, DSA revenue was $836.6 million, an increase of 36.7% from $612.2 million in 2015. Organic revenue growth was 8.9%. On a GAAP basis, the DSA segment operating margin decreased to 16.5% in 2016 from 19.9% in 2015. On a non-GAAP basis, the operating margin decreased to 22.7% in 2016 from 23.3% in 2015. For 2016, Manufacturing revenue was $350.8 million, an increase of 25.0% from $280.7 million in 2015. Organic revenue growth was 11.3%. On a GAAP basis, the Manufacturing segment operating margin increased to 29.8% in 2016 from 26.6% in 2015. On a non-GAAP basis, the operating margin increased to 33.8% in 2016 from 32.6% in 2015. Charles River completed the divestiture of its CDMO business on February 10, 2017, to Quotient Clinical, a portfolio company of specialist healthcare investment adviser GHO Capital Partners LLP, based in London, England, for $75.0 million in cash, subject to certain post-closing adjustments. The CDMO business, which represented approximately 1% of Charles River’s 2016 consolidated revenue, provides services to support the formulation design and manufacture of oral drug dosages for biopharmaceutical clients, specializing in high-potency compounds. Charles River acquired the CDMO business in April 2016 as part of the acquisition of WIL Research. Following a strategic review, Charles River determined that the CDMO business was not optimized within Charles River’s portfolio at its current scale, and that the capital could be better deployed in other long-term growth opportunities. The Company is providing the following revenue growth and earnings per share guidance for 2017. This guidance reflects the divestiture of the CDMO business. Earnings per share in 2017 are expected to benefit from both higher revenue and operating margin expansion. The benefit is expected to be partially offset by foreign exchange, which is expected to reduce 2017 earnings per share by approximately $0.10, and lower gains from the Company’s venture capital investments. The Company’s 2016 earnings per share included a $0.13 gain on venture capital investments, and 2017 guidance includes an estimated $0.04 gain on these investments, consistent with the Company’s expected return on invested capital. Footnotes to Guidance Table (1) The contribution from acquisitions reflects only those acquisitions which were completed in 2016. (2) Organic revenue growth is defined as reported revenue growth adjusted for acquisitions, the divestiture of the CDMO business, the 53rd week, and foreign currency translation. (3) GAAP earnings per share guidance does not include the expected net gain and tax impact related to the divestiture of the CDMO business because the disposition accounting has not yet been finalized. (4) These charges relate primarily to the Company’s planned efficiency initiatives in 2017, including site consolidation costs, asset impairments, and severance. Other projects in support of the global productivity and efficiency initiatives are expected, but these charges reflect only the decisions that have already been finalized. (5) These adjustments are related to the evaluation and integration of acquisitions and the divestiture of the CDMO business, and primarily include transaction, advisory, and certain third-party integration costs, as well as certain costs associated with acquisition-related efficiency initiatives. Charles River has scheduled a live webcast on Tuesday, February 14, at 8:00 a.m. ET to discuss matters relating to this press release. To participate, please go to ir.criver.com and select the webcast link. You can also find the associated slide presentation and reconciliations of GAAP financial measures to non-GAAP financial measures on the website. Charles River will present at the Leerink 6th Annual Global Healthcare Conference in New York on Thursday, February 16, at 9:30 a.m. ET. Management will provide an overview of Charles River’s strategic focus and business developments. A live webcast of the presentation will be available through a link that will be posted on the Investor Relations section of the Charles River website at ir.criver.com. A webcast replay will be accessible through the same website approximately three hours after the presentation and will remain available for approximately two weeks. The Company reports non-GAAP results in this press release, which exclude often one-time charges and other items that are outside of normal operations. A reconciliation of GAAP to non-GAAP results is provided in the schedules at the end of this press release. In addition, the Company reports results from continuing operations, which exclude results of the Phase I clinical business that was divested in 2011. The Phase I business is reported as a discontinued operation. Use of Non-GAAP Financial Measures This press release contains non-GAAP financial measures, such as non-GAAP earnings per diluted share, which exclude the amortization of intangible assets, inventory purchase accounting adjustments, and other charges related to our acquisitions; expenses associated with evaluating and integrating acquisitions and divestitures, as well as fair value adjustments associated with contingent consideration; charges related to modifications of purchase options on remaining non-controlled equity interests, and re-measurement of previously held equity interests; charges, gains and losses attributable to businesses or properties we plan to close, consolidate or divest; severance and other costs associated with our efficiency initiatives; executive transition costs; a reversal of indemnification assets associated with acquisitions and corresponding interest; write-off of and adjustments to deferred financing costs and fees related to debt financing; gain on bargain purchase; and costs related to a U.S. government billing adjustment and related expenses. This press release also refers to our revenue in both a GAAP and non-GAAP basis: “constant currency,” which we define as reported revenue growth adjusted for the impact of foreign currency translation, and “organic revenue growth,” which we define as reported revenue growth adjusted for foreign currency translation, acquisitions, the divestiture of the CDMO business, and the 53rd week. We exclude these items from the non-GAAP financial measures because they are outside our normal operations. There are limitations in using non-GAAP financial measures, as they are not prepared in accordance with generally accepted accounting principles, and may be different than non-GAAP financial measures used by other companies. In particular, we believe that the inclusion of supplementary non-GAAP financial measures in this press release helps investors to gain a meaningful understanding of our core operating results and future prospects without the effect of these often-one-time charges, and is consistent with how management measures and forecasts the Company's performance, especially when comparing such results to prior periods or forecasts. We believe that the financial impact of our acquisitions and divestitures (and in certain cases, the evaluation of such acquisitions and divestitures, whether or not ultimately consummated) is often large relative to our overall financial performance, which can adversely affect the comparability of our results on a period-to-period basis. In addition, certain activities and their underlying associated costs, such as business acquisitions, generally occur periodically but on an unpredictable basis. We calculate non-GAAP integration costs to include third-party integration costs incurred post-acquisition. Presenting revenue on a constant-currency basis allows investors to measure our revenue growth exclusive of foreign currency exchange fluctuations more clearly. Non-GAAP results also allow investors to compare the Company’s operations against the financial results of other companies in the industry who similarly provide non-GAAP results. The non-GAAP financial measures included in this press release are not meant to be considered superior to or a substitute for results of operations prepared in accordance with GAAP. The Company intends to continue to assess the potential value of reporting non-GAAP results consistent with applicable rules and regulations. Reconciliations of the non-GAAP financial measures used in this press release to the most directly comparable GAAP financial measures are set forth in this press release, and can also be found on the Company’s website at ir.criver.com. This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words such as “anticipate,” “believe,” “expect,” “intend,” “will,” “may,” “estimate,” “plan,” “outlook,” and “project,” and other similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These statements also include statements regarding our projected future financial performance including revenue (on both a reported, constant-currency, and organic growth basis), operating margins, earnings per share, the expected impact of foreign exchange rates, and the expected benefit of our life science venture capital investments; the future demand for drug discovery and development products and services, including our expectations for future revenue trends; our expectations with respect to the impact of acquisitions on the Company, our service offerings, client perception, strategic relationships, revenue, revenue growth rates, and earnings; the development and performance of our services and products; market and industry conditions including the outsourcing of services and spending trends by our clients; the potential outcome of and impact to our business and financial operations due to litigation and legal proceedings, including with respect to our ongoing investigation of inaccurate billing with respect to certain government contracts; and Charles River’s future performance as delineated in our forward-looking guidance, and particularly our expectations with respect to revenue, the impact of foreign exchange, and enhanced efficiency initiatives. Forward-looking statements are based on Charles River’s current expectations and beliefs, and involve a number of risks and uncertainties that are difficult to predict and that could cause actual results to differ materially from those stated or implied by the forward-looking statements. Those risks and uncertainties include, but are not limited to: the ability to successfully integrate businesses we acquire; the ability to execute our efficiency initiatives on an effective and timely basis (including divestitures and site closures); the timing and magnitude of our share repurchases; negative trends in research and development spending, negative trends in the level of outsourced services, or other cost reduction actions by our clients; the ability to convert backlog to revenue; special interest groups; contaminations; industry trends; new displacement technologies; USDA and FDA regulations; changes in law; continued availability of products and supplies; loss of key personnel; interest rate and foreign currency exchange rate fluctuations (including the impact of Brexit); changes in tax regulation and laws; changes in generally accepted accounting principles; and any changes in business, political, or economic conditions due to the threat of future terrorist activity in the U.S. and other parts of the world, and related U.S. military action overseas. A further description of these risks, uncertainties, and other matters can be found in the Risk Factors detailed in Charles River's Annual Report on Form 10-K as filed on February 12, 2016, as well as other filings we make with the Securities and Exchange Commission. Because forward-looking statements involve risks and uncertainties, actual results and events may differ materially from results and events currently expected by Charles River, and Charles River assumes no obligation and expressly disclaims any duty to update information contained in this news release except as required by law. Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit www.criver.com. (1) Charles River management believes that supplementary non-GAAP financial measures provide useful information to allow investors to gain a meaningful understanding of our core operating results and future prospects, without the effect of often-one-time charges and other items which are outside our normal operations, consistent with the manner in which management measures and forecasts the Company’s performance. The supplementary non-GAAP financial measures included are not meant to be considered superior to, or a substitute for results of operations prepared in accordance with U.S. GAAP. The Company intends to continue to assess the potential value of reporting non-GAAP results consistent with applicable rules, regulations and guidance. (2) This item includes operating losses related primarily to the Company's Shrewsbury, Massachusetts facility. (3) These adjustments are related to the evaluation and integration of acquisitions, which primarily include transaction, third-party integration, and certain compensation costs, and fair value adjustments associated with contingent consideration. (1) Charles River management believes that supplementary non-GAAP financial measures provide useful information to allow investors to gain a meaningful understanding of our core operating results and future prospects, without the effect of often-one-time charges and other items which are outside our normal operations, consistent with the manner in which management measures and forecasts the Company’s performance. The supplementary non-GAAP financial measures included are not meant to be considered superior to, or a substitute for results of operations prepared in accordance with U.S. GAAP. The Company intends to continue to assess the potential value of reporting non-GAAP results consistent with applicable rules, regulations and guidance. (2) These amounts represent the reversal of an uncertain tax position and an offsetting indemnification asset primarily related to the acquisition of BioFocus. (3) The amounts relate to the acquisition of Sunrise Farms, Inc. and represents the excess of the estimated fair value of the net assets acquired over the purchase price. (4) The amount represents a $1.5 million charge recorded in connection with the modification of the option to purchase the remaining 13% equity interest in Vital River, partially offset by a $0.7 million gain on remeasurement of previously held equity interest in an entity acquired in a step acquisition. (1) Charles River management believes that supplementary non-GAAP financial measures provide useful information to allow investors to gain a meaningful understanding of our core operating results and future prospects, without the effect of often-one-time charges and other items which are outside our normal operations, consistent with the manner in which management measures and forecasts the Company’s performance. The supplementary non-GAAP financial measures included are not meant to be considered superior to, or a substitute for results of operations prepared in accordance with U.S. GAAP. The Company intends to continue to assess the potential value of reporting non-GAAP results consistent with applicable rules, regulations and guidance. (2) The contribution from acquisitions reflects only those acquisitions which were completed during fiscal year 2016 and 2015. (3) Organic revenue growth is defined as reported revenue growth adjusted for acquisitions, the 53rd week, and foreign exchange.


Global Contract Research Organization (CRO) Market for Early-Stage Development Services and Last-Stage Development Services: Global Industry Perspective, Comprehensive Analysis and Forecast 2014 – 2020 The report covers forecast and analysis for the contract research organization (CRO) market on a global and regional level. The study provides historic data of 2014 along with a forecast from 2015 to 2020 based on revenue (USD billion). The study includes drivers and restraints for the contract research organization market along with the impact they have on the demand over the forecast period. Additionally, the report includes the study of opportunities available in the contract research organization market on a global level. In order to give the users of this report a comprehensive view on the contract research organization market, we have included a detailed buying criteria, product portfolio, competitive scenario, and analysis of key industry players. To understand the competitive landscape in the market, an analysis of Porter’s Five Forces model for the contract research organization market has also been included. The study encompasses a market attractiveness analysis, wherein product segments are benchmarked based on their market size, growth rate and general attractiveness. The study provides a decisive view on the contract research organization market by segmenting the market based on applications. All the end-user segments have been analyzed based on present and future trends and the market is estimated from 2014 to 2020. Key end-user market covered under this study include early-stage development services and last-stage development services. The regional segmentation includes the current and forecast demand for Americas, EMEA (Europe, Middle East & Africa) and Asia Pacific with its further bifurcation into major countries including U.S., China, and India. This segmentation includes demand for contract research organization market based on individual applications in all the regions and countries. This Report covered some of the key players involved globally in contract research organization market includes Covance, Parexel International, PRA Health Sciences, Quintiles Translational. Other prominent players in the contract research organization market includes Chiltern, Charles River Laboratories, Icon, Inventiv Health, QPS, Ricerca Biosciences, EPS , SynteractHCR, INC Research, WIL Research and WuXi AppTec.


News Article | November 4, 2016
Site: www.newsmaker.com.au

Zion Research has published a new report titled “Contract Research Organization (CRO) Industry for Early-Stage Development Services and Last-Stage Development Services: Global Market Perspective, Comprehensive Analysis and Forecast, 2014 - 2020.” According to the report, global Contract Research Organization market was valued at USD 34.00 billion in 2014 and is expected to reach USD 59.42 billion in 2020, growing at a CAGR of 9.80% between 2015 and 2020. CRO is the organization that supports outsourced research and development services for the various industries like pharmaceutical, biotechnology, medical devices industries, government institutions, foundations, and universities. The demand for contract research organizations has been fuelled by advanced clinical development programs and the demand for new pharmaceutical products across the globe. The research and development of pharmaceutical products typically needs around 15 years. In order to lower down the expenditure research and development and cut down the time required for product marketing, and focus on other operational activities, pharmaceutical vendors are outsourcing preclinical and other drug development phases to CROs. Moreover, the high failure rate of clinical trials is also expected to trigger the demand for CROs by pharmaceutical and biopharmaceutical vendors to outsource their R&D. Global CRO industry has witnessed the rise in strategic alliances, acquisitions, and joint ventures among vendors in the CRO market. These strategic initiatives are intended at extending service offerings and geographical presence across the world. Pharmaceutical manufacturing companies in emerging countries in Asia Pacific, Latin America and Eastern Europe account for the majority of outsourcing activities owing to easy access to large pools of treatment naïve patients, low labor and manufacturing costs, and a skilled medical workforce. The contract research organization market is segmented on the basis of the end-user segmentation which includes early-stage development services and last-stage development services. The late-stage development services segment includes phase II-IV clinical trials and central laboratory services. The last-stage development services was the largest end-user segment for the CRO market and accounted for over 70% share of the total market in 2014. Last-stage development services segment is also expected to exhibit fastest growth rate during the years to come. The contract research organization market is segmented on the basis of the regions such as Americas, EMEA (Europe, Middle East and Africa) and APAC (Asia Pacific). The Americas dominated the global CRO market with around 50% share of the total market in 2014. CRO market in Americas is led by U.S. Some of the key players involved globally in contract research organization market include Covance, Parexel International, PRA Health Sciences, Quintiles Translational. Other major players in the contract research organization market includes Chiltern, Charles River Laboratories, Icon, Inventiv Health, QPS, Ricerca Biosciences, EPS , SynteractHCR, INC Research, WIL Research and WuXi AppTec.


Dutta S.,Syracuse University | Mark-Kappeler C.J.,University of Arizona | Mark-Kappeler C.J.,WIL Research | Hoyer P.B.,University of Arizona | Pepling M.E.,Syracuse University
Biology of Reproduction | Year: 2014

Primordial follicle assembly is essential for reproduction in mammalian females. Oocytes develop in germ cell cysts that in late fetal development begin break down into individual oocytes and become surrounded by pregranulosa cells, forming primordial follicles. As they separate, many oocytes are lost by apoptosis. Exposure to steroid hormones delays cyst breakdown, follicle formation, and associated oocyte loss in some species. One model for regulation of follicle formation is that steroid hormones in the maternal circulation keep cells in cysts and prevent oocyte death during fetal development but that late in pregnancy hormone levels drop, triggering cyst breakdown and associated oocyte loss. However, herein we found that, while maternal circulating levels of progesterone drop during late fetal development, maternal estradiol levels remain high. We hypothesized that fetal ovaries were the source of hormones and that late in fetal development their production stops. To test this, mRNA and protein levels of steroidogenic enzymes required for estradiol and progesterone synthesis were measured. We found that aromatase and 3-beta-hydroxysteroid dehydrogenase mRNA levels drop before cyst breakdown. The 3-beta-hydroxysteroid dehydrogenase protein levels also dropped, but we did not detect a change in aromatase protein levels. The steroid content of perinatal ovaries was assayed, and both estradiol and progesterone were detected in fetal ovaries before cyst breakdown. To determine the role of steroid hormones in oocyte development, we examined the effects of blocking steroid hormone production in organ culture and found that the number of oocytes was reduced, supporting our model that steroid hormones are important for fetal oocyte survival. © 2014 by the Society for the Study of Reproduction, Inc.


Schlosser M.J.,MSR Pharma Services | Hosako H.,WIL Research | Radovsky A.,WIL Research | Butt M.T.,Tox Path Specialists | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Tedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low-, medium-, and high-dose levels (7.5, 15, and 30 mg/kg of body weight/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.8-, 3.9-, and 8.0-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated endpoints included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted, brain weights/sizes were recorded, and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphological assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (-6.7%) and females (-5.8%) compared with that seen in controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure. © 2015 American Society for Microbiology. All Rights Reserved.


Picut C.A.,WIL Research | Dixon D.,National Health Research Institute | Simons M.L.,WIL Research | Stump D.G.,WIL Research | And 2 more authors.
Toxicologic Pathology | Year: 2015

Histopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic-pituitary-gonadal axis matures. During the neonatal stage (postnatal day [PND] 0-7), ovarian follicle development is independent of pituitary gonadotropins (luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), and follicles remain preantral. Antral development of "atypical" follicles occurs in the early infantile period (PND 8-14) when the ovary becomes responsive to pituitary gonadotropins. In the late infantile period (PND 15-20), the zona pellucida appears, the hilus forms, and antral follicles mature by losing their "atypical" appearance. The juvenile stage (PND 21-32) is the stage when atresia of medullary follicles occurs corresponding to a nadir in FSH levels. In the peripubertal period (PND 33-37), atresia subsides as FSH levels rebound, and LH begins its bimodal surge pattern leading to ovulation. This report will provide pathologists with baseline morphologic and endocrinologic information to aid in identification and interpretation of xenobiotic effects in the ovary of the prepubertal rat. Copyright © 2014 by The Author(s).


Picut C.A.,WIL Research | Remick A.K.,WIL Research | Asakawa M.G.,WIL Research | Simons M.L.,WIL Research | Parker G.A.,WIL Research
Toxicologic Pathology | Year: 2014

In response to growing concerns that environmental chemicals may have adverse effects on human health by altering the endocrine system, the Endocrine Disruptor Screening Program (EDSP), under the auspices of the United States Environmental Protection Agency (U.S. EPA), recently instituted a Tier I battery of tests including a female pubertal assay. This assay requires dosing of female rats from postnatal day (PND) 22 through PND 42 (or 43), the period of pubertal development in the rat, to identify test articles that may have estrogenic or antiestrogenic effects, or may alter hormones or neurotransmitters. While certain landmarks in female rat reproductive development are published, little is published on the microscopic appearance of the female reproductive tract during prepubertal and pubertal development. In this study, reproductive tissues from three female Sprague-Dawley rats were collected each day from PND 20 through PND 50, such that tissues from a total of 93 rats were collected throughout the prepubertal and pubertal period. Tissues were formalin-fixed, trimmed, paraffin-embedded, sectioned at 5-μm thickness, and examined microscopically. The major histologic features of the female reproductive tract throughout this critical period were described in detail. This information will help pathologists interpret findings observed in female pubertal assays. © 2013 by The Author(s).


This report studies Drug Discovery Outsourcing in Global market, especially in North America, Europe, China, Japan, Southeast Asia and India, focuses on top manufacturers in global market, with capacity, production, price, revenue and market share for each manufacturer, covering Request a Sample Report @ https://www.wiseguyreports.com/sample-request/963107-global-drug-discovery-outsourcing-market-research-report-2017 Market Segment by Regions, this report splits Global into several key Regions, with production, consumption, revenue, market share and growth rate of Drug Discovery Outsourcing in these regions, from 2011 to 2021 (forecast), like North America Europe China Japan Southeast Asia India Split by product type, with production, revenue, price, market share and growth rate of each type, can be divided into Libraries Building Blocks Compound Synthesis Target Validation Split by application, this report focuses on consumption, market share and growth rate of Drug Discovery Outsourcing in each application, can be divided into Chemistry Services Biology Services Lead Optimisation Lead Identification and Screening Global Drug Discovery Outsourcing Market Research Report 2017 1 Drug Discovery Outsourcing Market Overview 1.1 Product Overview and Scope of Drug Discovery Outsourcing 1.2 Drug Discovery Outsourcing Segment by Type 1.2.1 Global Production Market Share of Drug Discovery Outsourcing by Type in 2015 1.2.2 Libraries 1.2.3 Building Blocks 1.2.4 Compound Synthesis 1.2.5 Target Validation 1.3 Drug Discovery Outsourcing Segment by Application 1.3.1 Drug Discovery Outsourcing Consumption Market Share by Application in 2015 1.3.2 Chemistry Services 1.3.3 Biology Services 1.3.4 Lead Optimisation 1.3.5 Lead Identification and Screening 1.4 Drug Discovery Outsourcing Market by Region 1.4.1 North America Status and Prospect (2012-2022) 1.4.2 Europe Status and Prospect (2012-2022) 1.4.3 China Status and Prospect (2012-2022) 1.4.4 Japan Status and Prospect (2012-2022) 1.4.5 Southeast Asia Status and Prospect (2012-2022) 1.4.6 India Status and Prospect (2012-2022) 1.5 Global Market Size (Value) of Drug Discovery Outsourcing (2012-2022) 7 Global Drug Discovery Outsourcing Manufacturers Profiles/Analysis 7.1 Albany Mlecular Research (AMRI) 7.1.1 Company Basic Information, Manufacturing Base and Its Competitors 7.1.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.1.2.1 Libraries 7.1.2.2 Building Blocks 7.1.3 Albany Mlecular Research (AMRI) Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.1.4 Main Business/Business Overview 7.2 Aptuit 7.2.1 Company Basic Information, Manufacturing Base and Its Competitors 7.2.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.2.2.1 Libraries 7.2.2.2 Building Blocks 7.2.3 Aptuit Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.2.4 Main Business/Business Overview 7.3 Charles River Labratries 7.3.1 Company Basic Information, Manufacturing Base and Its Competitors 7.3.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.3.2.1 Libraries 7.3.2.2 Building Blocks 7.3.3 Charles River Labratries Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.3.4 Main Business/Business Overview 7.4 Cvance 7.4.1 Company Basic Information, Manufacturing Base and Its Competitors 7.4.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.4.2.1 Libraries 7.4.2.2 Building Blocks 7.4.3 Cvance Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.4.4 Main Business/Business Overview 7.5 Cyprtex 7.5.1 Company Basic Information, Manufacturing Base and Its Competitors 7.5.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.5.2.1 Libraries 7.5.2.2 Building Blocks 7.5.3 Cyprtex Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.5.4 Main Business/Business Overview 7.6 Dmainex 7.6.1 Company Basic Information, Manufacturing Base and Its Competitors 7.6.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.6.2.1 Libraries 7.6.2.2 Building Blocks 7.6.3 Dmainex Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.6.4 Main Business/Business Overview 7.7 Evtec 7.7.1 Company Basic Information, Manufacturing Base and Its Competitors 7.7.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.7.2.1 Libraries 7.7.2.2 Building Blocks 7.7.3 Evtec Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.7.4 Main Business/Business Overview 7.8 GenScript 7.8.1 Company Basic Information, Manufacturing Base and Its Competitors 7.8.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.8.2.1 Libraries 7.8.2.2 Building Blocks 7.8.3 GenScript Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.8.4 Main Business/Business Overview 7.9 Pharmaceutical Prduct Develpment (PPD) 7.9.1 Company Basic Information, Manufacturing Base and Its Competitors 7.9.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.9.2.1 Libraries 7.9.2.2 Building Blocks 7.9.3 Pharmaceutical Prduct Develpment (PPD) Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.9.4 Main Business/Business Overview 7.10 Quintiles 7.10.1 Company Basic Information, Manufacturing Base and Its Competitors 7.10.2 Drug Discovery Outsourcing Product Type, Application and Specification 7.10.2.1 Libraries 7.10.2.2 Building Blocks 7.10.3 Quintiles Drug Discovery Outsourcing Production, Revenue, Price and Gross Margin (2015 and 2016) 7.10.4 Main Business/Business Overview 7.11 Selcia 7.12 Viva Bitech 7.13 WIL Research Labratries 7.14 WuXi AppTec For more information, please visit 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Flanagan S.,Cubist Pharmaceuticals Inc. | McKee E.E.,Central Michigan University | Das D.,Catholic University of Leuven | Das D.,Novartis | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μMversus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedi-zolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies. © 2015, American Society for Microbiology. All Rights Reserved.

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