Woodcliff Lake Research Articles

Erroneously Published Fospropofol Pharmacokinetic–Pharmacodynamic Data and Retraction of the Affected Publications

As described in a letter to the editor, published in Anesthesiology, Anesthesia and Analgesia , and the European Journal of Anaesthesiology ,1–3an analytical propofol assay inaccuracy was discovered after all six initial studies on the pharmacokinetic–pharmacodynamic and tolerability of fospropofol had been published.4–9This assay inaccuracy makes the measured propofol plasma concentrations in these previously published studies unreliable.All six affected studies were phase I and II studies sponsored by a pharmaceutical company (Guilford Pharma, Baltimore, MD, and later MGI Pharma, Baltimore, MD) and were performed in two independent academic-based phase I centers in Gent, Belgium, and Erlangen, Germany. Because of the stage of the drug testing, the study drugs were made available by the initial sponsor. As described previously,1–3the sponsor developed and validated a specific propofol assay. Both academic centers had no influence on the choice of methodology for sample handling and chemical analysis. For all six studies,4–9assays were performed at an external laboratory (MDS Pharma Services, Montreal, Canada) as per the sponsor's decision. Finally, the original publications were coauthored by both academic and sponsor-based investigators.In a letter to the editor,1–3the initial owner of the drug (MGI Pharma, not affiliated with the academic centers from the original studies) declared that additional studies were planned using an appropriate assay to describe the pharmacokinetics and pharmacodynamics of fospropofol in healthy volunteers and patients. They stated their intent to publish these results shortly along with an estimate of the degree of error from the previously published studies reporting results using the old assay. In the response article, the editors-in-chief of Anesthesiology, Anesthesia and Analgesia , and the European Journal of Anaesthesiology requested a publication within the next 12 months validating the new assay, analyzing the likely error and bias in each of the six articles in question, and determining how the error and its correction would influence the conclusions.The planning of studies was delayed primarily because of the transfer of ownership of the drug to another pharmaceutical company in mid 2009 (Eisai, Woodcliff Lake, NJ). As a result and although requested by the academic investigators immediately after the publication of the letter to the editor,1–3the investigators from the original studies were not able to reanalyze the pharmacokinetics–pharmacodynamics of fospropofol in human volunteers within the deadline of 12 months given by the editors-in-chief. As such, we, the undersigned corresponding and senior authors from the six original articles, in the name of all coauthors, request that the articles in question that provide flawed pharmacokinetic–pharmacodynamic data be retracted. We regret that we are unable to successfully resolve the problem within the given timeframe. (See a list of retracted articles from Anesthesiology on page 1058 of this issue .)*University of Groningen, Groningen, The Netherlands, and University of Ghent, Gent, Belgium. m.m.r.f.struys@anest.umcg.nl. †University of Erlangen-Nuremberg, Erlangen, Germany.

Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension

Megestrol acetate oral suspension (MAOS) is an appetite stimulant indicated for cachexia in patients with AIDS. It is available in its original formulation, Megace (MAOS), and as a nanocrystal dispersion, Megace ES (MA-ES). Three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions. An open-label, crossover trial was conducted in 24 healthy males randomized to MA-ES 625 mg/5 mL given with a high-calorie, high-fat meal, or after an overnight fast. Blood samples were drawn at multiple time points and pharmacokinetic parameters were determined. Two separate, open-label reference studies evaluated MAOS 800 mg/20 mL in 40 fed or 40 fasting healthy male volunteers. In fasting MA-ES subjects, the average maximum concentration (C(max)) was 30% less than the fed C(max) value. For MAOS, fasting C(max) was 86% less than fed C(max). In fasting subjects, the area under the curve was 12,095 ng.h/mL for MA-ES, and 8,942 ng.h/mL for MAOS. In fed subjects, the absorption of the two formulations was comparable. Bioavailability and absorption are greater for MA-ES than MAOS in fasting subjects. MA-ES may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced.

Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT II

The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m(2)/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss >or= 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.

Only Peru Balsam extracts or distillates are used in perfumery

Contact DermatitisVolume 54, Issue 3 p. 179-179 Only Peru Balsam extracts or distillates are used in perfumery Anne Marie Api, Corresponding Author Anne Marie Api Research Institute for Fragrance Materials, Woodcliff Lake, NJ, USAAnne Marie Api, Ph.D. Scientific Director Research Institute for Fragrance Materials 50 Tice Boulevard Woodcliff Lake, NJ 07677, USA e-mail: [email protected]Search for more papers by this author Anne Marie Api, Corresponding Author Anne Marie Api Research Institute for Fragrance Materials, Woodcliff Lake, NJ, USAAnne Marie Api, Ph.D. Scientific Director Research Institute for Fragrance Materials 50 Tice Boulevard Woodcliff Lake, NJ 07677, USA e-mail: [email protected]Search for more papers by this author First published: 07 March 2006 https://doi.org/10.1111/j.0105-1873.2006.00718.xCitations: 34Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume54, Issue3March 2006Pages 179-179 RelatedInformation

Politics trumps science at the FDA

In May, 2004, the US Food and Drug Administration (FDA) rejected an application to make the emergency contraceptive Plan B, a two-dose regimen of levonorgestrel (0·75 mg), available without prescription. In rejecting the emergency contraceptive, FDA officials ignored not only the advice of the outside experts serving on the agency's advisory committee but also the recommendations of their own internal reviewers. In the letter explaining the decision, the acting director of the FDA's Center for Drug Evaluation and Research said the application was being rejected because of concerns that Plan B might not be safe for use by women younger than 16 years. Advocates for over-the-counter access, however, scoffed at the claim: the concerns were not about the health of women, they charged, but politics. In response to the rejection, Plan B's manufacturer, Barr Pharmaceuticals (Woodcliff Lake, NJ, USA), resubmitted an application for over-the-counter access for women older than 16 years, but the agency has repeatedly delayed a decision. The handling of the application has been so irregular that the director of the agency's Office of Women's Health, Susan Wood, resigned in August in protest. A new report, released on Nov 14, adds further support to allegations that politics trumps science at the FDA. The report, prepared by the Government Accountability Office (GAO), an investigative agency of the US Congress, finds that four aspects of the FDA's review process were, as the report tactfully puts it, “unusual”. First, the directors of the offices that reviewed the application did not agree with the decision and did not sign the action letter rejecting the application. Ordinarily these officers would be responsible for signing such documents. Second, the GAO investigators found that high-level FDA managers were more involved in the review process than they have been in other so-called “OTC switch” applications. Third, and particularly worrying, GAO investigators wrote that they had heard conflicting accounts of whether the decision to reject had been made before the review process had been completed. And, fourth, the justification of the decision “was novel and did not follow FDA's traditional practices”. In particular, the investigators questioned the acting director's explanation that he made the decision because of concerns that marketing Plan B to younger adolescents might affect their behaviour, because of their level of cognitive development and because it was invalid to extrapolate safety data derived from older adolescents to younger individuals. Such considerations have never been raised for other applications requesting over-the-counter status for prescription drugs. If taken within 72 h of unprotected intercourse, the Plan B regimen has been shown to prevent 85% of the pregnancies that would be expected without treatment; this percentage increases to 95% if taken in the first 24 h. The later treatment is started, however, the less effective it is. Over-the-counter access would make it possible for women to obtain the drug quickly when it will be most effective. Although treatment is thought to prevent pregnancy by suppressing ovulation and interfering with fertilisation—ie, as a contraceptive—critics argue that because the drug may interfere with post-fertilisation events it is tantamount to abortion. In addition, opponents contend that making the contraceptive easily available will promote unsafe sexual activity in young people. The GAO report suggests that FDA officials, despite their protestations to the contrary, decided to sacrifice the agency's reputation for independence and scientific rigour to satisfy these critics, most of whom are strong political supporters of the Bush Administration. Ironically, because of the FDA officials' decision, more women are likely to have unwanted pregnancies and as a result there will be more, rather than fewer, abortions. The report is another blow to the FDA, which is coming under increasing scrutiny. Serious questions have been raised over its handling of drug-safety issues, in particular its handling of rofecoxib, the cyclo-oxygenase 2 inhibitor that was withdrawn from the market after being linked to an increased risk of myocardial infarction and stroke. And there are growing concerns that the agency, which now depends on fees from manufacturers for a substantial proportion of its budget for drug assessment and research, has become too dependent on the industry it is supposed to regulate. Trust in this agency is fast eroding. To restore the FDA's reputation, its leadership needs to move quickly. A first step would be to allow the Plan B review to proceed according to standard procedure without any further interference.

Creating an archives at the Richard Nixon Library and birthplace

On August 9,1974, in an atmosphere filled with the Cheshire cat grins of his opponents who had dismally failed to defeat him at the polls, Richard Nixon, 37th President of the United States, resigned his Office in disgrace over what catalogers would subsequently subject-title the “Watergate Affair.” Their victory, though, has proven to be a Pyrrhic one for contemporary Nixon scholars, who must now deal with the tempest which befell the president’s papers and cut off their lines of supply to records offering illumination into the true character of their subject, who even today is known by many only in caricature. Inevitably the winds of the tempest subsided, revealing two years ago the Nixon chronicle dispersed in three different geographical locations. Everything pertaining to the presidential years had been taken by the government and was located at the Nixon Presidential Materials Project, a section of the National Archives and Records Administration (NARA) in Alexandria, Virginia. The earlier material, known as “The Pre-Presidential Papers of Richard M. Nixon” and divided in 1968 between “deeded” and “undeeded” sections when President-elect Nixon gave portions of it to the government, was housed in the mammoth ziggurat building of the National Archives Pacific Southwest Region Center in Laguna Niguel, California. Finally, all correspondence, trip files, and notes and manuscripts relating to the former president’s impressive publishing activity of the postpresidential period were burgeoning in his busy office in Woodcliff Lake, New Jersey. That was two years ago. The preceding year in the unpretentious city of Yorba Linda, California, and a matter of yards away from the restored house where he had been born, former President Richard Nixon was finally honored with the opening of his own “Library” (see Figure 1). Although not a part of the Presidential Libraries system for it did not house

The Chestnut Pollen Decline as a Time Horizon in Lake Sediments in Eastern North America

Chestnut [Castanea dentata (Marsh.) Borkh.] was a dominant tree of the upland forests of eastern North America until its elimination by the blight fungus, Endothia parasitica Anders. The blight originated in New York City in 1904, and within 50 years, it spread throughout the entire range of Castanea dentata. The chestnut destruction is documented in lake sediments by a corresponding decline of chestnut pollen as illustrated in examples from Lakes Ontario and Erie, and Woodcliff Lake, New Jersey. According to the data from Woodcliff Lake, the decline can be assigned an age equivalent to the time of the chestnut die-out for the area. Thus, dates of 1930 A.D. and 1935 A.D. are taken to represent times of the chestnut pollen decline in Lakes Ontario and Erie, respectively. The Castanea pollen decline provides an excellent and very recent time horizon (above the Ambrosia pollen boundary) for determining sedimentation trends since the time of European settlement as well as recent sedimentation rates.