Aventis Pharmaceuticals Research Articles

Safety assessment for the combination of docetaxel, carboplatin, and thoracic radiotherapy in unresectable stage III non-small cell lung cancer (NSCLC): A report of the first 100 patients treated with chemoradiation on D0410

7701 Background: Concurrent chemoradiotherapy (chemoRT) is the preferred treatment for patients with unresectable stage III NSCLC. Limited safety information is available on the use of concurrent docetaxel, carboplatin and thoracic RT. We report the safety information on the initial 100 patients (pts) treated with this chemoRT as part of an ongoing US randomized phase III trial (D0410) evaluating the role of erlotinib/placebo following this concurrent chemoRT treatment. The sample size is 400 pts and the primary endpoint is progression-free survival. Methods: Pts with unresectable pathologically confirmed stage III NSCLC are randomized to receive either erlotinib 150 mg or placebo orally daily for 2 years following concurrent chemoRT with docetaxel 20 mg/m2, carboplatin AUC=2 intravenously weekly for 6 wks with thoracic RT of at least 61 Gy in 33 fractions over 6.5 weeks. The planned total lung volume exceeding 20 Gy (V20) was less than 32%. Only the chemoradiation safety information is being reported. This data was reviewed by an independent safety and data monitoring committee. Results: Pt characteristics; 59% males, median age 69 years (range 38 to 86), 21% adenocarcinoma, 48% squamous cell, 94% ECOG PS0–1, 49% stage IIIA, 15% weight loss = 10%. Of 600 planned chemotherapy treatments, 492 were administered (93 wk 1, 85 wk 2, 82 wk 3, 81 wk 4, 77 wk 5, 74 wk 6). There were 25 chemotherapy dose reductions; most commonly for esophagitis (8), neutropenia (5), renal dysfunction (3), hypersensitivity (2). There were no treatment-related deaths. There were 25 grade 3 and 3 grade 4 treatment-related adverse events. The most common grade 3/4 events were esophagitis (6), fatigue (3), odynophagia (2), neutropenia (1), thrombocytopenia (1), dematitis (1). Conclusions: This concurrent chemoradiation regimen appears to be safe. Enrollment to the phase III trial continues. There is a planned interim efficacy evaluation at 150 events (deaths or disease progression). Funded in part by Sanofi- Aventis, Genentech, and OSI Pharmaceuticals. [Table: see text]

Claim construction and the doctrine of equivalents in Amgen v Transkaryotic Therapies, Inc

The US Court of Appeals for the Federal Circuit has affirmed a District Court decision that Transkaryotic Therapies Inc and Aventis Pharmaceuticals Inc infringed Amgen's erythropoietin (EPO) patents; this decision upheld the validity of two of Amgen's EPO patents and the infringement by Transkaryotic of three patents, including a patent that does not expire until 2015.

Yeda Research and Development Co., Ltd. v. ImClone Systems Inc., and Aventis Pharmaceuticals, Inc.

Yeda Research and Development Co., Ltd. v. ImClone Systems Inc., and Aventis Pharmaceuticals, Inc.

Epidural Blood Patch in a Patient Receiving Large Dose Enoxaparin (Lovenox)

To the Editor: There is very little information concerning the performance of epidural blood patches on patients receiving enoxaparin (Lovenox™; Aventis Pharmaceuticals, Somerville, NJ) with regard to the safety of the intervention as well as the effectiveness of the blood patch. We present a case in which a successful epidural blood patch was performed in a female patient taking 1.3 mg/kg of enoxaparin twice daily, 30 h after the last dose was given. A 39-yr-old female taking enoxaparin, 100 mg orally twice a day, underwent an uneventful lumbar puncture by her neurologist to exclude pseudotumor cerebri. Soon afterwards the patient developed a debilitating headache in the occipital region that became excruciating in the upright position. Her history was significant for deep venous thrombosis (DVT). The patient was treated with IV hydration and IV caffeine for 24 h without relief. Thirty hours after the last dose of enoxaparin, an epidural blood patch was performed with 20 mL of autologous blood with complete resolution of her postural headache. Low molecular weight heparinoids (LMWH) are increasingly prescribed for systemic anticoagulation therapy and DVT treatment and prophylaxis (1–3). Gaiser et al. (4) reported a partially successful epidural blood patch in a female patient 24 h after 190 mg of LMWH administered subcutaneously. There appears to be a predictable and reproducible dose response to enoxaparin when dosed on a weight-adjusted basis in small doses for thromboprophylaxis (5). With the lack of predictability at larger doses pharmacokinetic simulation is extremely difficult. The terminal half-life of plasma anti-Xa activity of enoxaparin is between 3–4 h. Therefore, we elected to wait for more than 7 half-lives to perform an epidural blood patch. To our knowledge, a successful epidural blood patch on a patient receiving enoxaparin more than 1.5 mg/kg/day has not been reported. Nalini Vadivelu, MD Craig Freiberg, MD James Kim, MD Mathew Wallace, MD Raymond Sinatra, MD, PhD Department of Anesthesiology Yale University School of Medicine New Haven, CT [email protected]

Pulmonary alveolar proteinosis associated with a disease‐modifying antirheumatoid arthritis drug

Pulmonary alveolar proteinosis is an uncommon disorder marked by the abnormal accumulation of surfactant within the alveoli. Secondary pulmonary alveolar proteinosis develops in patients who are immunosuppressed, usually with corticosteroids. We present a case of biopsy-proven pulmonary alveolar proteinosis in a patient undergoing therapy with the disease-modifying antirheumatoid arthritis drug leflunomide (Arava; Aventis Pharmaceuticals, Bridgewater, NJ). He was treated with whole lung lavage and discontinuation of leflunomide with good results. This is the first reported association of secondary pulmonary alveolar proteinosis with leflunomide therapy. Pulmonary alveolar proteinosis should be considered in patients with diffuse lung disease that develops while on disease-modifying antirheumatoid arthritis drug therapy.

NewFill for Skin Augmentation: A New Filler or Failure?

New injectable materials for skin augmentation that promise to be the ideal filling material are introduced every year. Recently, we treated three patients with adverse reactions to a new substance for skin augmentation: polylactic acid (NewFill, Ashford Aesthetics Inc, Belgium). To present three cases in which serious adverse reactions had occurred after skin augmentation with a new filling substance, polylactic acid (NewFill). Because an identical substance (Sculptra, Aventis Pharmaceuticals, Bridgewater, NJ, USA) was recently introduced in the United States, we want to alert future users of these substances to possible adverse events. We report three cases with serious adverse events more than 12 months after skin augmentation with polylactic acid (NewFill). They were treated with intralesional steroid therapy and topical imiquimod application. Both intralesional steroid therapy and topical imiquimod application lead to moderate results. If feasible, surgical excision is the best available option. Great care should be taken when polylactic acid is used for intradermal injection because giant cell granulomatous reactions may be the result. Other than surgical excision, effective treatment options are lacking.

Pharmacodynamic Evaluation of Meropenem and Cefotaxime for Pediatric Meningitis

To determine the probability of meropenem (Merrem, AstraZeneca Pharmaceuticals L.P., Wilmington, DE, USA) and cefotaxime (Claforan, Aventis Pharmaceuticals Inc., Bridgewater, NJ, USA) achieving bactericidal exposures in the cerebrospinal fluid against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. A 5,000-patient Monte Carlo simulation in a population of 10-year-old children with meningitis was conducted. Pediatric pharmacokinetic data were derived from the literature. Pathogen minimum inhibitory concentrations (MICs) were obtained from common bacteria that had caused meningitis collected during pediatric clinical trials. Time above the MIC exposures in the cerebrospinal fluid was calculated. Bactericidal exposure or probability of target attainment was defined as 40% and 50% time above the MIC for meropenem and cefotaxime, respectively. High cumulative fractions of responses were defined as >90% probability of target attainment against the populations of bacteria. Meropenem was calculated to achieve 94.7%, 94.3%, and 96.1% cumulative fractions of response against S. pneumoniae, H. influenzae, and N. meningitidis, respectively. Cefotaxime only achieved a high likelihood of bactericidal attainment against N. meningitidis (91.6%). Against S. pneumoniae and H. influenzae, cefotaxime was only calculated to achieve 84.3% and 84.8% cumulative fractions of response, respectively. In a simulated population of 10-year-old children, meropenem had a high likelihood of attaining bactericidal exposures in the cerebrospinal fluid. Cefotaxime had a >90% cumulative fraction of response against only N. meningitidis. Therefore, at the doses simulated, meropenem may be a more appropriate empiric choice for the treatment of bacterial meningitis in pediatric patients presumed to be caused by these pathogens until culture and susceptibility data are available.

Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes

To investigate the role of brain insulin action in the pathogenesis and treatment of diabetes, we asked whether neuronal insulin signaling is required for glucose-lowering during insulin treatment of diabetes. Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. We conclude that hypothalamic insulin signaling via the IRS-PI3K pathway is a key determinant of the response to insulin in the management of uncontrolled diabetes.

High-Risk Localized Prostate Cancer: Integrating Chemotherapy

Docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) is the first agent to significantly extend survival in hormone-refractory prostate cancer. Because agents active in advanced cancers tend to be beneficial in earlier stage disease, docetaxel is now to be assessed, along with hormonal therapy, in the adjuvant setting among patients whose localized prostate cancer has features that put them at particular risk for recurrence and cancer-specific mortality. Data from a pilot study suggest that neo-adjuvant treatment with docetaxel may be appropriate for selected high-risk patients and that such treatment can be undertaken without increasing surgical morbidity. Gene-expression profiling of tissue before and after docetaxel treatment is providing further insight into its effects. A randomized trial, conducted by the Cancer and Leukemia Group B, will evaluate neoadjuvant docetaxel in high-risk patients, whereby patients will be randomized to either immediate radical prostatectomy or surgery preceded by hormonal therapy plus docetaxel. Another large randomized trial will be evaluating the effect of adjuvant hormonal therapy with or without docetaxel in high-risk men after radical prostatectomy.

Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer

The taxanes docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) and paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) have significant clinical activity in metastatic breast cancer. A number of clinical trials have evaluated the tolerability and efficacy of weekly taxane administration to optimize the benefit-to-risk ratio in metastatic breast cancer. Single-agent studies with docetaxel and paclitaxel in metastatic breast cancer show clinically significant antitumor activity even in advanced, heavily pretreated, resistant, and/or refractory disease. This activity is also evident with taxane-based combination regimens. Severe hematologic and nonhematologic toxicities are infrequent, with other toxicities noted based on the dose and weekly regimen selected. Weekly docetaxel and paclitaxel regimens represent valuable therapeutic options for women with metastatic breast cancer and have entered evaluation as part of adjuvant therapy for this disease.

Gene-Expression Profiling and the Future of Adjuvant Therapy

Gene-expression profiling can help distinguish between patients at high risk and those at low risk for developing distant metastases, and so identify patients for adjuvant therapy. For several years, the Netherlands Cancer Institute has been working on gene-expression profiling of breast cancer using a microarray platform containing 25,000 genes. Using supervised classification, a prognostic classifier consisting of 70 genes could be identified. In addition to providing prognostic information, gene profiling should also enable us to detect patients who are likely to respond to particular adjuvant interventions. Well-known predictors for response to systemic therapy include estrogen receptor status HER-2 status, c-kit mutation, and epidermal growth factor receptor mutation. Because of the long periods required for predicting responsiveness in the adjuvant setting, neoadjuvant trials promise far quicker results. Several neoadjuvant studies are under way or planned to investigate gene-expression profiling as a means of predicting the therapeutic response to docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), cyclophosphamide, and doxorubicin (Adriamycin; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) in breast cancer patients. It is expected that in the coming years an increasing number of novel prognostic and predictive tests will help in guiding the adjuvant systemic treatment of breast cancer and other malignancies.

A Phase II Study of Induction Docetaxel/Cisplatin with rhG-CSF and Concurrent Pulsed Docetaxel Chemoradiation for Stage III Non-Small Cell Lung Cancer (NSCLC)

Purpose/Objective: Both local failure and distant metastasis remain the main causes of poor survival outcome in the era of combined chemoradiation (CRT) for stage III NSCLC. A previous institutional study employing pulsed low-dose paclitaxel radiosensitizing chemoradiation for stage III NSCLC has yielded a 100% gross tumor response rate and a 98% local tumor control rate for large tumors of stage III NSCLC. The remarkable gross tumor response rate and local control were associated with only a modest survival gain when compared with historical results (Clin Cancer Res 9: 969–975, 2003). We report a subsequent institutional protocol designed to target distant micro-metastasis by one-cycle of full-dose, two-drug induction chemotherapy (CT) up-front, without further delay of local therapy. Induction chemotherapy is followed by low-dose sensitizing docetaxel (Doc) chemoradiation for gross chest tumors. Materials/Methods: Patients with inoperable stage III NSCLC were eligible. Induction CT consisted of docetaxel 75mg/m2 and cisplatin (Cis) 75mg/m2 on day 1, followed by rhG-CSF (150 μg/m2 s.q. days 2–10). Concurrent chemoradiation started 3–6 weeks after induction CT. The originally planned Doc dose of 12 mg/m2, twice weekly with daily RT, was lowered to 10 mg/m2 midway through the study due to toxicity. RT dose was 64.8 Gy to gross tumor and 45–57.6 Gy to subclinical disease. All patients enrolled were followed for toxicity. Results: Twenty-two patients have been enrolled since 2/2002 and 2 are currently under treatment. All received induction CT, except 2 with an anaphylactic reaction to Doc. Fourteen completed both induction CT and CRT. Four did not complete therapy due to: Doc intolerance in 1, intercurrent illness in 1, and disease progression during therapy in 2. Toxicities of induction CT were: grade 3 allergic reaction (10%), grade 3 infection with normal ANC (20%), grade 3 nausea/vomiting (10%), grade 3 hypertension (5%) along with grade 3 hyperglycemia (5%), grade 4 hyperglycemia (5%), grade 3 headache (5%), grade 3 fatigue (10%), and grade 4 fatigue (5%) along with grade 3 dyspnea (5%). There was no grade 3 or 4 hematologic toxicity from induction CT. Toxicity from concurrent CRT was primarily esophagitis. Fifty percent of patients (4/8) who completed chemoradiation treatment at the initial twice-weekly Doc dose of 12 mg/m2 developed grade 3 esophagitis. Subsequent subjects received reduced Doc dose to 10 mg/m2 and no further grade 3 esophagitis was observed after Doc dose reduction. Other grade 3 toxicities from CRT were fatigue (14%), loss of appetite (14%), flushing (7%), chest pain (7%), diarrhea (7%), and nausea & vomiting (28%). No patient developed grade 3 or 4 pneumonitis or any grade 4 toxicity. Conclusions: Induction chemoradiation of one-cycle, full-dose Doc/cisplatin with rhG-CSF followed by concurrent pulsed low-dose Doc CRT is well tolerated with low hematologic toxicity. 50% of pts in the study experienced grade 3 esophageal toxicity at Doc dose of 12 mg/m2 from CRT, although published MTD of twice-weekly Doc CRT was 15 mg/m2. Grade 3 esophagitis was not observed after Doc dose reduction to 10 mg/m2. We will be analyzing the tumor response and preliminary survival end point of this study. The patterns of failure will be compared with the previous institutional study of pulsed low-dose paclitaxel CRT without the induction CT to derive information of any benefit from the addition of one-cycle induction chemotherapy in targeting distant micrometastasis. This study is partially supported by Aventis Pharmaceuticals.

FDA Drug Approval Summary: Pemetrexed for Injection (Alimta®) for the Treatment of Non-Small Cell Lung Cancer

On August 19, 2004, pemetrexed for injection (Alimta); Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy. Approval was primarily based on a single, controlled, unblinded trial. Five hundred seventy-one protocol-eligible patients were randomized to receive either pemetrexed or docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com). The primary efficacy end point was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm. Neither superiority nor noninferiority for overall survival could be demonstrated, the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression. Comparable response rates, 9.1% for pemetrexed and 8.8% for docetaxel, times to progressive disease, and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely, however. In addition, pemetrexed was felt to have a more favorable safety profile than docetaxel. Of greatest importance, pemetrexed caused significantly less neutropenia, febrile neutropenia, neutropenic infections, and need for granulocyte/macrophage colony-stimulating factors.

A pilot study: Combined treatment of docetaxel with 3-D conformal radiation therapy followed by docetaxel consolidation chemotherapy for men with intermediate/high-risk prostate cancer (IHPC)

4795 Background: More than 1/3 of the patients (pts) with clinically localized IHPC will relapse from their diseases after receiving initial treatment. This pilot study is to evaluate feasibility and tolerability of the combined chemoradiotherapy (CRT) and adjuvant chemo-consolidation (ACC) using Docetaxel in an attempt to reduce the rate of disease recurrence. Methods: 15 men with histologically confirmed localized adenocarcinoma of the prostate are to be enrolled in this trial. Eligible pts must have either (1) Intermediate-risk features (any two of the following: PSA 10–20 ng/ml; Gleason score 7; T2b, T2c, or T1c≥2/6 or 4/12 positive cores) or (2) High-risk features (PSA ≥ 20 ng/ml; Gleason score ≥ 8 or T3). The pts receive Docetaxel 20 mg/m2 iv at Week (W) 1, 2, 3, 4, 5 plus conformal pelvic radiation (4500 cGy, W1–5) and prostate boost (2700 cGy EBRT OR Brachythrapy, W6–8), followed by ACC with Docetaxel at 35 mg/m2 iv weekly starting at W13 given 3 of 4 weeks for 4 cycles. Results: Five pts were enrolled since 6/2004 (3 currently evaluable): the median age of 76 (range 68–80), mean PSA of 11.27 ng/ml (4.84–23) and the median Gleason score of 8 (7–9). Mean PSA decrease was 59% (75,75,26) and 92% (89,95) before the 1st ACC and 2nd ACC cycle (not androgen-deprived), respectively. Therapy was well tolerated: no grade (G) 4 or unexpected toxicities detected. Observed clinical and laboratory abnormalities include G1–2 fatigue (G1, 1/3 and G2, 1/3 pts)/proctitis (G1, 2/3 and G2, 1/3 pts) and G1 anemia (2/3 pts)/hyperglycemia (2/3 pts), respectively. There was one episode of afebrile, spontaneously resolved neutropenia (G2) without subsequent treatment delay. Abnormal liver function tests (LFT: ALT-G3, AST-G2 and TB-G1) were detected in 1/5 pts after the initial dose of chemotherapy. Repeat LFTs on the following day and thereafter were normal. Conclusions: This exploratory trial of the combined CRT and ACC for the pts with the IHPC appeared to be well tolerated and clinically feasible without causing a delay to deliver radiotherapy. Support: Aventis Pharmaceuticals, Inc. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

Neoadjuvant docetaxel (T), carboplatin (C), with or without trastuzumab (H) for T3 and T4 breast cancer

845 Background: The neoadjuvant systemic treatment for locally advanced breast cancer offers the best treatment and provides an ideal opportunity to study the anti-tumor activity of novel therapy. In recent years, taxanes and targeted therapy are gaining popularity in treating breast cancer. This study examines the efficacy of neoadjuvant docetaxel (Taxotere)/ carboplatin/ trastuzumab (Herceptin) in treating women with T3/T4 breast cancer. Methods: Twenty-eight women enrolled between Oct 2002 and June 2004 have successfully completed the neoadjuvant phase of their treatment consisting of four cycles of T/C with or without Herceptin. Results: Nineteen (67.9%) had T3 and nine (32.1%) had T4 breast cancer. Twenty-three (82.1%) had infiltrating ductal cancer and five (17.9%) had infiltrating lobular cancer with 20 (71.4%) high grade, six (21.4%) intermediate grade and two low grade (7.1%) according to the MBR scores. Sixteen (57.1%) were hormone receptor positive and twelve (42.9%) were ER-/PR-. Twelve (42.9%) had HER-2 amplified tumor. Clinical complete response (cCR) were observed in 11 (39.3%), partial response (cPR) in 16 (57.1%) and marginal response in one (3.6%). All five pathological complete response (pCR) were observed in patients with T3 breast cancer (26.3%). Six patients with HER-2 amplified tumor were randomized to receive preoperative T/C/H and the other six received T/C. Only one received T/C/H was among the pCR and the two in the T/C group had minimal residual tumor ≤ 0.1mm. Eight were converted from the originally planned mastectomy to breast conservation surgery and all had achieved tumor-free margins. Conclusion: Our study suggests T/C ± H is effective in treating women with locally advanced breast cancer. Supported by: PHS/NCI RO1 CA 93736–01A, Aventis Pharmaceuticals, Genentech, Inc., and “Friends of the Breast Program at UCLA” Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, Genentech

Leflunomide: long-term clinical experience and new uses

Leflunomide (Arava®, Aventis Pharmaceuticals) is an oral pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory activity. This agent has demonstrated significant efficacy in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis in randomised, double-blind, placebo-controlled trials. Both the efficacy and safety of leflunomide are maintained with long-term administration in patients with RA. Leflunomide compares favourably with other biological and non-biological agents used to treat RA in the incidence of adverse events and serious adverse events. Economic studies indicate that leflunomide is a cost-effective option in the treatment of RA. New investigations with leflunomide have focused mainly on combination regimens for the treatment of RA and the use of leflunomide in other inflammatory or autoimmune disorders.

Look-alike, sound-alike drug errors with Reminyl and Amaryl

Since Reminyl (galantamine hydrobromide, Janssen Pharmaceutica Products, L.P.) was introduced in the United States in 2001 for the treatment of mild to moderate Alzheimer’s disease, at least 10 Reminyl prescriptions have been incorrectly filled with Amaryl (glimepiride, Aventis Pharmaceuticals), a

Implementing a learning management system globally: An innovative change management approach

This article describes how Aventis Pharmaceuticals, in partnership with IBM, is implementing a learning management system (LMS) globally both in the Research and Development organization and in clinical groups within the Commercial Operations organization. It also discusses how Aventis is applying an innovative change management approach that meets challenges to this implementation globally across its matrix organization. The LMS relies on strong business involvement to keep the system current and relevant. Two critical organizational solutions in this effort involved establishing (1) a two-tiered governance structure to globally manage the system's consistency on business and technical levels and (2) a network of LMS contacts to provide the necessary business support and material content to keep the LMS relevant and current across geographical regions. Governance boards and LMS contacts enable global communication and coordination, creating a robust learning environment. After only one year, the LMS has achieved widespread acceptance within the organization and has been implemented in three target regions, allowing rapid response to organizational change and new business requirements, and placing the company in a strong competitive position. Aventis is currently exploring extension of the LMS to external partners.

Systems Biology: The Big Picture

Genomics, proteomics, and metabolomics have all vastly advanced our understanding of human biology and disease. But the functioning of even a simple system such as a single yeast cell or bacterium is much more complicated than the sum of its genes or proteins or metabolites; it’s the activity of all those components and their relationships to one another that add up to a living organism. Recognizing that complexity, the emerging field of systems biology attempts to harness the power of mathematics, engineering, and computer science to analyze and integrate data from all the “omics” and ultimately create working models of entire biological systems. “Traditionally, scientists—toxicologists included—have relied on a reductionist approach to biology,” says William Suk, director of the NIEHS Center for Risk and Integrated Sciences. Even now, many studies examine complex systems by looking at cellular components in isolation. For instance, a common experiment involves using DNA microarrays to observe the effect of a chemical exposure on thousands of genes at once. This technique can quickly tell a scientist which genes may be vulnerable to that exposure. But a systems biology approach would attempt to model not only the chemical’s effect on gene expression but also how that expression will affect protein function, and in turn how the exposure will affect cell signaling. “There’s nothing wrong with what we’ve been doing,” Suk says. “But systems biology is going to take it to another level.”

A Comparison of Bedtime Insulin Glargine with Bedtime Neutral Protamine Hagedorn Insulin in Patients with Type 2 Diabetes: Subgroup Analysis of Patients Taking Once-Daily Insulin in a Multicenter, Randomized, Parallel Group Study

Basal insulin is frequently administered once daily. This subgroup analysis of a multicenter, randomized, parallel study compared insulin glargine (Lantus Aventis Pharmaceuticals, Bridgewater, NJ) with neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes, evaluating only patients treated previously with once-daily NPH insulin. Patients received bedtime insulin glargine or NPH insulin, with preprandial regular insulin. One hundred patients (mean age, 57.9 years; mean glycohemoglobin, 8.4%; mean fasting blood glucose, 167 mg/dL) were treated for up to 28 weeks. Patients treated with insulin glargine (n = 52) and NPH insulin (n = 48) achieved similar reductions from baseline in glycohemoglobin (-0.41% versus -0.46%) and fasting blood glucose (-22 mg/dL versus -22 mg/dL) at week 28. The proportion of patients reaching target fasting blood glucose (<120 mg/dL) at 28 weeks was 34.2% with insulin glargine and 24.4% with NPH insulin. Similar proportions of patients achieved glycohemoglobin less than 7% and less than 8% in both groups. Baseline and week-28 mean daily doses of insulin glargine (27.3 IU versus 36.4 IU) were similar to NPH insulin doses (25.5 IU versus 30.2 IU). However, significantly fewer patients reported one or more episodes of hypoglycemia with insulin glargine (46.2%) versus NPH insulin (60.4%; P < 0.05). Significantly fewer patients also reported one or more symptomatic episodes confirmed by blood glucose less than 50 mg/dL with insulin glargine (17.3%) versus NPH insulin (31.3%; P < 0.005). Bedtime insulin glargine is as effective as bedtime NPH insulin in improving glycemic control, with significantly less hypoglycemia.