Wyeth Pharmaceuticals Research Articles

Antiamyloid Therapy: Is the Party Over?

Antiamyloid Therapy: Is the Party Over?

Will lutein supplementation of lactating women affect the lutein content of milk and the lutein content of maternal and preterm infant plasma?

Breast milk and blood were obtained from 38 lactating women. Twenty one of these women took a lutein supplement of 12 mg per day weeks five through eight of lactation. Blood was also obtained from five preterm infants whose mothers took the supplement. Breast milk and plasma carotenoids were analyzed by high‐pressure liquid chromatography. Maternal plasma lutein increased 241 percent after four weeks of the lutein supplement (10.6 ± 7.3 to 36.1 ± 13.1 mcg/dL (p=0.000). By four weeks post supplement, plasma lutein returned to baseline (10.4 ± 3.3 mcg/dL). Non‐supplemented women had no change in plasma lutein (10.1 ± 5.4 mcg/dL [4 wks], 9.8 ± 5.1 mcg/dL [8 wks], 10.3 ± 5.6 mcg/dL [12 wks]). Breast milk lutein content in non‐supplemented women was 4.3 ± 3.4 mcg/dL (4 wks), 3.8 ± 3.6 mcg/dL (8 wks) and 4.5 ± 5.1 mcg/dL (12 wks). Lutein‐supplemented women had breast milk lutein increase from 3.1 ± 2.7 to 11.0 ± 7.7, after only one week, to 14.5 ± 16.4 mcg/dL (p=0.011) after four weeks and returned to baseline four weeks post supplement (3.8 ± 4.3 mcg/dL). Plasma lutein increased 535 percent (1.7 ± 1.1 to 10.8 ± 1.8 mcg/dL) in the five breast‐fed preterm infants after supplementation of their mothers with lutein for four weeks. Giving a lutein supplement to lactating women produced a dramatic increase in the lutein content of their plasma and breast milk and in the lutein content of preterm infant plasma. USDA grant and Wyeth Pharmaceuticals

The National Cancer Coalition (NCC) and Wyeth Pharmaceuticals have announced a pilot programme to assist cancer patients in Latin America

The National Cancer Coalition (NCC) and Wyeth Pharmaceuticals have announced a pilot programme to assist cancer patients in Latin America

CancerScope

CancerScope

Effects of Training on Suicide Risk Assessment

This study evaluated the impact of structured training in evidence-based risk assessment for suicide. Forty-five psychiatry and psychology trainees participated in a workshop on evidence-based risk assessment. A comparison group of ten psychiatry trainees participated in a different workshop on the application of evidence-based medicine to psychiatry that was not focused specifically on risk assessment. Before and after each workshop, participants rated their skills in assessing patients' risk of suicide and wrote progress notes regarding clinical vignettes that included the assessment of and plan regarding suicide risk. Researchers systematically rated the progress notes. Participation in risk assessment training predicted improvement on specific indicators of documentation quality, ratings of the overall quality of documentation of suicide risk, and self-rated competence in suicide risk assessment. Structured clinical training in evidence-based risk assessment can improve documentation of assessment and management of patients' risk of suicide.

An Evaluation of Tigecycline and Comparators in Asia/Pacific Rim for Often Difficult to Treat Pathogens

We gratefully acknowledge contributions of the investigators, laboratory personnel and all members of the T.E.S.T. program group. This study was supported by a grant from Wyeth Pharmaceuticals. REFERENCES Includes K. pneumoniae, K. oxytoca, K. ornithinolytica, K. ozaenae, K. planticola, K. pneum/oxytoca. ESBL producing E. coli, K. pneumoniae and K. oxytoca only. Interpretive criteria as defined by FDA, where available and CLSI breakpoints, where available; na = not available. Table 2. In vitro activity of tigecycline and comparative agents against selected grampositive organisms.

Factor VIII and Factor IX Mutation Analysis in 600 U.S. Hemophilia Patients: Correlation of Mutation Type with History of Inhibitor

More than 600 U.S. hemophilia patients have been genotyped as part of the pilot study for a prospective surveillance system for factor inhibitors conducted at 12 U.S. Hemophilia Treatment Centers. 80% of enrolled subjects had hemophilia A, 58% with severe disease, 24% moderate, and 18% mild. Age ranged from <1 to 84 years. 83% were white, 8% black, and 4% Hispanic. In hemophilia A patients, all exons, all intron-exon junction regions, and the 3′ untranslated region of the factor VIII (F8) gene were resequenced in both directions by automated sequencer. The VariantSEQr™ protocol was used for resequencing on a 3730 DNA Analyzer from Applied Biosystems. The PCR primers and M13 sequencing primers are described at http://www.ncbi.nlm.nih.gov/sites/entrez?db=probe with a few modifications to the PCR primers to enhance throughput and reproducibility. Data were analyzed with SeqScape®. Inversions of intron 22 and intron 1 in the F8 gene were examined by PCR. Among 477 hemophilia A patients, missense mutations were found in 196 (41%), intron 22 inversions in 139 (29%), frameshifts in 50 (10%), nonsense mutations in 41 (9%), large deletions in 18 (4%), intron 1 inversions in 9 (2%), splice site changes in 5 (0.6%), and insertion in 1 (0.2%). Two mutations were identified in 4 (0.8%). No mutation was identified in 18 (4%). 124/139 of int22 inversions were reported to result in severe hemophilia, as well as 18/18 large deletions, 44/50 frameshifts, 37/41 nonsense mutations, and 8/9 int1 inversions. Of 196 missense mutations, 56 resulted in severe disease, 55 in moderate, and 80 in mild. History of inhibitor was reported in 79 patients, 22.4% of those with severe, 11.8% of those with moderate, and 2.4% of those with mild disease. Inhibitors occurred in 61% of those with large deletions, 26% of intron 22 inversions, 22% of nonsense mutations, 14% of frameshifts, 11% of intron 1 inversions, 6% of missense mutations, 20% of splice site changes, and 11% of those with no mutation identified. 173 distinct mutations were observed, 81 of which have not been reported previously in the Hemophilia A Mutation Database (HAMSTeRS). Among the patients enrolled in the study, black patients with hemophilia A were more likely to have a history of inhibitor than white patients (p=0.02). In hemophilia B patients, the promoter, coding regions, and intron-exon junctions of the factor IX (F9) gene were resequenced as above. Among 123 hemophilia B patients, 90 (73%) had missense mutations, 9 (7%) had frameshift mutations, 8 (7%) had nonsense mutations, and 3 (2%) had deletions. Two enrolled patients had history of FIX inhibitor, one with a large deletion and one a missense mutation. Centralized testing with high-throughput systems allows genotype to be used as a variable in ongoing studies of inhibitor risk.This project is supported by the CDC Foundation through a grant from Wyeth Pharmaceuticals, which had no role in data analysis or abstract preparation.

Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM.METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance.RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses.Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.

Raising the profile of arthritis and musculoskeletal conditions

Ros Meek is the Director of the Arthritis and Musculoskeletal Alliance (ARMA). She took over from Steve Milton, the interim Director, earlier this year. Ros has trained as a nurse, worked in professional bodies such as the Community Practitioners’ and Health Visitors’ Association (CPHVA) and Royal College of Nursing on primary care policy and nursing development, and latterly managed Government Affairs at Wyeth Pharmaceuticals.

Phosphorylcholine Impairs Susceptibility to Biofilm Formation of Hydrogel Contact Lenses

To compare silicone-hydrogel, poly(2-hydroxyethyl methacrylate) (pHEMA), and phosphorylcholine-coated (PC-C) contact lenses in terms of their susceptibility to biofilm formation by Staphylococcus epidermidis and Pseudomonas aeruginosa. Laboratory investigation. Biofilm formation on colonized test lenses was evaluated with confocal microscopy and in vitro antibiotic susceptibility assays. The results of the latter assays were compared with those performed on planktonic cultures of the same organism. For both microorganisms, sessile colonies on silicone-hydrogel and pHEMA lenses displayed lower antibiotic susceptibility than their planktonic counterparts. In contrast, the susceptibility of cultures growing on PC-C lenses was comparable with that for planktonic cultures. In particular, minimum inhibitory concentration for Tazocin (piperacillin plus tazobactam; Wyeth Pharmaceuticals, Aprilia, Italy; S. epidermidis) and gentamicin (P. aeruginosa) was identical, either in the presence of PC-C support or in planktonic cultures (Tazocin, </= 0.2 mug/ml; gentamicin, 0.4 mug/ml). Minimum inhibitory concentration for imipenem (P. aeruginosa) was two-fold higher for PC-C lenses (0.4 mug/ml) with respect to planktonic cultures (0.2 mug/ml). Confocal microscopy of lenses colonized for 24 hours with P. aeruginosa green fluorescent protein-expressing cells revealed a sessile colonization on silicone-hydrogel lens and a few isolated bacterial cells scattered widely over the surface of the PC-C lens. An increase in antibiotic susceptibility of bacterial cultures was associated with diminished bacterial adhesion. Our results indicate that PC-C lenses seem to be more resistant than silicone-hydrogel and pHEMA lenses to bacterial adhesion and colonization. This feature may facilitate their disinfection.

Wyeth Pharmaceuticals has announced that product shipments have begun for its plasma/albumin-free recombinant factor VIII, moroctocog-α [Xyntha

Wyeth Pharmaceuticals has announced that product shipments have begun for its plasma/albumin-free recombinant factor VIII, moroctocog-α [Xyntha

Ovarian follicular flushing among low-responding patients undergoing assisted reproductive technology

A randomized comparison trial was performed to evaluate whether follicular reaspiration with use of a double-lumen retrieval needle improves oocyte recovery when compared with direct follicular aspiration among low-responding patients undergoing ART. There were no differences observed in the number of oocytes retrieved (single lumen: 6.5 +/- 2.2 oocytes, double lumen: 7.2 +/- 2.3 oocytes) whereas follicular reaspiration with the double-lumen retrieval needle resulted in a twofold increase in procedure time.

The Food and Drug Administration Approves Methylnaltrexone Bromide for Opioid-Induced Constipation

The US Food and Drug Administration (FDA) on April 24, 2008, approved methylnaltrexone bromide (Relistor) to help restore bowel function in patients with late-stage, advanced illness who are receiving opioids on a continuous basis to help alleviate their pain. Opioids are often prescribed on a continuous basis for patients with late-stage, advanced illness to help alleviate pain. This includes patients with a diagnosis of incurable cancer, end-stage chronic obstructive pulmonary disease, congestive heart failure, Alzheimer's disease with dementia, HIV/AIDS, or other advanced illnesses. The FDA says methylnaltrexone bromide acts by blocking opioid entrance into the cells, thus allowing the bowels to continue to function normally. “This new drug will be helpful to patients who experience severe constipation associated with the continuous use of morphine or other opioids, which are an important part of care for patients with late-stage, advanced illness,” said Joyce Korvick, MD, deputy director of the Division of Gastroenterology Products at the FDA. Methylnaltrexone bromide is injectable and can be administered as needed, but not to exceed 1 dose in a 24-hour period. The recommended starting schedule is 1 dose every other day as needed for patients with late-stage, advanced illness. The drug is not recommended for patients with known or suspected intestinal obstruction. The FDA notes that common side effects include abdominal pain, gas, nausea, dizziness and diarrhea. “If severe diarrhea, vomiting, nausea or abdominal pain occurs while taking methylnaltrexone bromide, patients should discontinue use of the medication in consultation with their health care professional,” the agency cautions. The safety and effectiveness of the drug was demonstrated in clinical studies conducted by the sponsors. The 2 randomized, double-blind, placebo-controlled studies involving a total of 287 participants were conducted over a 4-month period. The median age of the study participants was 68 years, and 51% of the participants were women. In both studies, all patients had advanced, late-stage illnesses with a life expectancy of <6 months. Before treatment with methylnaltrexone bromide, participants had either <3 bowel movements in the week before treatment or no bowel movement for >2 days. Patients treated with the drug had a significantly higher rate of elimination than those receiving placebo. The safety and efficacy of methylnaltrexone bromide have not been studied in pediatric populations. The drug is manufactured by Wyeth Pharmaceuticals Inc., Philadelphia, and Progenics Pharmaceuticals, Tarrytown, New York.

Relistor approved for opioid-related constipation

FDA has approved the marketing of methylnaltrexone bromide subcutaneous injection for the treatment of opioid-induced constipation in adults receiving palliative care for advanced illness. The product is sold by Wyeth Pharmaceuticals under the brand name Relistor. FDA-approved labeling for

Wyeth Pharmaceuticals Supports ICAAC ID Fellows Grant Program

Wyeth Pharmaceuticals Supports ICAAC ID Fellows Grant Program

Analysis of response to methylnaltrexone by response to previous dose in advanced illness patients with opioid-induced constipation

9626 Background: Methylnaltrexone is a selective mu-opioid receptor antagonist that blocks peripheral opioid side effects without affecting central analgesia. A 2-week QOD subcutaneous (SC) dosing study in advanced illness patients with opioid-induced constipation (OIC) showed that significantly more patients treated with methylnaltrexone (48.4%; n=62) than placebo (15.5%; n=71) had a laxation response within 4 hours after the first double-blind dose (DDW 2006). Methods: This subanalysis compared the clinical response (rescue-free laxation within 4 hours post-dosing) between methylnaltrexone and placebo by clinical response to previous doses during the 7 doses of the double-blind phase. All patients who had all doses up to the dose being analyzed were included in the analyses. Two-sided Fisher’s exact test was used to compare response rates between methylnaltrexone and placebo. Results: Of patients who failed to respond to the first dose, 34% and 9% responded to the second dose of methylnaltrexone or placebo, respectively (p=0.006). Of those who failed to respond to the first 2 doses, 26% and 12% responded to the third dose of methylnaltrexone or placebo, respectively (p=0.16). Of patients who did not respond to the first 3 doses, 7% and 8% responded to the fourth dose of methylnaltrexone or placebo, respectively. For each of the doses 2 to 7, the response rate among patients who had responses to all previous doses ranged from 57% to 100% in the methylnaltrexone group vs 0% to 11% in the placebo group. For doses 3 to 7 in patients with only 1 non-laxation response to previous doses, the likelihood of responding to the next dose was 38% to 67% for methylnaltrexone and 0% to 9% for placebo. Conclusions: 57% to 100% of patients who responded to all prior doses continued to respond to subsequent SC methylnaltrexone treatment at QOD dosing over 2 weeks, indicating a predictable and sustainable response. For those failing to respond to the first dose or possibly the first 2 doses, more patients responded to methylnaltrexone than placebo on the subsequent dose. However, these data suggest that patients who failed to respond to the first 3 consecutive doses were unlikely to respond to subsequent doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Progenics Pharmaceuticals, Inc., Wyeth Pharmaceuticals Wyeth Pharmaceuticals Progenics Pharmaceuticals, Inc., Wyeth Pharmaceuticals Progenics Pharmaceuticals, Wyeth Pharmaceuticals Wyeth Pharmaceuticals

Lessons to Take Home From CATIE

Lessons to Take Home From CATIE

Additional antihemophilic factor to be available

FDA announced February 21 that it approved the license for Wyeth Pharmaceuticals Inc. to manufacture Xyntha, a recombinant antihemophilic factor produced without plasma and albumin. A Wyeth spokesman said the company expects to introduce the product in the United States by the third quarter of 2008

Psychiatrists, Patients Disagree About Extent of Communication

Psychiatrists, Patients Disagree About Extent of Communication

Psychiatrists, Seriously Ill Patients Need to Improve Communication

Psychiatrists, Seriously Ill Patients Need to Improve Communication