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Biomedical subjects

B Schwartz

Publications and source records attributed to B Schwartz.

At least 19 recordsLinked to original sources
PubMed2007

Loss of AP-2alpha results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo.

Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2alpha in colon cancer progression. We provide evidence for the lack of AP-2alpha expression in the late stages of colon cancer cells. Re-expression of the AP-2alpha gene in the AP-2alpha-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2alpha in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2alpha resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5-14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2alpha. Chromatin immunoprecipitation assay showed that re-expressed AP-2alpha directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2alpha binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2alpha acts as a tumor suppressor gene in colon cancer..

Animals↗
PubMed2006

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

Adult↗
PubMed2006

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Adult↗
PubMed2006

A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group Study.

OBJECTIVE: BAY 12-9566 (tanomastat) is a biphenyl matrix metalloprotease inhibitor (MMPI) with antiangiogenic and antimetastatic properties in vivo. The objective of the study was to determine whether the addition of BAY 12-9566 after optimal response to chemotherapy could improve time to progression (TTP). PATIENTS AND METHODS: Patients enrolled in the study had received 6-9 cycles of platinum/paclitaxel containing chemotherapy for stage III or IV ovarian carcinoma, with a response of no evidence of disease, or complete or partial response with residual disease < 2 cm. Patients were then randomized to BAY 12-9566 800 mg p.o. b.i.d. or placebo. The primary endpoint was progression-free survival (PFS); secondary endpoints were quality of life, toxicity, changes in CA 125 levels, response, and overall survival (OS). The total planned sample size was 730. RESULTS: The study was closed after 243 patients had been randomized because of Bayer's decision to close all ongoing trials due to negative results from other phase III trials in pancreatic and small cell lung cancer. The final analysis was performed in August 2000 after the requisite number of events for the first planned interim analysis had occurred; 54% of patients had progressed and 18% had died. PATIENT CHARACTERISTICS: performance status was ECOG 0/1/2 in 65/33/2%; median age 57 years; 79% of patients were FIGO stage III; 41% were optimally debulked; 76% had serous histology, and 67% had > or = grade 3 histology. Toxicity was generally grade 1 or 2 in severity, with the most common (BAY 12-9566 vs. placebo) being nausea (26% vs. 13%), fatigue (24% vs. 12%), diarrhea (14% vs. 10%), rash (12% vs. 7%), grade 3/4 thrombocytopenia (3% vs. 1%), and grade 3/4 anemia (5% vs. 1%). Median time to progression (TTP) was 10.4 months (8.5-11.5) for BAY 12-9566 and 9.2 months (7.2-13.9) for placebo (P = 0.67). Median overall survival (OS) was 13.9 months (12.9-infinity) for BAY 12-9566 and 11.9 months (10.5-16.5) for placebo (P = 0.53). CONCLUSION: We conclude that BAY 12-9566 was generally well tolerated and at the time of the final analysis, there was no evidence of an impact of BAY 12-9566 on PFS or OS.

Adult↗
PubMed2006

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Administration, Oral↗
PubMed2006

Mass vaccination for annual and pandemic influenza.

Influenza virus causes annual epidemics and occasional pandemics. Frequent mutations in circulating influenza strains ("antigenic drift") result in the need for annual vaccination. More than two-thirds of persons in the U.S. are recommended for annual vaccination. Because influenza vaccine is available seasonally, mass vaccination strategies are well suited to its delivery. Although doctors offices are the most frequent setting for influenza vaccination overall, workplaces, clinics, and community sites (retail stores and pharmacies) also are common vaccination settings. Influenza vaccination also is delivered in mass vaccination clinics to health care workers and military personnel. Universal influenza vaccination, which has been recommended as a strategy to improve prevention by increasing vaccination coverage and providing indirect protection of adults by decreasing infection and transmission among children, would require expanded use of mass vaccination, for example in schools, as well as in the community. Influenza pandemics occur when a new influenza A subtype is introduced into the population ("antigenic shift"). Most or all of the population is susceptible to the pandemic virus and two doses of vaccine may be needed for protection. U.S. pandemic preparedness and response plans indicate that the entire population should be vaccinated beginning with defined priority groups including those who provide essential services including healthcare and those at highest risk of severe illness and death. Pandemic influenza vaccination will occur primarily through the public sector in mass clinic settings. Vaccination program planning must consider issues including coordination, staffing, clinic location and lay-out, security, record keeping, and communications. Exercising vaccination clinics is important for preparedness and can be done in the context of annual influenza vaccination.

Communication↗
PubMed2005

Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors.

BACKGROUND: BAY 43--9006, an oral multi-kinase inhibitor, targets serine-threonine kinases and receptor tyrosine kinases, and affects the tumor and vasculature in preclinical models. Based on its pharmacologic effect, it may be a useful cancer treatment. This study determined the maximum tolerated dose (MTD) of BAY 43-9006 in 42 patients with advanced, refractory metastatic or recurrent solid tumors. Dose-limiting toxicities (DLTs), safety, pharmacokinetics and tumor response were also evaluated. PATIENTS AND METHODS: In this open-label, phase I, dose-escalation study, BAY 43--9,006 was administered orally in repeated cycles of 35 days (28 days on/7 days off). Eight doses were investigated: from 50 mg every fourth day to 600 mg twice daily. Treatment continued until unacceptable toxicity, tumor progression or death. RESULTS: The MTD was 400 mg twice daily. BAY 43-9006 was well tolerated, with mild to moderate toxicities; only six patients discontinued study therapy due to adverse events. DLTs consisted of hand-foot skin reaction in three of seven patients receiving 600 mg twice daily. Stable disease was achieved in 22% of patients; median duration of stable disease was 7.2 months. Consistent with its observed half-life of approximately 27 h, BAY 43-9, 006 accumulated on multiple dosing. Increases in exposure were less than proportional to the increases in dose. CONCLUSIONS: Results indicate that further clinical investigation of BAY 43--9006 is warranted, and suggest it could be a promising future therapy for patients with cancer.

Administration, Oral↗
PubMed2005

Hospital-acquired invasive group a streptococcal infections in Ontario, Canada, 1992-2000.

BACKGROUND: A significant proportion of invasive group A streptococcal infections are hospital acquired. No large, prospective studies have characterized this subgroup of cases and evaluated the risk of transmission in hospitals. METHODS: We conducted prospective, population-based surveillance of invasive group A streptococcal infections in Ontario, Canada, from 1992 to 2000. Epidemiologic and microbiologic investigations were conducted to identify cross-transmission. RESULTS: We identified 291 hospital-acquired cases (12.4%) among 2351 cases of invasive group A streptococcal disease. Hospital-acquired invasive group A streptococcal infections are heterogeneous, including surgical site (96 cases), postpartum (86 cases), and nonsurgical, nonobstetrical infections (109 cases). Surgical site infections affected 1 of 100,000 surgical procedures and involved all organ systems. Postpartum infections occurred at a rate of 0.7 cases per 10,000 live births and exhibited an excellent prognosis. Nonsurgical, nonobstetrical infections encompassed a broad range of infectious syndromes (case-fatality rate, 37%). Nine percent of cases were associated with in-hospital transmission. Transmission occurred from 3 of 142 patients with community-acquired cases of necrotizing fasciitis requiring intensive care unit (ICU) admission, compared with 1 of 367 patients with community-acquired cases without necrotizing fasciitis admitted to the ICU and 1 of 1551 patients with other cases (P<.001). Fifteen outbreaks were identified; 9 (60%) involved only 2 cases. Hospital staff were infected in 1 of 15 outbreaks, but colonized staff were identified in 6 (60%) of 10 investigations in which staff were screened. CONCLUSIONS: Presentation of hospital-associated invasive group A streptococcal infections is diverse. Cross-transmission is common; illness occurs in patients but rarely in staff. Isolation of new cases of necrotizing fasciitis and intervention after a single nosocomial case may also prevent transmission.

Adult↗
PubMed2005

Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours.

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.

Adult↗
PubMed2005

An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin.

BACKGROUND: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies. PATIENTS AND METHODS: 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m(2), 60 mg/m(2) and 70 mg/m(2)) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred. RESULTS: Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC(0-12h) levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m(2) was declared. These toxicities were those that would have been expected from doxorubicin alone. CONCLUSIONS: BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m(2), however, further development of BAY 12-9566 has been abandoned.

Adult↗
PubMed2005

How often should a port-A-cath be flushed?

While it is important during treatment to flush the port-A-cath (PAC) with heparin regularly, catheter maintenance needs to be evaluated in those patients who, after completion of therapy, retained their ports for extended periods of time. The manufacturer has recommended monthly accession to maintain catheter patency and function. Our objective is to demonstrate that a longer interval between maintenance accessions of PACs still may be medically safe, convenient, and more efficient. We performed a retrospective review of all patients who had undergone PAC insertion from 1988 to 1993 at the Albert Einstein College of Medicine, and from 1997 to 2002 at the New York Hospital Medical Center of Queens. An adequate maintenance time is defined as a period of at least 6 months without chemotherapy or total parenteral nutrition. Data collected included date and location of PAC insertion, date of PAC accessions, PAC complications, and results of attempts at flushing the catheters with no venous blood return. All data were entered into an Excel spreadsheet and analyzed. The difference in interval accessions in patients without any complication to patients with complication was calculated using the Mann-Whitney "U" test. A total of 73 patients were included in the study. Compliance with visits for PAC maintenance varied considerably with the individual median accession times varying between 28 and 262 days with an overall median of 42 days. The individual means ranged from 29.5 to 244 days with an overall mean of 53.6 days. Seven patients in the group had episodes where the provider was unable to draw blood from the port during routine accession. The average intervals between accessions for each of these patients ranged from 38 to 244 days. The average intervals of accession among those patients who had no blood return during PAC accession was 79 days, versus 63 days for those without any difficulty. The difference was not statistically significant (p>0.05). Monthly maintenance of PAC is excessive, inconvenient for the patients, and expensive. Extending the interval of PAC maintenance proves to be medically safe and beneficial to the patients, the physicians and the health care system. Our clinical experience suggests that less frequent accessions of PACs is safe and feasible. We strongly advocate future prospective investigation of alternative PAC maintenance protocols in gynecologic cancer patients.

Catheterization, Central Venous↗
PubMed2004

HTS magnetometers for fetal magnetocardiography.

High temperature superconducting (HTS) SQUID sensors have adequate magnetic field sensitivity for adult magnetocardiography (MCG) measurements, but it remains to be seen how well they perform for fetal MCG (fMCG), where the heart signals are typically ten times smaller than the adult signals. In this study, we assess the performance of a prototype HTS SQUID system; namely, a three-SQUID gradiometer formed from three vertically-aligned HTS dc-SQUID magnetometers integrated into a fiberglass liquid nitrogen dewar of diameter 12.5 cm and height 30 cm. Axial gradiometers with short or long baseline, as well as a second order gradiometer, can be formed out of these magnetometers via electronic subtraction. The calibrated magnetometer sensitivities at 1 kHz are 109 fT/square root of Hz, 155 fT/square root of Hz and 51 fT/square root of Hz. Direct comparison is made between the HTS SQUID system and a LTS SQUID system by making recordings with both systems during the same session on adult and fetal subjects. Although the fMCG could be resolved with the HTS SQUID system in most near-term subjects, the signal-to-noise ratio was relatively low and the system could not be operated outside of a shielded room.

Cardiotocography↗
PubMed2003

Clinical criteria for the switch of treatment strategies in Parkinson's disease.

Along the years the treatment of Parkinson's disease with L-dopa has revealed unfavorable effects in general after 5-10 years. This has led to the present criteria for treatment of de novo patients that mainly relay on the age, the general strategy being to delay the use of L-dopa as long as possible. However, this practical approach lacks a scientific basis. In a retrospective study data of 155 patients with Parkinson's disease were analyzed with the goal of finding a clinical marker for the critical time point when L-dopa needs to be administrated. The clinical stage of the patients was assessed using the Hoehn and Yahr (H&Y) scale and the severity of the symptoms was measured using the UPDRS score. The results show that there was no relationship between the age of the patients and the therapy (L-dopa vs. no L-dopa) with regard to the clinical outcome. A significant interaction was found however, between the clinical stage (H&Y) and the therapy. Further analysis of this interaction showed that in the H&Y Stages 1-2.5 the UPDRS scores were lower in the patient groups treated without L-dopa. Remarkably, in the H&Y stages 3 and higher the UPDRS scores were lower in the patient groups treated with L-dopa. These results suggest that the clinical stage of the disease (H&Y) might be a better criterion than the age for the time point when L-dopa needs to be administered in de novo patients.

Adult↗
PubMed2003

Cystic fibrosis transmembrane conductance regulator and Na+ channel subunits mRNA transcripts, and Cl- efflux, show a different distribution in rat duodenum and colon.

AIM: We compared the distribution and putative association of Cl- channel transport, CFTR mRNA transcripts, and Na+ channel (ENaC) alpha- and beta-subunit mRNA transcripts in villus and crypt epithelial cells of duodenum, with corresponding surface and crypt cells of colon from sodium-depleted rats. METHODS: Cells were loaded with 36Cl- and forskolin-stimulated efflux was determined. RT-PCR was performed for CFTR mRNA transcripts and ENaC alpha- and beta-subunit mRNA. Duodenal epithelial cell response to VIP was assessed by measuring intracellular cAMP. RESULTS: Forskolin-stimulated Cl- efflux occurred with decreasing magnitude in duodenal crypt, duodenal villus, colonic crypt and colonic surface cells in Na(+)-depleted animals. CFTR expression was correlated directly with Cl- efflux (r=0.91, P<0.01). Na+ channel alpha-subunit was expressed in colon and duodenum in animals fed diets with a high or low sodium content. While the beta-subunit mRNA was detected in the colon of sodium-restricted rats, it was absent in the duodenum under control conditions and after Na+ restriction. There was an inverse correlation between mRNA transcripts for CFTR and the ENaC alpha-subunit (r=-0.93, P<0.003) and beta-subunit (r=-0.91, P<0.004) in colon. VIP-stimulated cAMP in duodenal epithelial cells was greater in crypt than villus (P<0.05). CONCLUSION: Cl- efflux, CFTR transcription and forskolin-stimulated cAMP activity occur in both crypt and villus epithelial cells in duodenum. Possible interaction between CFTR and Na+ channels is apparently limited to parts of the colonic crypt. Lack of duodenal beta-subunit expression makes ENaC activity unlikely.

Animals↗
PubMed2003

Prophylaxis in factor IX deficiency product and patient variation.

To determine the dosing needed to maintain a prophylactic level of factor IX (FIX) >/=2%, 15 non-inhibitor severe (</=1% FIX) deficient subjects participated in a double-blind, two-period crossover study to assess the pharmacokinetics of two FIX concentrates, Mononine (pd-FIX), an ultra-high-purity plasma-derived concentrate, and BeneFix (r-FIX), a recombinant product. The median recovery in the pd-FIX group was 1.67 IU dL(-1) per IU kg-1+/-1.07 vs. 0.86 IU dL(-1) per IU kg(-1)+/-0.32 in the r-FIX group (P = 0.0002). The median half-life for pd-FIX was 12.9 +/-1.7 h compared with 13.7 +/- 2.9 h for r-FIX (P = 0.016). Fitted dose activity curves were computer-simulated to depict multiple-dose activity curves for each patient with each product that would maintain prophylactic levels of >/=2%. Based on pharmacokinetic analysis the median amount of concentrate needed to maintain a prophylactic level >/=2% for 30 days when administered every third day is 677 IU kg(-1) pd-FIX (range 388-6005 IU kg(-1) pd-FIX) compared with 1168 IU kg(-1) r-FIX (range 268-13085 IU kg(-1) r-FIX). The median cost for 30 days of prophylaxis of an average 25-kg 8-year-old child at the current University of Iowa Price (0.87 US dollars Mononine/0.86 US dollars BeneFix as of December 2002) if given every third day would be 19,972 US dollars and 34,456 US dollars for r-FIX. However, because of wide inter-patient variability in recovery and half-life, pharmacokinetic evaluation of each patient is necessary to determine the appropriate dosing schedule and product best suited for prophylaxis.

Adolescent↗
PubMed2002

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line.

Over-expression of the adhesion molecule CD44 and its splice variants, especially CD44v6, is associated with poor prognosis and metastasis. We aimed at regulating the expression of CD44 in the highly metastatic human colon cancer cell line HM7 and thereby affecting its metastatic ability. HM7 cells show constitutive expression of CD44 standard and variants isoforms, which were significantly down-regulated by treatment with butyrate. Butyrate significantly inhibited transcription of the CD44 gene and abolished epidermal growth factor-mediated up-regulation of the reporter gene luciferase subcloned upstream to the CD44 promoter (-1.1 kb) and transfected to HM7 cells. Nuclear proteins from butyrate-treated cells bound to an epidermal growth factor receptor element motif present in the CD44 promoter. Epidermal growth factor receptor element-site directed mutations eliminated the inducibility of the luciferase reporter gene and did not allowed binding of nuclear proteins harvested from butyrate-treated cells. Butyrate induced CD44 gene repression by specifically interacting with an epidermal growth factor receptor element nuclear transcriptional factor. This interaction affects CD44 transcriptional activity vis-à-vis in vivo metastatic ability of HM7 cells. These results provide additional insight into the anticarcinogenic properties of butyrate.

Butyrates↗