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3583 Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies. [Table: see text]

2561 Background: Preclinical studies showed sequence dependent synergy of the combination of topoisomerase I inhibitors and platinum agents. This trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of carboplatin (carbo) and topotecan (topo) in patients (pts) with solid malignancies in two different schedules. Methods: In part 1, pts received carbo as a 60 min IV infusion on day 1 and topo as a 30 min IV infusion on days 1, 2 and 3 (C→T). The sequence of drug administration was reversed in part 2 of the study (T→C): topo on days 1, 2, and 3, followed by carbo on day 3. In both schedules, the PK was determined of each agent in plasma and the TopI catalytic activity and Pt-DNA adducts in white blood cells (WBC) and tumor tissue. Results: 41 pts were included in this trial. Dose-limiting toxicities (DLTs) during C→T included grade (G) 4 thrombocytopenia and febrile neutropenia. The MTD was reached at carbo target AUC 4 min.mg/mL and topo 0.5 mg/m2/day. DLTs during T→C included G4 neutropenia, thrombocytopenia and neutropenic fever, G3 nausea and G4 vomiting. Carbo target AUC 6 min.mg/mL and topo 0.9 mg/m2/day was the MTD in this schedule. No schedule dependent differences in PK were found (clearance (Cl) of unbound carbo: 0.6 vs 0.7 mL/min, p=0.14; Cl of total topo: 24.1 vs 29.6 L/h, p=0.08; Cl of topo lactone: 84.5 vs 83.7 L/h, p=0.96). WBC and tumor samples were collected from 30 and 27 pts, respectively. Pt-DNA levels were not schedule dependent in WBC (range C→T = 0.44–4.13, and T→C = 0.22–6.07 fmol*h/μg DNA) and in tumor tissue (range C→T = 0.20–0.96, and T→C = 0.62–1.8 fmol/μg DNA). Also, no schedule dependent effects were seen in TopI catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. One pt with ovarian cancer had a complete response (T→C schedule), 2 pts with ovarian cancer (C→T schedule) and 3 pts treated in the T→C schedule (ovarian, SCLC and gastric cancer) had a partial response. Conclusions: T→C was better tolerated as both hematological and non-hematological toxicities were milder. Other than the investigated PD factors must explain the schedule dependent differences in toxicities. No significant financial relationships to disclose.

3515 Background: Sunitinib (SU) is a tyrosine kinase inhibitor (TKI) with activity against vascular endothelial growth factor receptors (VEGFR). During VEGFR TKI withdrawal, increase in pain at sit...

3533 Background: AT7519M is a structure-based rationally designed Nan molar small molecular Cyclin-dependent Kinase (CDK) inhibitor (CDK 1, 2, 4, 5). It has been evaluated in a first in human trial...

2517 Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes and have been linked to tumorigenesis. Aurora kinase A is commonly amplifie...

6070 Background: Nimotuzumab (N) is a humanized MAb to EGFR that has shown evidence of efficacy in patients (pts) with advanced solid tumors, notably without provoking skin rash. Although lack of r...

3002 Background: Increased IGF-1 signaling mediates tumor proliferation, reduces apoptosis, and correlates with higher incidence and progression of common cancers. AMG 479, a fully human monoclonal antibody against IGF-1R, exhibited broad antitumor activity in xenograft models, both as a monotherapy and with chemotherapy. Methods: Patients (pts) entered escalating dose cohorts of AMG 479 (from 1 to 20 mg/kg administered intravenously [IV] every two weeks [Q2W]). Study objectives were to determine safety, maximum tolerated dose (MTD), pharmacokinetic (PK) parameters, pharmacodynamic (PD) parameters of tumor glucose metabolism (FDG PET/CT), human anti- AMG 479 antibody formation, IGF-1R occupancy in neutrophils, and tumor response (CT RECIST, and PET/CT criteria). Results: Sixteen pts with advanced malignancies were treated with doses from 1 to 20 mg/kg. The median number of cycles was 3 (range 1 to 16). Grade 3 thrombocytopenia was considered dose limiting in 1 pt at 20 mg/kg. Other grade 3/4 non-hematologic toxicities were observed in 2 pts; no hyperglycemia greater than grade 2 was observed. Anti-AMG 479 antibodies, but not neutralizing antibodies, were detected in 1 pt. One pt had an infusion reaction (grade 2 chills/rigors resolving in 15 minutes) but could be retreated following premedication. AMG 479 exhibited dose-linear PK in the dose range from 1 to 20 mg/kg, reaching steady state after 3 doses; mean terminal t1/2 ranged from 7 to 11 days; mean serum clearance ranged from 9 to 14 mL/day/kg; Css exceeded IC90 measured in preclinical models. PD results indicated a trend to dose-proportional occupancy of IGF-1R in neutrophils and increased levels of serum IGF-1 and IGF-BP3 (40% and 20% on day 3, respectively). By CT RECIST criteria, 1 pt with a neuroendocrine tumor had a confirmed partial response and 5 pts had durable stable disease. By FDG-PET/CT criteria, 1 pt with breast cancer had a mixed response. Conclusions: AMG 479 appears to be well tolerated at doses up to 20 mg/kg IV Q2W; dose escalation is complete. AMG 479 administration resulted in PK values adequate for activity in preclinical models, saturable binding of IGF-1R in neutrophils, and preliminary anti-tumor activity. [Table: see text]

6021 Background: EGFR activation up-regulates VEGF, which has been correlated with resistance to anti-EGFR agents. We previously reported early results (Vokes, JCO, 2005) of a phase I-II study of the EGFR inhibitor erlotinib (E) with the VEGF antibody bevacizumab (B) in recurrent or metastatic HNC. We now present results from the pharmacodynamic analysis as well as updated outcome data. Methods: Phase I/II trial of fixed dose erlotinib (E) 150 mg orally daily with escalation of bevacizumab (B) to a maximum of 15 mg/kg q 3 weeks and continued at 15 mg/kg in the phase II portion. Pts were randomized to receive the initial bevacizumab dose on either day 1 or 15. Paired biopsies were taken at baseline and after 2 weeks of treatment (after E alone or E+B) and analyzed by immunofluorescence and laser scanning analysis for target inhibition and apoptosis markers (VEGFR2/KDR, EGFR, CD31, and respective activated forms [pKDR, pEGFR]). Results: Paired biopsies were available from 20 patients. At baseline pKDR/KDR (ratio) correlated with clinical outcome and differed significantly between responses (CR>SD: pPD: pPD: p No significant financial relationships to disclose.

14030 Background: Nimotuzumab (N) is a humanized mAb against the EGFR extracellular ligand binding domain. Although well tolerated when combined with radiotherapy in previous studies and lacking usual toxicities of EGFR-targeting agents, the pharmacodynamics (PD) of N has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of N. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and ECOG PS = 0 - 2. IV N was administered weekly x 6 and then every other week (6 weeks = 1 treatment cycle). Tumor, skin and liver biopsies obtained pre- and 2 and 7 weeks post-treatment were evaluated using computer-based, whole mount assessment of immunohistochemical staining. Results: Accrual was completed 21/09/06, 17 patients (11m/6f, median age 63, 13 colorectal cancer, ECOG 0:1:2 = 6:10:1, prior therapy 1:2:3+ = 2:6:9) were registered and 16 patients were treated on 4 dose levels (100, 200, 400 and 800 mg) for a total of 43 treatment cycles (1 patient deemed ineligible after registration did not receive study therapy). Treatment was well tolerated. One dose-limiting toxicity was observed (dose level 1 - grade 3 fatigue possibly attributable to N) . Skin toxicity was mild (Gr 1/2 in 7/1 patients). Confirmed stable disease was seen in 6 patients, a confirmed partial response in 1 patient with prolonged progression-free status observed in 3 patients for 5.8, 14.1 and 18.7 months (the latter two remain on study). Baseline and week 2 biopsies of tumor/skin/liver were evaluable in 12/13/7 pts. Week 7 tumor/skin/liver biopsies in initially responding or stable patients were evaluable in 6/8/6 pts. Post treatment (week 2), EGFR staining decreased in 8/12 matched tumor [mean ratio (post/pre): 0.79 range: (0.37, 1.91)], 8/13 skin [0.96 (0.40, 1.31)] and 5/7 liver [0.88 (0.62, 1.17)] biopsies. No significant relationship was detected between pre/post-treatment EGFR expression with either response or toxicity. Evaluation of downstream targets of EGFR (in tumor, skin and liver) is ongoing and will be presented. Conclusions: Overall nimotuzumab was well tolerated and exhibits mild skin toxicity. Prolonged progression free-survival was observed in 3/16 of these heavily pre-treated patients. No significant financial relationships to disclose.

3512 Background: The combination of S and T is hypothesized to maximize pathway inhibition by concurrently targeting parallel signaling mechanisms and will abrogate potential resistance mechanisms directed towards the MAPK pathway through increased signaling via the survival pathway involving PI3K/Akt. Methods: Eligible patients (pts) were treated with escalating continuous oral doses of S (200 and 400 mg BID) and weekly T IV (15 mg, 25 mg). S began on day 8 of course 1 to permit PK evaluations of T. PD studies in PBMCs were performed serially in pts. Results: To date, 24 evaluable pts have received 85 courses [median 3;range1–12] in the following S/T dose cohorts; cohort 1: 200 mg/15 mg (n=6), cohort 2: 400 mg/15 mg (n=11), cohort 3: 400 mg/25 mg (n=6), and cohort 4: 200 mg/25 mg (n=1). Patients demographics were males/female 11/13, median age 54.5 [range 27–71] and PS of 0/1/2 : n=9/13/2. Dose limiting toxicities (DLT) were grade 3 typhlitis in 1/6 pts in cohort 1, and mucositis in 1/6 pts in cohort 2. Expansion of cohort 2 to 11 patients resulted in 4 additional DLTs (hand foot syndrome (HFS) x 2 pts, thrombycytopenia/rash x 1 pt, creatinine elevation x 1 pt). 3 of 6 pts in cohort 3 experienced DLT (HFS x 2 pts, thrombocytopenia x 1 pt). PK analyses show no evidence of S effect on T kinetics while Css,min values of S are consistent with those reported in single-agent studies (S 200mg BID median Css,min 4.42 μg/mL [SD 3.05], S 400 mg BID median Css,min 5.11 μg/mL [SD 4.35]). Apparent downregulation of 4E-BP1 and activated forms of p70S6 kinase and ERK was observed in some patients following treatment. Partial responses have occurred in NHL (1 pt) and papillary thyroid cancer (1 pt) and prolonged SD (> 12 mo) has been observed in RCC (1 pt). Conclusions: The combination of S and T demonstrate significant mucocutaneous toxicity at full doses of S, however preliminary PK analyses show no evidence of drug-drug interactions. Characterization of an intermediate dose of S 200 mg BID/T 25 mg IV is ongoing. [Table: see text]

Background Sorafenib is an oral antiangiogenic agent with activity in renal cell cancer (RCC). We conducted a randomized, placebo-controlled trial to investigate if dynamic contrast-enhanced MRI (DCE-MRI) is a pharmacodynamic (PD) marker for sorafenib. Method Patients were randomized in a double-blind manner to placebo, 200 mg bid sorafenib, or 400 mg bid sorafenib. DCE-MRI was performed at baseline and after 28 days of therapy, at which time placebo patients were rerandomized to low- or standard-dose sorafenib. RECIST-based progression was determined by CT scans performed every 12 weeks. DCE-MRI parameters, including the area under the contrast concentration versus time curve for 90 seconds after contrast injection (IAUC90), were calculated for a tumor region of interest in a blinded manner. Plasma steady-state sorafenib concentrations were obtained on day 28. Results To date, 43 of a planned 66 patients have been enrolled, and 34 have undergone two protocol-defined MRIs, of which 33 are technically evaluable for the study end points. All analyses were conducted using the log ratio of the mean IAUC90 at 4 weeks versus the mean at baseline. The estimates of the log ratio and the corresponding standard deviations in the placebo, 200 mg, and 400 mg cohorts were 0.032 (± 0.235), −0.066 (± 0.138), and −0.281 (± 0.430), respectively (p = .0156 for linear trend between dose and the log ratio of IAUC90). These correspond to relative changes of +3%, −6%, and −24% in the placebo, 200 mg, and 400 mg cohorts, respectively. In the 27 patients with available plasma sorafenib levels, change in IAUC90 did not correlate with sorafenib steady-state levels (p = .7507). Current median follow-up is 20 weeks. Using a Cox proportional hazards model, IAUC90 change is not a significant predictor of progression-free survival (p = .229). The mean arterial pressure increased with sorafenib dose, but no correlation with IAUC90 change was detected (p = .445). Conclusions DCE-MRI is a PD marker for sorafenib, and intrapatient variability is similar to previous reports, but the magnitude of effect in this prospective blinded study is less than previously reported. Ongoing analyses seek to assess the value of other DCE-MRI markers, such as Ktrans, and to correlate the DCE-MRI markers with more mature clinical follow-up data.

12010 Background: Calcitriol+ gemcitabine (gem) combination results in synergistic anti-tumor effect in preclinical models. Cytidine deaminase (CDD) inactivates gem into 2’,2’-difluorodeoxyuridine (dFdU) and its overexpression may lead to gem resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). Paricalcitol is cytotoxic in vitro and synergistic with several chemotherapeutic agents, including gem. We are conducting a phase I study of paricalcitol + fixed-dose gem. Objectives: The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of paricalcitol on gem PK, CDD activity in PBM and clinical outcome. Methods: Each cycle is 4 weeks: Gem 800 mg/m2 (over 80 min) weekly × 3, starting day 1; paricalcitol weekly, 24 h prior to gem, starting day 7. Standard 3+3 dose-escalation schema is used. Planned paricalcitol doses are 0.24, 0.72, 1.20, 1.8, 2.4 μg/kg, and 25% increments till MTD. Gem PK and CDD activity (PBM) are studied on days 1 and 8. Paricalcitol PK studies are obtained on day 7. Results: Fourteen pts with the following cancers: pancreatic (n=3), colon (n=3), lung (n=5), esophageal (n=1), bladder (n=1) and unknown primary (n=1) have been enrolled. No dose limiting toxicities have occurred. Median of 2 cycles were delivered (range 1–9). Grade 3 toxicities: anemia (n=3 pts), neutropenia (n=5), thrombocytopenia (n=3), thrombosis (n=2), anorexia (n=1), hypophosphatemia (n=1), dehydration (n=1), syncope (n=1), pneumonia (n=1) and chills (n=1). Grade 4 toxicities: anemia (n=1) and neutropenia (n=1). Hypercalcemia (> grade 1) did not occur. Stable disease occurred in 2 and progressive disease in 3. Conclusions: MTD was not reached at 1.8 μg/kg of paricalcitol with gem 800 mg/m2/week. Dose escalation is ongoing. PK data will be presented at meeting. Supported by NIH grants CA67267 and CA85142. [Table: see text]

3055 Background: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids. The objective of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor MS-275 in combination with 13-cis retinoic acid (CRA). Methods: Patients (pts) with advanced solid tumors were treated with MS-275 orally once weekly and CRA orally twice daily x 3 weeks every 4 weeks. The starting dose for MS-275 was 4 mg/m2 and the dose was escalated based on toxicity assessments. The fixed dose for CRA was 1 mg/kg/day. PK concentrations of MS-275 and CRA were determined by LC/MS/MS. Western Blot analysis on peripheral-blood mononuclear cells (PBMCs) and tumor samples (when feasible) were performed to evaluate target inhibition. Results: To date thirteen pts have been enrolled. Tumor types include prostate (4 pts), bladder and renal cell (2 pts), and others. The MTD was exceeded at the 5 mg/m2 dose level (G3 hyponatremia, neutropenia and anemia). Fatigue (G1 or G2) is a common side effect. MS-275 peak concentrations were 141.6±75.7ng/mL at 4mg/m2 and 139.5±30.9 ng/mL at 5mg/m2. MS-275 half-life and clearance were 108.2±47.9h and 9.4±6.0L/h/m2, which is consistent with prior reports for MS-275 as single agent. Median CRA steady-state trough levels were 182.4 ng/mL. The MTD was 4 mg/m2 MS-275 and 1 mg/kg CRA. Five pts remained on treatment for ≥ 4 months including pts with prostate cancer (3), pancreatic cancer (6 months) and a pt with renal cell carcinoma (12 months) who presented a partial response in the lungs. Histones isolated from PBMCs showed transient but consistent protein acetylation post-therapy. Tumor biopsy of a liver lesion from prostate carcinoma revealed post-therapy induced histone acetylation and decreased phosphorylated ERK and STAT3 protein expression consistent with HDAC inhibitory activity. Conclusions: Combination of MS-275 with CRA is reasonably well tolerated and 4 mg/m2 is the Phase II recommended dose for MS-275 in combination with CRA. Tumor response and PD data suggest clinical and biological activity for this combination strategy. [Table: see text]

3042 Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3rd dose level (DL 3, 600 mg/m2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head & neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m2/weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced > grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m2): mean Cmax 22.1, 37.0, and 50.8μg/mL, respectively; AUCinf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m2; and T1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented. [Table: see text]

3594 Background: Fibroblast activation protein (FAP) is selectively expressed by carcinoma stromal fibroblasts, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP potentiates tumor growth in a murine model of human epithelial cancers. Val-boro-Pro, a boronic acid inhibitor of FAP protease activity, attenuates tumor growth in a mouse colorectal cancer model characterized by FAP expression by tumor-associated fibroblasts. We therefore initiated this first clinical trial of Val-boro-Pro in patients with colorectal cancer. Methods: Patients (pts) with previously treated, measurable metastatic colorectal cancer (CRC) were initially treated with 400 μg of Val-boro-Pro orally twice daily continuously. Due to unacceptable toxicities in the first 3 patients (including 1 grade 5 renal failure), the starting dose was reduced to 200 μg orally twice daily, with intrapatient dose escalation to 300 μg bid permitted after 4 weeks. The primary endpoint is response rate, with secondary endpoints including time to progression, and in vivo laboratory correlates of FAP inhibitory activity. Results: 20 patients (12 women, 8 men) with ECOG performance status 0–1 have been treated at 200 μg orally twice daily. The median age is 58 (range 41–80). At 200 μg bid, grade 1–2 adverse events include fatigue (12 pts), anorexia (7 pts), edema (7 pts), and fever (5 pts). The most common laboratory abnormalities are grade 1–2 anemia (7 pts), elevated alkaline phosphatase (4 pts), and hypoalbuminemia (3 pts). Grade 3–4 events are elevated alkaline phosphatase (1 pt, grade 3) and headache/syncope (1 pt, grade 3). Analyses of the first 9 patient plasma samples demonstrate a 92% (S.D. 2%) inhibition of dipeptidyl peptidase activity, and 22% increase in the FAP substrate α2-antiplasmin. Conclusions: Val-boro-Pro 200 μg orally bid is biologically active and well-tolerated, with toxicities likely related to cytokine upregulation. A planned interim analysis for clinical response will be conducted after treatment of 23 evaluable patients. The selectivity of FAP expression for tumor fibroblasts provides a unique opportunity to investigate and manipulate stromal contributions to tumor growth and invasion. No significant financial relationships to disclose.

555 Background: The LEAP trial is an open, randomized, multicenter, Phase I pharmacodynamic study comparing the effects of the AIs L, E and A on safety parameters, such as serum markers of bone formation and resorption, lipid profiles, and adrenal function in healthy postmenopausal women with normal bone mineral density at the spine and hip. Elevated bone biochemical levels indicate high turnover of bone, and correlate with a loss in bone mineral density. It has been suggested that there are differences between the effect of the steroidal AIs (E) and non-steroidal AIs (A and L) on bone turnover, with steroidal AIs having a less negative effect. Methods: Healthy volunteersfrom the UK and Hungarywere randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Changes from baseline in log-transformed bone alkaline phosphatase (ALP), serum C-telopeptide crosslinks (CTX), parathyroid hormone (PTH) and propeptide of type I procollagen (PINP) at 24 weeks on A, were compared with those on L and E by ANCOVA, adjusting for treatment, baseline measurement, BMI, smoking status and baseline estradiol. No adjustments were made for multiple comparisons. Results: A total of 102 healthy volunteers were recruited, with 90 participants evaluable at 24 weeks (29 A, 29 L, 32 E). Participant demographics were similar between the treatment groups in terms of age, years since menopause, and history of hysterectomy and oophorectomy. Bone biochemical measurement changes are presented in the table . With the exception of PTH, where there is a greater decrease in PTH with E than with A (p=0.04), there were no statistically significant differences between the AIs. Conclusions: The steroidal and non-steroidal AIs appear to have similar effects on bone biochemical measurements, and thus bone turnover. All three licensed AIs result in increases in bone turnover. [Table: see text] [Table: see text]

5599 Background: Skin rash is the most frequent side effect associated with epidermal growth factor receptor inhibitors and it has been associated also with therapeutic outcome. Hence, an understan...

3070 Background: DNA methylation has been postulated to play an important role in tumour progression and increased DNA methyltransferase (DNMT) activity has been observed in many cancer cells. Phar...

3031 Background: BIBF 1120 is a potent, orally available triple angiokinase inhibitor (VEGFRs, PDGFRs, FGFRs) that suppresses tumor growth by angiogenesis inhibition. After an initial study with once daily dosing in advanced cancer patients, twice daily (bid) dosing was performed in order to increase drug exposure without increasing toxicity. Methods: Treatment cycles consisted of 28 days continuous administration of BIBF 1120 bid followed by 7 days off. The dose was escalated until dose limiting toxicity (DLT) was observed. Further treatment cycles were allowed in the absence of progressive disease and persistent toxicity. PK profiles were obtained at the beginning and at end of the 1st cycle. Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) was performed at baseline, day 3, day 30, and after each further cycle. Results: 36 patients (5 female, 31 male) were included, 33 completed treatment cycle 1, and 3 patients were excluded due to unrelated adverse events (AE) or DLT. The dose was escala...

With the objective to investigate the pharmacokinetic and pharmacodynamic profile of a single implant containing 3-ketodesogestrel (Implnnon@), 15 healthy women of fertile aged betvveen 20 and 35, with regular cycles, and not breastfeeding were recruitted. Blood sample were drawn before and after implant inserted according 1o schedule. Serum concentration of 3 keto-desogestrelfor the first six weeks after implant insertion was 709 pg/ml and had decreased to 388 pg/ml at six months. Thereafter concentration further decreased slowly with time ffifihyear mean 169 pg/ml, range 141 - 204 pg/ml, n=7). Maximum P concentrations remained below 16 nmol/l in the whole treatment period for the majority of subjects. In four subjects maximum P concentrations exceeding 16 nmol/I the first six weeks. Reduced E2 concentrations were obsertted durtng the first 12 months. Thereafter mean concentrations were close to, and sometimes exceeding, those observed before insertion. A large inter-subject and inlra-subject varintion was obsewed. During the first 11/2 year mean and median SHBG concentrations were below screening values. Thereaftea SHBG concentrations were close to the screening values. No pregnancies occured during teatmenL No subjects discontinued due to bleeding irregularities or amenorrhoea. Overall reference periods (RPs), the prevalence of a amenorrhoea ranged women 0 (for 9 out of 20 reference pertods) and 33.37o. No amenorrhoea occurred from RP 14 onwards. For infrequent bleeding the range was between 20.07o and 73.3Vo, for number of bleeding-spotting days RP ranged from 16.5 to 31.7. The mean nurnber of bleeding-spotting episodes rangedfrom 1.9 to 3.7. Two post-treatment pregnancies were reported. Retum offertilty, judgedfrom return of menses or retum of luteal phase progesterone levels, could be confirmed to occur within 3 months afier removal of the implant in seven out of eight available subjects.

Background : Mivacurium is mainly metabolized by plasma cholinesterase. However, the duration of action may be changed in various conditions such as liver dysfunction. To evaluate the action duration and recovery of mivacurium under the experimental acute renal failure, the pharmacodynamic studies were done. Methods : The pharmacodynamic studies were done using a common peroneal nerve-anterior tibialis muscle preparation in 12, either sex, adult cats(weight 2.0∼4.0 kg). The acute renal failure was made by the ligation of bilateral renal pedicles 1 hour prior to the pharmacodynamic study. All the cat received 5×ED95 of mivacurium. The action durations and recovery indices were measured. And plasma cholinesterase activities were measured at each event. Results : The duration of mivacurium was not prolonged with acute renal failure group(17.20 5.48 min.) compared to control group(13.48 4.30 min.). The recovery indices were not increased in the acute renal failure group(3.56 0.58 min.) as compaired with the control group(2.82 0.99 min.). Conclusions : The mivacurium-induced neuromuscular blockade is not prolonged by the experimental acute renal failure. (Korean J Anesthesiol 1997; 32: 874∼878)

To study the effects of succinylcholine on subsequent pharmacodynamics of nondepolarizing muscle relaxants, a comparative pharmacodynamic study was carried out in patients having balanced anesthesia (thiopental, fentanyl, nitrous oxide/oxygen) in whom equipotent doses of pipecuronium (80μg/kg) and pancuronium (100μg/kg) were given with or without prior administration of succinylcholine (1 mg/kg). Fifty–two patients were randomly assigned to one of the following four groups: 1, pancuronium (100μg/kg); 2, pipecuronium (80μg/kg); 3, succinylcholine (1 mg/kg) plus pancuronium (100μg/kg); and 4, succinylcholine (1 mg/kg) plus pipecuronium (80μg/kg). In groups 3 and 4, the nondepolarizing relaxant was given after succinylcholine when the twitch height recovered to 75% of its control value. For maintenance of neuromuscular blockade, additional increments of pancuronium (20μg/kg) or pipecuronium (15μg/kg) were given. Neuromuscular function was monitored throughout induction, maintenance, spontaneous recovery, and pharmacologic reversal of the neuromuscular block. Mean onset times for pancuronium (group 1) and pipecuronium (group 2) given without succinylcholine were (mean ± SEM) 2.5 ± 0.3 and 2.8 ± 0.2 min, respectively. Mean onset times (times to maximum twitch depression) of the two drugs given after succinylcholine (groups 3 and 4) were significantly shorter (1.4 ± 0.4 and 1.6 ± 0.1 min, respectively). Clinical durations (i.e., until 25% twitch recovery of pancuronium and pipecuronium) were not significantly different among the four groups, varying from 81.1 ± 5.4 (group 4) to 107.0 ± 17.0 (group 2) min. Incremental doses used for maintenance of neuromuscular blockade had durations of action ranging from 44.5 ± 5.1 min (group 1) to 52.8 ± 7.3 min (group 3) and were not altered by the prior administration of succinylcholine. After the administration of nondepolarizing relaxant, times for spontaneous recovery of twitch height from 10% to 25% of baseline levels were comparable in all groups (from 15.2 ± 1.7 to 19.8 ± 2.2 min). The response to reversal of residual neuromuscular blockade with neostigmine (2.5 mg) and glycopyrrolate (0.5 mg) was identical in all groups. We conclude that during balanced anesthesia, the use of succinylcholine for intubation does not necessitate subsequent alteration in doses of pancuronium or pipecuronium.

We compared thumb acceleration (Acc) and thenar electromyography (EMG) techniques by evaluating the neuromuscular blocking properties of alcuronium in 14 ASA physical status I patients. The dose-response curves determined by the two techniques were parallel but the EMG-curve was shifted 25% to the right (P less than 0.001). Acc reflected 8-11% greater neuromuscular block than simultaneous EMG in every patients (P less than 0.05). Concurrently, the duration of greater than 90% neuromuscular block maintained by alcuronium 280 micrograms/kg was significantly longer when measured by the Acc transducer (30 vs. 19 min, P less than 0.001). Although the TOF ratios were in good correlation (r2 = 0.82), clinically significant differences existed between the two simultaneous techniques. The results underline the importance of the method of assessment of neuromuscular transmission when evaluating the action of neuromuscular blocking drugs.

White Leghorn cockerels were fed commercial DDT at levels of 250, 500, and 1000 μg/day in the diet. The absorption, distribution, and metabolism of DDT in plasma, brain, liver, kidney, heart, breast muscle, intestinal tract, skin, and fat were investigated, using gas–liquid chromatography in the quantitation of the residues. To aid in assessing chlorinated hydrocarbon toxicity in wild birds, correlations between observed symptoms and the residue levels in possible target tissues were studied in conjunction with the mechanism of action of DDT. The results indicate that the sum of the residues of p,p′-DDD, o,p′-DDT, and p,p′-DDT (toxic residues) in the brain was the best parameter for diagnosing DDT poisoning in birds. Signs of DDT toxicity were observed in all birds with brain levels in excess of 35 p.p.m. The lowest level of toxic residues in the brains of dead birds was 27.7 p.p.m. The mean brain level of toxic residues in tremoring and dead birds was 54.2 p.p.m. Metabolism and the significance of the levels of DDT and metabolites detected in other tissues are discussed in relation to the physiological function and metabolic activity of the particular tissue.

Emulsified DDT was administered as a single intravenous dose to nonpregnant female rabbits at concentrations of 150, 100, 50, 25, and 12.5 mg/kg. Tremors and convulsions were observed in all animals receiving more than 12.5 mg/kg. Since DDT at 150 mg/kg proved lethal at an average time of 95.8 min, the animals receiving lower doses were sacrificed at 96 min. The results demonstrated that the distribution of an acute dose of a lipophilic insecticide to various tissues depended largely upon (1) hemodynamic factors such as the blood flow in the tissue, (2) the capillary density, and (3) the distribution of blood to various tissues from the site of injection. A positive correlation was observed between plasma levels of DDT and those found in the brain. The severity of the clinical signs of DDT poisoning coincided with the levels detected in the brain. In addition to whole brain assays, the DDT content of various regions of gray and white matter was determined in rabbits treated with 50 mg DDT/kg. The incidence of tremor coincided closely with the high levels detected in gray matter (cerebellum and neocortex). Predominantly white matter (brainstem and spinal cord) had significantly lower concentrations.

In an open sequential pharmacodynamic study in 40 patients, the rate of onset of neuromuscular blockade using tubocurarine or vecuronium was measured. Comparison was made between groups of 10 patients who received thiopentone followed by either blocker and a "reverse" sequence where the blocker was injected before thiopentone. There was a small difference between groups, amounting to a few seconds in rate of onset of block, but this was not suggestive of a systematic effect of the drug sequence.

The results of a study of the anatomy of the stem of Morinda citrifolia L. are described. A preliminary report of the pharmacodynamic study of a 95 per cent alcoholic extract of the root on the isolated uterine horn of an albino rat showed some measure of sedation using doses of 1 to 5,000 to 1 to 36,000. A water decoction of the crude whole root, injected intravenously in the anesthetized dog, in a dose representing 4 Gm. produced a marked lowering of blood pressure which lasted approximately twenty-six minutes. It appears that the hypotensor activity resides in the water-soluble fraction of the root of Morinda citrifolia . The results of in vivo experiments gave evidence of a low order of toxicity of Morinda citrifolia root.

Using the capillary resistance test as a method to study the cutaneous microvessels, a number of capillary active agents were investigated by applying them percutaneously in hydrophylic ointment base to manifestly allergic and definitely non-allergic volunteers. While the catecholamines and heparin increased capillary resistance in both allergic and non-allergic groups, metacholine, serotonin, the somatotropic hormone and nitroglycerin either did not change or decreased capillary resistance in the normal group and invariably increased it in the members of the allergic group. The effects of catecholamines were, completely or partially, blocked in the normal group by pretreatment of the skin with dibenzyline or propranolol. In the members of the allergic group, blockade was often weak or absent indicating some derangement in the adrenergic receptors. The significance of the findings is discussed.

In No. 563 of WHO’s Technical Report Series, “Guidelines for Evaluation of Drugs for Use in Man,”1 it is stated that preclinical “pharmacodynamic studies should be designed to demonstrate the expected therapeutic effect of the drug and, wherever practicable, its mechanism.” In many cases it is difficult, if not impossible, to comply with that request, especially with respect to the mechanism of action of many of the drugs in use, often for a long time, for which we do not know precisely how and where they act. Furthermore, problems may arise in planning experimental studies to show probable therapeutic effect because such experimental models either do not exist or are inadequate and do not allow us to draw conclusions about what may happen in man. Of course, each new chemical entity will be studied by appropriate in-vitro methods as well as in acute experiments in animals, to establish its pharmacodynamic profile. However, the pharmacological features of a new chemical give only limited information about its therapeutic usefulness. Despite the fact that the species of man does not differ fundamentally from various animal species with respect to pharmacodynamic responses, and that, consequently, human pharmacology resembles animal pharmacology, the therapeutic potential of a new substance cannot simply be derived from the pharmacodynamic effects demonstrable in acute studies.