Combined Infusion Research Articles

UJI PENDAHULUAN EFEK KOMBINASI ANTIJAMUR INFUS DAUN SIRIH (Piper betle L.), KULIT BUAH DELIMA (Punica granatum L.), DAN RIMPANG KUNYIT (Curcuma domestica Val.) TERHADAP JAMUR CANDIDA ALBICANS

Theinvestigation for antifungal effect of medicinal plants, combination infusion of Piper bettle leaves, Punica granatum Fructus Cortec, Curcuma domestica Rhizome. The tested demartophyta used Candida albicans. This research using dilution method to determine of minimum inhibitory concentration (MIC) and difusion method to determine zone inhibition around of disc. The results of determination of MIC showed that combination infusion Piper bettle leaves with Punica granatum Fructus Cortex against C. albicans respectively, 31,2 mg/ml : 7,8 mg/ml; 15,6 mg/ml : 15,6 mg/ml and 7,8 mg/ml : 31,2 mg/ml. The determination for zone inhibition from 3 concentration of infusion of Piper bettle leaves with 3 concentration of Punica granatum Fructus Cortex with 9 combination against C. albicans showed that combination of two infusion is the larger than the single infusion. Keywords: Punica granatum, Curcuma domestica, infeksi jamur Candida , antifungi Piper betle

A randomized comparison of automated intermittent mandatory boluses with a basal infusion in combination with patient-controlled epidural analgesia for labor and delivery

Background Automated mandatory boluses (AMB), when used in place of a continuous basal infusion, have been shown to reduce overall local anesthetic consumption without compromising analgesic efficacy in patient-controlled epidural analgesia (PCEA). We hypothesized that our PCEA + AMB regimen could result in a reduction of breakthrough pain requiring epidural supplementation in comparison with PCEA with a basal infusion (PCEA + BI). Methods We recruited sixty-two healthy ASA I nulliparous parturients in early labor. The parturients were randomized to receive 0.1% ropivacaine + fentanyl 2 μg/mL either via PCEA + BI (PCEA with basal continuous infusion of 5 mL/h) or PCEA + AMB (PCEA with AMB of 5 mL every hour instead of a basal infusion) immediately following successful induction of combined spinal–epidural (CSE) analgesia. Block characteristics, incidence of breakthrough pain requiring epidural supplementation, side effects, obstetric outcomes, Apgar scores and overall maternal satisfaction with analgesia were noted. Results The time-weighted hourly consumption of ropivacaine (PCEA and clinician supplementation for breakthrough pain) was significantly lower in the PCEA + AMB group (mean = 7.6 mL, SD 3.2) compared to the PCEA + BI group (mean = 9.3 mL, SD 2.5; P < 0.001). The mean time to first PCEA self-bolus following CSE was significantly longer in the PCEA + AMB group compared to the PCEA + BI group (268 min vs. 104 min; P < 0.001). Parturients in Group PCEA + AMB also gave higher satisfaction scores. The incidence of breakthrough pain was similar in both groups. Conclusion PCEA + AMB, when compared to PCEA + BI, confers greater patient satisfaction and a longer duration of effective analgesia after CSE despite reduced analgesic consumption.

A nonhuman primate model of Alzheimer’s disease generated by intracranial injection of amyloid-beta42 and thiorphan

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathological changes, including the deposition of amyloid-beta (Aβ) peptide. Aged monkeys have proven to be invaluable in the study of AD, as their brains naturally develop amyloid plaques similar to those in AD brains. However, spontaneous development of AD-like pathologies in aged monkeys is time-consuming, often taking several years. Here, we created an experimentally induced AD model in middle-aged (16-17years) rhesus monkeys by intracranial injection of Aβ42 and thiorphan, an inhibitor of neprilysin that is responsible for Aβ clearance. The working memory capacity of the monkeys in a delayed-response task was little affected following the delivery of Aβ42 and thiorphan. However, the administration of Aβ42 and thiorphan resulted in a significant intracellular accumulation of Aβ in the neurons of the basal ganglia, the cortex, and the hippocampus, accompanied by neuronal atrophy and loss. Moreover, immunohistochemistry revealed a degeneration of choline acetyltransferase-positive cholinergic neurons and an increase of glial fibrillary acidic protein-positive astrocytes. In conclusion, our data demonstrate a primate model of AD generated by combined infusion of Aβ42 and thiorphan, which duplicates a subset of neuropathological changes in AD brains, thereby having implications in the elucidation of this disease.

Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial

BackgroundRecent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium.Methods70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period.ResultsController performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively.ConclusionsNitrous oxide does not affect the infusion requirements of cisatracurium.Trial registrationClinicalTrials.gov NCT01152905; European Clinical Trials Database at http://eudract.emea.eu.int/2006-006037-41.

Expansion of Cord Blood CD34+ Cells in Presence of zVADfmk and zLLYfmk Improved Their In Vitro Functionality and In Vivo Engraftment in NOD/SCID Mouse

BackgroundCord blood (CB) is a promising source for hematopoietic stem cell transplantations. The limitation of cell dose associated with this source has prompted the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). However, the expansion procedure is known to exhaust the stem cell pool causing cellular defects that promote apoptosis and disrupt homing to the bone marrow. The role of apoptotic machinery in the regulation of stem cell compartment has been speculated in mouse hematopoietic and embryonic systems. We have consistently observed an increase in apoptosis in the cord blood derived CD34+ cells cultured with cytokines compared to their freshly isolated counterpart. The present study was undertaken to assess whether pharmacological inhibition of apoptosis could improve the outcome of expansion.Methodology/Principal FindingsCB CD34+ cells were expanded with cytokines in the presence or absence of cell permeable inhibitors of caspases and calpains; zVADfmk and zLLYfmk respectively. A novel role of apoptotic protease inhibitors was observed in increasing the CD34+ cell content of the graft during ex vivo expansion. This was further reflected in improved in vitro functional aspects of the HSPCs; a higher clonogenicity and long term culture initiating potential. These cells sustained superior long term engraftment and an efficient regeneration of major lympho-myeloid lineages in the bone marrow of NOD/SCID mouse compared to the cells expanded with growth factors alone.Conclusion/SignificanceOur data show that, use of either zVADfmk or zLLYfmk in the culture medium improves expansion of CD34+ cells. The strategy protects stem cell pool and committed progenitors, and improves their in vitro functionality and in vivo engraftment. This observation may complement the existing protocols used in the manipulation of hematopoietic cells for therapeutic purposes. These findings may have an impact in the CB transplant procedures involving a combined infusion of unmanipulated and expanded grafts.

Modern developments in mass spectrometry of chondroitin and dermatan sulfate glycosaminoglycans

Chondroitin sulfate (CS) and dermatan sulfate (DS) are special types of glycosaminoglycan (GAG) oligosaccharides able to regulate vital biological functions that depend on precise motifs of their constituent hexose sequences and the extent and location of their sulfation. As a result, the need for better understanding of CS/DS biological role called for the elaboration and application of straightforward strategies for their composition and structure elucidation. Due to its high sensitivity, reproducibility, and the possibility to rapidly generate data on fine CS/DS structure determinants, mass spectrometry (MS) based on either electrospray ionization (ESI) or matrix-assisted laser desorption/ionization (MALDI) brought a major progress in the field. Here, modern developments in MS of CS/DS GAGs are gathered in a critical review covering the past 5 years. The first section is dedicated to protocols for CS/DS extraction from parent proteoglycan, digestion, and purification that are among critical prerequisites of a successful MS experiment. The second part highlights several MALDI MS aspects, the requirements, and applications of this ionization method to CS/DS investigation. An ample chapter is devoted to ESI MS strategies, which employ either capillary- or advanced chip-based sample infusion in combination with multistage MS (MS(n)) using either collision-induced (CID) or electron detachment dissociation (EDD). At last, the potential of two versatile separation techniques, capillary electrophoresis (CE), and liquid chromatography (LC) in off- and/or on-line coupling with ESI MS and MS(n), is discussed, alongside an assessment of particular buffer/solvent conditions and instrumental parameters required for CS/DS mixture separation followed by on-line mass analysis of individual components.

Raltitrexed and oxaliplatin hepatic arterial infusion for advanced colorectal cancer: a retrospective study

The aim of this study was to evaluate the efficacy and safety of combined hepatic arterial infusion (HAI), which is a combination of raltitrexed and oxaliplatin, in refractory colorectal carcinoma with only liver metastases. Seventeen consecutive patients with unresectable metastatic colorectal cancer, after the failure of two lines of systemic chemotherapy, were treated with HAI raltitrexed (3 mg/m over 1 h) followed by oxaliplatin (130 mg/m over 2 h) every 3 weeks between January 2006 and January 2009. All patients presented with the metastatic disease limited to the liver and had failed at least two lines of chemotherapy, which contained oxaliplatin, irinotecan and a fluoropyrimidine. The median number of cycles was six (range 1-15). We observed three complete responses and eight partial responses among assessable patients (overall response rate in intention to treat, 65%; 95% confidence interval, 44.3-87.7%). The median time to progression was 10.5 months and the median survival time was 27.5 months. Toxicity included grade 3-4 neutropenia (in 17%), grade 3-4 thrombopenia (in 17%), and grade 2 abdominal pain (in 47%). In conclusion, the combination regimen of HAI raltitrexed and oxaliplatin is feasible and promising in patients who presented isolated hepatic metastases of colorectal cancer after failure of irinotecan and oxaliplatin treatment. Further evaluation of this combination is required.

Hemodynamic Effects of the Combination of Dexmedetomidine-Fentanyl versus Midazolam-Fentanyl in Children Undergoing Cardiac Surgery with Cardiopulmonary Bypass

To evaluate the efficacy of the combined infusion of dexmedetomidine and fentanyl on the hemodynamic response during cardiac surgery with cardiopulmonary bypass (CPB) in children. Thirty-two children, ages 1 month to 10 years, scheduled for cardiac surgery with cardiopulmonary bypass were randomly divided in two groups: the MDZ Group received midazolam 0.2 mg.kg(-1).h(-1), while the DEX group received dexmedetomidine 1 microg.kg(-1).h(-1) during one hour followed be a reduction by half in the rate of infusion in both groups. Both groups received fentanyl 10 microg.kg(-1), midazolam 0.2 mg.h(-1), and vecuronium 0.2 mg.kg(-1) for anesthesia induction. The same doses of fentanyl and vecuronium used during induction were infused during the first hour after induction, followed by a reduction to half. Infusions were initiated immediately after induction and maintained until the end of the surgery. Isoflurane was administered for a short time to control the hyperdynamic response to incision and sternotomy. In both groups, systolic blood pressure and heart rate reduced significantly after one hour of anesthetic infusion, but the increase in systolic and diastolic pressure and heart rate to skin incision were significantly lower in the DEX Group. A significantly lower number of patients demanded supplementation with isoflurane in the DEX Group. After CPB, patients in both groups had similar hemodynamic responses. Infusion of dexmedetomidine without bolus seems to be an effective adjuvant to fentanyl on the promotion of sedation and control of hemodynamic responses during surgery for congenital cardiopathies in children.

Comparative randomized study on the analgesic efficacy and side effects of iv PCA morphine versus a continuous infusion of a multimodal combination for cardiac surgery

Comparative randomized study on the analgesic efficacy and side effects of iv PCA morphine versus a continuous infusion of a multimodal combination for cardiac surgery

A Double-Blind, Placebo-Controlled Trial of Four Fixed Rate Infusion Regimens of Phenylephrine for Hemodynamic Support During Spinal Anesthesia for Cesarean Delivery

The administration of prophylactic phenylephrine infusions in combination with fluid cohydration significantly reduces the incidence of hypotension in women having cesarean delivery under spinal anesthesia. The ideal dosing regimen for this purpose is not known. In this study, we investigated the dose of phenylephrine that, when administered as a prophylactic fixed rate infusion, is associated with the least interventions needed to maintain maternal systolic blood pressure (SBP) within 20% of baseline. Women undergoing elective cesarean delivery were randomly allocated to receive placebo or prophylactic phenylephrine infusion at 25, 50, 75, or 100 μg/min immediately after spinal anesthesia in combination with a 2-L fluid coload. Maternal SBP was maintained within the target range using a predetermined algorithm. The number of physician interventions, hemodynamic performance, intraoperative nausea and vomiting, and umbilical cord blood gases were compared among the groups. One hundred one patients were included in the analysis. There were no differences between the placebo and phenylephrine groups in the number of interventions needed to maintain maternal SBP within the target range. Doses of phenylephrine of 25 and 50 μg/min were associated with significantly fewer interventions when compared with 100 μg/min (P = 0.004 vs 50 μg/min, P = 0.02 vs 25 μg/min). Predelivery hypotension was more frequent in the control group compared with all phenylephrine groups. Phenylephrine 75 and 100 μg/min groups were associated with a significantly higher incidence of predelivery hypertension compared with control (P < 0.001 vs 75 μg/min and 100 μg/min). There was a trend toward an increase in median magnitude of deviations of SBP above or below baseline (P = 0.006), and the bias of SBP to be above baseline (P < 0.001) with increasing rates of phenylephrine infusion. There were no differences in the incidence and severity of intraoperative nausea and vomiting and umbilical cord blood gases among the groups. The use of prophylactic fixed rate phenylephrine infusions did not significantly reduce the number of physician interventions needed to maintain maternal predelivery SBP within 20% of baseline compared with placebo. However, prophylactic phenylephrine infusions reduced the incidence and severity of maternal predelivery hypotension. Phenylephrine 25 and 50 μg/min administered as a prophylactic fixed rate infusion provided greater maternal hemodynamic stability than phenylephrine 75 and 100 μg/min. Prophylactic fixed rate infusions may have limited application in clinical practice, and future studies assessing the accuracy of hemodynamic control with variable rate phenylephrine infusions are needed.

Optimizing obatoclax administration schedule: Safety and efficacy of 3-hour versus 24-hour infusion in combination with carboplatin and etoposide for patients with extensive-stage small cell lung cancer (ES-SCLC).

e13531 Background: Previous studies with obatoclax (Ob), a pan-BCL-2 antagonist, identified infusional CNS effects as dose- limiting adverse events (AEs) that occur with greater frequency and intensity with 3-hr versus 24-hr infusions of Ob. This phase I study of Ob used both infusion schedules to compare the safety and efficacy when used in combination with carboplatin (Carb) and etoposide (Et). Methods: As previously reported (ASCO, 2009, Ab 3576) this phase I study evaluated Ob given on a 21-day (D) cycle together with Carb (AUC 5 D1) and Et (100 mg/m2 D1-3), in separate fixed dose escalations using Ob as a 3-hr infusion D1-3 (15 mg, 30 mg and 45 mg) and as a 24-hr infusion D1-3 (30 mg, 45 mg and 60 mg). Eligible patients (pts) had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate organ function. 3-6 pts were enrolled into ascending dose cohorts with standard DLT rules. Results: 25 pts were enrolled (14 males; median age 66). 18 pts were previously untreated (12 in 3-hr group; 6 in 24-hour group). Since only chemotherapy-naive pts were to be enrolled in phase II, safety and efficacy data from those pts are presented here. Preliminary safety data indicate that AEs of all grades with >33% difference between the arms were somnolence (83% in 3-hr vs. 0% in 24-hr), euphoric mood (58 vs. 0%), dysguesia (50 vs. 0%), hyponatremia (8 vs. 50%), and chest pain (42 vs. 0%). CNS AEs were generally transient and without sequelae. The RR, PDs during the planned 6 cycles of combination therapy, median PFS, and median OS all demonstrated a trend in favor of the 3-hr infusion arm. Minimum follow-up for all 18 pts is 10.4 months. Conclusions: Although associated with a higher incidence of some (particularly CNS) AEs, Ob 3-hr infusion in combination with Carb and Et showed a trend toward higher RR, PFS, and OS than 24-hour infusion. 3-hr infusions with Carb and Et have been studied further in a randomized, phase II trial in pts with chemotherapy-naïve ES-SCLC which has now completed enrollment. RR % Progression during 6 cycles Median PFS (days) Median OS (days) 3-hr 100 1/12 197 (126-390) 312+* (175-516+) 24-hr 66 2/6 185 (43-224) 198 (80-315+) * Median not reached No significant financial relationships to disclose.

Pharmacokinetic profile of the base-excision repair inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion with temozolomide (TMZ) in the first-in-human phase I clinical trial.

e13662 Background: MX, the first base excision repair (BER) inhibitor evaluated in humans, blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. Initial results of the administration of MX have been presented (AACR Annual Meeting 2009, abstract #5433). Pharmacokinetic (PK) analyses revealed a distinct PK profile different from that observed in mice and dogs, where half- life of MX was 19 minutes and 4.5 hours (h) respectively. In humans, MX half life is estimated to be 45.3 h (range: 32 − 68.8 h). As a result, the MX administration was adjusted from a 5-day intravenous (iv) continuous infusion (CI) to a 1-hour iv infusion. Methods: This ongoing phase I dose-escalation trial investigates the safety, PK, and pharmacodynamic (PD) profile of MX given as an one-hour iv infusion in combination with TMZ. PD markers, including analysis of AP sites measured on DNA extracted from patients' mononuclear cells (PBMCs) as well as DNA strand break determined by comet assay at multiple time points, are included. Results: 4 patients enrolled, at dose-level 1 (TMZ 100 mg/m2/day po, days 1-5 and MX 15 mg/m2 IV on day 1). Various primary tumors (lung, breast, pancreatic, skin adnexal) included. The average half-life of MX was 46.8 h (range: 20.4–62.7 h, based on 8 treatment cycles from 3 patients), not statistically different from the 5-day CI regimen. Treatment has been well tolerated. One grade 3 toxicity possibly treatment related (hallucinations in one patient with progressive disease and on opioids). PD results showed that administration of the combination of TMZ and MX resulted in 30–60% reduction in detectable AP sites. Comet assay results revealed that the combination of TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone. Conclusions: Initial data demonstrate that MX in combination with TMZ is well tolerated. MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. PD demonstration of MX's biologic activity on patients' mononuclear cells has been demonstrated even at the first dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON TRACON

Phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.

e13133 Background: ON 01910.Na is a new multikinase inhibitor, which induces mitotic catastrophe and apoptosis in cancer but not in normal cells. Multiple pathways are involved including polo-like kinase. Cell killing effects are exposure time-dependent in vitro. In addition, a combination of ON 01910.Na with oxaliplatin produced significant synergy in effect, prompting phase I evaluation in humans. Methods: Patients with advanced cancer received a starting dose of ON 01910.Na 250mg/m2 as a 24hr continuous infusion (CI) repeated weekly. Oxaliplatin was administered biweekly as 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Pharmacokinetic (PK) sampling is to be performed at the maximum tolerated dose (MTD) level. Results: 13 patients (pts) (all females; ages: 38-71 yrs) have received combination therapy. At the highest dose (1350 mg/m2), 2 pts have received 6 weeks of continuous therapy. The overall mean (range) number of weeks of continuous therapy delivered was 11.1 (3-42). Grade 2 toxicities (2-grade increase in toxicity) include anorexia (1 pt), nausea (2 pt), fatigue (1 pt), peripheral sensory neuropathy (1 pt), abdominal cramps (1 pt), neutropenia (1 pt) and vomiting (2 pt). Partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (26 wk, prior progressions on paclitaxel+carboplatin [carbo], topotecan+docetaxel, carbo+gemcitabine, doxorubicin hydrochloride liposome, paclitaxel+bevacizumab, and etoposide). Stable disease was observed in a pt with colon cancer (42 wk, prior progressions on FOLFOX-4 and FOLFIRI+bevacizumab), and in a pt with ovarian cancer (19 wk, prior progressions on carbo+paclitaxel, doxorubicin hydrochloride liposome, gemcitabine+carbo, topotecan, vinorelbine, and bevacizumab+paclitaxel). Conclusions: It is feasible to administer ON 01910.Na as a 24hr infusion in combination with oxaliplatin. Tumor response was seen in chemotherapy-refractory ovarian cancer. The toxicities are tolerable and dose escalation continues. Further analysis of response and toxicity as well as PK at the MTD dose level is planned as this study continues to enroll patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.

Oblimersen 1-hour IV infusion in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma.

8561 Background: Oblimersen (OBL), temozolomide (TMZ), and albumin-bound paclitaxel (ABP) are synergistic in melanoma cell lines. We recently reported promising results with this regimen in 18 patients with advanced melanoma and normal LDH. OBL was given as a 7-day continuous IV infusion (7 mg/kg/d, day 1-7, 22-28) in combination with TMZ (75 mg/m2/d, day 1-42) and ABP (175 or 260 mg/m2, day 7, 28 after OBL) in 56-day cycles. Response rate (33%) included 1 CR lasting > 25 months and 5 PRs lasting > 2 cycles. Seven pts (39%) had SD > 3 cycles and 5 (28%), disease progression. Based on the safety profile and PK of OBL given by short IV infusion, we evaluated a fixed dose of OBL given as a 1-hour IV infusion with TMZ and ABP. Methods: Chemotherapy-naïve patients with advanced melanoma, ECOG PS ≤ 2, and baseline LDH ≤ 1.1 × ULN received TMZ 75 mg/m2/d orally (day 1-42), OBL 900 mg as a 1-hour IV infusion (days 1,4,8,11,22,25,29,32), and ABP 175 mg/m2 as a 30-minute IV infusion (days 4,25) in 56-day cycles. Responses were evaluated per RECIST. Blood samples were obtained for OBL and ABP PK, and measurement of serum shed cryptic epitopes. Immunohistochemistry (IHC) staining for Bcl-2, Bcl-XL, BAK, and caspase 3 was performed on days -1, 4, and 28 tumor samples. Results: Ten patients have been treated with the OBL one-hour infusion. Two patients progressed after one cycle. Eight patients are continuing treatment; 3 have a PR, 4 have SD and one has not been evaluated yet. One patient with a PR demonstrated increased intra-tumoral caspase 3 and decreased Bcl-2 on day 4 due to an overall reduction in tumor burden, which correlated with a decrease in shed collagen epitopes and clinical response. The one-hour OBL IV infusion has been well tolerated. No grade 3 or 4 events other than a grade 3 preexisting pleural effusion have occurred. Planned enrollment of 14 pts is continuing. Conclusions: Preliminary data from this ongoing study appear to confirm the promising response and disease-control rates observed with this drug combination using a substantially more convenient dosing regimen. The OBL 1-hour IV infusion is well tolerated in combination with TMZ and ABP. Additional clinical data, as well as PK and IHC data, will be presented. No significant financial relationships to disclose.

Phase II study of fixed dose-rate infusion of gemcitabine and UFT combination chemotherapy in patients with advanced bile duct cancer: Daegu Gyeoungbuk Oncology Group.

e14547 Background: This phase II study evaluated efficacy of fixed dose rate (FDR) infusion of gemcitabine (10 mg/m2/min) and UFT combination in chemo-naïve patients with advanced bile duct cancer. Methods: This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received the FDR gemcitabine 1,000 mg/m2 for 3 consecutive weeks and UFT 400 mg/m2 on days 1-21. The cycle was repeated every 28 days. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST)-defined objective response rate. Secondary end points included clinical benefit response (CBR), safety, progression-free survival (PFS), and overall survival (OS). Clinical characteristics including four single nucleotide polymorphisms in DNA repair genes (RecQ1, RAD54L, XRCC1, ATM) were evaluated whether these influence the overall survival. Results: Between December 2006 and February 2008, fifty-one patients were enrolled, with a median age of 58 years. The majority of patients (76%) had intra-hepatic disease. Fourteen patients (27%) had a RECIST investigator- assessed, partial response (PR); disease control rate (PR + stable disease) was 55%. CBR was 14% among 37 evaluable patients. Hematologic toxicity was main grade 3 or 4 treatment-related adverse events. Median PFS was 4.0 months (95% CI, 2.9 to 5.1 months). Median OS was 7.0 months (95% CI, 3.5 to 10.5 months). Intrahepatic disease, poor performance, and, XRCC1 R194W C/C type were predictive markers of poor overall survival. Conclusions: FDR gemcitabine and UFT demonstrated apparent activity in patients with advanced bile duct cancer. However, this activity did not translate to prolong survival. The location of disease, performance status, and, polymorphic variants of DNA repair genes may affect clinical outcome of patients with advanced bile duct cancer. No significant financial relationships to disclose.

Development of a Complicated Pain Syndrome Following Cyanide Poisoning in a U.S. Soldier

A majority of modern war wounds are caused by blasts and high-energy ballistics. Extremity injuries predominate since modern body armor does not protect these areas due to mobility limitations. A less known and more insidious mechanism of enemy attack among our soldiers involves treachery by the local populace posing as noncombatants. One such recent event involved the contamination of tobacco with cyanide (CN). We describe a case of a soldier with CN intoxication due to ingestion of tobacco purchased from a local merchant. The soldier developed a complex neuropathic pain syndrome and was successfully treated with an inpatient high-dose intravenous ketamine infusion in combination with continuous peripheral nerve blockade.

Comparison of efficacy of continuous epidural infusion of morphine, fentanyl and combination of morphine and fentanyl with bupivacaine for postoperative analgesia in children

Forty-five children of ASA I & II aged 2-10 years scheduled for elective abdominal, urological and major orthopedic procedures were included in the study. They were divided into three groups of 15 each Group I children received continuous epidural infusion of morphine 6ug/kg/hr with 0.0625% bupivacaine group II patients received an epidural infusion of fentanyl 0.4 ug/kg/hr with 0.0625% bupivacaine, whereas patients in group III received continuous epidural infusion of fentanyl 0.2 ug/kg/hr and morphine 3 ug/kg/hr with 0.0625% bupivacaine.

Combined infusion of glutamine and arginine: does it make sense?

Glutamine and arginine are conditionally essential amino acids because depletion occurs in stressed conditions. Intravenous glutamine supplementation reduces morbidity and mortality in critically ill patients fed parenterally. In surgical patients, arginine-enriched diets have beneficial effects, but the use of supplemental arginine in critically ill patients should be avoided in most cases. In addition to its role as a fuel, glutamine regulates gut barrier function, immuno-inflammatory response and antioxidant status. Arginine metabolism leads to nitric oxide and/or polyamines and thus modulates the immuno-inflammatory response and wound healing. Glutamine and arginine metabolism are closely related, and therefore may give additive or antagonist effects on several pathways. The effects of combined arginine and glutamine are still poorly documented. Combined administration of arginine and glutamine resulted in additive or synergistic effects on gut barrier function and inflammatory response but arginine reduced glutamine protection against oxidative stress. Preliminary data indicate that the combination may be beneficial during intestinal inflammation, whereas data in surgical or critically ill patients are still lacking. Mostly speculative effects of combined infusion of arginine and glutamine are discussed. Future studies are needed in specific pathophysiological conditions to assess whether this combination is beneficial or detrimental.

Ambulation in Labor and Delivery Mode: A Randomized Controlled Trial of High-dose Versus Mobile Epidural Analgesia

In the comparative obstetric mobile epidural trial (COMET), the rate of instrumental vaginal delivery (IVD) was reduced among nulliparous women with 2 mobile epidural analgesic techniques, combined spinal epidural (CSE) or low-dose infusion (LDI), in comparison with the high-dose epidural technique. There was no loss of efficacy in pain relief with either mobile procedure. It is unclear whether maternal ambulation (women walking or adopting upright postures) during labor is causally related to a reduction in IVD or an increased likelihood of spontaneous vaginal delivery. The few randomized controlled trials have examined the effect of continuous epidural pain relief on maternal mobility in labor and not necessarily on labor outcome. This randomized trial investigated the effect of 2 mobile epidural techniques, CSE and LDI, on maternal motor power and ambulation as a predefined secondary outcome of the COMET trial in nulliparous women during labor. The 1054 study subjects were randomly allocated to 1 of 3 groups. The control group (n = 353) received high-dose epidural analgesia and was compared with the CSE group (n = 351) and the LDI group (n = 350). The mode of delivery (spontaneous vaginal delivery, IVD, or cesarean section) was the predefined study outcome. To determine the level of ambulation achieved by the study subjects after epidural insertion during first and second stages of labor, motor function was assessed hourly using modified Breen's Bromage power scores, until delivery. Compared to the control group, normal leg power was maintained throughout labor in significantly more women in the CSA and LDI groups (P < 0.01 for each hour). A greater proportion of women in the CSA group than in the LDI group maintained normal leg power during labor (P < 0.01 for each hour). However, there was no association between the level of ambulation and the delivery method. These findings do not support the assertion that a greater level of ambulation after epidural insertion during labor has a beneficial effect on the mode of delivery.

Effects of dinitrosyl iron complex with glutathione and its components on ischemic rat heart during reperfusion

The effects of the drug, a complex of dinitrosyl iron with glutathione lyophilized on dextrane, and its components: glutathione, nitrosoglutathione, dextrane, as well as nitric oxide released from dinitrosyl iron with glutathione--on the energy metabolism and functional recovery of isolated perfused rat heart subjected to global ischemia and reperfusion have been studied. The infusion of 100 nM dinitrosyl iron with glutathione after ischemia substantially enhanced the recovery of coronary flow, the cardiac contractile and pump functions during reperfusion with simultaneous preservation of myocardial high-energy phosphates, and cell membrane integrity. It was shown by the EPR method that these effects were associated with the transfer of Fe+(NO+)2 groups from dinitrosyl iron with glutathione to thiol-containing proteins of cardiomyocytes and coronary vessels. The combined infusion of 100 nM dinitrosyl iron with glutathione and 25 MM 2-(phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO), a nitric oxide scavenger, after ischemia profoundly reduced the metabolic and functional recovery of reperfused hearts. After the postischemic administration of a 100 nM aliquot of hydrolysate of dinitrosyl iron with glutathione (a completely decomposed complex), the recovery of coronary flow, the majority of cardiac function indices, as well as the myocardial metabolic state and cell membrane injury did not differ from those in control or were significantly lower. The results obtained demonstrate that that inclusion of Fe+(NO+)2 groups into myocardial tissue and a spontaneous release of nitric oxide trigger the cardioprotective mechanisms of action of dinitrosyl iron with glutathione on ischemic heart.