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Continuous Infusion (continuous + infusion)
Selected AbstractsReal Time Myocardial Contrast Echocardiography During Supine Bicycle Stress and Continuous Infusion of Contrast Agent.ECHOCARDIOGRAPHY, Issue 6 2007Cutoff Values for Myocardial Contrast Replenishment Discriminating Abnormal Myocardial Perfusion Background: Myocardial contrast echocardiography (MCE) is a new imaging modality for diagnosing coronary artery disease (CAD). Objective: The aim of our study was to evaluate feasibility of qualitative myocardial contrast replenishment (RP) assessment during supine bicycle stress MCE and find out cutoff values for such analysis, which could allow accurate detection of CAD. Methods: Forty-four consecutive patients, scheduled for coronary angiography (CA) underwent supine bicycle stress two-dimensional echocardiography (2DE). During the same session, MCE was performed at peak stress and post stress. Ultrasound contrast agent (SonoVue) was administered in continuous mode using an infusion pump (BR-INF 100, Bracco Research). Seventeen-segment model of left ventricle was used in analysis. MCE was assessed off-line in terms of myocardial contrast opacification and RP. RP was evaluated on the basis of the number of cardiac cycles required to refill the segment with contrast after its prior destruction with high-power frames. Determination of cutoff values for RP assessment was performed by means of reference intervals and receiver operating characteristic analysis. Quantitative CA was carried out using CAAS system. Results: MCE could be assessed in 42 patients. CA revealed CAD in 25 patients. Calculated cutoff values for RP-analysis (peak-stress RP >3 cardiac cycles and difference between peak stress and post stress RP >0 cardiac cycles) provided sensitive (88%) and accurate (88%) detection of CAD. Sensitivity and accuracy of 2DE were 76% and 79%, respectively. Conclusions: Qualitative RP-analysis based on the number of cardiac cycles required to refill myocardium with contrast is feasible during supine bicycle stress MCE and enables accurate detection of CAD. [source] Preclinical abuse potential assessment of the anticonvulsant zonisamideDRUG DEVELOPMENT RESEARCH, Issue 2 2001Jenny L. Wiley Abstract Zonisamide (Zonegran®) is a broad-spectrum antiepileptic agent that shares some pharmacological properties with other anticonvulsants, including phenytoin, carbamazepine, and valproic acid, but is differentiated from these agents by the ability to significantly block T-type calcium channels. Zonisamide interacts with the ,-amino-butyric acid (GABA) receptor in an allosteric manner, and thus does not modulate GABA receptor effects. However, given the potential of drugs within the latter class for drug abuse in humans, an evaluation of zonisamide for abuse potential is an important component of its potential side-effect profile. In the present study, zonisamide was tested in animal models of the subjective and reinforcing effects of central nervous system (CNS) depressant drugs, e.g., diazepam discrimination in rats and intravenous self-administration in rhesus monkeys, respectively. In addition, zonisamide was evaluated for physical dependence liability in a chronic infusion model using rats. Zonisamide did not substitute for diazepam in rats trained to discriminate 2.5-mg/kg diazepam from vehicle nor was it self-administered by rhesus monkeys experienced in methohexital-reinforced responding. Continuous infusion of zonisamide (400 or 600 mg/kg/day) did not prevent the loss of body weight associated with discontinued pentobarbital infusion. These doses of zonisamide did produce some incomplete attenuation of observable signs of pentobarbital withdrawal, likely due to direct sedative or depressant effects of these high doses. These results suggest that zonisamide would not produce diazepam-like intoxication in humans nor would it likely be subject to abuse when made more widely available. Further, when administered chronically, zonisamide would not be expected to produce physical dependence of the CNS depressant type. Taken together, these results support the prediction that zonisamide would have low abuse liability. Drug Dev. Res. 54:66,74, 2001. © 2001 Wiley-Liss, Inc. [source] Continuous infusion of factor concentrates in children with haemophilia A in comparison with bolus injectionsHAEMOPHILIA, Issue 3 2006C. BIDLINGMAIER Summary., Although the concept of continuous infusion (CI) of factor concentrates is well known, prospective paediatric data are rare. We present a prospective open-labelled non-randomized study focusing on safety, efficacy and factor VIII (FVIII) usage compared with bolus injections (BI) in children. In 43 consecutive patients (0.5,17 years; median: 9.6) undergoing different operations, CI was started with an initial FVIII-bolus of 70 IU kg,1 bodyweight, followed by a median infusion rate of 4.4 IU kg,1 h,1 (range: 2.8,9.5) dose adjusted for daily FVIII levels (target: 60,80%). No direct serious adverse events occurred; however, two out of 43 patients, both from the group of four patients with less than 20 exposure days (ED) before starting CI, developed a high-responding inhibitor. Two CI patients showed mild thrombophlebitis or rash. Infusion rates needed to achieve adequate FVIII levels were highly predictable and could be reduced because of decreasing FVIII clearance. Bleeding, requiring additional boli, was observed in eight out of 43 patients. Therapy duration and factor usage of CI were influenced by the procedure, but not by the product used or thrombophilia. Twelve of these CI patients were compared with 12 contemporary consecutive age- and procedure-matched BI patients. Compared with BI patients, CI patients saved 30% FVIII (812.9 vs. 563.2 IU kg,1, P < 0.006). We conclude that CI forms a safe and effective method for perioperative care in children and reduces factor usage. Because of the unknown risk of inhibitor development, we will use CI only in patients beyond 20 ED. [source] Thawed cryoprecipitate stored for 6 h at room temperature: a potential alternative to factor VIII concentrate for continuous infusionHAEMOPHILIA, Issue 6 2004L. M. B. Pesquera-Lepatan Summary., Continuous infusion (CI) of factor VIII concentrates has been demonstrated to be cost-effective method in maintaining stable levels of FVIII activity in haemophilia A patients with major bleeding or undergoing major surgery. Cryoprecipitates remain the major source of FVIII in developing countries-like the Philippines because of limited availability and high cost of concentrates. To support the use of cryoprecipitate as alternative to FVIII concentrate for CI in centres with no factor concentrates, FVIII levels in 37 bags of random cryoprecipitate were measured at 0, 2, 4 and 6 h after thawing, kept at room temperature with bacteriological culture studies performed on the sixth hour. The mean FVIII content at hour 0 was 108.10 U per bag. Type ORh+ blood had lower FVIII content (±78.91 U per bag) compared with blood types ARh+ (±121.64 U per bag) and BRh+ (±117.04 U per bag). The units stored <6 months had higher FVIII content (±117.74 U per bag) compared with those stored for over 6- but <12-months (±66.77 U per bag). The mean rate of decline of FVIII activity at 2, 4 and 6 h was statistically significant at 10.35% (P = 0.000), 21.49% (P = 0.000) and 29.41% (P = 0.000) from baseline, respectively, using the paired t-test. Similar finding was found across different blood types and storage duration. Only one of 37 bags grew Staphylococcus aureus on day 10 of incubation. [source] Haemostatic management of intraoral bleeding in patients with congenital deficiency of ,2-plasmin inhibitor or plasminogen activator inhibitor-1HAEMOPHILIA, Issue 5 2004Y. Morimoto Summary., Haemostatic management of intraoral bleeding was investigated in patients with congenital ,2-plasmin inhibitor (,2-PI) deficiency or congenital plasminogen activator inhibitor- 1 (PAI-1) deficiency. When extracting teeth from patients with congenital ,2-PI deficiency, we advocate that 7.5,10 mg kg,1 of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days. For the treatment of continuous bleeding, such as post-extraction bleeding, 20 mg kg,1 of tranexamic acid should be administered intravenously, and after achieving local haemostasis 7.5 mg kg,1 of tranexamic acid should be administered orally every 6 h for several days. In addition, when treating haematoma caused by labial or gingival laceration or buccal or mandibular contusion, haemostasis should be achieved by administering 7.5,10 mg kg,1 of tranexamic acid every 6 h. Tranexamic acid can also be used for haemostatic management of intraoral bleeding in patients with congenital PAI-1 deficiency, but is less effective when compared with use in patients with congenital ,2-PI deficiency. Continuous infusion of 1.5 mg kg,1 h,1 of tranexamic acid is necessary for impacted tooth extraction requiring gingival incision or removal of local bone. [source] Effect of nicotine on the pelvic afferent nerve activity and bladder pressure in ratsINTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2009Hitoshi Kontani Objectives: To record afferent nerve activity and bladder pressure in anesthetized male rats and to investigate whether increased afferent nerve activity induced by nicotine is able to evoke reflex bladder contractions. Methods: Using continuous infusion cystometrography, bladder pressure was measured via a bladder cannula. Afferent activity was recorded in the uncut L6 dorsal root. Nicotine was injected intra-arterially through a cannula placed near the bifurcation of the internal iliac artery a few minutes after micturition. Results: Nicotine (0.15,1.5 µmol) evoked a marked elevation of afferent discharge without a simultaneous increase in bladder pressure. Bladder contractions appeared about 43 and 19 s after bolus injection of nicotine at 0.45 and 1.5 µmol, respectively. Firing rates of afferent nerves were reduced when the contraction appeared. Continuous infusion of nicotine at 0.75 µmol/min for 20 min evoked marked elevation of afferent discharge, which was maintained during infusion of nicotine and after it had been withdrawn. Repetitive contractions were observed thereafter and disappeared when the L6 dorsal roots were bilaterally resected. Conclusions: A transient increase in afferent discharges induced by bolus injection of nicotine was unable to evoke reflex bladder contraction. Repetitive bladder contractions after withdrawal of continuous nicotine infusion were induced in a reflex manner by the increased afferent activity. [source] Continuous infusion of prostaglandin E1 via the superior mesenteric artery can prevent hepatic injury in hepatic artery interruption through passive portal oxygenationLIVER INTERNATIONAL, Issue 2 2000Tsutomu Sato Abstract:Aims/Background: Hepatic artery interruption (HAI) causes severe ischemic liver damage, especially following hepatopancreatobiliary surgery. In order to inhibit a decrease in oxygen delivery after HAI, continuous infusion of PGE1 via the superior mesenteric artery (SMA) was administered in pigs and changes in hepatic blood flow and oxygen delivery were investigated. Furthermore, its effectiveness in the prevention of liver injury was evaluated by histology and serum enzyme levels. Methods: Animals were subjected to HAI without PGE1 infusion (control group n=6) and to continuous infusion of PGE1 (0.02 ,g/kg/min) into the SMA (PGE1 group n=6). Results and Conclusion: PGE1 infusion via the SMA not only increased the portal blood flow but also elevated the oxygen content of the portal blood. The reduction in oxygen delivery to the liver was 50% in the control group, and only 13% in the PGE1 group. Serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels 24 h after HAI in the control group were 3415±1283 IU/L and 9839±2959 respectively while in the PGE1 group they were 939±426 IU/L and 5510±1545 IU/L respectively. Histological examination showed massive necrosis in the control group at 72 h but only focal liver cell necrosis in the PGE1 group. Based on this finding and the fact that this treatment can be performed easily and safely, continuous infusion of PGE1 via the SMA may be a useful intervention to prevent severe liver damage after hepatic artery interruption. [source] Continuous infusion of intermediate-dose cytarabine and fludarabine with idarubicin for patients younger than 60 years with resistant acute myeloid leukemia: A prospective, multicenter phase II study,AMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2009Hawk Kim We assessed continuous infusion (CI) of fludarabine and cytarabine (FLAG) plus idarubicin for patients under 60-years old with resistant acute myeloid leukemia (AML). Induction chemotherapy consisted of idarubicin (12 mg/m2 iv infusion over 30 min on Days 1,3), plus fludarabine (30 mg/m2/day) and cytarabine (1,000 mg/m2/day) on Days 1,5 as a 24-hr CI. G-CSF was added on Days 1,5. The 29 patients enrolled were of median age 40 years (range, 18,57 years); of these, 8 (27.6%) had primary refractory disease, 19 (65.5%) were in early relapse, and 1 each (3.4%) was in multiple relapse and relapse after SCT. In response to induction, 8 patients (27.6%) achieved CR, 2 (6.9%) achieved CRp, and 19 (65.5%) failed treatment; of the latter, 14 had aplasia, three had an indeterminate course, and two showed resistance. Seven patients remain alive, while two were lost to follow-up. Nineteen patients died, 14 of infection, one of toxicity during consolidation, three of relapse after SCT, and two of persistent disease. These findings indicate that although CI of FLAG plus idarubicin was effective for eradicating blasts, it carried a high risk of toxicity. Reduced doses are recommended for CI of FLAG plus idarubicin. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Effects of atrial natriuretic peptide on the extrasplenic microvasculature and lymphatics in the rat in vivoTHE JOURNAL OF PHYSIOLOGY, Issue 1 2005Zoë L. S. Brookes We developed a novel model using fluorescent intravital microscopy to study the effect of atrial natriuretic peptide (ANP) on the extrasplenic microcirculation. Continuous infusion of ANP into the splenic artery (10 ng min,1 for 60 min) of male Long,Evans rats (220,250 g, n= 24) induced constriction of the splenic arterioles after 15 min (,7.2 ± 6.6% from baseline diameter of 96 ± 18.3 ,m, mean ±s.e.m.) and venules (,14.4 ± 4.0% from 249 ± 25.8 ,m; P < 0.05). At the same time flow did not change in the arterioles (from 1.58 ± 0.34 to 1.27 ± 0.27 ml min,1), although it decreased in venules (from 1.67 ± 0.23 to 1.15 ± 0.20 ml min,1) and increased in the lymphatics (from 0.007 ± 0.001 to 0.034 ± 0.008 ml min,1; P < 0.05). There was no significant change in mean arterial pressure (from 118 ± 5 to 112 ± 5 mmHg). After continuous ANP infusion for 60 min, the arterioles were dilated (108 ± 16 ,m, P < 0.05) but the venules remained constricted (223 ± 24 ,m). Blood flow decreased in both arterioles (0.76 ± 0.12 ml min,1) and venules (1.03 ± 0.18 ml min,1; P < 0.05), but was now unchanged from baseline in the lymphatics (0.01 ± 0.001 ml min,1). This was accompanied by a significant decrease in MAP (104 ± 5 mmHg; P < 0.05). At 60 min, there was macromolecular leak from the lymphatics, as indicated by increased interstitial fluorescein isothiocyanate,bovine serum albumin fluorescence (grey level: 0 = black; 255 = white; from 55.8 ± 7.6 to 71.8 ± 5.9, P < 0.05). This study confirms our previous proposition that, in the extrasplenic microcirculation, ANP causes greater increases in post- than precapillary resistance, thus increasing intrasplenic capillary hydrostatic pressure (Pc) and fluid efflux into the lymphatic system. Longer-term infusion of ANP also increases Pc, but this is accompanied by increased ,permeability' of the extrasplenic lymphatics, such that fluid is lost to perivascular third spaces. [source] Late free-flap salvage with catheter-directed thrombolysisMICROSURGERY, Issue 4 2008Andrew P. Trussler M.D. Introduction: Despite high success rates with free-tissue transfer, flap loss continues to be a devastating event. Flap salvage is often successful if vascular complications are recognized and treated early. However, delayed presentation of flap compromise is an ominous predictor of flap loss. Late free-flap salvage has been described with poor long-term results. Catheter-directed thrombolysis (CDT) has only been described in context with free-tissue transfer in a case of distal bypass salvage. Objectives: The authors examined the efficacy of highly selective CDT in late salvage of free-flaps with vascular compromise. Methods: Two patients underwent highly selective CDT after delayed presentation (>5 days) of flap compromise. Patient 1 is a 59-year-old woman who underwent delayed breast reconstruction with a free TRAM flap and presented with arterial thrombosis 12 days postoperatively. Patient 2 is a 53-year-old man who underwent fibular osteocutaneous free-flap reconstruction of a floor of mouth defect who developed venous thrombosis 6 days postoperatively. Patient 2 underwent two attempted operative anastamotic revisions with thrombectomies and local thrombolysis prior to CDT. Results: The average time of presentation was 9 days, with the average time to CDT being 9.5 days. Patient 1 had an arterial thrombosis, whereas Patient 2 had a venous thrombosis. Both patients underwent successful thrombolysis after super-selective angiograms. Continuous infusions of thrombolytic agents were used in both patients for ,24 h. Average length of stay postCDT was 7 days with no perioperative complications. Long-term follow-up demonstrated complete flap salvage with no soft tissue loss. Conclusion: Despite extremely delayed presentation, aggressive CDT was successful in both breast, and head and neck reconstructions with excellent long-term flap results. CDT appears to be a useful modality in managing difficult cases of free-flap salvage. © 2008 Wiley-Liss, Inc. Microsurgery, 2008. [source] Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearanceDIABETIC MEDICINE, Issue 3 2005B. A. J. Veldman Abstract Introduction Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function. Aims As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR). Methods In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p-aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography. Results GFR (121 ± 21 resp. 104 ± 14 ml/min; P < 0.001) and ERPF (563 ± 127 resp. 516 ± 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 ± 4.5 resp. 13.4 ± 7 µmol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = ,0.43, P < 0.001; control subjects: r = ,0.39, P = 0.01). Conclusion GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR. [source] Prospective non-randomized study of preoperative concurrent platinum plus 5-fluorouracil-based chemoradiotherapy with or without paclitaxel in esophageal cancer patients: long-term follow-upDISEASES OF THE ESOPHAGUS, Issue 2 2010M. Zemanova SUMMARY Combined modality treatment for esophageal carcinoma seems to improve survival over surgery alone. Different combinations of cytotoxic drugs have been studied to improve antitumor efficacy and limit the toxicity of chemoradiotherapy (CRT) with inconsistent results. We present a prospective study of neoadjuvant CRT with or without paclitaxel in chemotherapy schedule. One hundred seven patients (93 males, 14 females), median age 59 years (range 44,76), with operable esophageal cancer were enrolled. They received the following neoadjuvant therapy: Carboplatin, area under curve (AUC) = 6, intravenously on days 1 and 22, 5-fluorouracil (5-FU), 200 mg/m2/day, continuous infusion on days 1 to 42, radiation therapy 45 grays/25fractions/5 weeks beginning on day 1. Forty-four patients (41%) were furthermore non-randomly assigned to paclitaxel 200 mg/m2/3 h intravenously on days 1 and 22. Nutritional support from the beginning of the treatment was offered to all patients. Surgery was done within 4,8 weeks after completion of CRT, if feasible. All patients were evaluated for grade 3 plus 4 toxicities: leukopenia (28%), neutropenia (30%), anemia (6%), thrombocytopenia (31%), febrile neutropenia (6%), esophagitis (24%), nausea and vomiting (7%), pneumotoxicity (8%). Seventy-eight patients (73%) had surgery and 63 of them were completely resected. Twenty-two patients (20%) achieved pathological complete remission, and additional 20 (19%) had node-negative and esophageal wall-positive residual disease. There were 10 surgery-related deaths, mostly due to pulmonary insufficiency. Twenty-nine patients were not resected, 15 for early progression, 14 for medical reasons or patient refusal. After a median follow-up of 52 months (range 27,80), median survival of 18.0 months and 1-, 2-, 3- and 5-year survival of 56.7, 37.5, 27.0 and 21% was observed in the whole group of 107 patients. Addition of paclitaxel to carboplatin and continual infusion of FU significantly increased hematologic and non-hematologic toxicity, but treatment results as overall survival or time to progression did not differ significantly in groups with and without paclitaxel. Patients achieving pathological complete remission or nodes negativity after neoadjuvant therapy had favorable survival prognosis, whereas long-term prognosis of node positive patients was poor. Distant metastases prevailed as a cause of the treatment failure. Factors significant for survival prognosis in multivariate analysis were postoperative node negativity, performance status, and grade of dysphagia. Addition of paclitaxel to carboplatin and continual FU significantly increased hematologic and non-hematologic toxicity without influencing efficacy of the treatment. This study confirmed improved prognosis of patients after achieving negativity of nodes. Distant metastases prevailed as cause of the treatment failure. Prospectively, it is important to look for a therapeutic combination with better systemic effect. [source] Efficacy of chemoradiotherapy with low-dose cisplatin and continuous infusion of 5-fluorouracil for unresectable squamous cell carcinoma of the esophagusDISEASES OF THE ESOPHAGUS, Issue 6 2009Ryo Takagawa SUMMARY We retrospectively investigated the efficacy of a chemoradiotherapy regimen using daily low-dose cisplatin and continuous 5-fluorouracil infusion in 71 registered patients with unresectable esophageal cancer. The overall response rate (complete response plus partial response) was 59%. The major toxicities observed were leukopenia and anorexia. The 1- and 3-year overall survival rates were 54.6% and 18.4%, respectively. A low preoperative C-reactive protein level was found to be associated with a good response. The pretreatment performance status and response results were both shown to be prognostic factors for overall survival. These findings confirmed that the chemoradiotherapy regimen had curative potential for unresectable esophageal cancer. [source] Selective dose escalation of chemoradiotherapy for locally advanced esophageal cancerDISEASES OF THE ESOPHAGUS, Issue 7 2008S. K. Seung SUMMARY., This phase II study assessed the use of concurrent continuous infusion of 5-fluorouracil and weekly carboplatin plus paclitaxel with selective radiation dose escalation for patients with localized esophageal cancer. Patients with esophageal carcinoma were staged by thoracic and abdominal computed tomography, endoscopic ultrasound, and positron emission tomography scans. Patients received a continuous infusion of 5-fluorouracil 225 mg/m2 on days 1 to 38 and intravenous paclitaxel 45 mg/m2 and carboplatin AUC 2 on days 1, 8, 15, 22, 29, and 36. Radiotherapy was delivered in 1.8-Gy fractions, 5 d/wk for 5.5 weeks. Six to 8 weeks after initial therapy, patients without metastatic progression but with a positive biopsy, or less than partial response received a 9-Gy boost with the same concurrent chemotherapy. Twenty-four patients were enrolled: 18 patients were enrolled initially; 6 additional patients were enrolled following a protocol amendment designed to reduce the esophagitis by adding the radioprotectant amifostine. Median follow-up was 30 months. Twenty (83%) patients had adenocarcinomas of the lower esophagus/gastroesophageal junction. Seventeen patients (81%) attained at least a partial response. Six patients received boost treatment. At 4 years, overall survival was 28%, cause-specific survival was 38%, locoregional control was 61%, and distant metastasis-free survival was 52%. Radiation delays ranged from 0 to 62 days (median, 8 d), primarily owing to esophagitis. In total, 28% of patients developed esophageal strictures requiring dilatations. There were no differences in esophageal strictures, local control, or survival with the addition of amifostine. [source] Long circulating nanoparticles of etoposide using PLGA-MPEG and PLGA-pluronic block copolymers: characterization, drug-release, blood-clearance, and biodistribution studiesDRUG DEVELOPMENT RESEARCH, Issue 4 2010Khushwant S. Yadav Abstract The anti-leukemic drug, etoposide (ETO), has variable oral bioavailability ranging from 24,74% with a short terminal half-life of 1.5,h i.v. necessitating continuous infusion for 24,34,h for the treatment of leukemia. In the present study, etoposide-loaded PLGA-based surface-modified nanoparticles (NPs) with long circulation were designed as an alternative to continuous i.v. administration. PLGA-mPEG and PLGA-PLURONIC copolymers were synthesised and used to prepared ETO-loaded NPs by high-pressure homogenization. The mean particle size of ETO-loaded PLGA-MPEG nanoparticles was 94.02±3.4,nm, with an Entrapment Efficiency (EE) of 71.2% and zeta potential value of ,6.9±1.3,mV. ETO-loaded PLGA-pluronic nanoparticles had a mean particle size of 148.0±2.1,nm, an EE of 73.12±2.7%, and zeta potential value of ,21.5±1.6,mV. In vitro release of the pure drug was complete within 4,h, but was sustained up to 7 days from PLGA-mPEG nanoparticles and for 5 days from PLGA-pluronic nanoparticles. Release was first order and followed non-Fickian diffusion kinetics in both instances. ETO and ETO-loaded PLGA nanoparticles labeled with 99mTc were used in blood clearance studies in rats where the two coated NPs, 99mTc- ETO-PLGA-PLU NP and 99mTc- ETO-PLGA-mPEG NP, were found to be available in higher concentrations in the circulation as compared to the pure drug. Biodistribution studies in mice showed that ETO-loaded PLGA-MPEG NP and PLGA-PLURONIC NP had reduced uptake by the RES due to their steric barrier properties and were present in the circulation for a longer time. Moreover, the NPs had greater uptake in bone and brain where concentration of the free drug, ETO, was negligible. Drug delivered from these NPs could result in a single i.v. injection that would release the drug for a number of days, which would be potentially beneficial and in better control of leukemia therapy. Drug Dev Res 71: 228,239, 2010. © 2010 Wiley-Liss, Inc. [source] Enantioselective analysis of ketamine and its metabolites in equine plasma and urine by CE with multiple isomer sulfated ,-CDELECTROPHORESIS, Issue 15 2007Regula Theurillat Abstract CE with multiple isomer sulfated ,-CD as the chiral selector was assessed for the simultaneous analysis of the enantiomers of ketamine and metabolites in extracts of equine plasma and urine. Different lots of the commercial chiral selector provided significant changes in enantiomeric ketamine separability, a fact that can be related to the manufacturing variability. A mixture of two lots was found to provide high-resolution separations and interference-free detection of the enantiomers of ketamine, norketamine, dehydronorketamine, and an incompletely identified hydroxylated metabolite of norketamine in liquid/liquid extracts of the two body fluids. Ketamine, norketamine, and dehydronorketamine could be unambiguously identified via HPLC fractionation of urinary extracts and using LC-MS and LC-MS/MS with 1,mmu mass discrimination. The CE assay was used to characterize the stereoselectivity of the compounds' enantiomers in the samples of five ponies anesthetized with isoflurane in oxygen and treated with intravenous continuous infusion of racemic ketamine. The concentrations of the ketamine enantiomers in plasma are equal, whereas the urinary amount of R -ketamine is larger than that of S -ketamine. Plasma and urine contain higher S - than R -norketamine levels and the mean S -/R -enantiomer ratios of dehydronorketamine in plasma and urine are lower than unity and similar. [source] Effect of amino acid and glucose administration following exercise on the turnover of muscle protein in the hindlimb femoral region of ThoroughbredsEQUINE VETERINARY JOURNAL, Issue S36 2006A. MATSUI Summary Reasons for performing study: In man, muscle protein synthesis is accelerated by administering amino acids (AA) and glucose (Glu), because increased availability of amino acids and increased insulin secretion, is known to have a protein anabolic effect. However, in the horse, the effect on muscle hypertrophy of such nutrition management following exercise is unknown. Objectives: To determine the effect of AA and Glu administration following exercise on muscle protein turnover in horses. We hypothesise that administration of AA and Glu after exercise effects muscle hypertrophy in horses, as already shown in man and other animals. Methods: Measurements of the rate of synthesis (Rs) and rate of degradation (Rd) of muscle protein in the hindlimb femoral region of thoroughbred horses were conducted using the isotope dilution method to assess the differences between the artery and iliac vein. Six adult Thoroughbreds received a continuous infusion of L-[ring- 2H5]-phenylalanine during the study, the stable period for plasma isotope concentrations (60 min), resting periods (60 min), treadmill exercise (15 min) and recovery period (240 min). All horses were given 4 solutions (saline [Cont], 10% AA [10-AA], 10% Glu [10-Glu] and a mixture with 10% AA and 10% Glu [10-Mix]) over 120 min after exercise, and the Rs and Rd of muscle protein in the hindlimb measured. Results: The average Rs during the 75,120 min following administration of 10-Mix was significantly greater than for the other solutions (P<0.05). The second most effective solution was 10-AA, and there was no change in Rs after 10-Glu. Conclusions: Administration of AA following exercise accelerated Rs in the hindlimb femoral region, and this effect was enhanced when combined with glucose, because of increasing insulin secretion or a decreased requirement for AA for energy. Potential relevance: Further studies are required regarding the effect on muscle hypertrophy of supplementing amino acids and glucose in the feed of exercising horses. [source] Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horseEQUINE VETERINARY JOURNAL, Issue 5 2001G. A. MEYER Summary This study aimed to identify blood serum lidocaine concentrations in the horse which resulted in clinical signs of intoxication, and to document the effects of toxic levels on the cardiovascular and cardiopulmonary systems. Nineteen clinically normal mature horses of mixed breed, age and sex were observed. Lidocaine administration was initiated in each subject with an i.v. loading dose of 1.5 mg/kg bwt and followed by continuous infusion of 0.3 mg/kg bwt/min until clinical signs of intoxication were observed. Intoxication was defined as the development of skeletal muscle tremors. Prior to administration of lidocaine, blood samples for lidocaine analysis, heart rate, mean arterial blood pressure, systolic blood pressure, diastolic blood pressure, respiratory rate and electrocardiographic (ECG) data were collected. After recording baseline data, repeat data were collected at 5 min intervals until signs of intoxication were observed. The range of serum lidocaine concentrations at which the clinical signs of intoxication were observed was 1.85,4.53 ,g/ml (mean ± s.d. 3.24 ± 0.74 ,g/ml). Statistically significant changes in P wave duration, P-R interval, R-R interval and Q-T interval were observed in comparison to control values, as a result of lidocaine administration. These changes in ECG values did not fall outside published normal values and were not clinically significant. Heart rate, blood pressures and respiratory rates were unchanged from control values. This study establishes toxic serum lidocaine levels in the horse, and demonstrates that there were no clinically significant cardiovascular effects with serum lidocaine concentrations less than those required to produce signs of toxicity. [source] Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of ,7 or ,6 subunit mRNA: an autoradiography and in situ hybridization study in rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002Manolo Mugnaini Abstract It is well established that exposure of experimental animals to nicotine results in upregulation of the ,4,2-subtype of neuronal nicotinic acetylcholine receptors (nAChRs). The aim of this study was to determine the effect of nicotine on the levels of ,7-nAChRs in rat brain, for which only partial information is available. Rats were infused with nicotine (3 mg/kg/day) or saline for 2 weeks and their brains processed for receptor autoradiography with [3H]methyllycaconitine (MLA), a radioligand with nanomolar affinity for ,7-nAChRs. In control rats binding was high in hippocampus, intermediate in cerebral cortex and hypothalamus, and low in striatum, thalamus and cerebellum. There was high correlation between the distribution of [3H]MLA binding sites and ,7 subunit mRNA (r = 0.816). With respect to saline-treated controls, nicotine-treated rats presented higher [3H]nicotine binding in 11 out of 15 brain regions analysed (average increase 46 ± 6%). In contrast, only four regions showed greater [3H]MLA binding, among which the ventral tegmental area (VTA) and cingulate cortex (mean increase 32 ± 3%). No changes in ,7 mRNA levels were observed after nicotine treatment. Similarly, there was no variation of ,6 subunit transcript in the VTA, a region which may contain MLA-sensitive (non-,7)-,6*-nAChRs (Klink et al., 2001). In conclusion, nicotine increased [3H]MLA binding, although to a smaller extent and in a more restricted regional pattern than [3H]nicotine. The enhancement of binding was not paralleled by a significant change of ,7 and ,6 subunit transcription. Finally, the present results provide the first anatomical description of the distribution of [3H]MLA binding sites in rat brain. [source] Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literatureHAEMOPHILIA, Issue 2 2008A. OBERGFELL Summary., Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven®) is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 ,g kg,1 bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences. [source] Safety and efficacy of a plasma-derived monoclonal purified factor VIII concentrate during 10 years of follow-upHAEMOPHILIA, Issue 6 2007E. P. MAUSER-BUNSCHOTEN Summary., In 1995, AAFACT®, a new monoclonal purified factor VIII concentrate (FVIII), derived from human plasma, was introduced in the Netherlands. The monoclonal purification based production process includes a viral inactivation step by solvent/detergent treatment. Products manufactured according to this procedure, for example Hemofil M® are used worldwide. The aim of the present study was to assess inhibitor development in a large cohort of previously treated patients (PTPs) who were followed up for 10 years. In addition, efficacy, HIV and hepatitis C virus (HCV) transmission, and allergic reactions were monitored. All 165 patients with severe haemophilia A (FVIII < 1%) known at the van Creveldkliniek who ever used AAFACT® during the period from October 1995 to September 2005 were included. Two of them were previously untreated patients (PUPs) and two others had <50 exposure days. Data on FVIII consumption, number of exposures, bleedings and hospitalization days were collected from start of AAFACT® until last clinical and laboratory evaluation while on this product. At the end of follow-up, 91 patients were still using this plasma-derived FVIII. Median age at start of follow-up was 26 years (range 1,52). None of the patients reported lack of efficacy. Median FVIII consumption per patient during follow-up was 2058 IU kg,1 bodyweight per year, and median number of exposures was 148 per year. During 1029 patient-years of follow-up, one inhibitor was diagnosed in a previously treated patient PTP. This patient developed high titre inhibitor following surgery for which he, during 1 week, had been treated with continuous infusion with recombinant FVIII. No inhibitor occurred during 68 cases of surgery using continuous infusion with AAFACT®. No viral transmissions or other adverse events occurred during 10 years of follow-up; AAFACT® appeared to be an effective and safe FVIII product. [source] Continuous infusion of factor concentrates in children with haemophilia A in comparison with bolus injectionsHAEMOPHILIA, Issue 3 2006C. BIDLINGMAIER Summary., Although the concept of continuous infusion (CI) of factor concentrates is well known, prospective paediatric data are rare. We present a prospective open-labelled non-randomized study focusing on safety, efficacy and factor VIII (FVIII) usage compared with bolus injections (BI) in children. In 43 consecutive patients (0.5,17 years; median: 9.6) undergoing different operations, CI was started with an initial FVIII-bolus of 70 IU kg,1 bodyweight, followed by a median infusion rate of 4.4 IU kg,1 h,1 (range: 2.8,9.5) dose adjusted for daily FVIII levels (target: 60,80%). No direct serious adverse events occurred; however, two out of 43 patients, both from the group of four patients with less than 20 exposure days (ED) before starting CI, developed a high-responding inhibitor. Two CI patients showed mild thrombophlebitis or rash. Infusion rates needed to achieve adequate FVIII levels were highly predictable and could be reduced because of decreasing FVIII clearance. Bleeding, requiring additional boli, was observed in eight out of 43 patients. Therapy duration and factor usage of CI were influenced by the procedure, but not by the product used or thrombophilia. Twelve of these CI patients were compared with 12 contemporary consecutive age- and procedure-matched BI patients. Compared with BI patients, CI patients saved 30% FVIII (812.9 vs. 563.2 IU kg,1, P < 0.006). We conclude that CI forms a safe and effective method for perioperative care in children and reduces factor usage. Because of the unknown risk of inhibitor development, we will use CI only in patients beyond 20 ED. [source] Thawed cryoprecipitate stored for 6 h at room temperature: a potential alternative to factor VIII concentrate for continuous infusionHAEMOPHILIA, Issue 6 2004L. M. B. Pesquera-Lepatan Summary., Continuous infusion (CI) of factor VIII concentrates has been demonstrated to be cost-effective method in maintaining stable levels of FVIII activity in haemophilia A patients with major bleeding or undergoing major surgery. Cryoprecipitates remain the major source of FVIII in developing countries-like the Philippines because of limited availability and high cost of concentrates. To support the use of cryoprecipitate as alternative to FVIII concentrate for CI in centres with no factor concentrates, FVIII levels in 37 bags of random cryoprecipitate were measured at 0, 2, 4 and 6 h after thawing, kept at room temperature with bacteriological culture studies performed on the sixth hour. The mean FVIII content at hour 0 was 108.10 U per bag. Type ORh+ blood had lower FVIII content (±78.91 U per bag) compared with blood types ARh+ (±121.64 U per bag) and BRh+ (±117.04 U per bag). The units stored <6 months had higher FVIII content (±117.74 U per bag) compared with those stored for over 6- but <12-months (±66.77 U per bag). The mean rate of decline of FVIII activity at 2, 4 and 6 h was statistically significant at 10.35% (P = 0.000), 21.49% (P = 0.000) and 29.41% (P = 0.000) from baseline, respectively, using the paired t-test. Similar finding was found across different blood types and storage duration. Only one of 37 bags grew Staphylococcus aureus on day 10 of incubation. [source] Efficacy and safety of a factor VIII,von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experienceHAEMOPHILIA, Issue 5 2002A. Lubetsky Summary., The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 ± 0.05% U,1 kg,1) compared withthat of the patients with types 1 (2.3 ± 0.52% U,1 kg,1) or 2A (2.0 ± 0.06% U,1 kg,1) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 ± 1.1 mL kg,1 h,1) compared with that of patients with type 2A (2.8 ± 0.7 mL kg,1 h,1) and type 1 (2.6 ± 1.0 mL kg,1 h,1) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 ± 0.6 h,1) compared with type 2A (12.7 ± 5.9 h,1) or type 1 (14 ± 1.2 h,1) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD. [source] Continuous factor VIII infusion therapy in patients with haemophilia A undergoing surgical procedures with plasma-derived or recombinant factor VIII concentratesHAEMOPHILIA, Issue 5 2002D. Dingli Summary., We describe the experience of a single medical centre with continuous factor VIII (FVIII) infusion therapy in a cohort of patients undergoing elective surgery. Twenty-eight patients had a total of 45 procedures. Intraoperative haemostasis was considered excellent in all 45 cases. FVIII levels were maintained between 46% and 191% of normal (median, 103%) for 2,7 days. Bleeding occurred after five procedures (11%) at times when factor VIII levels were within haemostatic range. No patient required reoperation to control bleeding. There were no cases of sepsis related to continuous infusion of factor VIII. We conclude that continuous infusion: (1) is a safe and effective means of replacement therapy in patients with haemophilia undergoing surgery; (2) provides easier monitoring and more constant coagulation factor levels; and (3) has the potential to decrease the cost of replacement therapy by reducing overall usage of product. [source] Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiencyHAEMOPHILIA, Issue 2 2002P. LAWLER Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL,1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL,1 with an inhibitor titre of 48 BU. She received 90 ,g kg,1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 ,g kg,1 h,1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117,Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy. [source] Recombinant factor IX (BeneFix®) by adjusted continuous infusion: a study of stability, sterility and clinical experienceHAEMOPHILIA, Issue 2 2001P. Chowdary The safety and efficacy of adjusted continuous infusion (CI) of recombinant factor IX (FIX; BeneFix®) was assessed in vitro and in a clinical study. BeneFix® was reconstituted at 100 IU mL,1 with or without unfractionated heparin (4 U mL,1) and stored at either 4 °C or room temperature. Reconstituted BeneFix® retained at least 90% activity over 14 days if stored at 4 °C but stability was reduced at room temperature. BeneFix® reconstituted in a sterile pharmacy was free of bacterial contamination. Six patients with haemophilia B received seven CIs of BeneFix® to cover routine surgery and severe bleeding episodes. The CIs lasted between 3 and 10 days. In all cases, haemostasis was excellent and the desired therapeutic FIX level was easily maintained. No thrombotic episodes or inhibitor development occurred but two patients developed thrombophlebitis at the infusion site when heparin was not added to the infusion. BeneFix® is not currently licensed for CI and we suggest that studies to enable licensing should be established as soon as possible. [source] High responding factor VIII inhibitors in mild Haemophilia , is there a link with recent changes in clinical practice?HAEMOPHILIA, Issue 2 2000White The development of high responding inhibitors is an increasingly recognized complication of mild Haemophilia. Inhibitors tend to develop in adolescence and adulthood and this is frequently preceded by high-intensity factor replacement therapy. We report two patients with mild Haemophilia who developed high responding inhibitors after continuous infusion with recombinant factor VIII (Kogenate) as prophylaxis for surgery. We discuss whether recent changes in clinical practice could be responsible for the apparent increase in high responding inhibitors in mild Haemophilia. [source] Induction chemotherapy with cisplatin and 5-fluorouracil followed by chemoradiotherapy or radiotherapy alone in the treatment of locoregionally advanced resectable cancers of the larynx and hypopharynx: Results of single-center study of 45 patientsHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2005Ozden Altundag MD Abstract Background. Induction chemotherapy with cisplatin and fluorouracil and radiotherapy is an effective alternative to surgery in patients with carcinoma of the larynx and hypopharynx who are treated for organ preservation. Methods. We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the larynx and hypopharynx. Forty-five eligible patients who were followed up between April 1999 and May 2001 were enrolled. Initially, these patients were treated with two cycles of induction chemotherapy consisting of cisplatin, 20 mg/m2/day on days 1 to 5, and 5-fluorouracil, 600 mg/m2/day by continuous infusion on days 1 to 5. Patients who had a complete response to chemotherapy were treated with definitive radiotherapy; patients who had a partial response to chemotherapy were treated with chemoradiotherapy. Cisplatin, 35 mg/m2/week, was introduced throughout the duration of radiotherapy. Patients who had no response or progressive disease underwent surgery with postoperative radiotherapy. Patients with N2 or N3 positive lymph nodes underwent neck dissection after the treatment. Results. The mean age was 56.6 years (range, 34,75 years). The overall response rate to induction chemotherapy was 71.1%, with a 17.8% complete response rate and 53.3% partial response rate. With a median follow-up of 13.7 months, 23 (51.1%) of all patients and 63.3% of surviving patients have had a preservation of the larynx or hypopharynx and remain disease free. The most common toxicities were nausea and vomiting and mucositis. Conclusion. Organ preservation, with multimodality treatment, may be achievable in some of the patients with resectable, advanced larynx or hypopharynx cancers without apparent compromise of survival. © 2004 Wiley Periodicals, Inc. Head Neck27: 15,21, 2005 [source] Neuropeptide Y delays hippocampal kindling in the ratHIPPOCAMPUS, Issue 5 2003Sophie Reibel Abstract Chronic intrahippocampal infusion of the neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to delay kindling epileptogenesis in the rat and several lines of evidence suggest that neuropeptide Y could mediate these inhibitory effects. Chronic infusion of BDNF leads to a sustained overexpression of neuropeptide Y in the hippocampus, which follows a time course similar to that of the suppressive effects of BDNF on kindling. In vivo, acute applications of neuropeptide Y or agonists of its receptors exert anticonvulsant properties, especially on seizures of hippocampal origin. In this study, we examined how chronic infusion of this neuropeptide in the hippocampus affected kindling epileptogenesis. A 7-day continuous infusion of neuropeptide Y in the hippocampus delayed the progression of hippocampal kindling in the rat, whereas anti-neuropeptide Y immunoglobulins had an aggravating effect. These results show that neuropeptide Y exerts anti-epileptogenic properties on seizures originating within the hippocampus and lend support to the hypothesis that BDNF delays kindling at least in part through upregulation of this neuropeptide. They also suggest that the seizure-induced upregulation of neuropeptide Y constitutes an endogenous mechanism counteracting excessive hippocampal excitability. Hippocampus 2003;13:557,560. © 2003 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||