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H Infusion (h + infusion)
Selected AbstractsRapid infusion of a phospholipid emulsion attenuates the effects of endotoxaemia in horsesEQUINE VETERINARY JOURNAL, Issue 3 2007J. N. MOORE Summary Reasons for performing study: Endotoxaemia currently is associated with a poor prognosis in horses. The results of recent trials in other species indicate that phospholipid emulsions reduce the deleterious effects of endotoxin (LPS). However, in a previous study in horses, a 2 h infusion of emulsion caused an unacceptable degree of haemolysis. Hypothesis: Rapid administration of a lower total dose of emulsion would reduce the effects of LPS and induce less haemolysis; the emulsion would reduce inflammatory effects of LPS in vitro. Methods: Twelve healthy horses received an i.v. infusion either of saline or a phospholipid emulsion (100 mg/kg), followed immediately by E. coli O55:B5 LPS (30 ng/kg). Clinical parameters, haematological profiles, serum tumour necrosis factor (TNF) activity, serum lipid profiles, urine analyses and severity of haemolysis were monitored before and at selected times after LPS. Monocytes were also incubated in vitro with LPS in the presence or absence of emulsion, after which TNF and tissue factor activities were determined. Results: Clinical signs of endotoxaemia were reduced in horses receiving the emulsion, including clinical score, heart rate, rectal temperature, serum TNF activity, and the characteristic leucopenic response to LPS, when compared to horses not receiving the emulsion. Three horses receiving the emulsion had none, 2 had mild and one had moderate haemolysis. There were no differences in urinalysis results and creatinine concentrations, either within the groups over time or between the groups. Serum concentrations of phosphatidylcholine, bile acids and triglycerides peaked immediately after the infusion; there were no significant changes in concentrations of nonesterified fatty acids or cholesterol. Incubation of equine monocytes with emulsion prevented LPS-induced TNF and tissue factor activities. Conclusions: Rapid administration of emulsion significantly reduced inflammatory effects of LPS in vivo and caused a clinically insignificant degree of haemolysis. The results of the in vitro studies indicate that emulsion prevents not only LPS-induced synthesis of cytokines, but also expression of membrane-associated mediators (i.e. tissue factor). Potential relevance: Rapid i.v. administration of emulsions containing phospholipids that bind endotoxin may provide a clinically useful method of treating endotoxaemia in horses. [source] Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelationEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2003H. Miskin Abstract: Objectives: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8,10 h) i.v. DFO. Patients: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. Results: The median age at diagnosis of cardiac disease was 17.5 yr (range 14,21), and the median follow-up time was 84 months (range, 36,120). In the majority of patients (seven of eight) high-dose DFO (mean 95 ± 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 ± 2016 ng/mL to 1585 ± 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 ± 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. Conclusions: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8,10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM. [source] Paclitaxel, ifosfamide, and nedaplatin (TIN) salvage chemotherapy for patients with advanced germ cell tumorsINTERNATIONAL JOURNAL OF UROLOGY, Issue 6 2007Norio Nonomura Background: The paclitaxel, ifosfamide, and cisplatin regimen has been used to treat metastatic testicular cancer with successful results. We investigated the usefulness of a paclitaxel, ifosfamide, and nedaplatin (TIN) regimen as salvage therapy for patients with advanced testicular germ cell tumors (GCTs). Methods: Eight patients with advanced GCTs were treated with TIN. The treatment was performed as salvage therapy for cases refractory to therapies, such as bleomycin, etoposide and cisplatin, and irinotecan with nedaplatin. The TIN regimen consisted of paclitaxel (200 mg/m2) by 24-h infusion on day 1, followed by ifosfamide (1.2 g/m2) infusions over 2 h on days 2,6, and nedaplatin (100 mg/m2) given over 2 h on day 2. Results: Seven out of eight patients achieved a disease-free status after chemotherapy, followed by surgical resection of the residual tumor. Six of the seven patients have continued to show no evidence of disease after salvage therapy, with a median follow-up period of 27 months, but one patient developed a ,growing teratoma syndrome' in the mediastinum 31 months after TIN chemotherapy. All patients developed grade 4 leukocytopenia. However, it could be managed by using granulocyte colony-stimulating factor. Only one patient developed grade 2 sensory neuropathy and no patient developed nephrotoxicity. Conclusion: The TIN regimen was efficacious and well-tolerated as salvage chemotherapy for Japanese patients with advanced GCTs. [source] Phase I,II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2006HER-SHYONG SHIAH Abstract Background:, Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. Methods:, Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. Results:, Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. Conclusions:, The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs. [source] Application of pharmacokinetic,pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in miceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2003Evelyn D. Lobo Abstract We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic,pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10 mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5 mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p,<,0.005) and mean nadir weight loss (p,<,0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p,<,0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1665,1676, 2003 [source] The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] Stimulating or conventional perineural catheters after hallux valgus repair: a double-blind, pharmaco-economic evaluationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 10 2006A. Casati Background:, We prospectively evaluated direct analgesia-related costs of continuous sciatic nerve block using either a stimulating or conventional catheter after hallux valgus repair. Methods:, The perineural catheter was inserted through a stimulating introducer either blindly (group Conventional, n= 38) or while stimulating via the catheter (group Stimulating, n= 38). Nerve block was induced with 25 ml of mepivacaine 15 mg/ml, and was followed 3 h later by a patient-controlled infusion of ropivacaine 2 mg/ml (basal infusion: 3 ml/h; incremental dose: 5 ml; lock-out time: 30 min). Rescue tramadol [100 mg intravenous (i.v.)] was given if required. Local anesthetic consumption, need for rescue tramadol and post-operative nausea and vomiting (PONV) treatment, and patient's satisfaction were recorded during first 24-h infusion. Cost calculations were based on the acquisition cost of drugs and devices. Results:, Both techniques were similarly effective, but local anesthetic consumption and need for rescue analgesics were lower in the Stimulating group [respectively, 120 vs. 153 ml (P= 0.004) and 21% vs. 60% (P= 0.001)]. The analgesia-related costs for 24 h were similar when 100-ml bags of ropivacaine 2 mg/ml were used (66 , vs. 67 ,; P= 0.26). When 200-ml bags of ropivacaine were used, the analgesia-related costs were higher in the Stimulating group than the Conventional group (75 , vs. 55 ,; P= 0.0005). Conclusions:, Direct costs of continuous sciatic nerve block ranged from 55 to 75 ,. Stimulating catheters reduced local anesthetic consumption and need for rescue analgesics. This was only cost effective when 100-ml bags of 2 mg/ml ropivacaine were used, while the cheapest combination was the use of conventional catheters and 200-ml bags of ropivacaine. [source] Incidence of side-effects associated with high-dose ferric gluconate in patients with severe chronic renal failureNEPHROLOGY, Issue 1 2003BAHAR BASTANI SUMMARY: Ferric gluconate complex in sucrose (FerrlecitÔ) has been associated with less side-effects than iron dextran; however, the recommended dose of 62.5,125 mg per treatment is only suitable for haemodialysis (HD) patients. We retrospectively analysed the incidence of the side-effects associated with a high dose of FerrlecitÔ infusion (20 treatments in 13 patients; 10 treatments of 250 mg/3,4 h, and 10 treatments of 500 mg/5 h infusion). The patients were in the age range of 32,75 years old, seven with chronic renal failure (CRF), and six on dialysis treatment. One (10%) of the 10 treatments using a 250 mg dose was complicated with severe nausea/vomiting, diarrhoea and a burning sensation in the feet. Three (30%) of the 10 treatments using a 500 mg dose were complicated with: chills, severe nausea/vomiting, hypotension and syncope in one; severe nausea/vomiting, diarrhoea and hypotension in one; and an episode of vomiting in one patient. A single treatment with a 250 mg dose resulted in no significant change in haematological parameters. A single treatment with a 500 mg dose resulted in a significant increase in haemoglobin (Hgb) and haematocrit (Hct), but only a rising trend in serum iron,% transferrin saturation and ferritin pre versus 1,2 months postinfusion. In conclusion, FerrlecitÔ doses of 250 or 500 mg are complicated with significant untoward reactions in 10,30% of patients, in a dose-dependent fashion. [source] Cardiovascular effects of endothelin-1 and endothelin antagonists in conscious, hypertensive ((mRen-2)27) ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000S M Gardiner SB 209670 is a potent antagonist of the vasoconstrictor (ETA - and ETB -receptor-mediated) and vasodilator (ETB -receptor-mediated) effects of endothelin, whereas SB 234551 is relatively selective for the constrictor (ETA -receptor-mediated) effects. Since we had previously found SB 209670 exerted antihypertensive, vasodilator effects in conscious, heterozygous, transgenic ((mRen-2)27) (abbreviated to TG) rats, here we compared the two antagonists in that model, and assessed their chronic effects on responses to exogenous endothelin-1. We did this to test our global hypothesis, namely, that SB 209670, but not SB 234551, would cause inhibition of the depressor effects of exogenous endothelin-1 in vivo, and that this differential effect would be associated with a more marked antihypertensive action of SB 234551 in TG rats. SB 209670 and SB 234551 (infused for 50 h) exerted similar, sustained, antihypertensive effects in TG rats. The antihypertensive effects of the antagonists occurred at times when the pressor effects of exogenous endothelin-1 were not significantly inhibited. Furthermore, SB 234551 did not exert a greater antihypertensive effect than SB 209670 at a time (i.e., 2,4 h) when the depressor effects of endothelin-1 were abolished by the latter, but not by the former (although this differential action was lost after 24 h infusion). The results caused us to reject the hypothesis that selective antagonism of the vasoconstrictor effects of endothelin-1 would result in SB 234551 exerting a greater antihypertensive effect than SB 209670 in TG rats. British Journal of Pharmacology (2000) 131, 1732,1738; doi:10.1038/sj.bjp.0703767 [source] Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-fACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010K. Sköld Sköld K, H-Stenstam B, Diaz AZ, Giusti V, Pellettieri L, Hopewell JW. Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f. Acta Neurol Scand: 2010: 122: 58,62. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives,,, To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). Materials and methods,,, The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. Results,,, MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3,14.0) months with 2 h infusion to 17.7 (95% CI: 13.6,19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3,4 adverse events was similar in the two studies at 13% and 14%, respectively. Conclusion,,, Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks. [source] CONTRIBUTION OF PROSTANOID TP RECEPTORS TO THE PRESSOR AND INTRARENAL HAEMODYNAMIC RESPONSE TO ENDOTHELINCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2006Jan Michael Williams SUMMARY 1Previous studies have shown that endothelin (ET)-1 stimulates thromboxane (Tx)A2 production and so we hypothesized that inhibiting prostanoid TP receptors would prevent the pressor and intrarenal haemodynamic response to an acute infusion of ET-1. 2Male Sprague-Dawley rats were anaesthetized with Inactin (Sigma Chemical, St Louis, MO, USA; 50 mg/kg) and catheters were inserted into the femoral artery and vein for recording mean arterial pressure (MAP) and infusion of ET-1 and receptor antagonists, respectively. A jugular vein catheter was used for the infusion of bovine serum albumin (6.2% in saline) during surgery (1.25% bodyweight). The pressor response to a 1 h infusion of ET-1 (6 pmol/kg per min) was determined in rats that had been pretreated with vehicle (0.9% NaCl) or the TP receptor antagonist SQ29548 (2 mg/kg per h). Laser Doppler single-optic fibres were implanted in the left kidney for the measurement of medullary blood flow (MBF) and cortical blood flow (CBF). 3Prostanoid TP receptor blockade completely inhibited the acute pressor response to ET-1; the change in MAP was 14 2% versus -3 4% in vehicle and SQ29548 groups, respectively (P < 0.05). Endothelin-1 reduced CBF (-15.2 3.3%), a response that was not significantly changed by SQ29548 (-6.2 7.6%). Similarly, the ET-1-mediated response in MBF was not altered by the TP receptor antagonist (7.7 4.9 vs 6.5 5.2%). 4To determine the influence of the ETB receptor in modulating the response to ET-1 during TP receptor blockade, additional groups were pretreated with A-192621, an ETB receptor-selective antagonist (10 mg/kg, i.v.). A-192621 potentiated the increase in MAP produced by ET-1 (32 5%; P < 0.05 vs ET-1 alone). SQ29548 significantly inhibited, but did not completely block, the increase in MAP produced by ET-1 during ETB antagonist treatment (18 4%; P < 0.05). Endothelin-1-induced decreases in CBF were significantly enhanced in rats that were pretreated with A-192621, whereas ET-1 also significantly decreased MBF following A-192621 treatment. During ETB receptor blockade, TP receptor inhibition had no effect on the ET-1-mediated response of CBF and MBF. 5These results suggest that TP receptor activation is not involved in the renal haemodynamic responses to ET-1. However, TP receptor activation contributes to the acute pressor response to ET-1, but does not account for the potentiated increase in MAP during ETB receptor blockade. [source] Acute And Chronic Sympathoinhibition On Carotid Artery Diameter Of Spontaneously Hypertensive Rats: Effects Of Clonidine And FlesinoxanCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2000H Dabiré SUMMARY 1. Hypertensive conduit arteries are thicker and stiffer than those of normotensive controls. Whether they are specifically sensitive to central sympathoinhibition has never been investigated. 2. The effects of acute (24 h infusion) and chronic (4 week infusion) treatments with clonidine (0.01 and 0.1 mg/kg per day) and flesinoxan (1 and 3 mg/kg per day) on carotid artery diameter were investigated in spontaneously hypertensive rats. At the end of treatment, blood pressure (BP) was recorded in the rats while they were conscious. Rats were then anaesthetized for carotid artery diameter measurements using an ultrasonic echo-tracking device. 3. In conscious rats, clonidine significantly decreased BP and heart rate (HR) following acute but not chronic treatment. In contrast, flesinoxan significantly decreased BP following both the acute and chronic treatment. In anaesthetized animals, the two agents have opposite effects on isobaric carotid artery diameter, with a decrease under clonidine and an increase under flesinoxan. After 4 weeks infusion, the reactivity of aortic rings was studied in organ chambers. Flesinoxan, but not clonidine, caused the relaxation of potassium chloride precontracted aortic segments. 4. The results indicate that although clonidine and flesinoxan are centrally acting antihypertensive agents, the drug-induced changes in isobaric carotid diameter may be influenced by local factors independent of the central action of the two drugs. [source] | ||||||||||