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Terms modified by High-dose Selected AbstractsInteraction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahuricaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KAZUHISA ISHIHARA The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2,- and 16,-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg,1 dose. 6,-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg,1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg,1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg,1), but not low dose (0.3 g kg,1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg,1. It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs. [source] Long-term follow-up of renal function after high-dose methotrexate treatment in childrenPEDIATRIC BLOOD & CANCER, Issue 4 2008Marika H. Grönroos MD Abstract Background High-dose methotrexate (HD-MTX) is commonly used in treatment of pediatric leukemias and lymphomas. Transient deterioration in renal function is frequently noted during HD-MTX treatment, but possible long-term changes are less well known. In this study we aimed to study long-term renal prognosis after HD-MTX treatment, and to find possible underlying risk factors for reduced renal function. Procedure Medical records of pediatric cancer patients treated with HD-MTX were reviewed retrospectively after follow-up of 1,10 years. Renal function before and after chemotherapy was investigated in a total of 28 patients. Assessment of glomerular and tubular function was prospectively evaluated in each case. Glomerular function was evaluated by either 51Cr-EDTA or 99mTc-DTPA clearance methods, and by urinary albumin excretion. Tubular function was assessed by measuring blood electrolyte levels and urinary ,1 - or ,2 -microglobulin. Results A decrease in glomerular filtration rate (GFR) was statistically significant as follow-up time increased (P,=,0.02). Age at the time of diagnosis and exposure to potentially nephrotoxic antibiotics during cancer treatment had no influence on GFR. However, albuminuria was observed more often in patients treated with amphotericin B or gentamycin (P,=,0.04). No changes in tubular function were observed. Conclusions Our results show that HD-MTX treatment significantly decreases GFR and may cause albuminuria in pediatric cancer patients several years after treatment. Long-term renal follow-up of these patients is therefore important. Pediatr Blood Cancer 2008;51:535,539. © 2008 Wiley-Liss, Inc. [source] High-dose interleukin-2 immunotherapy is safe for patients with metastatic renal cell carcinoma on dialysisBJU INTERNATIONAL, Issue 2 2006JOHN P. BRUSKY OBJECTIVE To report our experience of high-dose interleukin-2 immunotherapy for patients with metastatic renal cell carcinoma (RCC) on haemodialysis. PATIENTS AND METHODS Two anephric patients with metastatic RCC on haemodialysis received interleukin-2 (600 000 IU/kg) every 8 h for a maximum of 14 doses. The patients rested for 9 days and cycles were repeated as tolerated. A nephrologist followed the patients during treatment and they received nearly daily haemodialysis. RESULTS These two cases were treated with high-dose interleukin-2 and had no unusual toxicity or adverse events. The first patient tolerated five, five, four, four and one dose of interleukin-2 over five cycles. He had a partial response to treatment with a decrease in size of a mediastinal mass, but ultimately developed progressive disease and died 32 months later. The second patient had four cycles of interleukin-2 (13, 13, 14 and nine doses). He initially maintained stable disease throughout treatment, but the disease ultimately progressed and he died 19 months later. CONCLUSIONS We recommend considering high-dose interleukin-2 immunotherapy in highly selected dialysis patients with metastatic RCC. Further study is required to determine the safety, efficacy and optimum dosing in this group. [source] Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitusDIABETES OBESITY & METABOLISM, Issue 5 2009E. Bosi Aim:, To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment-naive patients with type 2 diabetes mellitus (T2DM). Methods:, This was a 24-week, randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA1c) of 7.5,11% (N = 1179) were randomized equally to receive vildagliptin plus high-dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low-dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high-dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA1c reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic-screening criteria [HbA1c >11% or fasting plasma glucose (FPG) >15 mmol/l (270 mg/dl)] could enter a 24-week, single-arm substudy. These patients (N = 94) received open-label vildagliptin plus high-dose metformin combination therapy (100 mg + 1000 mg twice daily). Results:, From comparable baseline values (8.6,8.7%), HbA1c decreased in all four treatment groups, to the greatest extent with vildagliptin plus high-dose metformin combination therapy. Mean (SE) HbA1c change from baseline was ,1.8% (0.06%), ,1.6% (0.06%), ,1.1% (0.06%) and ,1.4% (0.06%) with vildagliptin plus high-dose metformin combination therapy, vildagliptin plus low-dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between-group difference was superior with vildagliptin plus high-dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low-dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA1c values were linked to greater HbA1c reductions, with changes of ,3.2% (0.22%), ,2.7% (0.22%), ,1.5% (0.24%) and ,2.6% (0.26%) respectively, occurring in patients with baseline HbA1c,10%. Reductions in FPG were superior with vildagliptin plus high-dose metformin combination therapy [change from baseline ,2.63 (0.13) mmol/l] compared with both monotherapies [,1.26 (0.13) mmol/l and ,1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA1c lowering, the vildagliptin plus low-dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy. Conclusions:, In treatment-naive patients, combinations of vildagliptin and both high-dose and low-dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose-sparing effect of adding vildagliptin to low-dose metformin in preference to the up-titration of metformin may allow patients to achieve equivalent or superior HbA1c lowering without the GI tolerability issues associated with higher doses of metformin. [source] Vasodilator Stress Induces Infrequent Wall Thickening Abnormalities Compared to Perfusion Defects in Mild-to-Moderate Coronary Artery Disease: Implications for the Choice of Imaging Modality with Vasodilator StressECHOCARDIOGRAPHY, Issue 4 2004M.R.C.P., Ph.D., Prem Soman M.D. Background: Experimental evidence suggests that although vasodilator stress agents consistently induce regional flow disparity between stenosed and normal coronary vascular beds, the occurrence of functional myocardial ischemia is infrequent, especially in mild-to-moderate coronary artery stenosis. Thus, it is hypothesized that dipyridamole infusion, even at high doses, will result in a disproportionately higher frequency of perfusion defects compared to regional wall thickening abnormalities. Methods: We performed simultaneous high-dose (0.84 mg/kg) dipyridamole stress echocardiography (Echo) and Tc-99m sestamibi SPECT (MIBI, methoxyisobutyl isonitrile) in 46 patients with coronary artery diameter stenosis >50% and ,90% in one or two epicardial coronary arteries, and no previous myocardial infarction. Results: Of a total of 828 segments, MIBI showed 97 reversible defects while Echo showed only 23 reversible wall thickening abnormalities. Of the 97 segments with reversible MIBI defects, only 13 (13%) showed simultaneous reversible wall thickening abnormalities during dipyridamole infusion. There were 24 patients with MIBI defects, of whom 10 (41%) showed a corresponding wall thickening abnormality. The sensitivity of MIBI and Echo for the detection of coronary artery disease was 52% and 21%, respectively (P = 0.001). Conclusion: This suggests that vasodilator stress is not optimally suited for use with techniques that use regional wall thickening abnormality as a marker of ischemia for the diagnosis of coronary artery disease. (ECHOCARDIOGRAPHY, Volume 21, May 2004) [source] Morphine modulation of temporomandibular joint-responsive units in superficial laminae at the spinomedullary junction in female rats depends on estrogen statusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2008A. Tashiro Abstract The influence of analgesic agents on neurons activated by stimulation of the temporomandibular joint (TMJ) region is not well defined. The spinomedullary junction [trigeminal subnucleus caudalis (Vc)/C1,2] is a major site of termination for TMJ sensory afferents. To determine whether estrogen status influences opioid-induced modulation of TMJ units, the classical opioid analgesic, morphine, was given to ovariectomized (OvX) rats and OvX rats treated for 2 days with low-dose (LE2) or high-dose (HE2) 17,-estradiol-3-benzoate. Under thiopental anesthesia, TMJ units in superficial and deep laminae at the Vc/C1,2 junction were activated by injection of ATP (1 mm) directly into the joint space. In superficial laminae, morphine inhibited evoked activity in units from OvX and LE2 rats in a dose-related and naloxone-reversible manner, whereas units from HE2 rats were not inhibited. By contrast, in deep laminae, morphine reduced TMJ-evoked unit activity similarly in all groups. Morphine reduced the background activity of units in superficial and deep laminae and resting arterial pressure similarly in all groups. Morphine applied to the dorsal surface of the Vc/C1,2 junction inhibited all units independently of E2 treatment. Quantitative polymerase chain reaction and immunoblots revealed a similar level of expression for ,-opioid receptors at the Vc/C1,2 junction in LE2 and HE2 rats. These results indicated that estrogen status differentially affected morphine modulation of TMJ unit activity in superficial, but not deep, laminae at the Vc/C1,2 junction in female rats. The site(s) for estrogen influence on morphine-induced modulation of TMJ unit activity was probably outside the medullary dorsal horn. [source] Osteoblastic activity of the rabbit temporomandibular joint during distraction osteogenesis assessed by [18F]fluoride positron emission tomographyEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 2 2002Arja Muhonen The purpose of the study was to evaluate the effects of irradiation and hyperbaric oxygenation (HBO) on osteoblastic activity of the temporomandibular joint (TMJ) region during mandibular distraction osteogenesis. Unilateral distraction was performed on 19 rabbits, which were divided into five groups. One group served as a control group, while the others received either high- or low-dose irradiation in the TMJ region before surgery. Some of the animals were also given HBO 18 times at 2.5 ATA×90 min preoperatively. Osteogenesis was assessed by [18F]fluoride positron emission tomography at the end of the distraction. Osteoblastic activity was higher on the distracted side in all groups, except in the high-dose irradiated group without preceding HBO. HBO increased osteogenesis on both sides after radiotherapy. It is concluded that increased osteoblastic activity reflects increased pressure on the TMJ region of the distracted side, resulting from lengthening. It seems that more remodeling is required after irradiation than without preceding radiotherapy. After radiotherapy, HBO increased osteoblastic activity. [source] High-dose methylprednisolone influences the physiology and virulence of Candida albicans ambiguously and enhances the candidacidal activity of the polyene antibiotic amphotericin B and the superoxide-generating agent menadioneFEMS YEAST RESEARCH, Issue 2 2007Įgnes Gyetvai Abstract Although exposure of Candida albicans cells to high-dose (4 mM) methylprednisolone stimulated microbial growth, germination rate in serum and phospholipase release, it also promoted the recognition of C. albicans cells by polymorphonuclear leukocytes. Pretreatment of C. albicans cells with methylprednisolone did not result in any increase in the pathogenicity of the fungus in intraperitoneal and intravenous mouse assays. Therefore, the virulence of C. albicans is unlikely to increase in patients treated with comparably high-dose methylprednisolone on skin and mucosal membranes. Methylprednisolone treatments also increased the production of conjugated dienes and thiobarbituric acid-reactive substances, and the menadione sensitivity of C. albicans cells, which can be explained by a significant decrease in the specific activities of several antioxidant enzymes. The combination of methylprednisolone with oxidants, e.g. in topical applications, may be of clinical importance when the predisposition to candidiasis is high. Methylprednisolone treatments negatively affected membrane fluidity and decreased the antifungal effects of both the polyene antibiotic nystatin and the ergosterol biosynthesis inhibitor lovastatin, and also enhanced the deleterious effects of the polyene antimycotic amphotericin B on C. albicans cells. These corticosteroid,polyene drug interactions should be considered in the treatment of C. albicans infections in patients with prolonged topical application of corticosteroids. [source] Modification of cardiovascular risk in hemodialysis patients: An evidence-based reviewHEMODIALYSIS INTERNATIONAL, Issue 1 2007David W. JOHNSON Abstract Cardiovascular disease accounts for 40% to 50% of deaths in dialysis populations. Overall, the risk of cardiac mortality is 10-fold to 20-fold greater in dialysis patients than in age and sex-matched controls without chronic kidney disease. The aim of this paper is to review critically the evidence that cardiac outcomes in dialysis patients are modified by cardiovascular risk factor interventions. There is limited, but as yet inconclusive controlled trial evidence that cardiovascular outcomes in dialysis populations may be improved by antioxidants (vitamin E or acetylcysteine), ensuring that hemoglobin levels do not exceed 120 g/L (especially in the setting of known cardiovascular disease), prescribing carvedilol in the setting of dilated cardiomyopathy, and by using cinacalcet in uncontrolled secondary hyperparathyroidism. Similarly, there are a number of negative controlled trials, which have demonstrated that statins, high-dose folic acid, angiotensin-converting enzyme inhibitors, multiple risk factor intervention via multidisciplinary clinics, and high-dose or high-flux dialysis are ineffective in preventing cardiovascular disease. Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of chronic kidney disease or because the pathogenesis of cardiovascular disease in dialysis patients is different from that in the general population. Large, well-conducted, multicenter randomized-controlled trials in this area are urgently required. [source] A long-term cohort study of nonsteroidal anti-inflammatory drug use and disease activity in outpatients with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 6 2004Gregory F. Bonner MD Abstract Background and Aims: We examined whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) in outpatients with inflammatory bowel disease was associated with increased severity of disease activity. Methods: Outpatients with Crohn's disease (CD; n = 426) and with ulcerative colitis (UC; n = 203) were seen between November 1997 and April 2002. Patients were questioned at each visit regarding use of prescription or over-the counter NSAIDs and a clinical disease activity index (modified Harvey Bradshaw [MHB] or Lichtiger score) was obtained. Results: For the Crohn's patients, for 1315 visits no NSAIDs were used, on 215 visits low-dose NSAIDs were used, and for 139 visits high-dose NSAIDs were taken. For UC patient visits, 495 used no NSAIDs, 112 low-dose NSAIDs, and 49 high-dose NSAIDs. Average MHB score was 4.07 for the no-NSAID group, 4.24 for low-dose NSAIDs (P = 0.46), and 4.78 for high-dose (P = 0.0072 versus no NSAIDs). For the ulcerative colitis patients corresponding scores were 5.64, 5.46, and 6.20, respectively (P = not significant). The probability of moderately active disease as defined by crossing a threshold MHB or Lichtiger score, however, was not significantly affected by NSAID use. Subgroup analysis indicated the increase in disease activity among CD patients taking high-dose NSAIDs was limited to patients with colonic involvement. Conclusions: Use of low-dose NSAIDs was not associated with an increase in disease activity for these outpatients with either CD or UC. Use of high-doses of NSAIDs was associated with a higher numerical disease activity index score among CD patients with colonic involvement, but this was not reflected by an increase in significant disease flares. [source] Effect of Fish Oil Supplementation on Quality of Life in a General Population of Older Dutch Subjects: A Randomized, Double-Blind, Placebo-Controlled TrialJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2009Ondine Van De Rest MSc OBJECTIVES: To investigate the effect of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplementation on quality of life (QOL). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Independently living individuals from the general older Dutch population. PARTICIPANTS: Three hundred two individuals aged 65 and older without depression or dementia. INTERVENTION: 1,800 mg/d EPA-DHA (n=96), 400 mg/d EPA-DHA (n=100), or placebo capsules (n=106) for 26 weeks. MEASUREMENTS: QOL was assessed using the short version of the World Health Organization QOL questionnaire (WHOQOL-BREF). The WHOQOL-BREF covers four domains: physical health, psychological health, social relationships, and satisfaction with environment. The total score range is 26 to 130, with higher scores indicating a more favorable condition. RESULTS: Mean age of the participants was 70, and 55% were male. Plasma concentrations of EPA-DHA increased 238% in the high-dose and 51% in the low-dose EPA-DHA group, reflecting excellent adherence. Median baseline total WHOQOL scores ranged from 107 to 110 in the three groups and were not significantly different from each other. After 26 weeks, the mean difference from placebo was ,1.42 (95% confidence interval (CI)=,3.40,0.57) for the high-dose and 0.02 (95% CI=,1.95,1.99) for the low-dose fish oil group. Treatment with 1,800 mg or 400 mg EPA-DHA did not affect total QOL or any of the separate domains after 13 or 26 weeks of intervention. CONCLUSION: Supplementation with high or low doses of fish oil for 26 weeks did not influence the QOL of healthy older individuals. [source] Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatmentJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009P.J. Niziolek The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1,34 (0, 10, 30, or 90,µg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10,µg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30,µg), but the anabolic effects of high-dose PTH (90,µg) were consistently and significantly suppressed by rapamycin (,4,36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues. J. Cell. Physiol. 221: 579,585, 2009. © 2009 Wiley-Liss, Inc. [source] Increased bone formation around coated implantsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2009Bernd Stadlinger Abstract Aim: We hypothesized that coating threaded, sandblasted acid-etched titanium implants with collagen and chondroitin sulphate (CS) increases bone formation and implant stability, compared with uncoated controls. Materials and Methods: Three different implant surface conditions were applied: (1) sandblasted acid-etched (control), (2) collagen/chondroitin sulphate (low-dose , CS1), (3) collagen/chondroitin sulphate (high-dose , CS2). Sixty 9.5 mm experimental implants were placed in the mandible of 20 minipigs. Bone,implant contact (BIC) and relative peri-implant bone-volume density (rBVD , relation to bone-volume density of the host bone) were assessed after 1 and 2 months of submerged healing. Implant stability was measured by resonance frequency analysis (RFA). Results: After 1 month, coated implants had significantly more BIC compared with controls (CS1: 68%, p<0.0001, CS2: 63%, p=0.009, control: 52%). The rBVD was lower for all surface conditions, compared with the hostbone. After 2 months, BIC increased for all surfaces. No significant differences were measured (CS1: 71%, p=0.016, CS2: 68%, p=0.67, control: 63%). The rBVD was increased for coated implants. RFA values were 71,77 at implantation, 67,73 after 1 month and 74,75 after 2 months. Differences in rBVD and RFA were not statistically significant. Conclusions: Data analysis suggests that collagen/CS has a positive influence on bone formation after 1 month of endosseous healing. [source] Diabetic foot ulcer burden may be modified by high-dose atorvastatin: A 6-month randomized controlled pilot trialJOURNAL OF DIABETES, Issue 3 2009Odd Erik JOHANSEN Abstract Background:, Diabetic foot ulcers (DFUs) are common complications of diabetes mellitus (DM), with a complex pathogenesis. Treatment is difficult and no single treatment with measurable clinical impact is available. In the present clinical pilot trial, we investigated whether statins could be of use against some of the pathogenic factors in DFUs. Methods:, Thirteen diabetic patients (10 men; 11 with Type 2 DM; mean age 64 years; mean duration of DM 18 years) with neuropathic DFUs <4 months were randomized to treatment with either 10 mg (six patients; six ulcers) or 80 mg (seven patients; nine ulcers) atorvastatin for 6 months in addition to conventional DFU care (i.e. prompt debridement, DFU pressure relief, and management of any underlying infection). Results:, There were no significant differences in background factors (i.e. HbA1c 8.9%, micro- and macrovascular complications, concomitant medications) or DFU characteristics (duration, surface area, grading) between the two groups. All ulcers in the group receiving 10 mg atorvastatin healed, compared with six of nine ulcers in the group receiving 80 mg atorvastatin (NS). However, two previously healed DFUs recurred and six new DFUs developed in the low-dose group compared with none and one, respectively, in the high-dose group (P = 0.048). There was a significant decrease in C-reactive protein (,1.5 mg/L; P = 0.044) and a non-significant trend towards beneficial effects on lipids and the ankle,arm blood pressure index in the high-dose compared with the low-dose group. Conclusions:, We observed a possible beneficial effect of 6-months high-dose atorvastatin on DFUs, which should be tested in appropriately sized prospective studies. [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] Highly accelerated first-pass contrast-enhanced magnetic resonance angiography of the peripheral vasculature: Comparison of gadofosveset trisodium with gadopentetate dimeglumine contrast agentsJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 5 2009Jeffrey H. Maki MD Abstract Purpose: To investigate the blood pool agent gadofosveset trisodium for first-pass, dynamic peripheral contrast-enhanced magnetic resonance angiography (pMRA), and compare the results with a conventional gadolinium contrast agent. Materials and Methods: A total of 16 patients were imaged at 1.5T using a prototype peripheral vascular coil with high SENSE acceleration. Five received gadopentetate dimeglumine (,0.25 mmol/kg), and 11 received gadofosveset trisodium (five standard-dose 0.03 mmol/kg, six high-dose 0.05 mmol/kg). Quantitative contrast-enhancement and qualitative image quality evaluation was compared between agents and doses. Results: High-quality diagnostic images were uniformly obtained. The contrast ratio did not significantly differ between gadopentetate dimeglumine and high-dose gadofosveset trisodium, both of which were greater than standard-dose gadofosveset trisodium. High-dose gadofosveset trisodium was equivalent to gadopentetate dimeglumine in image quality and subjective vessel-to-background ratio, but significantly better for depicting small muscular arteries. Standard-dose gadofosveset trisodium showed equivalent image quality and small artery depiction with a slight but significant decrease in vessel-to-background ratio as compared to gadopentatate dimeglumine. Both gadofosveset trisodium doses trended toward more venous enhancement, but this was not a diagnostic problem. Conclusion: First-pass peripheral CE-MRA using gadofosveset trisodium is feasible, yielding image quality comparable to double to triple-dose gadopentetate dimeglumine. Increasing the gadofosveset trisodium dose to 0.05 mmol/kg yields further improvements. J. Magn. Reson. Imaging 2009;30:1085,1092. © 2009 Wiley-Liss, Inc. [source] USE OF HIGH-DOSE GADOLINIUM AS CONTRAST MEDIA TO AVOID RADIOCONTRAST MEDIA-INDUCED NEPHROPATHYJOURNAL OF RENAL CARE, Issue 1 2009Prajej Ruangkanchanasetr SUMMARY Patients at risk for radiocontrast media-induced nephropathy (RCIN) with suspected peripheral vascular disease were evaluated with high-dose (0.4 mmol/kg) gadolinium-based (Gd) contrast angiography (AG). The patients who were considered susceptible to RCIN were defined by having one or more of the following: (1) pre-existing serum creatinine (SCr) >124 ,mol/l, (2) diabetes mellitus and (3) age >60 years. An increase in SCr , 44 ,mol/l or , 25% of baseline was considered significant. Ten patients underwent peripheral AG using a high dose of Gd without any adverse reaction. The mean age was 67.8 years. Nine (90%) patients were diabetic. The quality of these images was satisfactory for diagnosis in eight out of 10 patients. None of these patients had significant change in SCr. The mean SCr (±SD) before, at 48 hours and at 72 hours after AG were 182 ± 97, 177 ± 99 and 177 ± 98 ,mol/l, respectively. Based on this limited study, Gd is a promising agent for peripheral angiographic study. In patients at risk for RCIN, the high dose of Gd appears to be safe without obvious nephrotoxicity. [source] Effects of postoperative ketamine infusion on pain control and feeding behaviour in bitches undergoing mastectomyJOURNAL OF SMALL ANIMAL PRACTICE, Issue 12 2007S. Sarrau Objectives: To determine if ketamine administered to bitches at the end of a mastectomy, followed by a six-hour constant rate infusion (CRI), improved postoperative opioid analgesia and feeding behaviour. Methods: The bitches were randomised into three groups: the placebo group received 0·09 ml/kg isotonic saline intravenously followed by a six-hour CRI of 0·5 ml/kg/hour, the low-dose ketamine received 150 ,g/kg ketamine intravenously followed by a six-hour CRI of 2 ,g/kg/minute and the high-dose ketamine group received 700 ,g/kg ketamine intravenously followed by a six-hour CRI of 10 ,g/kg/minute. Any additional opioids given were recorded at the time of extubation and at intervals after extubation. Food intake was evaluated eight (T8) and 20 (T20) hours after extubation by measuring the per cent coverage of basal energy requirements (BER). Results: No significant difference was observed for opioid requirements between the three groups. The mean percentages of BER coverage did not differ significantly at T8 but the difference between the high-dose and low-dose ketamine groups (P=0·014), and the high-dose ketamine and placebo groups (P=0·038) was significant at T20. Clinical Significance: This study demonstrated that 700 ,g/kg ketamine given intravenously postoperatively followed by a six-hour ketamine CRI of 10 ,g/kg/minute improved patient feeding behaviour. [source] The effects of high-dose esomeprazole on gastric and oesophageal acid exposure and molecular markers in Barrett's oesophagusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2010A. Abu-Sneineh Aliment Pharmacol Ther 2010; 32: 1023,1030 Summary Background, Acid reflux is often difficult to control medically. Aim, To assess the effect of 40 mg twice daily esomeprazole (high-dose) on gastric and oesophageal pH and symptoms, and biomarkers relevant to adenocarcinoma, in patients with Barrett's oesophagus (BO). Methods, Eighteen patients, treated with proton pump inhibitors as prescribed by their treating doctor, had their therapy increased to high-dose esomeprazole for 6 months. Results, At entry into the study, 9/18 patients had excessive 24-h oesophageal acid exposure, and gastric pH remained <4 for >16 h in 8/18. With high-dose esomeprazole, excessive acid exposure occurred in 2/18 patients, and gastric pH <4 was decreased from 38% of overall recording time and 53% of the nocturnal period to 15% and 17%, respectively (P < 0.001). There was a reduction in self-assessed symptoms of heartburn (P = 0.0005) and regurgitation (P < 0.0001), and inflammation and proliferation in the Barrett's mucosa. There was no significant change in p53, MGMT or COX-2 expression, or in aberrant DNA methylation. Conclusions, High-dose esomeprazole achieved higher levels of gastric acid suppression and control of oesophageal acid reflux and symptoms, with significant decreases in inflammation and epithelial proliferation. There was no reversal of aberrant DNA methylation. [source] Review article: metoclopramide and tardive dyskinesiaALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010A. S. RAO Summary Background, Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a black box warning regarding long-term or high-dose use of this medication because of the risk of developing tardive dyskinesia. Aims, To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide-induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug. Methods, We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p-glycoprotein, risk factors, gastroparesis, outcome, natural history. Results, Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 1,10% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications. Conclusion, Community prevalence and pharmacogenetic mechanisms involved in metoclopramide-induced tardive dyskinesia require further study to define the benefit-risk ratio more clearly. [source] ,Well days' after sublingual immunotherapy with a high-dose 6-grass pollen preparationALLERGY, Issue 7 2009M. Worm No abstract is available for this article. [source] Allyl isothiocyanate as a cancer chemopreventive phytochemicalMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 1 2010Yuesheng Zhang Abstract Allyl isothiocyanate (AITC), which occurs in many common cruciferous vegetables, is widely and often frequently consumed by humans. Besides antimicrobial activity against a wide spectrum of pathogens, it showed anticancer activity in both cultured cancer cells and animal models, although the underlining mechanisms remain largely undefined. Bioavailability of AITC is extremely high, as nearly 90% of orally administered AITC is absorbed. AITC absorbed in vivo is metabolized mainly through the mercapturic acid pathway and excreted in urine. Available data suggest that urinary concentrations of AITC equivalent are at least ten times higher than in the plasma, and tissue levels of AITC equivalent in the urinary bladder were 14,79 times higher than in other organs after oral AITC administration to rats. These findings suggest that AITC may be most effective in the bladder as a cancer chemopreventive compound. AITC at high-dose levels also exhibit a low degree of cytotoxicity and genotoxicity in animal studies, but such adverse effects are unlikely in humans exposed to dietary levels of AITC. Overall, AITC exhibits many desirable attributes of a cancer chemopreventive agent, and further studies are warranted in order to elucidate its mechanism of action and to assess its protective activity in humans. [source] Regulation of immune responses to Strongyloides venezuelensis challenge after primary infection with different larvae dosesPARASITE IMMUNOLOGY, Issue 3 2010H. C. SCHILTER Summary Nematode infections are generally followed by high rates of reinfection, leading to elevated prevalence in endemic areas. Therefore, the effective control of nematode infections depends on understanding the induction and regulation of protective mechanisms. However, most experimental models for protective immune response against nematodes use high parasite exposure, not always reflecting what occurs naturally in human populations. In this study, we tested whether infecting mice with different Strongyloides venezuelensis larvae loads would affect protective responses against reinfection. Interestingly, we found that a previous infection with 10,500 larvae conferred high rate of protection against reinfection with S. venezuelensis in mice, by destroying large numbers of migrating larvae. However, low-dose priming did not abolish adult worm maturation, as detected in high-dose primed group. Results also indicated that a previous low-dose infection delayed the development of cellular infiltrate, while a high inoculum rapidly induced these inflammatory features. Cytokine production by splenocyte cultures of challenge infected mice demonstrated that low-dose priming had increased production of IL-4 and IFN-,, while high-dose induced IL-4 production but not IFN-,. Our data support the hypothesis that low-dose nematode infection does not induce a polarized type-2 immune response, allowing adult worm survival. [source] Long-term follow-up of renal function after high-dose methotrexate treatment in childrenPEDIATRIC BLOOD & CANCER, Issue 4 2008Marika H. Grönroos MD Abstract Background High-dose methotrexate (HD-MTX) is commonly used in treatment of pediatric leukemias and lymphomas. Transient deterioration in renal function is frequently noted during HD-MTX treatment, but possible long-term changes are less well known. In this study we aimed to study long-term renal prognosis after HD-MTX treatment, and to find possible underlying risk factors for reduced renal function. Procedure Medical records of pediatric cancer patients treated with HD-MTX were reviewed retrospectively after follow-up of 1,10 years. Renal function before and after chemotherapy was investigated in a total of 28 patients. Assessment of glomerular and tubular function was prospectively evaluated in each case. Glomerular function was evaluated by either 51Cr-EDTA or 99mTc-DTPA clearance methods, and by urinary albumin excretion. Tubular function was assessed by measuring blood electrolyte levels and urinary ,1 - or ,2 -microglobulin. Results A decrease in glomerular filtration rate (GFR) was statistically significant as follow-up time increased (P,=,0.02). Age at the time of diagnosis and exposure to potentially nephrotoxic antibiotics during cancer treatment had no influence on GFR. However, albuminuria was observed more often in patients treated with amphotericin B or gentamycin (P,=,0.04). No changes in tubular function were observed. Conclusions Our results show that HD-MTX treatment significantly decreases GFR and may cause albuminuria in pediatric cancer patients several years after treatment. Long-term renal follow-up of these patients is therefore important. Pediatr Blood Cancer 2008;51:535,539. © 2008 Wiley-Liss, Inc. [source] Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney functionPEDIATRIC BLOOD & CANCER, Issue 6 2003Lutz Hempel MD Abstract Background The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment. Patients and Methods Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2,34.1)] suffering from acute lymphoblastic leukemia (ALL, n,=,28), Non Hodgkins lymphoma (NHL, n,=,13), osteosarcoma (n,=,8), malignant brain tumor (n,=,6), or an ALL relapse (n,=,3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N -acetyl-,- D -glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m2 BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX. Results The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX. Conclusion MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance. Med Pediatr Oncol 2003;40:348,354. © 2003 Wiley-Liss, Inc. [source] Successful high-dose methotrexate chemotherapy in a patient with acute lymphocytic leukemia who developed acute renal failure during the initial treatmentPEDIATRICS INTERNATIONAL, Issue 6 2007TAKESHI ISODA No abstract is available for this article. [source] Coronary risks after high-dose ,-globulin in children with Kawasaki diseasePEDIATRICS INTERNATIONAL, Issue 5 2000Yoshiyuki Morikawa Abstract Objectives: The goals of the present study were to develop a predictive coronary risk scoring system after intravenous ,-globulin (IVGG) therapy of any dose for the different preparations currently used in the treatment of children with Kawasaki disease and to determine the predictive value of the system. The previously reported scoring systems were based on treatment with high-dose IVGG therapy at limited doses and were determined using investigative methods. Methods: Four hundred and fifty-one patients were randomized into one of three groups and received either i.v. polyethylene glycol-treated human immunoglobulin at a dose of either 200 (n=147) or 400 mg/kg per day (n=152) or freeze-dried sulfonated human immunoglobulin at 200 mg/kg per day (n=152) for 5 consecutive days. We documented 31 cases of coronary abnormalities (CA). Univariate and multivariate logistic regression was performed using 49 clinical variables and the resulting predictive model was validated. Results: The duration of fever (odds (1 day)/odds (, 5 days)=0.158; 95% confidence interval (CI) 0.0385,0.648), hemoglobin (odds (Q1=10.3)/odds (Q3=11.6) = 3.97; 95% CI 1.92,8.20), IgG (odds (Q1=1900)/odds (Q3=2658)=2.72, 95% CI 1.18,6.25) and IgA (odds (Q1=72)/odds (Q3=160) =0.415; 95% CI 0.253,0.680) levels after completion of ,-globulin infusion were independent predictors. The model is quasi-cross validated and has acceptable sensitivity and selectivity. The estimated risk and observed occurence of CA coincide. Conclusions: Determinants of the risk of CA after IVGG therapy are a longer duration of fever, a lower IgG level, a higher IgA level and a lower hemoglobin level after IVGG infusion. This model is applicable for IVGG doses from 1 to 2 g/kg and for at least two different ,-globulin preparations. [source] Adult female crickets, Gryllus texensis, maintain reproductive output after repeated immune challengesPHYSIOLOGICAL ENTOMOLOGY, Issue 2 2007KELLY L. SHOEMAKER Abstract Both immunity and reproduction are thought to be energetically costly and therefore likely to make trade-offs with one another. To assess whether increasing immune system activity results in a decline in egg production, the immune system in the cricket Gryllus texensis is activated over a period of 12 days with regular injections of lipopolysaccharide (LPS) derived from Serratia marcescens, and the number of eggs laid during this time counted. Egg quality is also assessed by measuring total protein of eggs laid, fertilization and hatching success, and the weight of individual eggs laid after the series of injections. Indirect evidence suggests that LPS induces an immune response in G. texensis. However, the number of eggs produced is not affected. There is also no effect of repeated LPS injections on female weight, egg protein content, or fertilization and hatching success. Taken together, these results suggest that with food and water provided ad libitum, females can protect many aspects of fitness in the face of increased immune system activity. However, there is some evidence to suggest that large (100 ,g) doses of LPS lead to reduced female longevity, and also in egg weight that could affect offspring success. Although the possibility exists that the decline in lifespan and egg weight after high-dose injections reflects a trade-off between reproduction and immune investment, another possibility is that these doses yield nonspecific effects, or that the high-dose induces an overwhelming immune response that leads to self-damage. [source] Casual Chocolate Consumption and Inhibition of Platelet FunctionPREVENTIVE CARDIOLOGY, Issue 4 2007Bryan Bordeaux DO Observational studies have associated reduced cardiovascular mortality with chocolate consumption. Feeding studies of high-dose, flavanol-rich chocolate show antiplatelet effects, but the effect of casual chocolate consumption on platelet function is unknown. Healthy adults (N=1535) were proscribed from consuming foods affecting platelet function, including chocolate, for 48 hours and completed a 24-hour dietary recall before ex vivo platelet testing with the Platelet Function Analyzer (PFA)-100 (Dade Behring, Inc, Deerfield, IL) test and in vivo testing with urinary 11-dehydro thromboxane B2 (Tx-M) measurements. Some participants (n=141) reported ignoring the prohibition of consuming chocolate before platelet testing. Despite having similar baseline characteristics, chocolate consumers had longer PFA closure times (130 vs 123 seconds, P=.005) and decreased Tx-M levels (175 vs 290 ng/mol creatinine, P=.03). Chocolate remained a significant independent predictor of both ex vivo and in vivo platelet function testing after adjusting for confounders. The authors concluded that even consuming modest amounts of commercial chocolate has important antiplatelet effects. [source] Effect of different challenge doses after repeated citalopram treatment on extracellular serotonin level in the medial prefrontal cortex: In vivo microdialysis studyPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 5 2008Ihoko Muraki md Aims:, In order to elucidate the relevance between the delayed onset of clinical efficacy of selective serotonin re-uptake inhibitors (SSRI) and extracellular 5-HT levels in the medial prefrontal cortex, the present study compared the ability of low-dose (3 mg/kg) and high-dose (30 mg/kg) citalopram to increase extracellular 5-HT levels in the medial prefrontal cortex following repeated citalopram treatment using in vivo microdialysis. Methods:, An SSRI, citalopram, was given 10 mg/kg, s.c. twice daily for 6 days and once on the seventh day in rats. On the eighth day, rats received a single injection of citalopram (3 or 30 mg/kg s.c.), and extracellular 5-HT levels were assessed in the medial prefrontal cortex of rats using in vivo brain microdialysis. Results:, There was no significant difference in basal extracellular 5-HT levels between the repeated citalopram group and the repeated saline group. The low-challenge dose of citalopram (3 mg/kg) produced significantly greater increases (170,200% at each time point) in the repeated citalopram group than in the repeated saline group (150%). The high-challenge dose of citalopram (30 mg/kg), however, increased extracellular 5-HT levels by 200,250% of basal levels in the repeated citalopram group, which was similar to the increases in the repeated saline group. Conclusions:, Repeated SSRI treatment enhances the effect of low-dose SSRI on extracellular 5-HT levels but not that of high-dose SSRI. [source] | |||||||||||||||||||||||||||||||