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IV Infusion (iv + infusion)
Selected AbstractsColonic sarcoidosis, infliximab, and tuberculosis: A cautionary taleINFLAMMATORY BOWEL DISEASES, Issue 4 2004Prof. Dario Sorrentino MD Abstract The antitumor necrosis factor, infliximab, has been recently shown to be effective in refractory sarcoidosis including the intestinal form of this disease. We have tried this therapy in a 55-year-old woman under immunosuppressive therapy for longstanding sarcoidosis presenting with abdominal pain apparently caused by a colonic localization of the disease. The latter diagnosis was based, as recommended, on the presence of nonnecrotizing granulomas in mucosal biopsies, the presence of systemic disease, and the careful exclusion of other granulomatous diseases, including tuberculosis. After the first IV infusion (10 mg/kg BW), she quickly improved, but the wellbeing lasted approximately 4 weeks. She then received another dose of infliximab, but she soon developed low-grade fever and weakness and shortly succumbed of miliary tuberculosis. Likely, infliximab precipitated a pre-existing mycobacterial infection of the intestine. Given the likelihood of underdiagnosing intestinal tuberculosis,and the risks associated with infliximab treatment,this case suggests that this drug should be used with extreme caution, if at all, when a diagnosis of colonic sarcoidosis is suspected. [source] Wound infiltration with magnesium sulphate and ropivacaine mixture reduces postoperative tramadol requirements after radical prostatectomyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2009P. TAUZIN-FIN Purpose: This prospective, randomized, double-dummy study was undertaken to compare the effects of magnesium sulphate (MgSO4) administered by the intravenous vs. the infiltration route on postoperative pain and analgesic requirements. Methods: Forty ASA I or II men scheduled for radical retropubic prostatectomy under general anaesthesia were randomized into two groups (n=20 each). Two medication sets A and B were prepared at the pharmacy. Each set contained a minibag of 50 ml solution for IV infusion and a syringe of 45 ml for wound infiltration. Group MgSO4.IV patients received set A with 50 mg/kg MgSO4 in the minibag and 190 mg of ropivacaine in the syringe. Group MgSO4/L received set B with isotonic saline in the minibag and 190 mg of ropivacaine +750 mg of MgSO4 in the syringe. The IV infusion was performed over 30 min at induction of anaesthesia and the surgical wound infiltration was performed during closure. Pain was assessed every 4 h, using a 100-point visual analogue scale (VAS). Postoperative analgesia was standardized using IV paracetamol (1 g/6 h) and tramadol was administered via a patient-controlled analgesia system. The follow-up period was 24 h. Results: The total cumulative tramadol consumption was 221 ± 64.1 mg in group MgSO4.IV and 134 ± 74.9 mg in group MgSO4.L (P<0.01). VAS pain scores were equivalent in the two groups throughout the study. No side-effects, due to systemic or local MgSO4 administration, were observed. Conclusion: Co-administration of MgSO4 with ropivacaine for postoperative infiltration analgesia after radical retropubic prostatectomy produces a significant reduction in tramadol requirements. [source] Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy VolunteersALCOHOLISM, Issue 5 2009Vijay A. Ramchandani Background:, Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. Methods:, This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (Cmax), times of peak BrAC (Tmax), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. Results:, The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean Cmax, Tmax, and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in Cmax and AUC were both 11%, while the mean %difference for Tmax was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. Conclusions:, Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response. [source] The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascitesALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2010V. L. Misra Aliment Pharmacol Ther 2010; 32: 1044,1050 Summary Background, Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha-1 agonist, has been shown to improve GFR in non-azotemic patients with cirrhosis. Aim, To conduct a randomized, double-blind, placebo-controlled, cross-over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non-azotemic cirrhotics with ascites. Methods, All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6-h urine sodium excretion and 6-h total urine volume. Results, A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6-h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6-h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). Conclusions, Oral midodrine does not increase the natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites. [source] Effects of Lidocaine Infusion during Experimental Endotoxemia in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2010J.R. Peiró Background: The clinical efficacy of IV infusion of lidocaine for treatment of equine endotoxemia has not been studied. Hypothesis: Lidocaine infusion after exposure to lipopolysaccharide (LPS) will inhibit the inflammatory response and have inhibitory effects on the hemodynamic and cytokine responses to endotoxemia. Animals: Twelve horses. Methods: Two equal groups (n = 6): saline (GI) and lidocaine (GII). In all animals, endotoxin (500 ng/kg body weight [BW]) was injected intraperitoneally over 5 minutes. Twenty minutes later, animals received a bolus of GI or GII (1.3 mg/kg BW) over 5 minutes, followed by a 6-hour continuous rate infusion of GI or GII (0.05 mg/kg BW/min). Treatment efficacy was judged from change in arterial blood pressure, peripheral blood and peritoneal fluid (PF) variables (total and differential cell counts, enzyme activities, and cytokine concentrations), and clinical scores (CS) for behavioral evidence of abdominal pain or discomfort during the study. Results: Compared with the control group, horses treated with lidocaine had significantly lower CS and serum and PF tumor necrosis factor-, (TNF-,) activity. At several time points in both groups, total and differential cell counts, glucose, total protein and fibrinogen concentrations, and alkaline phosphatase, creatine kinase, and TNF-, activities were significantly different from baseline values both in peripheral blood and in PF. Conclusions and Clinical Importance: Lidocaine significantly decreased severity of CS and inhibited TNF-, activity in PF. [source] Clinical Evaluation of Gemcitabine in Dogs with Spontaneously Occurring MalignanciesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2005Carrie E. Kosarek We conducted a clinical evaluation of gemcitabine in 19 dogs with spontaneously occurring malignancies. The principal objectives of this study were to characterize toxicity and seek preliminary evidence of antitumor activity of gemcitabine administered every 2 weeks (biweekly) as a 30-minute IV infusion. A total of 64 doses, ranging from 300 mg/m2 to 675 mg/m2, were administered during the initial 8-week evaluation period, and an additional 131 doses were administered during the extended evaluation period. The total cumulative dose for the 10 dogs receiving gemcitabine in the extended evaluation period ranged from 1,500 mg/m2 to 24,300 mg/m2. Clinical evidence of toxicity was minimal. Cumulative myelosuppression was not apparent. Unexplained retinal hemorrhages occurred in 1 dog. No complete or partial remissions were observed during the initial evaluation period; however, objective responses were observed in 2 dogs during the extended evaluation period. Gemcitabine is a promising new chemotherapeutic agent that can be used safely in dogs with cancer. Biweekly administration of doses of 675 mg/m2 IV results in minimal and acceptable toxicity. [source] Platinum pharmacokinetics in sulphur-crested cockatoos (Cacatua galerita) following single-dose cisplatin infusionAUSTRALIAN VETERINARY JOURNAL, Issue 6 2000LJ FILIPPICH Objective To determine the pharmacokinetics of platinum (Pt) in cockatoos. Design A pharmacokinetic study of Pt, following a single IV infusion of cisplatin, was done in six healthy sulphur-crested cockatoos (Cacatua galerita). Procedure Birds were hydrated for 1 h before and 2 h after a 1-h cisplatin infusion (1 mg/kg, IV). Serial blood samples were collected for 96 h after initiation of the infusion and urine was collected for 2 h during the hydration period after cisplatin administration. Tissue samples from 10 organs were obtained at necropsy, 96 h after cisplatin infusion. Total Pt and filterable Pt in plasma, urinary Pt and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma and urine data. Results For total Pt and filterable Pt, the respective mean systemic clearances were 0.373 and 0.699 L/kg hourly, the steady state volumes of distribution were 4.19 and 0.356 L/kg, and the mean residence times were 111 and 0.512 h. Total plasma Pt displayed a bi-exponential decay profile with average half-lives of 0.398 and 79.0 h, while filterable Pt had a monoexponential decay with mean half-life of 0.413 h. The renal clearance during the 2-h postinfusion period was 0.167 L/kg hourly. The kidneys had the highest Pt accumulation (4.54 u.g/g DM). Conclusions and Clinical Relevance Cisplatin infusion in cockatoos was well tolerated and Pt plasma concentrations were similar to those measured during treatment of solid tumours in human patients. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of Pt in the cockatoo shares some features with the kinetics reported previously in rodents, dogs and human beings. [source] Emergency Department Use of Intravenous Procainamide for Patients with Acute Atrial Fibrillation or FlutterACADEMIC EMERGENCY MEDICINE, Issue 12 2007Ian G. Stiell MD Objectives Acute atrial fibrillation and flutter are very common arrhythmias seen in emergency department (ED) patients, but there is no consensus for their optimal management. The objective of this study was to examine the efficacy and safety of intravenous (IV) procainamide for acute atrial fibrillation or flutter. Methods This health records review included a consecutive cohort of ED patients with acute-onset atrial fibrillation or atrial flutter who received IV procainamide at one university hospital ED during a five-year period. The standard clinical protocol involved IV infusion of 1 g of procainamide over 60 minutes, followed by electrical cardioversion if necessary. A trained observer extracted data from the original clinical records. Outcome measurements included conversion to sinus rhythm, adverse events, and relapse up to seven days. Results The 341 study patients had a mean age of 63.9 years (SD ± 15.5 years), and 56.6% were male. The conversion rates were 52.2% (95% confidence interval = 47% to 58%) for 316 atrial fibrillation cases and 28.0% (95% confidence interval = 13% to 46%) for 25 atrial flutter cases. Mean dose given was 860.7 mg (SD ± 231.2 mg), and median time to conversion was 55 minutes. Adverse events occurred in 34 cases (10.0%): hypotension, 8.5%; bradycardia, 0.6%; atrioventricular block, 0.6%; and ventricular tachycardia, 0.3%. There were no cases of torsades de pointes, cerebrovascular accident, or death. Most patients (94.4%) were discharged home, but 2.9% of patients returned with a recurrence of atrial fibrillation within seven days. Conclusions This study of acute atrial fibrillation or flutter patients treated in the ED with IV procainamide suggests that this treatment is safe and effective in this setting. Procainamide should be prospectively compared with other ED strategies. [source] Effect of Intravenous Albumin Infusion on Brain Salicylate ConcentrationACADEMIC EMERGENCY MEDICINE, Issue 6 2007Steven C. Curry MD Background:Salicylate poisoning appears to result in death, despite supportive care, once a critical brain salicylate concentration is reached. The binding of salicylate to albumin is saturable; free plasma salicylate concentrations rise disproportionately to total drug levels. Because unbound salicylate distributes into the brain, the authors questioned whether an intravenous (IV) infusion of albumin would cause a redistribution of salicylate from the brain back into the plasma, which might allow enough time for hemodialysis to be instituted. Objectives:To determine if IV albumin infusion would lower brain salicylate concentrations through redistribution in a porcine model of acute salicylate poisoning. Methods:In a randomized controlled trial, 17 swine under anesthesia and controlled ventilation received 400 mg/kg of sodium salicylate IV over 15 minutes. At 60 minutes, nine animals received 1.25 g/kg albumin (25% solution) IV over 15 minutes, while eight control animals received an equal volume of normal saline (5 mL/kg). Arterial pH was maintained between 7.45 and 7.55. Serial measurements of serum albumin as well as free and total salicylate concentrations were obtained, and urine was collected for measurement of total salicylate excretion. At 180 minutes, animals were killed and brains harvested for measurement of brain salicylate concentrations. Results:Average peak serum total salicylate concentrations of 105.5 and 109 mg/dL were achieved in control and albumin-treated animals, respectively. Albumin infusion was accompanied by statistically significant increases in serum total salicylate concentrations (median from 79.5 to 86.9 mg/dL at 75 minutes), while levels decreased slightly in control animals. Serum free salicylate concentrations decreased slightly in albumin-treated animals, but the difference was not statistically significant. Median brain salicylate concentrations were about 14% lower in the albumin treatment group (17.8 mg/100 g brain) compared with controls (20.5 mg/100 g brain); this approached statistical significance (p = 0.075). Median urinary salicylate excretion was higher in the albumin-treated group (0.83 vs. 0.48 g; p = 0.072), with similar urinary pH and volumes in both groups. Conclusions:In this animal model of salicylate poisoning, IV infusion of 1.25 g/kg albumin was accompanied by a 14% decline in median brain salicylate concentrations, which approached statistical significance. [source] Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trialCLINICAL CARDIOLOGY, Issue 6 2000Peter E. Pool M.D. Abstract Background: Although suppression of premature ventricular contractions (PVCs) is not a predictor of mortality over the long term, the extent of PVC suppression is an important characteristic of any antiarrhythmic drug. Hypothesis: This study was undertaken to determine whether intravenous (IV) dofetilide has the ability to suppress PVCs in patients who have frequent occurrences. Methods: Subjects were men and women, aged 18 to 75 years, with > 30 PVCs/h on two consecutive 24-h Holter recordings while drug free, and > 50 PVCs/h during a 2-hour telemetric electrocardiogram. The study was randomized, double-blind, and placebo controlled. Subjects received a single-blind, IV infusion of placebo and were randomized (3:1) to receive a double-blind second infusion of placebo or an infusion of dofetilide (a 15-min loading infusion of 4 g/kg followed by a 60-min maintenance infusion of 3.5 g/kg, for a total dose of 7.5 g/kg). Results: Dofetilide produced an 82.6% and placebo a 2.9% median reduction in PVCs. Drug responder rate, defined as 80% reduction in PVCs, was 50% in the dofetilide group and 0% in the placebo group. Conclusion: Intravenous dofetilide significantly reduced PVCs in patients who had > 30 PVCs/h at baseline, and it produced , 80% reduction in PVCs in 50% of all subjects. [source] Dexmedetomidine and arousal affect subthalamic neurons,MOVEMENT DISORDERS, Issue 9 2008William Jeffrey Elias MD Abstract Stereotactic neurosurgeons hesitate to employ sedation in cases requiring microelectrode recording (MER). We report our experience with dexmedetomidine during MER of subthalamic nucleus (STN). Eleven Parkinsonian patients received dexmedetomidine during deep brain stimulation surgery. Seven received continuous IV infusions during MER in the STN. The bispectral index (BIS) was used to estimate the level of consciousness. The quality of MER was evaluated as a function of BIS, clinical arousal, and dexmedetomidine dose. MER during wakefulness (BIS > 80; 0.1 to 0.4 mcg/kg/hr dexmedetomidine) was similar to the unmedicated state. Subthalamic MER was reduced when the patient was asleep or unarousable (BIS < 80). Anxiolysis persisted for hours. Arousal affects STN neurons. Dexmedetomidine "cooperative sedation," from which the patient is easily aroused, provides interpretable STN MER and prolonged anxiolysis. We suggest dexmedetomidine infusions without a loading dose, a relatively low infusion rate, and discontinuation after completion of the bur holes. © 2008 Movement Disorder Society [source] The Salty Dog: Serum Sodium and Potassium Effects on Modern Pacing ElectrodesPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 1 2007RICK McVENES Background: This study was conducted to characterize the behavior of chronic modern endocardial electrodes with capacitively coupled constant voltage pulse generators in canines. Methods: Five animals were studied with chronic paired unipolar microporous platinum, and porous steroid-eluting electrodes in the ventricle. Screw-in and passive fixation electrodes were also implanted in the atrium. IV infusions of 500,800 mL of 50 meq KCl in 500 mL Ringer's solution, and 3% NaCl were given over periods of 120 and 80 minutes, respectively, during separate anesthetized monitors. Results: Mean maximum Na+ and K+ achieved was 158 and 8.3 meq/L, respectively. During KCl infusion, ventricular threshold, current, and energy decreased. In the atrium, half the leads went to exit block at ,7.0 meq/L K+. Others continued to perform acceptably. The atrial electrogram decreased 70% with no change in the ventricular signal. No change in impedance occurred. During NaCl infusion, no changes in atrial or ventricular threshold occurred while current increased 21%,32%. This resulted in a 40%,55% increase in energy due to a 20% decrease in impedance. The atrial electrogram decreased 32%,36% while the ventricular amplitude decreased 25%. Slew rate decreased 19%,27%. Control studies for effects of heart rate, fluid volume, and anesthesia duration did not cause any changes. Conclusion: These data support the conclusion that threshold is a voltage mediated response. Thus, voltage thresholds, not energy, current or pulse duration is the most relevant parameter for safety margin determination. Atrial parameters should be followed during electrolyte imbalances. Correlation in humans is needed. [source] Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: Results of a randomized, double-blind, placebo-controlled, phase I/II study,ARTHRITIS & RHEUMATISM, Issue 8 2010Mikkel Østergaard Objective To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to ,1 disease-modifying antirheumatic drug. Methods This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. Results AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. Conclusion Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA. [source] Pharmacodynamics and pharmacokinetics of YM128, a GPIIb/IIIa antagonist prodrugDRUG DEVELOPMENT RESEARCH, Issue 3 2002Ken-ichi Suzuki Abstract We examined the biochemical properties of YM-57029 ({4-[4-(4-Carbamimidoylphenyl)-3-oxopiperazin-1-yl]piperidino}acetic acid monohydrochloride trihydrate) and the pharmacodynamics and pharmacokinetics of its prodrug, YM128 (Ethyl (Z)-(4-{4-[4-(N2 -hydroxycarbamimidoyl)phenyl]-3-oxopiperazin-1-yl}piperidino)acetate), an orally-active glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist. YM-57029 strongly inhibited aggregation of human platelets induced by various agonists, with IC50 values ranging from 3.6 to 51 nM. YM-57029 specifically inhibited fibrinogen binding to purified GPIIb/IIIa about 1,000-fold more potently than Arg-Gly-Asp-Ser (RGDS). Moreover, YM-57029 effectively inhibited an Arg-Gly-Asp (RGD) peptide binding to platelets, suggesting that YM-57029 competed with the RGD sequence of ligand. YM-57029 or YM128 dose-dependently inhibited ex vivo platelet aggregation after iv bolus injection or oral administration to beagle dogs and cynomolgus monkeys. However, YM128 exerted more potent and prolonged inhibitory effects on platelet aggregation than YM-57029 after oral administration to cynomolgus monkeys. Furthermore, YM-57029 prolonged template bleeding time at a dose that inhibited ex vivo platelet aggregation during cumulative iv infusion to cynomolgus monkeys. Metabolic and pharmacokinetic studies showed that YM128 effectively converted into YM-57029 in liver microsomes from humans as well as dogs and monkeys, and that bioavailabilities of YM128 in dogs and monkeys were 32.3 and 22.2%, respectively. These results suggest that YM128, a prodrug of YM-57029, may be a valuable GPIIb/IIIa antagonist with good bioavailability in humans. Drug Dev. Res. 55:149,161, 2002. © 2002 Wiley-Liss, Inc. [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] 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] Modulatory effects of static magnetic fields on blood pressure in rabbitsBIOELECTROMAGNETICS, Issue 6 2001Hideyuki Okano Abstract Acute effects of locally applied static magnetic fields (SMF) on pharmacologically altered blood pressure (BP) in a central artery of the ear lobe of a conscious rabbit were evaluated. Hypotensive and vasodilator actions were induced by a Ca2+ channel blocker, nicardipine (NIC). Hypertensive and vasoconstrictive actions were induced by a nitric oxide synthase (NOS) inhibitor, N, -nitro- L -arginine methyl ester (L-NAME). The hemodynamic changes in the artery exposed to SMF were measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, BP changes in a central artery contralateral to that of the exposed ear lobe were monitored. SMF intensity was 1,mT and the duration of exposure was 30,min. A total of 180 experimental trials were carried out in 34 healthy adult male rabbits weighing 2.6,3.8,kg. Six experimental procedures were chosen at random: (1) sham exposure without pharmacological treatment; (2) SMF exposure alone; (3) decreased BP induced by a single intravenous (iv) bolus injection of NIC (100,,M/kg) without SMF exposure; (4) decreased BP induced by injection of NIC with SMF exposure; (5) increased BP induced by a constant iv infusion of L-NAME (10,mM/kg/h) without SMF exposure; (6) increased BP induced by infusion of L-NAME with SMF exposure. The results demonstrated that SMF significantly reduced the vasodilatation with enhanced vasomotion and antagonized the reduction of BP via NIC-blocked Ca2+ channels in vascular smooth muscle cells. In addition, SMF significantly attenuated the vasoconstriction and suppressed the elevation of BP via NOS inhibition in vascular endothelial cells and/or central nervous system neurons. These results suggest that these modulatory effects of SMF on BP might, in part, involve a feedback control system for alteration in NOS activity in conjunction with modulation of Ca2+ dynamics. Bioelectromagnetics 22:408,418, 2001. © 2001 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 18 2008Article first published online: 3 OCT 200 Inhaled steroids for all children with asthma? Some children with mild well-controlled asthma may not need a daily inhaled steroid, a Scandinavian study suggests (Arch Dis Child 2008;93:654-9). A total of 176 children aged 5-10 years were randomised to treatment with cromoglicate (Intal) or budesonide. Initially high doses of budesonide (400,g twice daily) were reduced after one month to 200,g twice daily for four months; subsequent treatment for a further year was 100,g twice daily as required for exacerbations or 100,g twice daily regularly. Budesonide was associated with greater improvement in lung function and fewer exacerbations compared with cromoglicate, but after 18 months lung function improvements did not differ. Regular budesonide was associated with fewer exacerbations than as-required administration (0.97 vs 1.69 per patient in months 7-18) but no difference in asthma-free days or use of rescue medication. Growth suppression was slightly greater with continuous budesonide. Interventions to reduce atypicals weight gain A systematic review has found that techniques such as cognitive behaviour therapy and nutritional counselling can reduce weight gain associated with atypical antipsychotics (Br J Psychiatry 2008;193:101-7). Analysis of 10 randomised trials lasting eight weeks to six months found that nonpharmacological intervention increased mean weight loss by about 2.5kg compared with usual care. Check flu vaccine delivery Production of flu vaccine is proceeding according to plan, the Director of Immunisation has told GPs. Practices should now contact their suppliers to confirm a delivery schedule so that clinics can be arranged. New BNF for Children The fourth BNF for Children has been published, containing new sections on HPV vaccination, contraception, treatment of pelvic inflammatory disease and the use of continuous iv infusions in neonates. BNFC 2008 is available online at bnfc.org/bnfc. MMR catch-up ,urgent' The DoH has called for urgent action to reduce the risk of a measles epidemic. Following years of relatively low uptake of MMR vaccine, the pool of unprotected children is now large enough to raise the prospect of 30 000-100 000 measles cases in England. A catch-up campaign will now target children and young people who have never been vaccinated, followed by those who have not completed their course of immunisation. Resource materials are available at www.immunisation.nhs.uk. , A new brand of MMR vaccine is now available. Sanofi Pasteur MSD has replaced MMRII with a new formulation and presentation, MMRvaxPro. The new vaccine is equivalent to its predecessor and interchangeable with Priorix. Early primary prevention with low-dose aspirin? GPs should consider prescribing low-dose aspirin for primary prevention for men aged 48 and women aged 57, say UK researchers (Heart 2008; published online 15 August 2008. doi:10.1136/hrt.2008.150698). Using data from the THIN network of electronic patient records, they modelled the age at which 10-year coronary risk changed from <10 per cent to >10 per cent in men and women without diabetes, not taking lipid-lowering therapy and with no history of cardiovascular disease. Does COPD therapy slow progression? Treatment with an inhaled steroid and long-acting beta-agonist may slow progression of COPD, according to a new analysis of the TORCH study (Am J Respir Crit Care Med 2008;178:332-8). TORCH was designed to determine the effects of COPD treatment on mortality; the primary analysis found no significant difference between fluticasone/salmeterol (Seretide) and placebo (N Engl J Med 2007;356:775-89). This analysis found that the rate of decline in FEV1 (a marker of disease progression) was significantly greater with placebo (55ml per year) than with salmeterol or fluticasone monotherapy (both 42ml per year) or their combination (39ml per year). Faster decline in FEV1 was associated with current smoking, lower BMI and more frequent exacerbations. Copyright © 2008 Wiley Interface Ltd [source] | ||||||||||||||||||||||