Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.

A sample of 15 patients participating in an injectable methadone trial and of 15 patients in an oral methadone maintenance treatment, who admitted injecting part or all of their methadone take-home doses, were compared to 20 patients in maintenance treatment who use methadone exclusively by mouth. The present study confirms the poorer general health, the higher levels of emotional, psychological or psychiatric problems, the higher use of illicit drugs, and the higher number of problems related to employment and support associated with the use of the intravenous mode of administration of methadone. As expected, due to the shunt of metabolism in the gut wall and of the liver first-pass effect, higher concentration to dose ratios of (R)-methadone, which is the active enantiomer, were measured in the intravenous group (23% increase). This difference reached an almost statistically significant value (P = 0.054). This raises the question whether the effect of a higher methadone dose could be unconsciously sought by some of the intravenous methadone users.

Intravenous thrombolysis in nonagenarians with ischemic stroke.

Background and Purpose-Demographic changes will result in a rapid increase of patients age >= 90 years (nonagenarians), but little is known about outcomes in these patients after intravenous thrombolysis (IVT) for acute ischemic stroke. We aimed to assess safety and functional outcome in nonagenarians treated with IVT and to compare the outcomes with those of patients age 80 to 89 years (octogenarians).Methods-We analyzed prospectively collected data of 284 consecutive stroke patients age >= 80 years treated with IVT in 7 Swiss stroke units. Presenting characteristics, favorable outcome (modified Rankin scale [mRS] 0 or 1), mortality at 3 months, and symptomatic intracranial hemorrhage (SICH) using the National Institute of Neurological Disorders and Stroke (NINDS) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria were compared between nonagenarians and octogenarians.Results-As compared with octogenarians (n=238; mean age, 83 years), nonagenarians (n=46; mean age, 92 years) were more often women (70% versus 54%; P=0.046) and had lower systolic blood pressure (161 mm Hg versus 172 mm Hg; P=0.035). Patients age >= 90 years less often had a favorable outcome and had a higher incidence of mortality than did patients age 80 to 89 years (14.3% versus 30.2%; P=0.034; and 45.2% versus 22.1%; P=0.002; respectively), while more nonagenarians than octogenarians experienced a SICH (SICHNINDS, 13.3% versus 5.9%; P=0.106; SICHSITS-MOST, 13.3% versus 4.7%; P=0.037). Multivariate adjustment identified age >= 90 years as an independent predictor of mortality (P=0.017).Conclusions-Our study suggests less favorable outcomes in nonagenarians as compared with octogenarians after IVT for ischemic stroke, and it demands a careful selection for treatment, unless randomized controlled trials yield more evidence for IVT in very old stroke patients. (Stroke. 2011; 42: 1967-1970.)

Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.

Stimulation of thermogenesis in men after combined glucose-long-chain triglyceride infusion.

The effect of combined long-chain triglyceride infusion (Intralipid 20%) with graded doses of insulin/glucose on energy expenditure was examined in 17 healthy young male volunteers by using the euglycemic insulin clamp technique in combination with indirect calorimetry. Intralipid was infused for 90 min at a constant rate of 0.23 g/min; plasma free fatty acids increased from base-line values of 380 +/- 8 mumol/l to steady state levels of 650 +/- 12 mumol/l. After 90 min the Intralipid was continued and insulin was infused at three rates (0.5, 2, and 4 mU/kg . min) to achieve steady state hyperinsulinemic plateaus of 63 +/- 4, 167 +/- 10, and 410 +/- 15 microU/ml. Plasma glucose concentration was maintained constant at basal euglycemic levels (insulin clamp technique) by infusing glucose at 0.24, 0.48, and 0.59 g/min, respectively. Glucose storage during the insulin clamp (ie, glucose uptake minus glucose oxidation) was 0.13, 0.33, and 0.40 g/min for each group and exogenous lipid storage was 0.17, 0.18, and 0.19 g/min, respectively. The net increment in energy expenditure was 0.15, 0.24, and 0.26 kcal/min, respectively, which represents 8.5% of the energy content of the total amount of glucose and lipid stored. The experimentally determined value (approximately 9%) for the cost of storing both glucose and lipid was found to be significantly greater than predicted by stoichiometric calculations. However, the experimental value for the combined infusion was less than that observed for glucose storage alone (12%). This finding provides support for the use of combined glucose/fat infusions in parenteral nutrition as it is used more economically than when glucose is infused alone.

Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture.

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction (P = 0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P = 0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P = 0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic-acid group (P = 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and improved survival. (ClinicalTrials.gov number, NCT00046254.).

Is intracerebral hemorrhage a time-dependent phenomenon after successful combined intravenous and intra-arterial therapy?

BACKGROUND AND PURPOSE: Onset-to-reperfusion time (ORT) has recently emerged as an essential prognostic factor in acute ischemic stroke therapy. Although favorable outcome is associated with reduced ORT, it remains unclear whether intracranial bleeding depends on ORT. We therefore sought to determine whether ORT influenced the risk and volume of intracerebral hemorrhage (ICH) after combined intravenous and intra-arterial therapy. METHODS: Based on our prospective registry, we included 157 consecutive acute ischemic stroke patients successfully recanalized with combined intravenous and intra-arterial therapy between April 2007 and October 2011. Primary outcome was any ICH within 24 hours posttreatment. Secondary outcomes included occurrence of symptomatic ICH (sICH) and ICH volume measured with the ABC/2. RESULTS: Any ICH occurred in 26% of the study sample (n=33). sICH occurred in 5.5% (n=7). Median ICH volume was 0.8 mL. ORT was increased in patients with ICH (median=260 minutes; interquartile range=230-306) compared with patients without ICH (median=226 minutes; interquartile range=200-281; P=0.008). In the setting of sICH, ORT reached a median of 300 minutes (interquartile range=276-401; P=0.004). The difference remained significant after adjustment for potential confounding factors (adjusted P=0.045 for ICH; adjusted P=0.002 for sICH). There was no correlation between ICH volume and ORT (r=0.16; P=0.33). CONCLUSIONS: ORT influences the rate but not the volume of ICH and appears to be a critical predictor of symptomatic hemorrhage after successful combined intravenous and intra-arterial therapy. To minimize the risk of bleeding, revascularization should be achieved within 4.5 hours of stroke onset.

Effects of infused amino acids and lipids on glucose metabolism in healthy lean humans.

The effects of infusion of a triglyceride emulsion (which induces peripheral insulin resistance) and amino acids (which stimulate gluconeogenesis) on glucose metabolism were investigated in healthy lean humans during exogenous infusion of glucose. One group of subjects (n = 5) was infused for 7.5 h with 11.1 mumol/kg/min glucose; during the last 4 h, amino acids were also infused at a rate of 3.33 mg/kg/min. A second group of subjects (n = 5) was infused with glucose+lipids (Lipovenös, 10% 10 ml/min) for 7.5 h and amino acids were added during the last 4 h. Infusion of lipids suppressed the increase in glucose oxidation observed during infusion of glucose alone (delta glucose oxidation: -2.1 +/- 1.1 vs. + 4.5 +/- 1.4 mumol/kg/min; P < 0.05) and during infusion of glucose+amino acids (delta glucose oxidation: + 1.6 +/- 1.4 vs. + 10.6 +/- 1.2 mumol/kg/min; P < 0.05). Gluconeogenesis (determined from 13C glucose synthesis during infusion of 13C bicarbonate) increased from 1.1 +/- 0.2 mumol/kg/min during infusion of glucose and 1.6 +/- 0.3 during infusion of glucose+lipids to 3.2 +/- 0.4 and 3.1 +/- 0.4, respectively, when amino acid infusion was superimposed (P < 0.05 in both instances). Plasma glucose concentrations were identical during infusion of glucose alone or glucose+amino acids, with or without lipids. Insulin concentrations were significantly increased by lipids both during infusion of glucose alone and of glucose+amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Carence en fer sans anémie: où en est-on en 2012 [Iron deficiency without anemia: where are we in 2012?].

Should we treat iron deficiency without anemia? The simple fact that the question can be formulated already leads to controversies. During the past years, the development of a new formulation of intravenous iron has helped fuel the controversy. What is the situation in 2012? This article gives a practical point of view on the actual situation and provides indications on the use of new intravenous medications.

Site of the action of a synthetic atrial natriuretic peptide evaluated in humans.

The renal site of the natriuretic effect of human, atrial natriuretic peptide (hANP) was studied using clearance techniques in eight salt-loaded normal volunteers undergoing maximal water diuresis. Lithium was used as a marker of proximal sodium reabsorption. According to a two-way, single blind, crossover design, hANP (Met12-(3-28)-eicosahexapeptide, (2 micrograms/min) or its vehicle (Ve) were infused for two hours, followed by a two-hour recovery period. Blood pressure, heart rate and insulin clearance remained unchanged. During hANP infusion, the filtration fraction increased slightly from 19.6 to 24.3% (P less than 0.001), fractional water excretion rose transiently at the beginning of the infusion. Fractional excretion of sodium increased markedly from 2.2% to 7.4% (P less than 0.001) but remained unchanged with Ve. ANP increased fractional excretion of lithium slightly from 46 to 58% (P less than 0.01), while it remained stable at 47% during Ve. The distal tubular rejection fraction of sodium calculated from sodium and lithium clearances rose markedly from 4.7 to 13% (P less than 0.001) and returned to 6.2% at the end of the recovery period. Thus, under salt loading and water diuresis conditions, hANP infusion did not alter GFR, but reduced proximal reabsorption of sodium, and markedly enhanced the fraction of sodium escaping distal tubular reabsorption, suggesting that hANP-induced natriuresis is due, for an important part, to inhibition of sodium reabsorption in the distal nephron.

Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis.

The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16 years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9 mg/kg once daily) for 14 days or intravenous ceftriaxone (50 mg/kg once daily) for 3 days followed by oral ceftibuten for 11 days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6 years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14 days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6 months to 16 years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these children.

Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: a randomized controlled trial.

BACKGROUND: Fish oil (FO) has antiinflammatory effects, which might reduce systemic inflammation induced by a cardiopulmonary bypass (CPB). OBJECTIVE: We tested whether perioperative infusions of FO modify the cell membrane composition, inflammatory responses, and clinical course of patients undergoing elective coronary artery bypass surgery. DESIGN: A prospective randomized controlled trial was conducted in cardiac surgery patients who received 3 infusions of 0.2 g/kg FO emulsion or saline (control) 12 and 2 h before and immediately after surgery. Blood samples (7 time points) and an atrial biopsy (during surgery) were obtained to assess the membrane incorporation of PUFAs. Hemodynamic data, catecholamine requirements, and core temperatures were recorded at 10-min intervals; blood triglycerides, nonesterified fatty acids, glucose, lactate, inflammatory cytokines, and carboxyhemoglobin concentrations were measured at selected time points. RESULTS: Twenty-eight patients, with a mean ± SD age of 65.5 ± 9.9 y, were enrolled with no baseline differences between groups. Significant increases in platelet EPA (+0.86%; P = 0.0001) and DHA (+0.87%; P = 0.019) were observed after FO consumption compared with at baseline. Atrial tissue EPA concentrations were higher after FO than after control treatments (+0.5%; P < 0.0001). FO did not significantly alter core temperature but decreased the postoperative rise in IL-6 (P = 0.018). Plasma triglycerides increased transiently after each FO infusion. Plasma concentrations of glucose, lactate, and blood carboxyhemoglobin were lower in the FO than in the control group on the day after surgery. Arrhythmia incidence was low with no significant difference between groups. No adverse effect of FO was detected. CONCLUSIONS: Perioperative FO infusions significantly increased PUFA concentrations in platelet and atrial tissue membranes within 12 h of the first FO administration and decreased biological and clinical signs of inflammation. These results suggest that perioperative FO may be beneficial in elective cardiac surgery with CPB. This trial was registered at clinicaltrials.gov as NCT00516178.

Iron Supplementation Therapy in a Large Swiss Cohort of Inflammatory Bowel Disease Patients: Shift from Oral to Intravenous Therapy over Time

Background a nd A ims: T he 2 007 ECCO g uidelines o nanemia in inflammatory bowel disease (IBD) favour intravenous(iv) over oral (po) i ron supplementation due to bettereffectiveness and tolerance. Application of guidelines in clinicalpractice m ay r equire time. We a imed to determine thepercentage of IBD patients under iron supplementation therapyand its application mode over time in a large IBD cohort.Methods: Helsana, a leading Swiss health insurance companyprovides c overage f or approximately 18% of t he Swisspopulation, corresponding to about 1.2 million enrollees.Patients with Crohn's disease (CD) and ulcerative colitis (UC)were identified b y keyword search from t he a nonymisedHelsana database.Results: I n total, 6 29 CD ( 61% female) a nd 4 03 UC ( 56%female) patients w ere identified, mean retrospectiveobservation time w as 2 0.4 m onths f or CD and 13 m onths f orUC patients. Of t he entire study population, 29.3% wereprescribed iron. O ccurrence of iron prescription was 21.3% inmales a nd 31.2% in f emales ( odds r atio [OR] 1 .69, 95%-confidence interval [CI] 1.26-2.28). The prescription of iv i ronincreased from 2006/2007 ( 48.8% w ith iv i ron) to 2 008/2009(65.2% with iv iron) by a factor of 1.89.Conclusions: One third of the IBD population was treated withiron supplementation. A gradual s hift from oral t o iv iron wasobserved over time in a large Swiss IBD cohort. This switch inprescription habits g oes a long with the implementation of theECCO consensus guidelines on anemia in IBD.

Hemodynamic effects of sodium bicarbonate in critically ill neonates.

OBJECTIVE: To analyze the cardiovascular effects of sodium bicarbonate in neonates with metabolic acidosis. DESIGN: Prospective, open, non-randomized, before-after intervention study with hemodynamic measurements performed before and 1, 5, 10, 20, and 30 min after bicarbonate administration. SETTING: Neonatal intensive care unit, tertiary care center. PATIENTS: Sequential sample of 16 paralysed and mechanically ventilated newborn infants with a metabolic acidosis (pH < 7.25 in premature and < 7.30 in term infants, base deficit > -8). INTERVENTION: An 8.4% sodium bicarbonate solution diluted 1:1 with water (final osmolality of 1000 mOsm/l) was administered in two equal portions at a rate of 0.5 mmol/min. The dose in mmol was calculated using the formula "base deficit x body weight (kg) x 1/3 x 1/2". MEASUREMENTS AND RESULTS: Sodium bicarbonate induced a significant but transient rise in pulsed Doppler cardiac output (CO) (+27.7%), aortic blood flow velocity (+15.3%), systolic blood pressure (BP) (+9.3%), (+14.6%), transcutaneous carbon dioxide pressure (PtcCO2) (+11.8%), and transcutaneous oxygen pressure (PtcO2) (+8%). In spite of the PaCO2 elevation, pH significantly improved (from a mean of 7.24 to 7.30), and the base deficit decreased (-39.3%). Calculated systemic vascular resistance (SVR) (-10.7%) and diastolic BP (-11.7%) decreased significantly, while PaO2 and heart rate (HR) did not change. Central venous pressure (CVP) (+6.5%) increased only slightly. By 30 min after bicarbonate administration all hemodynamic parameters, with the exception of the diastolic BP, had returned to baseline. CONCLUSION: Sodium bicarbonate in neonates with metabolic acidosis induces an increase in contractility and a reduction in afterload.

Iron supplementation in a large Swiss Cohort of Inflammatory Bowel Disease patients demonstrates a shift form oral to intravenous therapy over time

Background and Aims: The 2007 European Crohn's and Colitis Organization guidelines on anemia in inflammatory bowel disease (IBD) favour intravenous (iv) over oral (po) iron supplementation due to better effectiveness and tolerance. We aimed to determine the percentage of IBD patients under iron supplementation therapy and the dynamics of prescription habits (iv versus po) over time. Methods: Helsana, a leading Swiss health insurance company provides coverage for approximately 18% of the Swiss population, corresponding to about 1.2 million enrollees. Patients with Crohn's disease (CD) and ulcerative colitis (UC) were analyzed from the anonymised Helsana database. Results: In total, 629 CD (61% female) and 398 UC (57% female) patients were identified, mean observation time was 31.8 months for CD and 31.0 months for UC patients. Of the entire study population, 27.1% were prescribed iron (21.1% in males and 31.1% in females). Patients treated with IBD-specific drugs (steroids, immunomodulators, anti-TNF agents) were more frequently treated with iron compared to patients without any medication (35.0% vs. 20.9%, OR 1.91, 95%-CI 1.41-2.61). The prescription of iv iron increased from 2006/2007 (48.8% of all patients receiving any iron priscription) to 65.2% in 2008/2009 by a factor of 1.89. Conclusions: One third of the IBD population was treated with iron supplementation. A gradual shift from oral to iv iron was observed over time. This switch in prescription habits goes along with the implementation of the ECCO consensus guidelines on anemia in IBD.