Amitriptyline: linear or nonlinear kinetics in every day practice?

An experimental study on the effects of ethanol and folic acid deficiency, alone or in combination, on pregnant Swiss mice

Editor – We would like to comment on an article published by Doi et al.1 The report was based on a review of studies examining the effectiveness of low and high administered doses of radioiodine for the ablation of thyroid remnant among patients with differentiated thyroid cancer. Their analysis was based on a previously published systematic review conducted by Hackshaw et al2 which concluded that there is currently insufficient evidence to reliably say whether a low dose is associated with a lower ablation success rate than a high dose. Doi et al, however, use the same studies to conclude that a low dose is worse, but there are fundamental problems with their analysis and interpretation. First, they combine studies with very different designs into a single meta-analysis producing a relative risk which appears to be precise and highly statistically significant. The relative risk of having a successful ablation in the low dose group compared to the high dose group was 0.73, 95% confidence interval (CI) 0.61–0.81. The 22 studies, on which this particular result is based, are a mixture of cohort studies, retrospective reviews of patient medical records, and randomized trials. It is inappropriate to combine these studies when the observational studies are likely to be affected by inherent biases and confounding, but the randomized trials are not. Indeed, meta-analyses of observational studies need to be interpreted with great care because the effect of potential confounding in each study could be magnified when the studies are combined, thus producing a spuriously precise effect.3 Sixteen of the 22 studies (73%) were observational, so their results will contribute most to the pooled result. The best evidence must come from randomized clinical trials. Second, when their analysis was restricted to the 6 randomized trials (in which no comparison was based on more than 150 patients in total), the pooled relative risk was 0.68 (95% CI 0.43–1.07), which was not statistically significant (P-value of 0.093). The correct interpretation is that, while there is some evidence of a lower ablation rate when using a low dose, the effect could be due to chance because the CI includes the no-effect value and P >0.05 (i.e., there could be no true difference). However, no comment was made on this. Third, the dose level that defines ‘low’ and ‘high’ differs greatly between these trials. For example, a low dose could be 30 or 50 mCi (a difference of two-thirds), and a high dose could be 50 or 100 mCi (a difference of two-fold). Because of this, it is best to not combine all the trials to produce a single relative risk. Once these considerations have been taken into account, there is no analysis that allows firm conclusions to be made about the comparison of low and high dose radioiodine in treating differentiated thyroid cancer. While some clinicians prefer to administer a high dose at present, it is misleading to rule out the use of a low dose based on current evidence. There are clear potential advantages, such as less time spent in isolation in hospitals and lower risk of future second malignancies.2 What is needed is a large randomized trial, and there are two such trials in progress in the UK and France, each based on several hundred patients.4 These trials will determine with sufficient certainty whether a low dose should be avoided, or could be used instead of a high dose.

BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

A retrospective study of 29 patients with active chronic hepatitis treated over 38 different periods with azathioprine was carried out with particular attention to the effects of high (above 1.5 mg/kg) and low (below 1.5 mg/kg) doses. Early side‐effects (within 4 weeks) occurred in 7 of 10 patients using above 2 mg/kg and in 6 of 11 patients on 1.5–2 mg/kg azathioprine. Of the patients treated with the low azathioprine dose only 4 of 17 had early side‐effects. Eighteen patients were treated up to 2 years, among whom 2 of 12 on low dose and 3 of 6 on high dose had late side‐effects. Of 9 patients treated for more than 2 years (average 2 3/4 years) on a low azathioprine dose late side‐effects occurred in 2. The clinical course of the liver disease in these patients showed that 5 of 8 treated on high dose were unchanged or improved compared to 15 of the 21 on the low dose. Serum γ‐globulin and SGPT decreased significantly in the patients on the low azathioprine dose concomitantly with a non‐significant increase in serum albumin. These changes were not less marked on low than on high dose. Our experiences thus favor doses below 1.5 mg/kg when azathioprine is used in active chronic hepatitis.

Low concentrations of nitroimidazoles: Effective radiosensitizers at low doses

Report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids* PRACTICE guidelines are systematically developed recommendations that assist the practitioner and patient in making decisions about health care.These recommendations may be adopted, modified, or rejected according to clinical needs and constraints, and are not intended to replace local institutional policies.In addition, practice guidelines developed by the American Society of Anesthesiologists (ASA) are not intended as standards or absolute requirements, and their use cannot guarantee any specific outcome.Practice guidelines are subject to revision as warranted by the evolution of medical knowledge, technology, and practice.They provide basic recommendations that are supported by a synthesis and analysis of the current literature, expert and practitioner opinion, open forum commentary, and clinical feasibility data.This document updates the "Practice Guidelines for the Prevention, Detection and Management of Respiratory Depression Associated with Neuraxial Opioid Administration" adopted by ASA in 2007, and includes new survey data and recommendations pertaining to monitoring for respiratory depression.

Radiological protection is based on the assumption that any additional exposure to ionizing radiation produces an increased risk of stochastic adverse health effects. The ICRP has adopted linear no-threshold (LNT) dose-response relationships to derive health risks associated with low doses of radiation and this implies that the risks of cancer and hereditary effects are directly proportional to the dose received, no matter how small the dose. The LNT assumption has been criticised over the years both by those who consider that it underestimates the risk and by those who believe that it is overly conservative. A few years ago, most of the pressure on ICRP came from those who believed that the risks per unit dose adopted at low doses were too small, but in recent years the pressure has been coming from the opposite direction. Strictly speaking, ICRP feels that the most likely form of the dose-response relationship for low LET radiation is linear-quadratic (i.e. sub-linear at low doses), and for cancer they approximate this by two linear relations, that for the low dose region having a slope (risk per unit dose) half of that for the high dose region, represented by a DDREF of 2. Nevertheless, there are those (particularly in the US and France) who argue that there is no direct evidence for stochastic effects being produced by low doses of radiation, and that the appropriate dose-response relationship has a threshold dose below which no risk to health exists, or even that low doses of radiation are beneficial (`radiation hormesis').

Curcumin (CCM) has antioxidant and chemopreventive properties at low dose. However, at high dose, it exhibits prooxidant activity. Recently, we showed using pharmacometabolomics that MCF7 cells response to docetaxel (DTX) involved, at low dose (1 nM), blockade of glutathione (GSH) biosynthesis, whereas, at high dose (5 µM), extensive GSH consumption. Cytotoxicity was significant even at low dose DTX. Here, we investigated whether CCM at 10 mg/l, a dose stimulating GSH synthesis, may interfere with GSH metabolism, reactive oxygen species (ROS) production, and cytotoxicity when combined to DTX at low and high doses. MCF7 cells were exposed for 72h to DTX at 1 nM and 5 µM in combination with 10 mg/l CCM as a 24h-pretreatment (PRE), cotreatment (CO) and 24h- and 48h-posttreatment (POST24 and POST48). Cytotoxicity was assessed from DNA content (Hoescht 33342), and ROS production from DNA strand breaks (Comet assay). Metabolomics analysis used high resolution magic angle spinning 1H-NMR spectroscopy, 2D spectral acquisitions and a new 2D-based quantification procedure, enabling to measure 32 metabolites. We focused on the variations of 13 metabolites from the GSH metabolism. Overall cytotoxicity of combinations increased according to POST48<POST24<CO<PRE (all, P<0.05), and ROS production was increased in PRE and CO (both, P<0.05), at low and high dose DTX. Metabolomics analysis of PRE at low and high dose DTX involved the preservation of GSH levels but an accumulation of 5-oxoproline (OP, X3.85 at 1 nM and X5.90 at 5 µM, both P<0.05), suggesting a blockade at oxoprolinase (OPase), step of the GSH cycle. Metabolomics analysis of CO at low dose DTX showed an increase in GSH (X1.25, P<0.05), together with starvation of most GSH precursors: glycine (Gly, X0.26, P<0.05) and homocysteine (Hcy, X0.24, P<0.05)). At high dose DTX, the GSH level was unchanged, but OP was increased (X4.26, P<0.05). Metabolomics analysis of POST24 at low dose DTX involved an increase in GSH (X1.22, P<0.05) suggesting increased biosynthesis of GSH but at the expense of taurine (X0.44, P=NS). At high dose DTX, GSH level was maintained, but associated with an increase in glutamate (Glu, X1.73, P<0.05). Metabolomics analysis of POST48 at low dose DTX showed an increase in GSH (X1.21, P<0.05) without signs of blockade of transsulfuration (Hcy X0.80, P=NS). At high dose DTX, the GSH level was maintained with mild signs of precursor starvation (Gly, X0.27, P<0.05), and decreased Glu derivatives (P<0.05), suggesting increased GSH biosynthesis and consumption. In all combinations, CCM at 10 mg/l generated an antioxidant response in MCF7 cells, with preserved or increased GSH levels. However, the underlying biochemical mechanism was different. Maximal cytotoxicity was obtained in PRE conditions involving ROS production, probable OPase blockade with the accumulation of biomarker OP. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3653.

Dynamic CT myocardial perfusion imaging has the potential to provide both functional and anatomical information regarding coronary artery stenosis. However, radiation dose can be potentially high due to repeated scanning of the same region. The purpose of this study is to investigate the use of statistical iterative reconstruction to improve parametric maps of myocardial perfusion derived from a low tube current dynamic CT acquisition. Four pigs underwent high (500 mA) and low (25 mA) dose dynamic CT myocardial perfusion scans with and without coronary occlusion. To delineate the affected myocardial territory, an N-13 ammonia PET perfusion scan was performed for each animal in each occlusion state. Filtered backprojection (FBP) reconstruction was first applied to all CT data sets. Then, a statistical iterative reconstruction (SIR) method was applied to data sets acquired at low dose. Image voxel noise was matched between the low dose SIR and high dose FBP reconstructions. CT perfusion maps were compared among the low dose FBP, low dose SIR and high dose FBP reconstructions. Numerical simulations of a dynamic CT scan at high and low dose (20:1 ratio) were performed to quantitatively evaluate SIR and FBP performance in terms of flow map accuracy, precision, dose efficiency, and spatial resolution. Forin vivo studies, the 500 mA FBP maps gave -88.4%, -96.0%, -76.7%, and -65.8% flow change in the occluded anterior region compared to the open-coronary scans (four animals). The percent changes in the 25 mA SIR maps were in good agreement, measuring -94.7%, -81.6%, -84.0%, and -72.2%. The 25 mA FBP maps gave unreliable flow measurements due to streaks caused by photon starvation (percent changes of +137.4%, +71.0%, -11.8%, and -3.5%). Agreement between 25 mA SIR and 500 mA FBP global flow was -9.7%, 8.8%, -3.1%, and 26.4%. The average variability of flow measurements in a nonoccluded region was 16.3%, 24.1%, and 937.9% for the 500 mA FBP, 25 mA SIR, and 25 mA FBP, respectively. In numerical simulations, SIR mitigated streak artifacts in the low dose data and yielded flow maps with mean error <7% and standard deviation <9% of mean, for 30 × 30 pixel ROIs (12.9 × 12.9 mm(2)). In comparison, low dose FBP flow errors were -38% to +258%, and standard deviation was 6%-93%. Additionally, low dose SIR achieved 4.6 times improvement in flow map CNR(2) per unit input dose compared to low dose FBP. SIR reconstruction can reduce image noise and mitigate streaking artifacts caused by photon starvation in dynamic CT myocardial perfusion data sets acquired at low dose (low tube current), and improve perfusion map quality in comparison to FBP reconstruction at the same dose.

Corticosteroids are currently used routinely in the management of acute severe asthma. The optimal dose and route of administration continues to be debated. Some investigators have reported a greater benefit of higher doses of corticosteroids in the management of severe asthma, while others have not. To determine whether higher doses of systemic corticosteroids (oral, intravenous or intramuscular) are more effective than lower doses in the management of patients with acute severe asthma requiring hospital admission. Randomised controlled trials were identified from the Cochrane Airways Group Asthma Register. In addition, primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies, known reviews and texts were also searched. Studies were selected for inclusion in the review if they met the following broad inclusion criteria: described as randomised controlled trials, included patients with acute severe asthma, compared different doses of corticosteroids (any route) in 2 or more treatment arms, and had a minimum period of follow up of 24 hours. Two reviewers independently assessed the studies for inclusion and disagreement was resolved by third party adjudication. Data were extracted independently by two reviewers if the authors were unable to verify the validity of information. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed as weighted mean differences (WMD) for primary pulmonary function outcomes using a fixed effects model. For the purposes of the review, three broad categories of corticosteroid dose (equivalent dose of methylprednisolone in 24 hours) were defined in advance: low dose (< or = 80 mg), medium dose (> 80 mg and < or = 360 mg) and high dose (> 360 mg). There were thus 3 main comparison groups: low versus medium dose, medium versus high dose and low versus high dose. Nine trials were included; a total of 344 adult patients have been studied (96 with low dose, 85 with medium dose and 163 with high dose corticosteroids). Only 6 trials provided sufficient data for the meta-analysis. There were no clinically or statistically significant differences detected in % predicted FEV1 among comparison groups after 24, 48 or 72 hours. At 48 hours, the weighted mean difference was -3.3% predicted (95% confidence interval -12.4 to + 5.8) for the low vs medium dose comparison, -1. 9% predicted (95% CI -8.1 to + 4.3) for the medium vs high dose comparison and + 0.5% predicted (95% CI - 7.8 to + 8.8) for the low vs high dose comparison. There appeared to be no significant differences in side effects or rates of respiratory failure among the varying doses of corticosteroids. No differences were identified among the different doses of corticosteroids in acute asthma requiring hospital admission. Low dose corticosteroids (< or = 80 mg/day of methylprednisolone or < or = 400 mg/day of hydrocortisone) appear to be adequate in the initial management of these adult patients. Higher doses do not appear to offer a therapeutic advantage.

An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo

An Antibody Delivery System for Regulated Expression of Therapeutic Levels of Monoclonal Antibodies In Vivo

B-PO04-012 ACUTE TESTOSTERONE ADMINISTRATION DOES NOT SHORTEN ACTION POTENTIAL DURATION IN LANGENDORFF PERFUSED RABBIT VENTRICLES

Effect of ethanol concentration on rates of ethanol elimination in normal and alcohol-treated rats in vivo

We evaluated the fractional absorption of L-carnitine, a gamma-amino acid essential cofactor for the transfer of long-chain fatty acids, in rats in vivo after oral administration to determine its absorption behavior. At both low (0.05 micromol/rat) and high (100 micromol/rat) doses, L-carnitine was recovered only from the region of the cecum and below at 10 h after administration. During a major shift in distribution from cecum at 10 h to feces at 24 h, there was no significant change in the total recovery at each dose, suggesting that L-carnitine absorption is negligible in the cecum and the large intestine (colon and rectum). However, the recovery of L-carnitine was incomplete and the fraction recovered was larger at the high dose than at the low dose. The fractions absorbed were estimated to be 96.7 and 33.0% for the low and high doses, respectively, as these were the fractions that disappeared from the gastrointestinal tract. These values were comparable with 100 and 42%, respectively, of bioavailability values by the pharmacokinetic analysis of plasma concentration data in our preceding study [Matsuda et al., Biopharmaceutics & Drug Disposition, in press]. These results suggest that L-carnitine is significantly absorbed only in the small intestine, without undergoing first-pass degradation, and in a dose-dependent manner presumably due to the involvement of saturable transport by L-carnitine carriers. Consistent with the suggestions in vivo, L-carnitine absorption in the closed intestinal loop in situ was concentration-dependent in the small intestine but not in the large intestine, and the apparent membrane permeability in the large intestine was smaller by an order of magnitude than that of passive transport in the small intestine. These findings support our preceding kinetic modeling strategy assuming the small intestine to be the sole absorption site, and should be of help in guiding studies on development of more efficient oral L-carnitine delivery strategies.