A comparative analysis by means of quantum molecular similarity measures of density distributions derived from conventional ab initio and density functional methods

A procedure based on quantum molecular similarity measures (QMSM) has been used to compare electron densities obtained from conventional ab initio and density functional methodologies at their respective optimized geometries. This method has been applied to a series of small molecules which have experimentally known properties and molecular bonds of diverse degrees of ionicity and covalency. Results show that in most cases the electron densities obtained from density functional methodologies are of a similar quality than post-Hartree-Fock generalized densities. For molecules where Hartree-Fock methodology yields erroneous results, the density functional methodology is shown to yield usually more accurate densities than those provided by the second order Møller-Plesset perturbation theory

Two complementary molecular energy decomposition schemes: the Mayer and Ziegler-Rauk methods in comparison

In the present paper we discuss and compare two different energy decomposition schemes: Mayer's Hartree-Fock energy decomposition into diatomic and monoatomic contributions [Chem. Phys. Lett. 382, 265 (2003)], and the Ziegler-Rauk dissociation energy decomposition [Inorg. Chem. 18, 1558 (1979)]. The Ziegler-Rauk scheme is based on a separation of a molecule into fragments, while Mayer's scheme can be used in the cases where a fragmentation of the system in clearly separable parts is not possible. In the Mayer scheme, the density of a free atom is deformed to give the one-atom Mulliken density that subsequently interacts to give rise to the diatomic interaction energy. We give a detailed analysis of the diatomic energy contributions in the Mayer scheme and a close look onto the one-atom Mulliken densities. The Mulliken density ρA has a single large maximum around the nuclear position of the atom A, but exhibits slightly negative values in the vicinity of neighboring atoms. The main connecting point between both analysis schemes is the electrostatic energy. Both decomposition schemes utilize the same electrostatic energy expression, but differ in how fragment densities are defined. In the Mayer scheme, the electrostatic component originates from the interaction of the Mulliken densities, while in the Ziegler-Rauk scheme, the undisturbed fragment densities interact. The values of the electrostatic energy resulting from the two schemes differ significantly but typically have the same order of magnitude. Both methods are useful and complementary since Mayer's decomposition focuses on the energy of the finally formed molecule, whereas the Ziegler-Rauk scheme describes the bond formation starting from undeformed fragment densities

Opioid maintenance therapy in Switzerland: an overview of the Swiss IMPROVE study.

BACKGROUND/AIMS: Switzerland's drug policy model has always been unique and progressive, but there is a need to reassess this system in a rapidly changing world. The IMPROVE study was conducted to gain understanding of the attitudes and beliefs towards opioid maintenance therapy (OMT) in Switzerland with regards to quality and access to treatment. To obtain a "real-world" view on OMT, the study approached its goals from two different angles: from the perspectives of the OMT patients and of the physicians who treat patients with maintenance therapy. The IMPROVE study collected a large body of data on OMT in Switzerland. This paper presents a small subset of the dataset, focusing on the research design and methodology, the profile of the participants and the responses to several key questions addressed by the questionnaires. METHODS: IMPROVE was an observational, questionnaire-based cross-sectional study on OMT conducted in Switzerland. Respondents consisted of OMT patients and treating physicians from various regions of the country. Data were collected using questionnaires in German and French. Physicians were interviewed by phone with a computer-based questionnaire. Patients self-completed a paper-based questionnaire at the physicians' offices or OMT treatment centres. RESULTS: A total of 200 physicians and 207 patients participated in the study. Liquid methadone and methadone tablets or capsules were the medications most commonly prescribed by physicians (60% and 20% of patient load, respectively) whereas buprenorphine use was less frequent. Patients (88%) and physicians (83%) were generally satisfied with the OMT currently offered. The current political framework and lack of training or information were cited as determining factors that deter physicians from engaging in OMT. About 31% of OMT physicians interviewed were ≥60 years old, indicating an ageing population. Diversion and misuse were considered a significant problem in Switzerland by 45% of the physicians. CONCLUSION: The subset of IMPROVE data presented gives a present-day, real-life overview of the OMT landscape in Switzerland. It represents a valuable resource for policy makers, key opinion leaders and drug addiction researchers and will be a useful basis for improving the current Swiss OMT model.

Rituximab treatment in Myasthenia gravis: an open-label trial

Myasthenia gravis (MG), an antibody (AB)-mediated autoimmune disorder, responds to treatments targeting the humoral response such as intravenous immunoglobulines (IVIG) and plasma exchange treatments (PEX). Rituximab (RTX), a monoclonal anti-CD20 AB that depletes the specific B lymphocyte population should be efficient and is being used for resistant MG patients in small cohorts. Objectives: This is an observational prospective study that aims to determine the efficacy of RTX in MG, the duration of the clinical effect after treatment and the possible sparing effect on other immunosuppressive drugs.Methods: Between January 2009 and December 2010, 8 MG (2 with anti-MUSK AB) patients (62.5% female) with mean age of 41 years (range 24-79 yo), were treated by RTX. The patients treated were those who experienced serious side-effects and/or treatment failure. In three cases the criteria for treatment was the need to spare frequent recurrent plasmapheresis or IGIV treatment. We compared the functional tests before and prospectively after the treatment (schema used for one cure: 2 9 1gr within 15 days interval), the duration of the efficiency (follow-up of 4-24 months) and we repeated the cures based on clinical criteria.Results: Two patients (25%) underwent 3 RTX cures, 2 (25%) underwent 2 cures and the others (50%) one cure. No adverse events were observed. Six patients (75%) showed a clinical response with improvement of the functional scores and reduction of the concomitant immunosuppressive treatments (75% for prednisone, 35% for other immunosuppressive drugs) that persists over a period of 4-9 months. Follow-up of clinical state and lymphocyte count showed an inverse correlation between the CD 19 count and the clinical state of the patients.Conclusion: In this small series of patients RTX treatment shows significant improvement of clinical state of MG refractory to conventional treatment patients, without side-effects reported, even in patients that were retreated. Larger studies should be held to determine if RTX could be an alternative to plasmapheresis and IVIG as second-line treatment in MG.

Effectiveness of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy on placental malaria, maternal anaemia and birthweight in areas with high and low malaria transmission intensity in Tanzania.

OBJECTIVE: To assess the effectiveness of IPTp in two areas with different malaria transmission intensities. METHODS: Prospective observational study recruiting pregnant women in two health facilities in areas with high and low malaria transmission intensities. A structured questionnaire was used for interview. Maternal clinic cards and medical logs were assessed to determine drug intake. Placental parasitaemia was screened using both light microscopy and real-time quantitative PCR. RESULTS: Of 350 pregnant women were recruited and screened for placental parasitaemia, 175 from each area. Prevalence of placental parasitaemia was 16.6% (CI 11.4-22.9) in the high transmission area and 2.3% (CI 0.6-5.7) in the low transmission area. Being primigravida and residing in a high transmission area were significant risk factors for placental malaria (OR 2.4; CI 1.1-5.0; P = 0.025) and (OR 9.4; CI 3.2-27.7; P < 0.001), respectively. IPTp was associated with a lower risk of placental malaria (OR 0.3; CI 0.1-1.0; P = 0.044); the effect was more pronounced in the high transmission area (OR 0.2; CI 0.06-0.7; P = 0.015) than in the low transmission area (OR 0.4; CI 0.04-4.5; P = 0.478). IPTp use was not associated with reduced risk of maternal anaemia or low birthweight, regardless of transmission intensity. The number needed to treat (NNT) was four (CI 2-6) women in the high transmission area and 33 (20-50) in the low transmission area to prevent one case of placental malaria. CONCLUSION: IPTp may have an effect on lowering the risk of placental malaria in areas of high transmission, but this effect did not translate into a benefit on risks of maternal anaemia or low birthweight. The NNT needs to be considered, and weighted against that of other protective measures, eventually targeting areas which are above a certain threshold of malaria transmission to maximise the benefit.

Relationship between imatinib population pharmacokinetics and alpha-1-acid glycoprotein

Objectives: Considering the large inter-individual differences in the function of the systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is alpha-1-acid glycoprotein (AGP), a circulating protein that strongly binds imatinib. This observational study aimed to explore the influence of plasma AGP on imatinib pharmacokinetics. Methods: A population pharmacokinetic analysis was performed using NONMEM based on 278 plasma samples from 51 oncologic patients, for whom both total imatinib and AGP plasma concentrations were measured. The influence of this biological covariate on oral clearance and volume of distribution was examined. Results: A one-compartment model with first-order absorption appropriately described the data. A hyperbolic relationship between plasma AGP levels and oral clearance, as well as volume of distribution was observed. A mechanistic approach was built up, postulating that only the unbound imatinib concentration was able to undergo first-order elimination through an unbound clearance process, and integrating the dissociation constant as a parameter in the model. This approach allowed determining an average (± SEM) free clearance of 1310 (± 172) L/h and a volume of distribution of 301 (± 23) L. By comparison, the total clearance previously determined was 14 (± 1) L/h. Free clearance was affected by body weight and pathology diagnosis. Moreover, this model provided consistent estimates of the association constant between imatinib and AGP (5.5?106 L/mol) and of the average in vivo free fraction of imatinib (1.1%). The variability observed (17% for free clearance and 66% for volume of distribution) was less than the one previously reported without considering AGP impact. AGP explained indeed about one half of the variability observed in total imatinib disposition. Conclusion: Such findings clarify in part the in vivo impact of protein binding on imatinib disposition and might raise again the question whether high levels of AGP could represent a resistance factor to imatinib. This remains however questionable, as it is not expected to affect free drug concentrations. On the other hand, would imatinib be demonstrated as a drug requiring therapeutic drug monitoring, either the measurement of free concentration or the correction of the total concentration by the actual AGP plasma levels should be considered for accurate interpretation of the results.

Determinants of persistence in hypertensive patients treated with irbesartan: results of a postmarketing survey.

BACKGROUND: Persistence is a key factor for long-term blood pressure control, which is of high prognostic importance for patients at increased cardiovascular risk. Here we present the results of a post-marketing survey including 4769 hypertensive patients treated with irbesartan in 886 general practices in Switzerland. The goal of this survey was to evaluate the tolerance and the blood pressure lowering effect of irbesartan as well as the factors affecting persistence in a large unselected population. METHODS: Prospective observational survey conducted in general practices in all regions of Switzerland. Previously untreated and uncontrolled pre-treated patients were started with a daily dose of 150 mg irbesartan and followed up to 6 months. RESULTS: After an observation time slightly exceeding 4 months, the average reduction in systolic and diastolic blood pressure was 20 (95% confidence interval (CI) -19.6 to -20.7 mmHg) and 12 mmHg (95% CI -11.4 to -12.1 mmHg), respectively. At this time, 26% of patients had a blood pressure < 140/90 mmHg and 60% had a diastolic blood pressure < 90 mmHg. The drug was well tolerated with an incidence of adverse events (dizziness, headaches,...) of 8.0%. In this survey more than 80% of patients were still on irbesartan at 4 month. The most important factors predictive of persistence were the tolerability profile and the ability to achieve a blood pressure target < or = 140/90 mmHg before visit 2. Patients who switched from a fixed combination treatment tended to discontinue irbesartan more often whereas those who abandoned the previous treatment because of cough (a class side effect of ACE-Inhibitors) were more persistent with irbesartan. CONCLUSION: The results of this survey confirm that irbesartan is effective, well tolerated and well accepted by patients, as indicated by the good persistence. This post-marketing survey also emphasizes the importance of the tolerability profile and of achieving an early control of blood pressure as positive predictors of persistence.

Influence of preoperative leg pain and radiculopathy on outcomes in mono-segmental lumbar total disc replacement: results from a nationwide registry.

PURPOSE: Currently, many pre-conditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). Radiculopathy is one among them. In Switzerland it is left to the surgeon's discretion when to operate if he adheres to a list of pre-defined indications. Contraindications, however, are less clearly specified. We hypothesized that, the extent of pre-operative radiculopathy results in different benefits for patients treated with mono-segmental lumbar TDR. We used patient perceived leg pain and its correlation with physician recorded radiculopathy for creating the patient groups to be compared. METHODS: The present study is based on the dataset of SWISSspine, a government mandated health technology assessment registry. Between March 2005 and April 2009, 577 patients underwent either mono- or bi-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. A total of 416 cases with a mono-segmental procedure were included in the study. The data collection consisted of pre-operative and follow-up data (physician based) and clinical outcomes (NASS form, EQ-5D). A receiver operating characteristic (ROC) analysis was conducted with patients' self-indicated leg pain and the surgeon-based diagnosis "radiculopathy", as marked on the case report forms. As a result, patients were divided into two groups according to the severity of leg pain. The two groups were compared with regard to the pre-operative patient characteristics and pre- and post-operative pain on Visual Analogue Scale (VAS) and quality of life using general linear modeling. RESULTS: The optimal ROC model revealed a leg pain threshold of 40 ≤ VAS > 40 for the absence or the presence of "radiculopathy". Demographics in the resulting two groups were well comparable. Applying this threshold, the mean pre-operative leg pain level was 16.5 points in group 1 and 68.1 points in group 2 (p < 0.001). Back pain levels differed less with 63.6 points in group 1 and 72.6 in group 2 (p < 0.001). Pre-operative quality of life showed considerable differences with an 0.44 EQ-5D score in group 1 and 0.29 in group 2 (p < 0.001, possible score range -0.6 to 1). At a mean follow-up time of 8 months, group 1 showed a mean leg pain improvement of 3.6 points and group 2 of 41.1 points (p < 0.001). Back pain relief was 35.6 and 39.1 points, respectively (p = 0.27). EQ-5D score improvement was 0.27 in group 1 and 0.41 in group 2 (p = 0.11). CONCLUSIONS: Patients labeled as having radiculopathy (group 2) do mostly have pre-operative leg pain levels ≥ 40. Applying this threshold, the patients with pre-operative leg pain do also have more severe back pain and a considerably lower quality of life. Their net benefit from the lumbar TDR is higher and they do have similar post-operative back and leg pain levels as well as the quality of life as patients without pre-operative leg pain. Although randomized controlled trials are required to confirm these findings, they put leg pain and radiculopathy into perspective as absolute contraindications for TDR.

Simulation methods with extended stability for stiff biochemical kinetics

Background: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, τ, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where τ can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called τ-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as τ grows. Results: In this paper we extend Poisson τ-leap methods to a general class of Runge-Kutta (RK) τ-leap methods. We show that with the proper selection of the coefficients, the variance of the extended τ-leap can be well-behaved, leading to significantly larger step sizes.Conclusions: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original τ-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.