Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin.

AIMS: The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin. METHODS: This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events. RESULTS: Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated. CONCLUSIONS: Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1).

AIMS: To assess the efficacy and safety of one- and two-step dose-increase regimens of lixisenatide once daily in participants with Type 2 diabetes mellitus insufficiently controlled with metformin. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre study enrolling participants with Type 2 diabetes (n = 484) treated with metformin. Participants were randomized to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks, followed by a ≥ 52-week variable double blind period. Primary outcome was HbA1c reduction at week 24. RESULTS: Lixisenatide one-/two-step once daily significantly improved HbA1c at week 24 compared with placebo (P < 0.0001) and allowed more participants to achieve HbA1c < 53 mmol/mol (< 7.0%) (P ≤ 0.0005). Improvements were observed in fasting plasma glucose (-0.5/-0.6 vs. +0.1 mmol/l; P < 0.001) and body weight (-2.6/-2.7 vs. -1.6 kg; P < 0.005). At week 24, adverse events were reported by 67.7/70.8/65.6% of participants treated with lixisenatide one-/two-step/placebo, respectively--nausea and vomiting being reported most frequently. Symptomatic hypoglycaemia occurred in 1.9/2.5% of participants on one-/two-step lixisenatide and 0.6% with placebo, with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable double-blind extension period of at least 52 weeks. CONCLUSIONS: Lixisenatide one- or two-step dose-increase regimens significantly improved glycaemic control and decreased body weight over 24 weeks and during a long-term extension period without increasing hypoglycaemia. The study confirmed that tolerability in the one-step group was at least similar to the two-step dose increase, with nausea/vomiting and hypoglycaemia frequency being lower in the one-step regimen.

Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the dose-response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycated haemoglobin (HbA(1c)) > or = 7.0 and < 9.0% (> or = 53 and < 75 mmol/mol)] on metformin (> or = 1000 mg/day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 microg once daily or twice daily or placebo. The primary end-point was change in HbA(1c) from baseline to 13 weeks in the intent-to-treat population. RESULTS: Lixisenatide significantly improved mean HbA(1c) from a baseline of 7.55% (59.0 mmol/mol); respective mean reductions for 5, 10, 20 and 30 microg doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol/mol), on once-daily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol/mol) on twice-daily administrations vs. 0.18% (2.0 mmol/mol) with placebo (all P < 0.01 vs. placebo). Target HbA(1c) < 7.0% (53 mmol/mol) at study end was achieved in 68% of patients receiving 20 and 30 microg once-daily lixisenatide vs. 32% receiving placebo (P < 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from -2.0 to -3.9 kg with lixisenatide vs. -1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea. CONCLUSIONS: Lixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose-response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 microg once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, once-daily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies.

Testing the portal imager GLAaS algorithm for machine quality assurance.

BACKGROUND: To report about enhancements introduced in the GLAaS calibration method to convert raw portal imaging images into absolute dose matrices and to report about application of GLAaS to routine radiation tests for linac quality assurance procedures programmes. METHODS: Two characteristic effects limiting the general applicability of portal imaging based dosimetry are the over-flattening of images (eliminating the "horns" and "holes" in the beam profiles induced by the presence of flattening filters) and the excess of backscattered radiation originated by the detector robotic arm supports. These two effects were corrected for in the new version of GLAaS formalism and results are presented to prove the improvements for different beams, detectors and support arms. GLAaS was also tested for independence from dose rate (fundamental to measure dynamic wedges). With the new corrections, it is possible to use GLAaS to perform standard tasks of linac quality assurance. Data were acquired to analyse open and wedged fields (mechanical and dynamic) in terms of output factors, MU/Gy, wedge factors, profile penumbrae, symmetry and homogeneity. In addition also 2D Gamma Evaluation was applied to measurement to expand the standard QA methods. GLAaS based data were compared against calculations on the treatment planning system (the Varian Eclipse) and against ion chamber measurements as consolidated benchmark. Measurements were performed mostly on 6 MV beams from Varian linacs. Detectors were the PV-as500/IAS2 and the PV-as1000/IAS3 equipped with either the robotic R- or Exact- arms. RESULTS: Corrections for flattening filter and arm backscattering were successfully tested. Percentage difference between PV-GLAaS measurements and Eclipse calculations relative doses at the 80% of the field size, for square and rectangular fields larger than 5 x 5 cm2 showed a maximum range variation of -1.4%, + 1.7% with a mean variation of <0.5%. For output factors, average percentage difference between GLAaS and Eclipse (or ion chamber) data was -0.4 +/- 0.7 (-0.2 +/- 0.4) respectively on square fields. Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: 0.1 +/- 1.0, 0.7 +/- 0.8, 0.1 +/- 0.4 (1.0 +/- 1.4, -0.3 +/- 0.2, -0.1 +/- 0.2) respectively. Similar minimal deviations were observed for flatness and symmetry. For Dynamic wedges, percentage difference of MU/Gy between GLAaS and Eclipse (or ion chamber) was: -1.1 +/- 1.6 (0.4 +/- 0.7). Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: 0.4 +/- 1.6, -1.5 +/- 1.8, -0.1 +/- 0.3 (-2.2 +/- 2.3, 2.3 +/- 1.2, 0.8 +/- 0.3) respectively. For mechanical wedges differences of transmission factors were <1.6% (Eclipse) and <1.1% (ion chamber) for all wedges. Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: -1.3 +/- 0.7, -0.7 +/- 0.7, -0.2 +/- 0.2 (-0.8 +/- 0.8, 0.7 +/- 1.1, 0.2 +/- 0.3) respectively. CONCLUSION: GLAaS includes now efficient methods to correct for missing "horns" and "holes" induced by flattening filter in the beam and to compensate for excessive backscattering from the support arm. These enhancements allowed to use GLAaS based dosimetric measurement to perform standard tasks of Linac quality assurance with reliable and consistent results. This fast method could be applied to routine practice being also fast in usage and because it allows the introduction of new analysis tools in routine QA by means, e.g., of the Gamma Index analysis.

[Factors influencing secondary prevention of atherothrombotic disease in the private outpatient cardiology setting: results of the Prisma survey]. / Etude sur les facteurs influençant les prescriptions en prévention secondaire de la maladie athérothrombotique en pratique de ville: résultats de l'étude Prisma.

From March to July 1999, 940 private cardiologists in France recruited 100,429 patients of whom 30,430 (30%) had a previous history of atherothrombotic disease. The prevalence of patients with a previous history of Myocardial Infarction (MI), Ischemic Stroke (IS) or Peripheral Arterial Disease (PAD) was 19.7%, 7.2% and 10.7% respectively. Among patients with a history of atherothrombotic disease, myocardial infarction was the most frequent diagnosis responsible for 65% of all consultations. Each cardiologist described the secondary prevention treatment for 3 consecutive patients among whom 1 corresponded to each of the 3 atherothrombotic territories. The most frequent cardiovascular risk factors were hypercholesterolemia for myocardial infarction (77.9%), smoking for PAD (32.5%) and hypertension for IS (73.2%). Diabetes mellitus (1/4 patients), obesity (1/3) and sedentary way of life (1/3) were equally prevalent for each of the atherothrombotic territories. More than 90% of the patients received an antithrombotic drug. Antiplatelet agents were largely prescribed, anticoagulants being more frequently used for patients with atrial fibrillation, symptomatic cardiac heart failure or stroke of embolic origin. Thienopyridines represent 17.9% of the prescriptions. The prescription rate of statins after MI (58.9%) is lower than in published studies in secondary prevention. The lack of lipid measurement and the delay since last measurement are non-prescription factors. The rates of prescription are even lower in case of PAD (44.6%) or IS history (33.3%). More than half of the patients (56.6%) are treated with beta-blockers and 40.1% with ACE inhibitors. These rates are similar to what has been published. Atherothrombotic disease represents a large part of the daily activity of private cardiologists and is not limited to coronary heart disease. Despite their proven efficacy, drugs for secondary prevention for MI, except antithrombotic drugs, are insufficiently prescribed. This under-prescription is even higher in patients with PAD or IS history and may be related to the lack of clinical trials in these specific territories.

Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease.

Activated glial cells observed in the substantia nigra in Parkinson's disease may participate in the mechanism of nerve cell death by providing toxic substances such as cytokines. Among these compounds, tumor necrosis factor-alpha (TNF) is of interest because it can provoke cell death. We detected TNF-immunoreactive glial cells in the substantia nigra of parkinsonian patients but not in those of control subjects. Immunoreactivity for TNF receptors was found in cell bodies and processes of most dopaminergic neurons of control and parkinsonian subjects, suggesting that nigral dopaminergic neurons might be sensitive to TNF produced in Parkinson's disease. These results suggest that TNF may participate in the degenerative processes occurring in Parkinson's disease, at least after a primary insult inducing a reactive gliosis.

Tubular proteinuria after perinatal hypoxia.

Urinary total protein (UTP) and urinary protein pattern have been studied in 23 newborn infants with Apgar scores less than or equal to 3 at one minute or acidosis (pH less than or equal to 7.15) on the first day. On the first and second day UTP excretion was increased in 13 out of 18 patients. At this time the excretion of low molecular weight microproteins (T-4 and T-5) was elevated in 12 patients without increased plasma urea concentration in any case. The increased excretion of the smallest microproteins T-4/T-5 is an early sign of an impaired tubular function.

Incorporation of foreign compound metabolites into plant and soil constituents.

Recent developments in the technology of removal and characterization of bound residues of two herbicides, nitrofen and profluralin, from plants and soil will be reviewed. 14C-Nitrofen was found to be metabolized into starch in wheat grain as well as bound into the lignin fraction of wheat straw. Profluralin and its metabolites were found to be bound to field aged soil in several ways probably including hydrogen bonding and covalent bonding. The bound metabolites of profluralin in soil could be categorized according to the type of bonding occurring as well as to the physicochemical characteristics of the bound pesticide. By assessing the type of bonding involved between pesticide and plants or soil, some assessment of the bioavailability of these bound residues to the environment can be made. When applied to tissues of food producing animals, these techniques would help release bound drug residues and provide technology for characterization of the released material.