Toxicities of acetogenin-based bioacaricides against two-spotted spider mite and selectivity to its phytoseiid predators.

Tetranychus urticae is the main pest of strawberry crops and can cause up to 80% of productivity losses under high infestations. Aiming to search T. urticae management alternatives compatible with eco-friendly or organic-based food production systems, this study evaluated the lethal and sublethal toxicities of formulated derivatives from Annonaceae (rich in acetogenins) against this pest species. In addition, it also evaluated the selectivity of the most promising formulation to the predatory mites Neoseiulus californicus and Phytoseiulus macropilis, which are largely applied in biological control in Brazil. Among the derivatives tested, the emulsion from the ethanolic seed extract of Annona mucosa-ESEAm (major component: acetogenin bis-tetrahydrofuran rolliniastatin-1) caused pronounced mortality of T. urticae after 120 h of exposure (LC50 = 465.5 mg L-1), in a comparable or superior manner to an abamectin-based synthetic acaricide used as positive control (LC50 = 1243.4 mg L-1). Moreover, ESEAm exposure resulted in a significant decrease in the number of eggs laid by females and caused the most pronounced ovicidal action for T. urticae, with only 5% embryonic viability. However, ESEAm also showed high toxicity to the predatory mites tested, causing 100% mortality for both species after 120 h exposure, similar to abamectin. The interaction between these bioacaricides and biological control agents should be tested under field conditions to further assess the potential ecological selectivity of these derivatives.

Is this scaling nonlinear?

One of the most celebrated findings in complex systems in the last decade is that different indexes y (e.g. patents) scale nonlinearly with the population x of the cities in which they appear, i.e. y∼x (ß) ,ß≠1. More recently, the generality of this finding has been questioned in studies that used new databases and different definitions of city boundaries. In this paper, we investigate the existence of nonlinear scaling, using a probabilistic framework in which fluctuations are accounted for explicitly. In particular, we show that this allows not only to (i) estimate ß and confidence intervals, but also to (ii) quantify the evidence in favour of ß≠1 and (iii) test the hypothesis that the observations are compatible with the nonlinear scaling. We employ this framework to compare five different models to 15 different datasets and we find that the answers to points (i)-(iii) crucially depend on the fluctuations contained in the data, on how they are modelled, and on the fact that the city sizes are heavy-tailed distributed.

A pharmacokinetic/pharmacodynamic study of controlled-release oxycodone.

A single-dose, analytically blinded, randomized, crossover study was conducted in 22 healthy male volunteers to compare the bioavailability of one 20 mg with two 10 mg controlled-release (CR) oxycodone tablets. In addition, pharmacodynamic effects were assessed using both objective and subjective measures for up to 48 hr after dosing. The two treatments were bioequivalent, with comparable rates (Cmax of one 20 mg tablet was 109% of two 10 mg tablets; 90% confidence limits: 98.4%-120%) and extents (AUC0-infinity: 107%; 100%-114%) of absorption. In addition, no significant differences between tablets were found for mean values of Tmax, T/12abs, or T/12elim. Correlations between plasma oxycodone concentrations and most pharmacodynamic measures were significant. The strongest correlations were observed for pupil size (r = -0.53) and subjects' assessment of drug effect (r = 0.53), with changes in plasma concentration accounting for more than 25% of the observed changes in these variables. This study demonstrated bioequivalence of two 10 mg and one 20 mg CR oxycodone tablet, with significant correlation between plasma oxycodone concentrations and pharmacodynamic effects in normal volunteers.

Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution.

The effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40 mg controlled-release (CR) tablet or a 20 mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36 h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0-infinity and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0-infinity increasing to 120% (CI = 109-132%) and the mean value for Cmax decreasing to 82% (CI = 47-91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Steady-state bioavailability of controlled-release oxycodone in normal subjects.

The steady-state bioavailability of a controlled-release (CR) oxycodone tablet was compared with that of an immediate-release (IR) oxycodone solution in a randomized, analytically masked, multiple-dose, crossover study in 24 normal subjects. Each subject received either one 10-mg CR oxycodone tablet every 12 hours for 4 days or 5 mL of a 1-mg/1 mL IR oxycodone solution every 6 hours for 4 days. Steady state was achieved after approximately 1 day of dosing. The mean (+/- SD) maximum plasma oxycodone concentrations for CR oxycodone and IR oxycodone were 15.1 +/- 4.7 ng/mL and 15.6 +/- 4.4 ng/mL, respectively. The time to maximum concentration (Tmax) was approximately twice as long for CR oxycodone (3.2 +/- 2.2 hours) as for IR oxycodone (1.4 +/- 0.7 hours) (P = 0.005). The area under the plasma concentration-time curve from 0 to 12 hours at steady state was 103.6 +/- 40.0 ng.h/mL for CR oxycodone and 99.0 +/- 35.8 ng.h/mL for IR oxycodone. Except for Tmax, there were no significant differences in pharmacokinetic parameters between treatments. Approximately twice as many adverse experiences, several of longer duration than noted with CR oxycodone, were reported with IR oxycodone. The bioavailability of the CR tablet was equal to that of the IR solution; however, the rate of oxycodone absorption from the CR tablet was slower than that from the IR solution, as shown by the Tmax value. The use of CR oxycodone will allow selection of the most clinically appropriate nonopioid analgesic, as well as independent titration and dosing, thereby enhancing therapeutic flexibility.

Pharmacokinetics of morphine sulfate in patients with burns.

Morphine sulfate (MS) pharmacokinetics was evaluated in seven patients with a mean body surface area burn of 21.5% to ascertain a rational basis for the management of pain in patients with burns. Treatments included a MS constant rate infusion followed by an oral MS solution (MS-OS) (5 to 15 mg administered every 3 hours) and then a 30 mg MS-controlled release tablet (MS-CR) every 8 hours. Each treatment was separated by a washout period when sampling of morphine was done. The apparent terminal half-life for MS-OS was 3 hours, which is similar to that of patients without burns, but the apparent terminal half-life for the MS-CR in patients with burns was substantially longer at 14.7 hours. The mean time to reach peak concentration for MS-CR was delayed relative to MS-OS 1.4 versus 0.5 hours, and the peak concentration was attenuated. The mean release time of the MS for the CR tablet is about 15 hours. The renal clearances of the MS-CR (114 ml/min) and MS-OS (147 ml/min) were less than the measured creatinine clearance (177 ml/min) but greater than the creatinine clearance (106 ml/min) predicted for a healthy individual. The prolonged release of MS-CR makes the MS-CR a good choice in the management of pain in patients with burns on an 8- to 12-hour dosing schedule, even though the patient might exhibit an increased clearance.

Determination of CGS 16617 and stable isotope-labeled CGS 16617, an angiotensin-converting enzyme inhibitor, in human plasma by gas chromatography/mass spectrometry.

An analytical method has been developed for the simultaneous determination of a novel orally active angiotensin-converting enzyme inhibitor (CGS 16617) and a stable isotope-labeled analog. Both compounds are isolated from human plasma using an ion-exchange column, derivatized with pentafluoropropionic anhydride and pentafluoropropanol, and analyzed by gas chromatography/mass spectrometry. After splitless injection on a methyl-silicon column, the compound is detected using negative ion chemical ionization with nitrous oxide as a reagent gas. CGS 16617 labeled with four deuteriums and two 13C is used as an internal standard. The accuracy and precision of the method, expressed as the overall mean +/- SD recovery obtained from two sets of 36 quality-control samples used during a clinical study (concentration range 0.2-100 ng ml-1 plasma), was 96.1 +/- 16.2% for unlabeled drug and 97.6 +/- 14.4% for the D4-labeled drug (concentration range 0.2-100 ng ml-1 plasma). The limit of quantification using 1 ml plasma is 0.2 ng ml-1 for both labeled and unlabeled drug.