Myricitrin, a nitric oxide and protein kinase C inhibitor, exerts antipsychotic-like effects in animal models.

Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action.

Uncertainty in hyperthermia treatment planning: the need for robust system design.

Hyperthermia treatment planning (HTP) is an important tool to improve the quality of hyperthermia treatment. It is a practical way of designing new hyperthermia systems and can be used to optimize the phase and amplitude settings to achieve optimal heating. One of the main challenges to be dealt with however is the uncertainty in the modeling parameters. The role of dielectric and combined dielectric and perfusion uncertainty on optimization was investigated by means of HTP for six different systems: the 70 MHz AMC-4 (AMC: Academic Medical Center) and AMC-8 system, a 130 MHz version of the AMC-8 system, a three-ring AMC-12 system operating at 130 MHz, the BSD SigmaEye applicator and a dipole applicator with three rings each containing six dipole pairs operated at 150 MHz. For five patients with cervix uteri carcinoma, a patient model was created based on a hyperthermia planning CT. Variation of tissue parameters resulted in 16 dielectric models for every patient. In addition, four thermal models were created to study the combined effect of perfusion and dielectric uncertainty. The impact of dielectric uncertainty on optimization is found to be clearly dependent on the number of channels and increased from 0.5 °C for four channels to 1.5 °C for the 18-channel system. As a result, the potential gain relative to the AMC-4 system for the 70 MHz AMC-8 system was found to be largely compromised, while for the remaining systems a robust improvement in T(90) was observed. The dipole applicator showed the best target heating for two out of five patients, while for three others heating efficacy was comparable to the 130 MHz AMC-12 system or the 130 MHz AMC-8 system (one patient). Considering the increase in complexity when the number of channels is increased from 12 to 18, the AMC-12 system is considered as a good compromise between heating efficacy and robustness while still being a manageable heating system in clinical practice.

Optimization in hyperthermia treatment planning: the impact of tissue perfusion uncertainty.

PURPOSE: Hyperthermia treatment planning (HTP) potentially provides a valuable tool for monitoring and optimization of treatment. However, one of the major problems in HTP is that different sources of uncertainty degrade its reliability. Perfusion uncertainty is one of the largest uncertainties and hence there is an ongoing debate whether optimization should be limited to power-based strategies. In this study a systematic analysis is carried out addressing this question. METHODS: The influence of perfusion uncertainty on optimization was analyzed for five patients with cervix uteri carcinoma heated with the AMC-8 70 MHz phased-array waveguide system. The effect of variations (up to +/- 50%) in both the muscle and tumor perfusion level was investigated. For every patient, reference solutions were calculated using constrained temperature-based optimization for 25 different and known perfusion distributions. Reference solutions were compared to those found by temperature-based optimization using standard perfusion values and four SAR-based optimization methods. The effect of heterogeneity was investigated by creating 5 x 100 perfusion distributions for different levels of local variation (+/- 25% and +/- 50%) and scale (1 and 2 cm). Here the performance of the temperature-based optimization method was compared to a SAR-based method that showed good performance in the previous analysis. RESULTS: Solutions found with temperature-based optimization using a deviating perfusion distribution during optimization were found within 1.0 degrees C from the true optimum. For the SAR-based methods, deviations up to 2.9 degrees C were found. The spread found in these deviations was comparable, typically 0.5-1.0 degrees C. When applying intramuscle variation to the perfusion, temperature-based optimization proved to be the best strategy in 95% of the evaluated cases applying +/- 50% local variation. CONCLUSIONS: Temperature-based optimization proves to be superior to SAR-based optimization both under variation of perfusion level as well as under the application of intratissue variation. The spread in achieved temperatures is comparable. These results are valid under the assumption of constant perfusion at hyperthermic levels. Although similar results are expected from models including thermoregulation, additional analysis is required to confirm this. In view of uncertainty in tissue perfusion and other modeling uncertainties, the authors propose feedback guided temperature-based optimization as the best candidate to improve thermal dose delivery during hyperthermia treatment.

Pharmacokinetics of propofol infusions, either alone or with ketamine, in sheep premedicated with acepromazine and papaveretum.

The pharmacokinetics of propofol were investigated in two groups of five Scottish blackface sheep undergoing surgery for the implantation of subcutaneous tissue pouches. After premedication with acepromazine and papaveretum, anaesthesia was induced with either propofol at 4 mg kg-1 intravenously (group 1) or with a mixture of propofol at 3 mg kg-1 and ketamine at 1 mg kg-1 intravenously (group 2). Anaesthesia was maintained with a variable infusion rate of either propofol alone (group 1) or propofol and ketamine (group 2). Both regimens produced satisfactory conditions for superficial surgery of the body surface. The mean (SD) duration of anaesthesia was 64.8 (3.1) minutes for group 1 and 60 (0) minutes for group 2; the mean total dose of propofol given to the sheep in group 1 was 801 (84) mg, and the sheep in group 2 received 470 (46) mg of propofol and 267 (30) mg of ketamine. The mean elimination half-life of propofol was 56.6 (13.1) minutes in group 1 and 50.3 (21.4) minutes in group 2; the mean volume of distribution at steady state was 1.037 (0.480) litre kg-1 in group 1 and 1.515 (0.939) litre kg-1 in group 2; the mean body clearance was 85.4 (28.0) ml kg-1 min-1 in group 1 and 128.0 (35.0) ml kg-1 min-1 in group 2; the mean residence time corrected for a bolus injection was 12.1 (4.2) minutes in group 1 and 11.9 (6.6) minutes in group 2; for the infusion, the mean residence time was 72.1 (4.2) minutes in group 1 and 69.9 (7.9) minutes in group 2. There were wide variations in the blood propofol concentrations reached in individual sheep by using this standard dosing regimen. All the sheep recovered quickly from anaesthesia; the mean times to extubation, sternal recumbency and standing for the animals in group 1 were 2.8 (0.4), 6.3 (1.2) and 10.9 (1.6) minutes from the end of the infusion, and the times for group 2 were 5.3 (0.9), 11.2 (1.7) and 15.1 (2.2) minutes.