Territory aggression and energy budget in food-restricted striped hamsters.

Food resource availability is one of the most important factors affecting interindividual competition in a variety of animal species. However, the energy budget and territory aggression strategy of small mammals during periods of food restriction remain uncertain. In this study, metabolic rate, body temperature, territory aggression behavior, and fat deposit were measured in male striped hamster (Cricetulus barabensis) restricted by 20% of ad libitum food intake with or without supplementary methimazole. Serum thyroid hormone (tri-iodothyronine, T3 and thyroxine, T4), and cytochrome c oxidase (COX) activity in liver, brown adipose tissue, and skeletal muscle, were also measured. Attack latency, total attack times and duration, and the interval duration between attacks of resident hamsters were not significantly changed during food restriction, which was not significantly affected by supplementary methimazole. Metabolic rate and body temperature was significantly increased in food-restricted hamsters following introduction of an intruder, which was not completely blocked by supplementary methimazole. Serum T3 and T4 levels and BAT COX activity were not significantly changed following aggression, and were significantly decreased by supplementary methimazole. These findings suggest that striped hamsters increase energy expenditure for territory aggression during food restriction, and consequently lead to excessive energy depletion. Territory aggression behavior may decrease the capacity to cope with food shortage, which may be independent of thyroid hormone.

Pharmacokinetic/pharmacodynamic analysis of voriconazole against Candida spp. and Aspergillus spp. in children, adolescents and adults by Monte Carlo simulation.

The objective of this study was to investigate the cumulative fraction of response of various voriconazole dosing regimens against six Candida and six Aspergillus spp. in immunocompromised children, immunocompromised adolescents, and adults. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations (MCSs) were conducted to evaluate the ability of simulated dosing strategies in terms of fAUC/MIC targets of voriconazole. According to the results of the MCSs, current voriconazole dosage regimens were all effective for children, adolescents and adults against Candida albicans, Candida parapsilosis and Candida orthopsilosis. For adults, dosing regimens of 4 mg/kg intravenous every 12 h (q12h) and 300 mg orally q12h were sufficient to treat fungal infections by six Candida spp. (C. albicans, C. parapsilosis, Candida tropicalis, Candida glabrata, Candida krusei and C. orthopsilosis) and five Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger and Aspergillus nidulans). However, high doses should be recommended for children and adolescents in order to achieve better clinical efficacy against A. fumigatus and A. nidulans. The current voriconazole dosage regimens were all ineffective against A. niger for children and adolescents. All voriconazole dosage regimens were not optimal against Aspergillus versicolor. This is the first study to evaluate clinical therapy of various voriconazole dosing regimens against Candida and Aspergillus spp. infections in children, adolescents and adults using MCS. The pharmacokinetic/pharmacodynamic-based dosing strategy provided a theoretical rationale for identifying optimal voriconazole dosage regimens in children, adolescents and adults in order to maximise clinical response and minimise the probability of exposure-related toxicity.

Assessment of echinocandin regimens by pharmacokinetic/pharmacodynamic analysis against Candida spp. in paediatric patients.

This study aimed to investigate the cumulative fraction of response of various echinocandin (caspofungin, micafungin and anidulafungin) dosing regimens against Candida spp. in paediatric patients with invasive fungal infections (IFIs). Monte Carlo simulations were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the ability of each echinocandin regimen in terms of fAUC/MIC (free drug area under the concentration-time curve/minimum inhibition concentration ratio) targets of caspofungin, micafungin and anidulafungin. Pharmacodynamic targets were attained in paediatric patients by both caspofungin regimens as well as by a high micafungin dosing regimens against Candida albicans and Candida glabrata. However, the results for anidulafungin suggested that the dosing regimens recommended were not optimal for paediatric patients. In addition, the predicted efficacy of all of the echinocandins against Candida parapsilosis was low. This is the first study to assess caspofungin, micafungin and anidulafungin therapy using Monte Carlo simulation. These results rationalise and optimise the dosage regimens of caspofungin, micafungin and anidulafungin against C. albicans, C. glabrata and C. parapsilosis for paediatric patients with IFIs.

A pharmacokinetic/pharmacodynamic analysis of a standard voriconazole regimen in different CYP2C19 genotypes by Monte Carlo simulation.

OBJECTIVES: The objective of this study was to evaluate the standard voriconazole dosage regimen (maintenance dose was 200 mg bid orally) against Aspergillus infections in different CYP2C19 genotypes from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. METHOD: Monte Carlo simulation (MCS) was applied to simulate 5,000 patients by integrating published pharmacokinetic (PK) parameters, variability of PK parameters on CYP2C19 genotypes and microbiological data. RESULTS: The standard dosage regimen for poor metabolizers (PM) with Aspergillus infections was effective except A. versicolor, for heterozygous extensive metabolizers (HEM), Aspergillus fumigatus, A. terreus and A. nidulans infections could be treated effectively with the standard dosage regimen; for extensive metabolizers (EM), the standard voriconazole dosage regimen failed to achieve the best outcome for the six Aspergillus spp. Increasing dose (e.g. 300 mg bid) or even changing the antifungal drug was needed for EM and most HEM patients with Aspergillus infection. CONCLUSION: Instead of using a standard dosage regimen for all patients, the voriconazole dosage regimen needs to be optimized for patients with different CYP2C19 genotypes.