Probability of achieving optimal molecular response to imatinib in chronic myeloid leukemia (CML) patients: Pharmacokinetic/Pharmacodynamic (PK/PD) relationships observed under field-conditions

Objectives: Imatinib has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations (Cmin) correlate with response rates in CML patients. This analysis aimed to evaluate the impact of imatinib exposure on optimal molecular response rates in a large European cohort of patients followed by centralized TDM.¦Methods: Sequential PK/PD analysis was performed in NONMEM 7 on 2230 plasma (PK) samples obtained along with molecular response (PD) data from 1299 CML patients. Model-based individual Bayesian estimates of exposure, parameterized as to initial dose adjusted and log-normalized Cmin (log-Cmin) or clearance (CL), were investigated as potential predictors of optimal molecular response, while accounting for time under treatment (stratified at 3 years), gender, CML phase, age, potentially interacting comedication, and TDM frequency. PK/PD analysis used mixed-effect logistic regression (iterative two-stage method) to account for intra-patient correlation.¦Results: In univariate analyses, CL, log-Cmin, time under treatment, TDM frequency, gender (all p<0.01) and CML phase (p=0.02) were significant predictors of the outcome. In multivariate analyses, all but log-Cmin remained significant (p<0.05). Our model estimates a 54.1% probability of optimal molecular response in a female patient with a median CL of 14.4 L/h, increasing by 4.7% with a 35% decrease in CL (percentile 10 of CL distribution), and decreasing by 6% with a 45% increased CL (percentile 90), respectively. Male patients were less likely than female to be in optimal response (odds ratio: 0.62, p<0.001), with an estimated probability of 42.3%.¦Conclusions: Beyond CML phase and time on treatment, expectedly correlated to the outcome, an effect of initial imatinib exposure on the probability of achieving optimal molecular response was confirmed in field-conditions by this multivariate analysis. Interestingly, male patients had a higher risk of suboptimal response, which might not exclusively derive from their 18.5% higher CL, but also from reported lower adherence to the treatment. A prospective longitudinal study would be desirable to confirm the clinical importance of identified covariates and to exclude biases possibly affecting this observational survey.

Vital Statistics of Panstrongylus geniculatus (Latreille 1811) (Hemiptera: Reduviidae) under Experimental Conditions

A statistical evaluation of the population dynamics of Panstrongylus geniculatus is based on a cohort experiment conducted under controlled laboratory conditions. Animals were fed on hen every 15 days. Egg incubation took 21 days; mean duration of 1st, 2nd, 3rd, 4th, and 5th instar nymphs was 25, 30, 58, 62, and 67 days, respectively; mean nymphal development time was 39 weeks and adult longevity was 72 weeks. Females reproduced during 30 weeks, producing an average of 61.6 eggs for female on its lifetime; the average number of eggs/female/week was 2.1. Total number of eggs produced by the cohort was 1379. Average hatch for the cohort was 88.9%; it was not affected by age of the mother. Age specific survival and reproduction tables were constructed. The following population parameters were evaluated, generation time was 36.1 weeks; net reproduction rate was 89.4; intrinsic rate of natural increase was 0.125; instantaneous birth and death rates were 0.163 and 0.039 respectively; finite rate of increase was 1.13; total reproductive value was 1196 and stable age distribution was 31.2% eggs, 64.7% nymphs and 4.1% adults. Finally the population characteristics of P. geniculatus lead to the conclusion that this species is a K strategist.

Population Biology of Rhodnius domesticus Neiva & Pinto, 1923 (Hemiptera: Reduviidae) under Laboratory Conditions

The entire life cycle of Rhodnius domesticus, fed weekly on mice, was studied under controlled conditions. Aspects related to hatching, life time, mortality, feeding behaviour and fecundity for each stage of the insect life-cycle were evaluated. The hatching rate observed in 100 eggs was 57% and the mean time of hatching was 15.6 days. Forty-six nymphs (80.7%) completed the cycle and the mean time from NI to adult was 93.8 days. The average span in days for each stage was 12.4 for NI, 9.8 for NII, 14.2 for NIII, 16.8 for NIV and 25.0 for NV. The number of bloodmeals in each nymphal stage varied from 1 to 3. The mortality rate was 12.3% for NI, 3.5% for NII and 1.7% for NIII and NV nymphs. The mean number of eggs laid per female in a 9-month period was 333.1. Average adult survival rates were 287.6 +133 and 328 +73 days for males and females respectively.

Improving the accuracy of heat balance integral methods applied to thermal problems with time dependent boundary conditions

In this paper the two main drawbacks of the heat balance integral methods are examined. Firstly we investigate the choice of approximating function. For a standard polynomial form it is shown that combining the Heat Balance and Refined Integral methods to determine the power of the highest order term will either lead to the same, or more often, greatly improved accuracy on standard methods. Secondly we examine thermal problems with a time-dependent boundary condition. In doing so we develop a logarithmic approximating function. This new function allows us to model moving peaks in the temperature profile, a feature that previous heat balance methods cannot capture. If the boundary temperature varies so that at some time t & 0 it equals the far-field temperature, then standard methods predict that the temperature is everywhere at this constant value. The new method predicts the correct behaviour. It is also shown that this function provides even more accurate results, when coupled with the new CIM, than the polynomial profile. Analysis primarily focuses on a specified constant boundary temperature and is then extended to constant flux, Newton cooling and time dependent boundary conditions.

Life Cycle and Reproductive Patterns of Triatoma rubrofasciata (De Geer, 1773) (Hemiptera: Reduviidae), under Laboratory Conditions

The life cycle and reproductive patterns of Triatoma rubrofasciata were studied along with laboratory conditions for the establishment of a prolific colony. The insects were divided into four groups: two of them were maintained at room temperature (20.5°C to 33°C and 85% ± 5% of relative humidity), the other two in a climatic chamber (CC) (temperature: 29°C, humidity: 80% ± 5%). The groups were fed weekly or fortnightly on Swiss mice. The females from the group kept in the CC and fed weekly had longer life span, as well as a higher number of eggs, fertile eggs and hatchings; the group kept in the CC and fed fortnightly had a shorter life span for the 1st, 2nd and 3rd instars and a lower mortality rate for all instars. It was concluded that a constant high temperature (CC at 29°C) is the most suitable condition for the maintenance of a colony of T. rubrofasciata regardless of the interval between repasts.

Resistance to Starvation of Triatoma rubrofasciata (De Geer, 1773) under Laboratory Conditions (Hemiptera: Reduviidae: Triatominae)

The present work aims at learning the period of resistance to starvation (molting/death) of Triatoma rubrofasciata in different stages of development and the respective loss of weight until death. Eggs of specimens from the greater area of the city of São Luis in the State of Maranhão, Brazil, yielded approximately 300 nymphs. These nymphs were placed in labelled Borrel glasses, in which they were weekly fed on rats (Rattus norvegicus), until reaching the stage to be observed. The experiments were conducted in a climatic chamber regulated at 29 ± 1° C, 70% relative humidity and 12 hr photoperiod. The resistance to starvation increased according to the stage of development, except for adult bugs, whose results were similar to the 3rd stage nymphs. In all these development stages there was an abrupt loss of weight in the first week, followed by a gradual loss until death. Comparing this work with those of other authors, it was observed that T. rubrofasciata is among the less resistant triatomine species.

Pale and dark reddish melanic tawny owls differentially regulate the level of blood circulating POMC prohormone in relation to environmental conditions.

Knowledge of the hormonal pathway controlling genotype-specific norms of reaction would shed light on the ecological factors to which each genotype is adapted. Environmentally mediated changes in the sign and magnitude of covariations between heritable melanin-based colouration and fitness components are frequent, revealing that extreme melanin-based phenotypes can display different physiological states depending on the environment. Yet, the hormonal mechanism underlying this phenomenon is poorly understood. One novel hypothesis proposes that these covariations stem from pleiotropic effects of the melanocortin system. Melanocortins are post-translationally modified bioactive peptides derived from the POMC prohormone that are involved in melanogenesis, anti-inflammation, energy homeostasis and stress responses. Thus, differential regulation of fitness components in relation to environmental factors by pale and dark melanic individuals may be due to colour-specific regulation of the POMC prohormone. Accordingly, we found that the degree of reddish melanic colouration was negatively correlated with blood circulating levels of the POMC prohormone in female tawny owls (Strix aluco) rearing a brood for which the size was experimentally reduced, but not when enlarged, and in females located in rich but not in poor territories. Our findings support the hypothesis that the widespread links between melanin-based colouration and fitness components may be mediated, at least in part, by the melanocortin system.

Survival, development and growth of larvae of the blue swimmer crab, Portunus pelagicus, cultured under different photoperiod conditions

The blue swimmer crab is a commercially important species of the tropical Indo-Pacific regions that shows substantial potential as a candidate species for aquaculture. Optimization of larval rearing conditions, including photoperiod, is therefore important to establish a method for the intensive hatchery culture of this species. Newly hatched larvae of Portunuspelagicus in first zoeal stage (ZI) were reared under five photoperiod regimes 0L: 24D, 6L: 18D, 12L: 12D, 18L: 6D, and 24L: 0D (5 replicates per treatment) till they metamorphosed to megalopae (ranged from 8.5 ± 0.3 days (18L: 6D) to 10.8 ± 1.8 days (0L: 24D) at 29 ± 1 °C). Daily, larvae of each treatment were fed an identical diet of mixed rotifer and Artemia nauplii, and the survival and molt to successive stages was monitored. Newly hatched ZI larvae of P. pelagicus could successfully develop to the megalopal stage under all tested photoperiod conditions, but we detected significant differences in survival among treatments (p & 0.05). The constant darkness treatment (0L: 24D) had the lowest (19.2 ± 7.2%, mean ± S.E.) cumulative survival from ZI to the megalopal stage, while the 18L: 6D treatment achieved the highest survival (51.2 ± 23.6%). Similarly, the photoperiod significantly affected zoeal development. Constant darkness led to the longest cumulative zoeal duration (10.8 ± 1.8 days), whereas the 18L: 6D treatment rendered the shortest larval development (8.5 ± 0.3 days). In addition, larvae reared under constant darkness resulted in the smallest megalopae (carapace length = 1.44 ± 0.09 mm) and the lowest dry weight (0.536 ± 0.188 mg). In conclusion, photoperiod significantly affected the survival, development, and growth of P. pelagicus zoeal larvae. Constant darkness led to the lowest larval survival and developmental rate, while a photoperiod regime of 18L: 6D appeared to be the most suitable condition for the rearing of zoeal larvae of P. pelagicus.

Development of Rhodnius prolixus (Hemiptera: Reduviidae) under Constant and Cyclic Conditions of Temperature and Humidity

Development of Rhodnius prolixus after eclosion until the adult stage was studied at constant temperatures (T), 15, 20, 25, 28, 35°C, and relative humidities (RH), 75, 86 and 97%, and fluctuating (16/8 hr) temperatures, T I/II, 15/28°C, 20/25°C, 25/28°C and 25/35°C, and relative humidities, RH I/II, 86/75% and 97/75%. Eclosion or molting were not observed at 15°C and 86 or 97% RH, respectively. At 35°C and 75% RH only few insects molted. By alternating T I/II, 15/28°C and 25/35°C, insects developed at high frequency. Cumulating the average lengths of the interphases within independent groups for each instar, R. prolixus reached the adult stage most rapidly (86.7 days) and at highest frequency per instar (mean: 91.8%) at 28°C and 75% RH. Under fluctuating T I/II, development was completed within 100 days or less at 25/28°C and 25/35°C with high rates of hatch and molting. Development was slowest at fluctuating TI/II, 15/28°C and 20/25°C (>185 days), and at constant 20°C (>300 days). Mortality was higher at constant 97% RH or fluctuating RH I, 97%, than at constant or fluctuating 86% RH. Refeeding was minimal at optimal conditions of T and RH for development. The most refeeding was observed at a constant 35°C.