Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Neonatal rat exposure to pyrethroid and organophosphate insecticides: A physiological and biochemical trial of progeny

A manufactured product (Ectoplus®) composed by a cypermethrin (44.7%) and dichlorvos (4.2%) mixture was administered (10mg/kg/day, orally, by gavage) to pregnant rats, during the periods of gestation+lactation, gestation, and lactation. Control mothers received vehicle aqueous solution during the gestation+lactation period. With the progeny, in the 1-15 post-natal days (PNDI-15) there were observed alterations in the periods of occurrence of teeth, hair, unfolding of ears, and in the developmental period for following reflexes: postural, palmar grasp, negative geotaxis, and acoustic startle reflex. After weaning (PND21), there were observed the presence of cypermethrin and dichlorvos in the blood brain and liver; decrease in weight of liver, of cholinesterase activity in the plasma, liver, and brain, and hepatic metabolizing activity of drugs; alterations of levels of gamma glutamyl transferase enzymes, of creatinine, and of potassium in the serum of the animals. In conclusion, neonatal exposure to a formulated mixture of cypermethrin and dichlorvos is inductive to alterations in characteristics that indicate somatic and neuromuscular development of the progeny, and in certain biochemical parameters. The results suggest that enzymatic assessment associated with somatic and neuromotor assessment can be important markers of developmental characteristics in neonatal toxicity by pesticide formulations based on mixtures of insecticides.

Does magnesium chloride modify aldrin-induced neurotoxicity in rats?

Magnesium chloride (MgCl2) has been proposed for the treatment of seizures of different etiologies. The present study investigated the effect of MgCl2 on aldrin-induced seizures. Initially, 50 male rats received 60 mg aldrin/kg po and the effects were classified as muscular twitches, clonic convulsions or tonic-clonic convulsions. Another group of 40 rats dosed with 60 mg aldrin/kg po received 0, 4, 8, or 12 mg MgCl2/kg im. The percentage of tonic-clonic convulsant rats that resulted from MgCl2 treatment were 90% at 0 mg/kg; 50% at 4 mg/kg, 40% at 8 mg/kg and 20% at 12 mg MgCl2/kg. The percentage of survivors in the group receiving 12 mg MgCl2/kg was 80% while the control group had 20% survival. The clonic convulsions were not modified by MgCl2 treatment. Blood and brain concentrations of aldrin and dieldrin (metabolite of aldrin) did not differ among groups. The MgCl2 administration decreased the neuroexcitability induced by aldrin and increased survivability.

Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery

The use of the nasal route for drug delivery has attracted much interest in recent years in the pharmaceutical field. Local and principally systemic drug delivery can be achieved by this route of administration. But the nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration due to poor membrane permeability, rapid clearance and enzymatic degradation into the nasal cavity. Thus, alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems including liposomes, cyclodextrins, micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally. This review article discusses recent progress and specific development issues relating to colloidal drug delivery systems in nasal drug delivery. © 2006 Bentham Science Publishers Ltd.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas

Background: The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer. Methods: Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases. Results: A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid. Conclusions: The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting. Copyright © 2009 John Wiley & Sons, Ltd.

细胞外信号调节蛋白激酶-cAMP反应元件结合蛋白信号通路在应激所致抑郁行为障碍中的作用

Stress is the most important factor in the vulnerability to depression and other behavioral disorders, but the mechanisms that stress signals are transferred into depression are far from understanding. To date, the neurotransmitters, neurotrophins and signal pathway have been concerned in the topic focusing on the pathophysiology of depression, but there are still many puzzles. Increasing evidence has indicated that the alteration in neuronal plasticity is the “trace” of stress-induced damages. The extracellular signal-regulated protein kinase(ERK)-cyclic-AMP-responsive element（CRE）-binding protein(CREB)signal pathway is a powerful intracellular signal transduction pathway participating in neuronal plasticity which is involved in higher brain cognitive functions such as learning and memory. However, so far, little is known about the role of the ERK-CREB signal pathway in response to stress and emotional modulations. Thus the aim of the study was to systematically investigate the role of the ERK-CEB signal pathway in depressive-like behaviors induced by stress. Depression animal models, antidepressant agent treatment and disruption of signal pathway in specific brain regions were applied. In the present study, three experiment sessions were designed to make sure whether the ERK-CREB signal pathway was indeed one of pathophysiological mechanisms of depressive-like behaviors induced by stress. In experiment one, two different stress animal models were applied, chronic forced swim stress and chronic empty water bottle stress. After stress, all animals were tested behaviorally using open-field, elevated-plus maze and saccharine preference test, and brain samples were processed for determination of ERK, P-ERK, CREB and P-CREB using western blot. The relationships between the proteins of ERK, P-ERK, CREB and P-CREB in the brain and the behavioral variables were also analyzed. In experiment two, rats were treated with antidepressant agent fluoxetine once a day for 21 consecutive days, then the brain levels of ERK, P-ERK, CREB and P-CREB was determined, the depressive-like behaviors were also examined. In experiment three, mitogen activated extracellular-signal-regulated kinase kinase (MEK) inhibitor U0126 was administrated to inhabit the activation of ERK in the hippocampus and prefrontal cortex respectively, then behavioral measurements and protein detection were conducted. The main results of the study were as the following: (1) Chronic forced swim stress induced animals to suffer depression and disrupted the ERK-CREB signal pathway in hippocampus and prefrontal cortex. There were significant correlations between P-ERK2, P-CREB and multiple variables of depressive-like behaviors. (2) Chronic empty water bottle stress did not induce depressive-like behaviors. Such stress decreased the brain level of P-ERK2 in hippocampus and prefrontal cortex, but the level of P-CREB in the hippocampus was increased. (3) The antidepressant agent fluoxetine relieved depressive-like behaviors and increased the activities of the ERK-CREB signal pathway in stressed animals. (4) Animals treated with U0126 injection into hippocampus showed decreased activities of the ERK-CREB signal pathway in the hippocampus, and suffered depression comorbid with anxiety. (5) Animals treated with U0126 injection into prefrontal cortex showed decreased activities of the ERK-CREB signal pathway in the prefrontal cortex, and exhibited depressive-like behaviors. In conclusion, The ERK-CREB signal pathway in the hippocampus and prefrontal cortex was involved in stress responses and significantly correlated with depressive-like behaviors; The ERK-CREB signal pathway in the hippocampus and prefrontal cortex participated in the mechanism that fluoxetine reversed stress-induced behavioral disorders, and might be the target pathway of the therapeutic action of antidepressants; The disruption of the ERK-CREB signal pathway in the hippocampus or prefrontal cortex led to depressive-like behaviors in animals, suggesting that disruption of ERK-CREB pathway in the hippocampus or prefrontal cortex was involved in the pathophysiology of depression, and might be at least one of the mechanisms of depression induced by stress.

烟草依赖者的注意偏向研究

Relapse has been a great challenge in clinical treatment and experimental studies of drug addiction. Recent studies suggest that psychological dependence may play a major role in addiction relapse, even more important than physiological dependence. Then a fundamental question arises: how to measure the psychological dependence? How to examine whether an addict has psychologically quitted when leaving drug rehabilitation centers? Self-report, a commonly used evaluation approach, is inevitably vulnerable to various cognitive influences, particularly in explicit tasks. Therefore, an objective index is necessary to evaluate the subliminal psychological drug dependence level. The objective of the current study was to develop such a psychological paradigm to probe the unaware attentional bias of in smoking addicts. Experiment 1 adapted the interocular suppression technique of binocular rivalry to study the attentional bias to cigarette pictures in smokers and age-matched nonsmoker. Results show that the smokers demonstrated similar attentional bias in both visible and unaware conditions, while non-smokers showed attentional bias only in the visible condition, and there was a significant interaction between experiment conditions and subject groups. These results provide compelling evidence for addiction-specific attentional bias in cigarette smokers, by minimizing the influence of confounding conscious factors. Furthermore, attentional bias of smokers in unawareness state was negatively correlated with their cigarette dependence levels, while their pre-test cigarette craving levels was positively correlated with their attnetional bias in the visible condition. This pair of correlations further demonstrated the advantages of unawareness state in disclosing stable dependence states, therefore supporting the effectiveness of the paradigm used in this study. Another interesting finding of Experiment 1 is that non-smokers also showed attentional bias in the visible condition. To exclude the possibility that the attentional bias found in experiment 1 was task-specific, experiment 2 adapted the most commonly-used visual dot probe task with smoking scenes as in relevant reference. The result in experiment 1 was well replicated, i.e., nonsmokers in experiment 2 also showed significant attentional bias to smoking-related stimuli, We interpenetrate this interesting finding as an effect of environmental influence, as the participants of the current study live in a highly smoking-exposed and smoking-encouraged environment, which is quite different with the participants of studies reported in the literature. A series of questionnaires and scales administered in the current study indeed show that most smokers smoked due to influence of the environment. They also acknowledged that smoking as an important media of social communication in China, and even considered that away from the smoking environment would effectively help them to quit. The current study also found that the disgust level towards cigarette pictures and smoking-related scenes of non-smokers was positively correlated with their attnentional bias in the visible condition of experiment 1. It is likely that in a highly smoking-encouraged environment, the remaining few on-smokers have severe disgust to cigarettes and smoking scenes; and their attentional bias might be caused by disgust avoidance. In conclusion, the current study represents the first study showing the existence of unaware attentional bias to smoking related stimuli in cigarette smokers by applying the interocular suppression paradigm, providing a reference to study of dependence of other drugs. The current study also found that our non-smoking participants also showed attentional bias to smoking related stimuli, which may be due to the possible influence of highly smoking-exposed environment of our participants.

The processing of number and gender agreement in Spanish: an event related potential investigation of the effects of structural distance

Previous research suggests that the processing of agreement is affected by the distance between the agreeing elements. However, the unique contribution of structural distance (number of intervening syntactic phrases) to the processing of agreement remains an open question, since previous investigations do not tease apart structural and linear distance (number of intervening words). We used event related potentials (ERPs) to examine the extent to which structural distance impacts the processing of Spanish number and gender agreement. Violations were realized both within the phrase and across the phrase. Across both levels of structural distance, linear distance was kept constant, as was the syntactic category of the agreeing elements. Number and gender agreement violations elicited a robust P600 between 400 and 900ms, a component associated with morphosyntactic processing. No amplitude differences were observed between number and gender violations, suggesting that the two features are processed similarly at the brain level. Within-phrase agreement yielded more positive waveforms than across-phrase agreement, both for agreement violations and for grammatical sentences (no agreement by distance interaction). These effects can be interpreted as evidence that structural distance impacts the establishment of agreement overall, consistent with sentence processing models which predict that hierarchical structure impacts the processing of syntactic dependencies. However, due to the lack of an agreement by distance interaction, the possibility cannot be ruled out that these effects are driven by differences in syntactic predictability between the within-phrase and across-phrase configurations, notably the fact that the syntactic category of the critical word was more predictable in the within-phrase conditions.

fMRI evidence for the involvement of the procedural memory system in morphological processing of a second language

Behavioural evidence suggests that English regular past tense forms are automatically decomposed into their stem and affix (played  = play+ed) based on an implicit linguistic rule, which does not apply to the idiosyncratically formed irregular forms (kept). Additionally, regular, but not irregular inflections, are thought to be processed through the procedural memory system (left inferior frontal gyrus, basal ganglia, cerebellum). It has been suggested that this distinction does not to apply to second language (L2) learners of English; however, this has not been tested at the brain level. This fMRI study used a masked-priming task with regular and irregular prime-target pairs (played-play/kept-keep) to investigate morphological processing in native and highly proficient late L2 English speakers. No between-groups differences were revealed. Compared to irregular pairs, regular pairs activated the pars opercularis, bilateral caudate nucleus and the right cerebellum, which are part of the procedural memory network and have been connected with the processing of morphologically complex forms. Our study is the first to provide evidence for native-like involvement of the procedural memory system in processing of regular past tense by late L2 learners of English.

EXPOSICAO DE CIRURGIOES-DENTISTAS AO MERCURIO

The professional exposure of dental surgeons to mercury has attracted a great deal of attention from governmental organs and institutions in different countries. Considering that the normal ratio is 10 μg/1000 ml of urine, it was verified from tests that 72.7% of the professionals working in the dental practice in the city of Araraquara (SP) Brazil, show mercury levels above this limit. These results demonstrated the almost complete unawareness of many dentists to mercury and, consequently, precautionary measures were almost nonexistent.

Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females) aged 17 to 58 years. Twenty one (53.84%) of the patients presented a slow acetylating phenotype and 18 (46.16%) a fast acetylating phenotype. Glucose-6-phosphate-dehydrogenase (G6PD) activity was decreased in 5(23.80%) slow acetylators and in 4 (22.22%) fast acetylators. Glutathione reductase activity was decreased in 14 (66.66%) slow acetylators and in 12(66.66%) fast acetylators. Serum levels of free and total sulfadoxin were higher in slow acetylator (p _ 0.02). Analysis of the results permitted us to conclude that serum sulfadoxin levels are related to the acetylator phenotype. Furthermore, sulfadoxin levels were always above 50 μg/ml, a value considered therapeutic. Glutathione reductase deficiency observed in 66% of patients may be related to the intestinal malabsorption of nutrients, among them riboflavin, a FAD precursor vitamin, in patients with paracoceidioidomycosis.