Current Drug Metabolism (v.18, #3)

Meet Our Editorial Board Member by Babu L. Tekwani (173-173).

Status Epilepticus: An Overview by Venkata Ramesh Yasam, Venkatachalam Senthil, Satya Lavanya Jakki, Natarajan Jawahar (174-185).
Status epilepticus (SE) is an emergency situation, where immediate and effective treatment is required in least possible time as it is associated with neuronal damage, systemic complications, substantial morbidity and mortality depending on status type, duration, age and etiology. In the past few years, morbidity and mortality rate were improved, probably may be due to aggressive use of anti-epileptic drugs in emergency situations. Present literature gives an overview of the conditions leading to SE and its management guidelines in hospital and out of hospital setting emphasizing on the available drug therapies.

Toxicities of Receptor Tyrosine Kinase Inhibitors in Cancer Pharmacotherapy: Management with Clinical Pharmacology by Ken-ichi Fujita, Hiroo Ishida, Yutaro Kubota, Yasutsuna Sasaki (186-198).
A number of molecularly targeted anticancer drugs that efficiently inhibit receptor tyrosine kinases, socalled receptor tyrosine kinase inhibitors (TKIs), have been developed. Although these receptor TKIs are generally well tolerated, unexpected toxicities sometimes occur in various organs. TKI-induced adverse events not only lower the quality of life of cancer patients but also reduce dose intensity, and sometimes result in treatment discontinuation. To reduce adverse drug events and increase treatment efficacy, oncologists and clinical pharmacologists have made efforts to establish strategies to treat patients via optimal selection and dosing of TKIs. Drug efficacy and safety are generally determined by the interplay of multiple processes that regulate pharmacokinetics and pharmacodynamics (toxicodynamics). In this review article, we first provide an overview of adverse events caused by receptor TKIs, focusing on gefitinib, erlotinib, sorafenib and sunitinib, followed by a discussion on the association between pharmacokinetics and toxicities induced by these TKIs, with a focus on establishing optimal personalized treatment strategies by controlling pharmacokinetic properties. Finally, we introduce new findings on the molecular mechanisms of TKIinduced toxicities, elucidated using a new strategy, systems toxicology.

Insight to Pharmacokinetics of TKIs: Optimizing Practical Guidelines for Individualized Therapy by Ruiqing Wang, Chaoqin Zhong, Chen Zhang, Mingqiang Hua, Daoxin Ma (199-206).
Objective: Tyrosine kinase inhibitors (TKIs) are widely used drugs which have high availability in reducing the activity of BCR-ABL1 tyrosine kinase, therefore they play an indispensable role in the treatment of Chronic myeloid leukemia (CML). Imatinib, dasatinib and nilotinib have been proved to have absolute bioavailability and stable blood concentration in humans. TKIs pharmacokinetics has close relationships with the clinical response and clinical treatment of CML.

Method: We conducted a systematic PubMed search to look for studies relating to TKIs pharmacokinetics with proper inclusion/exclusion criteria. After looking through a large number of references, we investigated that different generations of TKIs could be influenced by many factors. We chose some typical factors which were closely linked to the common treatment of CML. These factors contain daily dose, diet, individual variability, drug-drug interaction, drugs resistance and drug withdrawal.

Results: By summarizing up these influence factors, we hope it can make a contribution to clinical therapy. Above all, the relationship between influence factors and the clinical therapeutic effect is the key point that our research pays attention to.

Conclusion: This review highlights certain influence factors of TKIs clinical pharmacokinetics.

The Physiological/Pathophysiological Significance of Vitamin D in Cancer, Cardiovascular Disorders and Beyond by Manaf AlMatar, Husam AlMandeal, Essam A. Makky, Begum Kayar, Emel Yarar, Is|l Var, Fatih Koksal (207-224).
Background: Vitamin D, a molecular precursor of the potent steroid hormone calcitriol, has crucial functions and roles in physiology and pathophysiology. Tellingly, calcitriol has been shown to regulate various cellular signalling networks and cascades that have crucial role in cancer biology and diagnostics. Mounting lines of evidences from previous clinical and preclinical investigations indicate that the deficiency of vitamin D may contribute to the carcinogenesis risk. Concomitantly, recent reports suggested that significant reduction in the cancer occurrence and progression is more likely to appear after vitamin D supplementation. Furthermore, a pivotal role functioned by vitamin D in cardiovascular physiology indicates that the deficiency of vitamin D is significantly correlated with enhanced prevalence of stroke, hypertension and myocardial infarction. Notably, vitamin D status is more likely to be used as a lifestyle biomarker, since poor and unhealthy lifestyles are correlated with the deficiency of vitamin D, a feature which may result in cardiovascular complications. Moreover, recent reports revealed that the effect of vitamin D is to cover not only cardiovascular system but also skeletal system.

Objective: Herein, we are highlighting the recent knowledge of vitamin D roles and functions with respect to pathophysiological disorders such as cancer, cardiovascular diseases, rheumatoid arthritis (RA) and debate the potential avails of vitamin D on slowing cancer, cardiovascular disease and RA progression.

Conclusion: The findings of this review confirm that the importance of vitamin D metabolites or analogues which can provide a helpful platform to target some kinds of cancer, particularly when used in combination with existing therapies. Moreover, the correlation between vitamin D deficiencies with cardiovascular diseases and rheumatoid arthritis (RA) progression might suggest a pivotal role of vitamin D in either initiation or progression of these diseases.

Background: Classical thyroid hormones have an established necessary role in the normal development of the central nervous system, and they have been recently considered as decisive factors influencing cognitive functions in the adult brain and involved in the development of Alzheimer's disease. The picture summarizing thyroid hormone effects on the adult brain, however, does not only include classical thyroid hormones but also the products of their peripheral metabolism. These latter have been considered as inactive breakdown products for long but recently were proved to produce significant biological effects.

Objective: In this review article we presented recent evidence supporting the hypothesis that thyroid hormones exert a neuroprotective effect in the brain areas involved in learning and memory. Moreover, we summarized the evidence that suggests that non-classical thyroid hormones produce significant neurological effects in the adult brain. We also discussed the possible role of thyroid hormones in the cognitive impairment, typical of Alzheimer's disease.

Methods: A comprehensive review of the literature based on the current knowledge of the effects of classical and nonclassical thyroid hormones on the adult brain and their role in Alzheimer's disease was performed.

Results: The available literature suggests that both classical and non-classical thyroid hormones act as neuroprotective agents in the brain areas related to learning and memory. Their role in these areas supports the idea that they may be involved in the development of Alzheimer's disease.

Conclusion: Thyroid hormones produce significant neurological effects, act as neuroprotective agents and might be considered as future diagnostic and therapeutic tools for Alzheimer's disease.

Reduction of Doxorubicin-Induced Cardiotoxicity Using Nanocarriers: A Review by Michaela Fojtu, Jaromir Gumulec, Tibor Stracina, Martina Raudenska, Anna Skotakova, Marketa Vaculovicova, Vojtech Adam, Petr Babula, Marie Novakova, Michal Masarik (237-263).
Background: Anthracycline antibiotic doxorubicin (DOX) is a very potent and extensively prescribed chemotherapeutic drug. It is widely utilized in the therapy of variety of haematological and solid tumours, although its administration is commonly accompanied with several severe side effects. The most serious one is a development of dose-dependent and cumulative cardiotoxicity. In the course of time, many strategies have been investigated in order to avoid or at least to diminish DOX-induced cardiac dysfunction; these include reduction of toxic effect by coadministration with iron chelators (dexrazoxane), trastuzumab, taxanes, statins, and ACE-inhibitors. However, the attenuation of cardiotoxic effect is still not satisfactory yet.

Objective: This review represents an overall appraisal of studies concerning with the utilization of various doxorubicinloaded nanoparticles in the cancer treatment with specific emphasis on those studies evaluating their influence on the reduction of heart tissue damage.

Conclusion: Introduction of nanoscale drug delivery systems undoubtedly represents nowadays one of the most promising tools for lowering systemic toxicity. Nanoparticles enable to target the therapeutic payload directly towards the tumor tissue, thus leading to the increased accumulation of the drug in the desired tissue and simultaneously protecting surrounding healthy tissues.