Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

Do we care enough about the medication in the elderly? (Case of the geriatric care facility at Military University Hospital Prague).

OBJECTIVE: The aim of this paper is a complex evaluation of clients medication in the geriatric care facility Domov Vlčí mák (DVM) with regard to the most common drug related risk factors in elderly. The paper shows ways of identification, resolution and prevention of drug related problems from the perspective of a clinical pharmacist. METHODS: The medication was evaluated in 74 DVM clients. The sample consisted of 45 women (61 %) and 29 men (39 %) with an average age of 90 years. The project took place in the period from April to June 2020. Patients pharmacotherapy was graded as low, medium or high risk in accordance with the methodology and concept of clinical pharmaceutical care in the Czech Republic developed by the Czech Professional Society of Clinical Pharmacy ČLS JEP. For all clients, medication was also assessed in terms of the risk of falls. RESULTS: There was a total of 62 (84 %) high, 4 (5 %) medium and 8 (11 %) low risk clients. A plan for medication adjustments was proposed for a total of 67 clients in the form of pharmacotherapeutic recommendations. A total of 170 drug related problems was identified and pharmacotherapeutic intervention was performed. The most common problem (in 42 % of cases) was a missing drug in terms of effective therapy. Medication discontinuation was recommended in 33 % of cases, mainly due to the risk of side effects, missing indications or drug necessity. Inadequate dosing was found in 15 % of cases, usually it was recommended to reduce the dose to the so-called “senior dose”. In 6 % of cases laboratory testing was indicated and in 4 % of cases timing of the drug administration was changed. CONCLUSION: Identified drug related problems did not represent major errors that could endanger the quality or safety of the healthcare provided. One of the reasons for the good outcome is an established multidisciplinary cooperation in this facility.

Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer.

BACKGROUND: Previously identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. BRCA1 plays a central role in DNA damage response (DDR. It undergoes phosphorylation by various DDR kinases at different serine residues, of which ser1524 is known to be specifically phosphorylated by ATM in response to genotoxic stress. METHODS: We performed BRCA1 immunohistochemistry on several tissue microarrays (TMAs) of 113 early (I, II stage) and advanced (III, IV stage) NSCLCs, using MS110 antibody against the BRCA1 N-terminal and S1524 antibody against the phosphorylated form of BRCA1 protein at ser1524 (Abcam). Patients with III and IV stage disease were treated by adjuvant cisplatin-based chemotherapy. Staining results were correlated with overall survival (OS), disease free survival (DFS) and with the occurrence of brain metastases. RESULTS: BRCA1 S1524 nuclear positivity was significantly correlated with longer OS and DFS in stage I and II patients (P<0.05), while OS and DFS were shorter in S1524 positive stage III and IV patients (P<0.05). No significant correlation was found with brain metastases. CONCLUSION: The results show that BRCA1 phosphorylaton, at least in ser1524, differentiates the fate of early and advanced NSCLC as well as response to chemotherapy, but the underlying mechanisms are not completely understood. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC.

The immunohistochemical expression of BNIP3 protein in non-small-cell lung cancer: a tissue microarray study.

Drug resistance is one of the reasons for chemotherapy failure in non-small-cell lung carcinoma (NSCLC). One of the major mechanisms of drug resistance is the inhibition of chemotherapy-induced apoptosis. Therefore, the study of novel cell death pathways could possibly enable us to overcome resistance to apoptosis in NSCLC. One of the non-caspase types of cell death is autophagy. BNIP3 protein, a Bcl-2 family member, highly expressed in some tumours, plays a key role in the induction of autophagy. In the present study, we investigated the immunohistochemical expression and subcellular localization of BNIP3 in a series of early- and late-stage non-small-cell lung carcinomas and normal bronchial tissues, and correlated this expression with the occurrence of metastasis and survival. BNIP3 was strongly expressed in the nucleus of cancer cells in 16/79 (20.3%) cases. This BNIP3 positivity did not correlate with histological grade, stage, histology type, metastatic potential, or expression of BNIP3 according to median values. No significant correlation was observed between the expression of BNIP3 and the overall survival of NSCLC patients (p = 0.55). Nor did we find any significant correlation between BNIP3 expression and the occurrence of site-specific metastasis (p = 0.85).

Identification of CD133+/nestin+ putative cancer stem cells in non-small cell lung cancer.

AIMS: No effective treatment for lung cancer exists currently. One reason for this, is the development of drug resistance, assumed to be associated with cancer stem cell (CSCs) emergence within the tumour. This pilot study aimed to identify CSCs in 121 non-small cell lung cancer (NSCLC) patient samples via detection of the expression of stem cell markers - CD133 and nestin. MATERIAL AND METHODS: Archived paraffin blocks of 121 patient samples were prepared as Tissue Microarrays (TMA). Indirect immunohistochemical staining was used to determine the level of expression of CD133 and nestin. Double immunofluorescence staining was used to investigate the co-expression of these two markers. To determine the correlation between expression of nestin and CD133 with the length of asymptomatic period and overall patient survival we used the Kaplan-Meyer analysis. RESULTS: CD133 expression was detected in 22 (19%), nestin in the epithelium in 74 (66%) and vasculature in 78 (70%) of patients. Co-expression of these two markers was found in 21 (17%) patients in less than 1% of positive cells without impact on disease free or overall survival. CONCLUSIONS: We identified CD133(+)/nestin(+) cells as novel potential markers of lung cancer CSCs.

Tpl-2/Cot and COX-2 in breast cancer.

BACKGROUND: Breast cancer is the most common cancer in women worldwide and although mortality (129,000/year) stagnates, incidence (370,000/year) is increasing. In addition to histological type, grade, stage, hormonal and c-erbB2 status there is therefore a strong need for new and reliable prognostic and predictive factors. METHODS AND RESULTS: This minireview focuses on two potential prognostic and predictive candidates Tpl2/Cot and COX-2 and summarise information about them. CONCLUSION: Tumor progression locus 2 (Tpl2/Cot) is a serine/threonine protein kinase belonging to the family of MAP3 kinases. Activated Tpl2/Cot leads to induction of ERK1/2, JNK, NF-kappaB and p38MAPK pathways. The first study on Tpl2/Cot mRNA in breast cancer showed its increase in 40 % of cases of breast cancer but no available data exist on protein expression. Cyclo-oxygenase 2 (COX-2) is inducible by growth and inflammatory factors and contributes to the development of various tumours. Expression of COX-2 in breast cancer varied from 5-100 % in reviewed papers with significantly higher values in poorly differentiated tumours. Tpl2/Cot and COX-2 have their importance in different intracellular pathways and some of these are involved in cancer development. Briefly, the results from recent studies suggest that Tpl2/Cot and COX-2 could be prognostic factors in breast cancer.

Immunohistochemical assessment of E-cadherin and beta-catenin in trichofolliculomas and trichoepitheliomas.

BACKGROUND: Trichofolliculomas and trichoepitheliomas are benign skin neoplasms originating from hair follicle cells. They result from defects in the signaling pathways that regulate hair follicle morphogenesis and regeneration. Thus they seem to be an excellent model of these processes. It is known that the E-cadherin/beta-catenin system of adhesion molecules plays a crucial role in the maintenance of tissue architecture. AIM: The aim of the present study was to investigate their involvement in benign hair follicle tumor development. METHODS: Semiquantitative intensity of expression were examined in formalin-fixed and paraffin-embedded tissue sections of 53 trichoepitheliomas, 15 trichofolliculomas and 19 normal skin samples by indirect immunohistochemistry. RESULTS: The intensity of E-cadherin/beta-catenin expression in tumor cells did not differ from controls. However, normal hair follicles cells exhibited membranous E-cadherin/beta-catenin expression, whereas both types of tumors, particularly trichoepitheliomas, showed E-cadherin/beta-catenin expression with a predominantly cytoplasmic localization. CONCLUSIONS: We suggest that this dystopic distribution of the E-cadherin/beta-catenin complex in hair follicle tumor cells may be a marker of cell-cell adhesion disruption which may contribute to the tumor formation.