Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review.

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.

High vs. low-dose leucovorin in regimens with fluorouracil in colorectal cancer therapy.

The problem of unavailability of drugs and shortages have been a common problem in recent years. Shortages may threaten some treatment regimens for oncological patients. This article presents a systematic review of studies evaluating the efficacy and safety of chemotherapy regimens combining fluorouracil and standard or low-dose leucovorin in treating colorectal cancer. A total of 13 prospective and retrospective studies were included in the review. Meta-analyses and review papers were excluded. It is apparent from the systematic review that a lower dose of leucovorin does not fundamentally affect the efficacy of regimens combining 5-fluorouracil with leucovorin in treating patients with colorectal cancer. Similarly, even in the case of safety, reducing the dose of leucovorin did not influence the frequency and severity of observed adverse effects. Surprisingly, in three studies, some of the adverse effects occurred more often with the higher dose of leucovorin. Furthermore, the article presents the results of a questionnaire survey of the management of leucovorin shortages at the departments of preparation of cytostatics (N = 46) within the Czech Republic. In total, 35 workplaces provided feedback. In 17 cases, the departments for the preparation of cytostatics in the Czech Republic had to accept restrictions on administering the full dose of leucovorin. These restrictions consisted of reducing the dose of the injectable form of leucovorin, changing the chemotherapy regimen, administering the oral form of calcium folinate, forcing a therapeutic break, or a combination of these approaches.

Processing and Microstructure of As-Cast Ti-45Al-2W-xC Alloys.

The metallurgical preparation and microstructure of as-cast Ti-45Al-2W-xC (in at.%) alloys were investigated. Five alloys with carbon content ranging from 0.38 to 1.96 at.% were prepared by vacuum induction melting (VIM) in graphite crucibles, followed by centrifugal casting into graphite moulds. A master 15W-85Al (at.%) alloy with a relatively low melting point and TiC powder were used to facilitate fast dissolution of W during VIM and to achieve the designed content of C in the as-cast alloys, respectively. The increase in the content of C affects the solidification path of the studied alloys. Differential thermal analysis (DTA) and microstructural observations show that the alloys with carbon content up to 0.75 at.% solidify with ß primary phase and their dendritic as-cast microstructure consists of the α2(Ti3Al) + γ(TiAl) lamellar regions, retained B2 phase enriched by W and single γ phase formed in the interdendritic region. The increase in the content of C above 0.75 at.% leads to the formation of primary lathe-shaped Ti2AlC carbides, which act as effective heterogeneous nucleation sites of ß dendrites during the solidification and grain refinement of the alloys with 1.15 and 1.96 at.% C. The increase in the content of C leads to an increase in Vickers hardness and elastic modulus in the alloys containing 1.96 at.% C.

Longitudinal Monitoring of Hair Cortisol Using Liquid Chromatography-Mass Spectrometry to Prevent Hypercortisolism in Patients Undergoing Glucocorticoid Replacement Therapy.

OBJECTIVE: Currently available methods for endogenous cortisol monitoring in patients with hormonal insufficiency rely on measurements of plasma levels only at a single time point; thus, any kind of chronic exposure to cortisol is challenging to evaluate because it requires collecting samples at different time points. Hair cortisol levels acquired longitudinally better reflected chronic exposure (both cortisol synthesis and deposition) and may significantly contribute to better outcomes in glucocorticoid replacement therapies. DESIGN: Twenty-two patients on cortisol substitution therapy were monitored for plasma, urinary, and hair cortisol levels for 18 months to determine whether hair cortisol may serve as a monitoring option for therapy setting and adjustment. METHODS: Plasma and urinary cortisol levels were measured using standardized immunoassay methods, and segmented (∼1 cm) hair cortisol levels were monitored by liquid chromatography coupled to mass spectrometry. A log-normal model of the changes over time was proposed, and Bayesian statistics were used to compare plasma, urinary, and hair cortisol levels over 18 months. RESULTS AND CONCLUSIONS: Hair cortisol levels decreased over time in patients undergoing substitutional therapy. The residual variance of hair cortisol in comparison to plasma or urinary cortisol levels was much lower. Thus, longitudinal monitoring of hair cortisol levels could prove beneficial as a noninvasive tool to reduce the risk of overdosing and improve the overall patient health.

Structural and Magnetic Properties of Inverse-Heusler Mn2FeSi Alloy Powder Prepared by Ball Milling.

Ternary Mn2FeSi alloy was synthesized from pure elemental powders by mechanical alloying, using a high-energy planetary ball mill. The formation of an inverse-Heusler phase after 168 h of milling and subsequent annealing at 1173 K for 1.5 h was confirmed by X-ray diffraction. The diffractogram analysis yielded XA structure and the lattice parameter 0.5677 nm in a good agreement with the theoretically obtained value of 0.560 nm. The final powder was formed by particles of irregular shape and median diameter D50 of 3.8 µm and their agglomerates. The chemical analysis resulted in the mean composition of 49.0 at.% Mn, 25.6 at.% Fe and 25.4 at.% Si. At room temperature, the prepared samples featured a heterogeneous magnetic structure consisting of dominant paramagnetic phase confirmed by Mössbauer spectrometry and a weak ferro-/ferrimagnetic contribution detected by magnetization curves. From the field-cooled and zero-field-cooled curves the Néel temperature of 67 K was determined.

Cannabidiol and the possibilities of its use in veterinary medicine of dogs and horses: A brief review.

In connection with the use of cannabinoids for therapeutic purposes in human medicine, there is increased attention for their use in veterinary medicine, particularly by the owners of companion animals and horses. Therefore, veterinarians are expected to face this interest and have the corresponding knowledge on these substances. Presently, it is not possible to use medical marijuana (in terms of the dried cannabis flowers) for veterinary purposes in many countries, but there is increasing evidence that isolated cannabinoids also have beneficial effects (namely cannabidiol - CBD). Thus, this review summarises the possible therapeutic implications of CBD within the scope of evidence-based medicine, particularly in dogs and horses in association with the treatment of pain, epilepsy and anxiety in order to provide veterinarians with a concise overview of scientific findings in this field.

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient.

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.

Structure and Properties of Cast Ti-Al-Si Alloys.

Intermetallic compounds based on Ti-Al- (Si) are attractive materials with good thermal stability and low density. However, the production of these materials is quite complicated. Partially modified conventional methods of melting metallurgy are most often used due to availability, possible high productivity, and relatively low production costs. Therefore, some technologies for the production of intermetallics based on Ti-Al are currently available, but with certain disadvantages, which are caused by poor casting properties or extreme reactivity of the melt with crucibles. Some shortcomings can be eliminated by modifying the melting technology, which contributes to increasing the cost of the process. The work deals with the preparation of Ti-Al-Si intermetallic compounds with different contents of aluminum and silicon, which were produced by centrifugal casting in an induction vacuum furnace Linn Supercast-Titan. This process could contribute to the commercial use of these alloys in the future. For this research, the TiAl15Si15(in wt.%) alloy was selected, which represents a balanced ratio of aluminides and silicides in its structure, and the TiAl35Si5 alloy, which due to the lower silicon content allows better melting conditions, especially with regard to the melting temperature. This alloy was also investigated after HIP ("Hot Isostatic Pressing") treatment.

Bilayer mucoadhesive buccal films with prolonged release of ciclopirox olamine for the treatment of oral candidiasis: In vitro development, ex vivo permeation testing, pharmacokinetic and efficacy study in rabbits.

The incidence of fungal infections has increased in recent decades not only in patients with predisposing and risk factors, but it has also spread up due to the widespread use of broad-spectrum antibiotics, immunosuppressants and corticosteroids. A limited number of drugs are currently used to treat oral candidiasis (OC). There is an emerging need to look for new antifungals, to rework or to explore the already known molecules. Ciclopirox olamine (CPX), a broad-spectrum antifungal agent, is currently used for topical dermatologic treatment. In this study, bilayer mucoadhesive buccal films (MBFs) containing poly(ethylene oxide) (PEO) and Eudragit® NM 30D (EU) with the prolonged release of ciclopirox olamine, were developed for the treatment of oral candidiasis. During ex vivo testing it was found that CPX does not pass through the porcine buccal tissue but it accumulates in it, which may be beneficial for the treatment of candidiasis in the oral cavity. In a pharmacokinetic study, the drug release from mucoadhesive films was prolonged with the maximum plasma concentration at 3.4 (1.4; 5.5) h. All rabbits with stomatitis showed progressive healing after the treatment with CPX bilayer mucoadhesive buccal films without organ pathologies.

Effect of Hot Isostatic Pressing on Porosity and Mechanical Properties of 316 L Stainless Steel Prepared by the Selective Laser Melting Method.

The manufacturing route primarily determines the properties of materials prepared by additive manufacturing methods. In this work, the microstructural features and mechanical properties of 316 L stainless steel prepared by the selective laser method have been determined. Three types of samples, (i) selective laser melted (SLM), (ii) selective laser melted and hot isostatic pressed (HIP) and (iii) selective laser melted and heat treated (HT), were characterized. Microstructural analysis revealed that SLM samples were formed by melt pool boundaries with fine cellular-dendritic-type microstructure. This type of microstructure disappeared after HT or HIP and material were formed by larger grains and sharply defined grain boundaries. The SLM-prepared samples contained different levels of porosity depending on the preparation conditions. The open interconnected LOF (lack of fusion) pores were observed in the samples, which were prepared with using of scanning speed 1200 mm/s. The blowhole and keyhole type of porosity were observed in the samples prepared by lower scanning speeds. The HIP caused a significant decrease in internal closed porosity to 0.1%, and a higher pressure of 190 MPa was more effective than the usually used pressure of 140 MPa, but for samples with open porosity, HIP was not effective. The relatively high yield strength of 570 MPa, tensile strength of 650 MPa and low ductility of 30-34% were determined for SLM samples with the lower porosity content than 1.3%. The samples after HIP showed lower yield strengths than after SLM (from 290 to 325 MPa) and relatively high ductility of 47.8-48.5%, regardless of the used SLM conditions.

The Effect of Temperature and Milling Process on Steel Scale Utilized as a Pigment for Ceramic Glaze.

This study is focused on the evaluation of the re-utilizability of scale originated during the steel casting and steel rolling processes as a pigment for glazes. Non-oiled scale with Fe3O4 as the major phase were used as a coloring component of transparent glaze matrix in: (i) as received state, (ii) thermally pre-treated at 700 and 900 °C, (iii) mechanically treated in planetary ball mill (60, 120 and 240 min) and (iv) mechanically treated in vibratory disc mill (60 and 120 min). Prepared glazes were applied on the surface of ceramic tiles prepared from a commercially available white ceramic slurry. The resulting tiles with given glaze were thermally treated at 800, 900 and 1060 °C. The pigments were characterized by X-ray powder diffraction method (XRD), X-ray fluorescence spectroscopy (XRF), granulometry (PSD), thermogravimetric analysis (TG) and differential thermal analysis (DTA), scanning electron microscopy (SEM/EDAX). The color of the samples was described by the coordinates L*a*b* from CIELAB color space. The results showed that the non-oiled scale is suitable as the pigment for ceramic glazes. Careful control of the scale treatment process (mechanical as well as thermal) together with the temperature of final glaze firing is necessary to obtain the glaze of desired color and quality.

Metallurgical Preparation of Nb-Al and W-Al Intermetallic Compounds and Characterization of Their Microstructure and Phase Transformations by DTA Technique.

The possibilities of metallurgical preparation of 40Nb-60Al and 15W-85Al intermetallic compounds (in at.%) by plasma arc melting (PAM) and vacuum induction melting (VIM) were studied. Both methods allow easy preparation of Nb-Al alloys; however, significant evaporation of Al was observed during the melting, which affected the resulting chemical composition. The preparation of W-Al alloys was more problematic because there was no complete re-melting of W during PAM and VIM. However, the combination of PAM and VIM allowed the preparation of W-Al alloy without any non-melted parts. The microstructure of Nb-Al alloys consisted of Nb2Al and NbAl3 intermetallic phases, and W-Al alloys consisted mainly of needle-like WAl4 intermetallic phase and Al matrix. The effects of melting conditions on chemical composition, homogeneity, and microstructure were determined. Differential thermal analysis was used to determine melting and phase transformation temperatures of the prepared alloys.

Lycopene increases metabolic activity of rat liver CYP2B, CYP2D and CYP3A.

BACKGROUND: Lycopene as a naturally occurring carotenoid is a common part of the human diet. Several beneficial properties of lycopene have been identified, with the most studied being anti-cancer and antioxidant activity. However, no evidence of possible drug-drug or drug-food supplement interactions has been found. METHODS: We studied the in vivo effect of lycopene on the selected rat liver cytochromes P450 (CYPs): CYP1A2, CYP2B, CYP2C11, CYP2C6, CYP2D, and CYP3A. Lycopene was administered to rats intragastrically at doses of 4, 20, and 100 mg/kg/day for 10 consecutive days. Total protein content, P450 Content, and metabolic activity of selected CYPs were evaluated in the rat liver microsomal fraction. RESULTS: Increased CYP2B, CYP2D, and CYP3A metabolic activities were observed in animals treated with the lycopene dose of 100 mg/kg/day. The content of CYP3A1 protein was increased by the dose of 100 mg/kg/day and CYP3A2 protein was increased by all administered doses of lycopene. CONCLUSION: The results of our study indicate that lycopene increased the metabolic activity of enzymes that are orthologues to the most clinically important human enzymes involved in xenobiotic metabolism. The risk of pharmacokinetic interactions between lycopene dietary supplements and co-administered drugs should be evaluated.

Therapeutic Drug Monitoring of Sunitinib in Gastrointestinal Stromal Tumors and Metastatic Renal Cell Carcinoma in Adults-A Review.

BACKGROUND: Sunitinib is an inhibitor of multiple receptor tyrosine kinases and is a standard-of-care treatment for advanced and metastatic renal cell carcinoma and a second-line treatment in locally advanced inoperable and metastatic gastrointestinal stromal tumors. A fixed dose of the drug, however, does not produce a uniform therapeutic outcome in all patients, and many face adverse effects and/or toxicity. One of the possible causes of the interindividual variability in the efficacy and toxicity response is the highly variable systemic exposure to sunitinib and its active metabolite. This review aims to summarize all available clinical evidence of the treatment of adult patients using sunitinib in approved indications, addressing the necessity to introduce proper and robust therapeutic drug monitoring (TDM) of sunitinib and its major metabolite, N-desethylsunitinib. METHODS: The authors performed a systematic search of the available scientific literature using the PubMed online database. The search terms were "sunitinib" AND "therapeutic drug monitoring" OR "TDM" OR "plasma levels" OR "concentration" OR "exposure." The search yielded 520 journal articles. In total, 447 publications were excluded because they lacked sufficient relevance to the reviewed topic. The remaining 73 articles were, together with currently valid guidelines, thoroughly reviewed. RESULTS: There is sufficient evidence confirming the concentration-efficacy and concentration-toxicity relationship in the indications of gastrointestinal stromal tumors and metastatic renal clear-cell carcinoma. For optimal therapeutic response, total (sunitinib + N-desethylsunitinib) trough levels of 50-100 ng/mL serve as a reasonable target therapeutic range. To avoid toxicity, the total trough levels should not exceed 100 ng/mL. CONCLUSIONS: According to the current evidence presented in this review, a TDM-guided dose modification of sunitinib in selected groups of patients could provide a better treatment outcome while simultaneously preventing sunitinib toxicity.

Heavy water enhancement of fluorescence signal in reversed-phase liquid chromatography.

Liquid chromatography with fluorescence detection has been used in analyses demanding high sensitivity and selectivity. As majority systems rely on reversed-phase columns with water being the main component of the mobile phase, fluorescent compounds with emission maxima higher than 500 nm might be dynamically quenched. A simple replacement of H2O with D2O enhanced the sensitivity for selected compounds by 10-200%. Affected compounds included an anti-cancer drug doxorubicin, a luminescent probe fluorescein, and naturally occurring forms of vitamin B2. Similar levels of enhancement were obtained by fluorescence spectrometry. Such simple yet effective approach may greatly improve HPLC analyses coupled to fluorescence detection.

Effect of Endocannabinoid Oleamide on Rat and Human Liver Cytochrome P450 Enzymes in In Vitro and In Vivo Models.

The endocannabinoid system is important for many physiologic and pathologic processes, but its role in the regulation of liver cytochromes P450 (P450s) remains unknown. We studied the influence of the endocannabinoid oleamide on rat and human liver P450s. Oleamide was administered intraperitoneally to rats at doses of 0.1, 1, and 10 mg/kg per day for 7 days. The content and activity of key P450s were evaluated in rat liver microsomes. Moreover, interactions with nuclear receptors regulating P450 genes and serum levels of their ligands (prolactin, corticosterone, and free triiodothyronine) were tested in in vitro P450 inhibition assays. Decreased protein levels and metabolic activities of CYP1A2, CYP2B, and CYP2C11, along with a drop in metabolic activity of CYP2D2, were observed in animals treated with oleamide (10 mg/kg per day). The activities of CYP2C6, CYP2A, and CYP3A and the levels of hormones were not altered. In vitro, oleamide exhibited a weak inhibition of rat CYP1A2, CYP2D2, and CYP2C6. The activities of rat CYP2A, CYP2B, CYP2C11, and CYP3A and human CYP1A2, CYP2B6, CYP2C9, and CYP3A4 were not altered. Oleamide did not interact with human pregnane X, constitutive androstane, or aryl hydrocarbon receptors in reporter gene experiments and did not regulate their target P450 genes in primary human hepatocytes. Our results indicate that oleamide caused the downregulation of some rat liver P450s, and hormones are not mediators of this effect. In vitro oleamide inhibits mainly rat CYP2C6 and is neither an agonist nor antagonist of major human nuclear receptors involved in the regulation of xenobiotic metabolism.

Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice.

The use of cannabis for medical purposes has been recently legalised in many countries including the Czech Republic. As a result, there is increased interest on the part of physicians and patients in many aspects of its application. This mini review briefly covers the main active substances of the cannabis plant and mechanisms of action. It focuses on two conditions, cancer pain and spasticity in multiple sclerosis, where its effects are well-documented. A comprehensive overview of a few cannabis-based products and the basic pharmacokinetics of marijuana's constituents follows. The review concludes with an outline for preparing cannabis (dried inflorescence) containing drug dosage forms that can be produced in a hospital pharmacy.

Pharmacokinetics of Ciclopirox Olamine after Buccal Administration in Rabbits.

BACKGROUND: Prevalence of oral mucosal fungal infections increases with the frequent administration of antibiotics, corticosteroids and immunosuppressive drugs. Therapeutically used antifungals are usually associated with a variety of drug interactions. Furthermore, there has been a noticeable increase in microorganisms resistant to these preparations. Mucoadhesive buccal films represent a modern therapeutic system for the treatment of oral mucosal fungal infection paired with a high degree of patient compliance. Ciclopirox olamine applied directly onto the oral mucosa offers an attractive alternative to treatment with systemic antifungals thanks to its low incidence of resistance and side effects. OBJECTIVE: The aim of this work was to evaluate the pharmacokinetic parameters of ciclopirox olamine after the buccal application of mucoadhesive film prepared by the solvent casting method. METHOD: A chromatographic method using an internal standard was developed and validated for evaluation of ciclopirox olamine plasma concentrations. Method accuracy was 88.5-104.6% and 89.5-99.7% for interday and intraday assays, respectively. RESULTS: The pharmacokinetic properties of ciclopirox olamine were studied in New Zealand White rabbits. The mucoadhesive films containing ciclopirox olamine in a total dose of 34.4 (33.0; 35.9) mg kg-1 were applied to all the rabbits. Plasma ciclopirox olamine concentrations were determined during the 12 h following application. The time taken to reach maximum plasma concentration was 1.7 (1.1; 2.2) h after the drug administration with cmax 5.73 (4.18; 7.28) µg mL-1. Overall elimination half-life was 3.8 (1.9; 10.8) h. CONCLUSION: The experiment suggests that oral mucoadhesive film may be a valuable alternative ciclopirox olamine administration.

[Rhodiola rosea and its neuropsychotropic effects]. / Rozchodnice ruzová a její neuropsychotropní úcinky.

The paper reviews the neuropsychotropic effects of Rhodiola rosea, a succulent perennial plant which is native to dry, high-altitude regions of the northern hemisphere. The most valued part of the plant is its rhizome, which has a rose-like fragrance. In the available literature, there is a large number of mentions of its healing properties; nonetheless, only few of them are based on reliable scientific evidence. Of the neuropsychotropic effects, there are mentions of anxiolytic, antidepressant, neuroprotective and pro- cognitive properties and nonspecific "adaptogenic" effects. These effects are well established according to the preclinical studies; nonetheless many of clinical studies have serious drawbacks in design or interpretation of results. Extracts of R. rosea are well tolerated in general and thus regarded as safe. On the other hand, some pharmacokinetic interactions at the level of cytochrome P450 enzymes cannot be omitted. The extracts of R. rosea, are considered, according to the regulation of the Ministry of Health, as food supplements. According to the long standing use of R. rosea, it may be used for traditional treatment of symptoms of fatigue or mental weakness, but it seems that there is not enough evidence for general recommendation of use of R. rosea extracts in clinical practice.Key words: Rhodiola rosea neuropsychotropic effects phytomedicine.

Identification of metabolites of selected benzophenanthridine alkaloids and their toxicity evaluation.

Selected benzo[c]phenathridine alkaloids were biotransformed using rat liver microsomes and identified by liquid chromatography and mass spectrometry. While the metabolites of commercially available sanguinarine and chelerythrine have been studied in detail, data about the metabolism of the minor alkaloids remained unknown. Reactions involved in transformation include single and/or double O-demethylation, demethylenation, reduction, and hydroxylation. Two metabolites, when isolated, purified and tested for toxicity, were found to be less toxic than the original compounds.