Beta-lactams are the cornerstone of therapy for the treatment of the most serious infections in the intensive care unit (ICU) setting. However, individualization of dosing remains challenging because pharmacokinetics are highly variable and difficult to predict in critically ill patients. The objective of this study was to evaluate whether administration of full-dose beta-lactam antibiotics to critically ill subjects during the first 24 h of treatment, irrespective of baseline renal function, achieves predefined target concentration ranges (Cmin [free minimum concentration] 1–10 × MIC [minimum inhibitory concentration] and 4–10 × MIC). This trial was a retrospective, observational cohort study. A total of 377 critically ill patients over 18 years admitted to the ICU who received full doses of meropenem, piperacillin–tazobactam, or cefepime were analyzed. Blood sampling for determination of antibiotic trough concentration was performed 24 h after initiation of full-dose therapy. When targeting a Cmin of 4–10 × MIC, a high proportion of patients remained underdosed (42.7

The article discusses the effect of vitamin D on primary and secondary prevention of fractures and its effect on conditions after selected orthopaedic procedures. Fractures can be divided into traumatic, fatigue and pathological according to the cause. One of the complications of fracture is the formation of a nonunion. In addition to dealing with fractures, a total joint replacement is another common procedure in orthopaedic surgery. Because insufficient muscle strength can increase the risk of falls and thus result in a fracture, these topics are also mentioned in this article. Due to the impact of vitamin D deficiency on various musculoskeletal disorders, orthopaedic surgeons should pay more attention to the patients vitamin D status and be familiar with different strategies for preventing hypovitaminosis D, although clear evidence-based medical recommendations are still insufficient.

The article discusses the effect of vitamin D on primary and secondary prevention of fractures and its effect on conditions after selected orthopaedic procedures. Fractures can be divided into traumatic, fatigue and pathological according to the cause. One of the complications of fracture is the formation of a nonunion. In addition to dealing with fractures, a total joint replacement is another common procedure in orthopaedic surgery. Because insufficient muscle strength can increase the risk of falls and thus result in a fracture, these topics are also mentioned in this article. Due to the impact of vitamin D deficiency on various musculoskeletal disorders, orthopaedic surgeons should pay more attention to the patients vitamin D status and be familiar with different strategies for preventing hypovitaminosis D, although clear evidence-based medical recommendations are still insufficient.

Hyponatremie patří mezi poměrně časté a vážné komplikace u ambulantních i hospitalizovaných pacientů. Je spojena se zvýšenou mortalitou a morbiditou. Klinická manifestace je velmi různorodá a za jejím rozvojem stojí velké množství příčin, včetně polékově iatrogenně navozených. Faktory podílející se na vzniku hyponatremie se mohou vzájemně kombinovat, příčiny nejsou často jednoznačně identifikovány, a proto zůstávají polékové hyponatremie nerozpoznány a poddiagnostikovány. Cílem tohoto sdělení je přinést literární přehled o potenciálu jednotlivých léčiv hyponatremii vyvolat, popsat patofyziologický mechanismus vzniku tohoto nežádoucího účinku a usnadnit management jeho řešení v klinické praxi. Klíčová slova: hyponatremie, osmolarita, léky, diuretika, antidepresiva, antipsychotika, antiepileptika.

Early and appropriate antibiotic therapy remains the key intervention for successful treatment of infection in critically ill patients, particularly in the current era of increasing antibiotic resistance. Optimization of the antimicrobial dosing regimens to achieve therapeutic plasma concentrations and concentrations at the site of infection is crucial for maximizing the therapeutic response and minimizing the risk of organ toxicity and is also an important tool to avoid the resistance emergence. Beta-lactam antibiotics have been considered relatively safe and, as opposed to aminoglycosides, therapeutic drug monitoring as a tool conventionally used primarily to minimize toxicity in drugs with narrow therapeutic window or complex pharmacokinetics, has not been provided routinely yet. However, emerging data suggest that optimal antibiotic exposure may not be achieved with traditional dosing strategies in a significant number of critically ill patients and, on the contrary, concerns about insufficient plasma concentrations leading to microbiological and clinical failure are warranted. The treatment of infections in the intensive care unit (ICU) patients is often challenging because of disease complexity, pathophysiologic alterations they undergo and reduced susceptibility of nosocomial pathogens. Therefore, it is of paramount importance to update current recommendations on dosing of beta-lactam antibiotics in severe infections and therapeutic drug monitoring may be regarded as the only exact method to ensure pharmacodynamics target achievement. Na Homolce Hospital is one of the first medical institutions in the Czech Republic where the practice of routine TDM of beta-lactam antibiotics in ICU-patients has been established. In this paper, we introduce our experience and first case reports.

Estrogen‐induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase‐1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol‐induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 μmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down‐regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up‐regulated Mrp3 (348%, P ≤ 0.05). Heme pre‐treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up‐regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol‐treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme‐induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up‐regulation (Mrp2/Mrp4) or down‐regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2‐dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol‐induced cholestasis.

Uvod:Furosemid je klickove diuretikum použivane při stavech retence tekutin. Nutnost podani vysokých davek je důsledkem jeho snižene ucinnosti způsobene nižsi dosaženou koncentraci na mistě ucinku v lumen ledvinneho tubulu a vlivem adaptacnich mechanizmů. Vysoke davky jsou spojovany s rozvojem iontove dysbalance, přime toxicity a intravaskularni fluktuaci objemu. Možnosti ovlivněni ucinnosti a bezpecnosti furosemidu jsou v literatuře rozporuplně hodnoceny v souvislosti se způsobem jeho podavani (intermitentně vs kontinualně). Cil:Cilem teto prace je analyzovat dostupna literarni data týkajici se zhodnoceni ucinnosti a bezpecnosti intermitentnich vs kontinualnich davkových režimů. Metodika:Systematicka literarni reserse v databazi PubMed od roku 1990 do roku 2013 s použitim klicových slov - furosemid, klickove diuretikum, bolusove podani, kontinualni infuze, ucinnost, bezpecnost, srdecni selhani, intenzivni pece, ICU. Zavěr:Farmakokineticke a farmakodynamicke znalosti furosemidu vytvařeji urcitý teoretický předpoklad pro preferenci kontinualnich infuzi před intermitentnimi bolusy. Zhodnoceni dostupných literarnich dat vsak zatim v klinicke praxi neprokazalo jednoznacne výhody jednoho způsobu podavani oproti druhemu.

INTRODUCTION:Furosemide is a loop diuretic used in states of volume overload. The need for high doses is due to its reduced efficacy caused by lower concentration of furosemide achieved at the site of action in the renal tubule lumen and adaptation mechanisms. High doses have been associated with the development of ionic dysbalance, direct toxicity and intravascular volume fluctuations. The way of furosemide administration (intermitent versus continuously) to influence efficacy and safety is contradictory evaluated in EBM.AIM:The aim of this study is to analyze the available data for evaluation of the efficacy and safety of intermittent versus continuous dose regimens.METHODS:A systematic search on PubMed from 1990 to 2013 using the keywords - furosemide, loop diuretic, bolus, continuous infusion, efficacy, safety, heart failure, ICU, critical care.CONCLUSION:The pharmacokinetic and pharmacodynamic knowledge of furosemide create a theoretical assumption for the preference of continuous infusions before intermittent boluses. Assessement of available studies, however, yet in clinical practice did not proof the advantage of one over the other route of administration.

Carbon monoxide (CO), a product of heme oxygenase (HMOX), has many beneficial biological functions and is a promising therapeutic agent for many pathological conditions. However, the kinetics of inhaled CO and its protective role in endotoxin-induced cholestasis is not fully known. Thus, our objective was to characterize the kinetics of inhaled CO and then investigate its use in early phase experimental endotoxin-induced cholestasis. Female Wistar rats were randomly divided into 4 groups: CON (control), LPS (lipopolysaccharide, 6 mg/kg), CO (250 ppm COx1h), and CO + LPS. Rats were sacrificed at 0-12 h after LPS administration. Tissues and blood were collected for liver injury markers and tissue CO distribution measurements. Livers were harvested for measurements of Hmox activity, Hmox1 mRNA expression, cytokines (IL10, IL6, TNF), and bile lipid and pigment transporters. Half-lives of CO in spleen, blood, heart, brain, kidney, liver, and lungs were 2.4 ± 1.5, 2.3 ± 0.8, 1.8 ± 1.6, 1.5 ± 1.2, 1.1 ± 1.1, 0.6 ± 0.3, 0.6 ± 0.2 h, respectively. CO treatment increased liver IL10 mRNA and decreased TNF expression 1 h after LPS treatment and prevented the down-regulation of bile acid and bilirubin hepatic transporters (Slc10a1, Abcb11, and Abcc2, p < 0.05), an effect closely related to the kinetics. The protective effect of CO against cholestatic liver injury persisted even 12 h after CO exposure, as shown by attenuation of serum cholestatic markers in CO-treated animals. CO exposure substantially attenuated endotoxin-induced cholestatic liver injury and was directly related to the kinetics of inhaled CO. This data underscores the importance of the kinetics of inhaled CO for the proper design of experimental and clinical studies of using CO as a treatment strategy.

BACKGROUNDCyproterone acetate is associated with hepatotoxicity during prostate cancer treatment. The information about its toxic mechanism and risk factors is limited, based on pharmacovigilance reports and published case reports only.CASEWe describe a case of a patient treated with cyproterone acetate (200 mg/day for 9 months) for adenocarcinoma of the prostate. The 75-year-old patient was admitted for the development of jaundice and loss of appetite to the T. Bata Regional Hospital in Zlin, Czech Republic. Laboratory values ALT 994 U/l, AST 1,046 U/l, ALP 193 U/l, GGT 1,128 U/l, bilirubin 177 µmol/l, conjugated bilirubin 138 µmol/l, albumin 26 g/l, Quick time INR 1.23. The concomitant medication included atorvastatin 10 mg daily. Clinical and laboratory outcomes showed acute fulminant liver failure caused pre-dominantly by hepatocellular damage. Hepatotoxicity induced by cyproteron acetate was diagnosed after exclusion of other causes, with a gradual improvement after discontinuation of the respective drug treatment.CONCLUSIONAll patients treated with cyproteron acetate for prostate cancer are in risk for the development of liver failure and therefore should be monitored and well educated. More information is needed to sufficiently identify risk factors and explain mechanism of damage.

Lecba erektilni dysfunkce (ED) u pacientů s poskozenou penilni inervaci např. po radikalni prostatektomii je stale aktualni otazkou u řady pacientů. Soucasna terapie (terapie 1. linie) erektilni dysfunkce je větsinou založena na použivani inhibitorů fosfodiesterazy V. (PDE5i), sildenafilu, tadalafilu, vardenafilu, atd. Tato lecba, dana svým mechanizmem ucinku, vsak vyžaduje aspoň castecně zachovalou penilni inervaci, ktera umožni přenos vzruchu při sexualni stimulaci. V tomto clanku popisujeme připad 48leteho pacienta po radikalni prostatektomii pro karcinom, kdy se lecba samotnými inhibitory PDE5 neosvědcila, a proto bylo nutne zavest lokalni vazodilatacni lecbu (lecba 2. linie) pomoci intrakavernozně aplikovaneho alprostadilu (prostaglandin E1). Davka byla titrovana od 20 až do 60 μg, ale vedla pouze k semierekci, ktera sice umožňovala vaginalni penetraci, ale byla pro pacienta bolestiva a nepohodlna. Proto jsme se rozhodli na zakladě zkusenosti publikovaných v literatuře vyzkouset fixni intrakavernozni kombinaci alprostadil 20 μg + papaverin 20 mg + fentolamin 1,5 mg, ktera se ukazala u tohoto pacienta jako velmi ucinna. Při předepisovani výse uvedených kombinaci jsme vsak narazili na problem komercni nedostupnosti papaverinu a fentolaminu na nasem trhu. Tento nas přispěvek si tedy mimo jine klade za cil konkretni prakticke doporuceni, jak postupovat v uvedenem připadě.

An elevated production of hydrogen peroxide mediates the increased rate of apoptosis of cells derived from individuals with Down's syndrome. The mechanism via which this occurs is unknown. Here we show that Ets-2, a transcription factor located on human chromosome 21 and already overexpressed in multiple tissues in Down syndrome (DS, trisomy 21), is induced by low concentrations of hydrogen peroxide. Moreover, cells with an imbalance in the antioxidant enzymes SOD-1/GPX-1, such as occurs in DS through the overexpression of the chromosome 21 gene SOD-1, also results in increased Ets-2 expression. The increase in Ets-2 expression is dependent on mRNA transcription. Importantly, we further demonstrate that 3T3 fibroblasts that overexpress Ets-2 are sensitized to hydrogen peroxide-induced apoptosis. These data implicate Ets-2 in the regulation of oxidant-induced apoptosis and provide a possible rationale for both the (5- to 7-) fold increase in Ets-2 protein level in DS tissues, above the expected gene dosage of 1.5-fold, and the elevated rate of apoptosis in DS cells.

This work studied a relationship between HO-1/CO system and lipid peroxidation with consequent effects on liver functions and NOS-2. We focused on curcumin pretreatment in rat toxic model of d-galactosamine and lipopolysaccharide. Hepatocyte viability, lipid peroxidation, antioxidant status, ALT and AST were evaluated. HO-1 and NOS-2 expressions and respective enzyme activity were determined. Curcumin caused decreases in ALT and AST levels as well as in lipid peroxidation. Furthermore, curcumin pretreatment increased liver HO-1 (2.4-fold, p=0.001), but reduced NOS-2 (4.1-fold, p=0.01) expressions. In conclusion, the tuning of CO/NO pathways is important in shedding light on curcumin's cytoprotective effects in this model.

Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. This study is focused on addressing the mutual relationship and early signals of these mechanisms in the D-galactosamine and lipopolysaccharide (D-GalN/LPS) hepatotoxicity model, with the help of standard liver function and biochemistry tests, histology, and measurement of gene expression by RT-PCR. Intraperitoneal injection of 400 mg/kg D-GalN and 50 μg/kg LPS was able to induce hepatotoxicity in rats, as evidenced by significant increases in liver enzymes (ALT, AST) and raised bilirubin levels in plasma. Heme oxygenase-1 and nitric oxide synthase-2 gene expressions were significantly increased, along with levels of their products, bilirubin and nitrite. The gene expression of glutathione peroxidase 1 remained unchanged, whereas a decrease in superoxide dismutase 1 gene expression was noted. Furthermore, the significant increase in the gene expression of apoptotic genes Bid, Bax and caspase-3 indicate early activation of apoptotic pathways, which was confirmed by histological evaluation. In contrast, the measured caspase-3 activity remained unchanged. Overall, the results have revealed differential oxidative stress and apoptotic responses, which deserves further investigations in this hepatotoxicity model.