Milica Bajcetic

Mitochondria-Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury

Kidney ischemia/reperfusion injury emerges in various clinical settings as a great problem complicating the course and outcome. Ischemia/reperfusion injury is still an unsolved puzzle with a great diversity of investigational approaches, putting the focus on oxidative stress and mitochondria. Mitochondria are both sources and targets of ROS. They participate in initiation and progression of kidney ischemia/reperfusion injury linking oxidative stress, inflammation, and cell death. The dependence of kidney proximal tubule cells on oxidative mitochondrial metabolism makes them particularly prone to harmful effects of mitochondrial damage. The administration of antioxidants has been used as a way to prevent and treat kidney ischemia/reperfusion injury for a long time. Recently a new method based on mitochondria-targeted antioxidants has become the focus of interest. Here we review the current status of results achieved in numerous studies investigating these novel compounds in ischemia/reperfusion injury which specifically target mitochondria such as MitoQ, Szeto-Schiller (SS) peptides (Bendavia), SkQ1 and SkQR1, and superoxide dismutase mimics. Based on the favorable results obtained in the studies that have examined myocardial ischemia/reperfusion injury, ongoing clinical trials investigate the efficacy of some novel therapeutics in preventing myocardial infarct. This also implies future strategies in preventing kidney ischemia/reperfusion injury.

N‐acetylcysteine as a Novel Prophylactic Treatment for Ifosfamide‐Induced Nephrotoxicity in Children: Translational Pharmacokinetics

Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N‐acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO‐induced renal cell death and nephrotoxicity in both LLCPK‐1 cells and a rat model. To facilitate the use of NAC in preventing IFO‐induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM·h (range, 9.92–30.02 mM·h), compared to the mean systemic exposure found in treated children (14.48 mM·h; range, 6.22–32.96 mM·h). They also report 2 pediatric cases in which NAC‐attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NACs potential to protect against IFO‐induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children.

Effects of Everolimus on Oxidative Stress in Kidney Model of Ischemia/Reperfusion Injury

Background/Aims: Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI. Methods: C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys. Results: In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals. Conclusion: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

Pharmacokinetics of Oral Doses of Telmisartan and Nisoldipine, Given Alone and in Combination, in Patients With Essential Hypertension

This randomized, single‐blind, parallel‐group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once‐daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUCss (132%; P < .01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/fss (−54%; P < .05) and Vz/fss (−72%; P < .05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavailability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use.

Redox therapy in neonatal sepsis: reasons, targets, strategy, and agents.

ABSTRACT Neonatal sepsis is one of the most fulminating conditions in neonatal intensive care units. Antipathogen and supportive care are administered routinely, but do not deliver satisfactory results. In addition, the efforts to treat neonatal sepsis with anti-inflammatory agents have generally shown to be futile. The accumulating data imply that intracellular redox changes intertwined into neonatal sepsis redox cycle represent the main cause of dysfunction of mitochondria and cells in neonatal sepsis. Our aim here is to support the new philosophy in neonatal sepsis treatment, which involves the integration of mechanisms that are responsible for cellular dysfunction and organ failure, the recognition of the most important targets, and the selection of safe agents that can stop the neonatal sepsis redox cycle by hitting the hot spots. Redox-active agents that could be beneficial for neonatal sepsis treatment according to these criteria include lactoferrin, interleukin 10, zinc and selenium supplements, ibuprofen, edaravone, and pentoxifylline.

Use of antibiotics in paediatric primary care settings in Serbia.

Objective The aim of the study was to compare the quality of antibiotic use among children in primary settings with the internationally developed disease-specific quality indicators and with National Guidelines. Design Prescriptions of systemic antibiotics to the paediatric population (<18 years) at the primary level of healthcare for the period between 2011 and 2013 were analysed by using the National Health Insurance Funds outpatient reimbursement database. Results The mean annual number of antibiotic prescriptions was 1.887.615, while the mean annual number of children receiving antibiotics was 728.285. The prescription rate slightly decreased by 10% from 1.516 antibiotic prescriptions per 1000 persons per year in 2011 to 1.365 in 2013. The highest percentage of prescribed antibiotics was observed in the group of children aged 2–23 months. The mean annual prevalence of antibiotic prescriptions was 54%. The percentage of patients prescribed an antibiotic for acute upper respiratory tract infections, acute tonsillitis and acute otitis media (AOM) was above the proposed range (≤20), 87% –96%. These three diagnoses represent more than 69% of all indications for prescribing antibiotics. The percentage of patients prescribed a recommended antibiotic was below the proposed range (≥80%), 1% –17%, while the adherence rate to National Guidelines was low, 19%–28%. The percentage of patients prescribed quinolones was above the proposed range for AOM (≤5%), 7%. There were no significant differences in indicators value at the regional level in Serbia. Conclusions Antibiotic use among children in Serbia is extremely high compared with that in most other European countries. Major problems are frequent use of antibiotics for indications that usually receive no benefit from this treatment and the use of broad-spectrum antibiotics.

Opposite Effects of Ethanol and Nitrendipine on Nicotine-Induced Emesis and Convulsions

The effects of ICV injections were investigated in unanesthetized cats of ethanol alone and in combination with the dihydropyridine calcium antagonist, nitrendipine, on emesis and the convulsions produced by nicotine, which was similarly injected by the ICV route. In the first series of experiments, short lasting convulsions and emesis were the most prominent symptoms after the ICV injection of nicotine in a dose of 1.0 mg. In the second series of experiments the pretreatment of cats with ethanol given ICV in doses of 0.03, 0.2, and 0.3 ml reduced the emesis and prevented the convulsions induced by 1.0 mg dose of ICV nicotine. In the third series of experiments, the ICV injection of nitrendipine in doses of 0.024, 0.16, and 0.24 mg incorporated in the solution of ethanol, given in volumes of 0.03, 0.2, and 0.3 mt, respectively, blocked emesis but not the convulsions induced by the 1.0 mg dose of nicotine given ICV. The results suggest, therefore, that at least two different mechanisms underlie these phenomena. First, the synergistic effects at the neuronal nicotinic ionophores in the brain would act to underlie the antagonistic action of ethanol and nitrendipine on the emetic response. Second, conformational changes brought about by ethanol at voltage-dependent calcium channels in the brain may antagonize the inhibitory effect of the dihydropyridine calcium antagonist, producing the reversal of convulsions.

Heart Failure Pharmacotherapy: Differences Between Adult and Paediatric Patients

During the last decades, the introduction of new, more efficient drugs, has significantly improved the heart failure (HF) therapy of adults. Therapeutic focus has shifted from simple hemodynamic manipulation to include neurohumoral modulation as a consequence of the better understanding of mechanisms of HF formation, in particular at the cellular level. The aetiologies of HF in children are remarkably different and more varied than in the adult population. Cardiac failure is usually caused by congenital heart disease and cardiomyopathy in children, whereas in adults, coronary artery disease, hypertension and myocardial infarction are the most common causes. Despite this fact, pharmacotherapy of children is based on the same drugs, usually extrapolated from adult HF regimens. A recently published study in children treated with the drugs known to be efficient in adult HF therapy, provides encouragement that the outcomes might be similarly beneficial. On the other hand, some reports outline that children with HF, especially patients with systemic right ventricles or single ventricle physiology, require specific drug guidelines. A general characteristic of HF pharmacotherapy in children is the lack of paediatrically designed drugs. Drugs currently used in the treatment of HF in paediatric patients are designed for adults, and their efficacy, safety and quality have generally not been confirmed by clinical studies of children. Aside from this, availability of commercial paediatric drug formulations labelled for treatment of HF in children significantly influences the quality and efficacy of therapy.

Developmental pharmacology: a moving target

The main characteristic of pediatric and neonatal pharmacotherapy still is the insufficient availability of drugs with confirmed efficacy and safety data in children. Children differ from adults in the physiological, psychological and developmental terms and this subsequently results in differences in anticipated drug potency, efficacy and toxicity. This paper is focused on the most prominent issues of the contemporary developmental pharmacology. Childs age and development can significantly affect drug pharmacokinetics (PK) processes. The dosage of drugs for children must be based on the physiological characteristics, as well as PK parameters of the drug obtained from the clinical trials with children. While knowledge about the impact of developmental changes on drug PK is increasing, information regarding pharmacodynamics (PD) is still more limited. The examples from clinical and animal data on ontogeny of receptors resulted in strong evidence for changes in drug response during development, in addition to but independent from PK alterations. In order to improve the use of medicines in children, it is essentially to know the complex processes of growth and development into the pediatric drug development programs. This is because absence of PK/PD data leads to increased risk of over- or under-dosing, adverse reactions or inefficiency.

Antioxidative system in the erythrocytes of preterm neonates with sepsis: the effects of vitamin E supplementation

Background Vitamin E is routinely supplemented to preterm babies, including those with neonatal sepsis. Our aim was to examine the effects of neonatal sepsis and vitamin E on antioxidative system (AOS) in the blood. Methods A prospective, randomized, open label study involved 65 preterm neonates (control/sepsis – 34/31), which were divided into two subgroups – non-supplemented and supplemented with vitamin E (25 IU/day for 60 days). The activities of superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) were determined in erythrocytes at days 0, 30, and 60, following sepsis diagnosis. Results There was no difference in the activity of AOS between controls and neonates with ongoing sepsis. At 60 days, septic neonates showed higher CAT activity compared to controls (P = 0.027), and lower GPx activity compared to 0 days (P = 0.022). The later was mitigated by vitamin E, which on the other hand provoked lower GPx activity at 30 days, compared to untreated septic neonates (P = 0.014). In addition, vitamin E suppressed GR activity in septic neonates (P = 0.025 and P = 0.017 at 30 and 60 days). Finally, vitamin E supplementation in control neonates provoked a significant increase of GPx activity (P = 0.015 at 60 days). Conclusions The absence of altered redox settings in the blood of neonates during sepsis episode, and vitamin E-provoked decrease in the activity of some components of AOS, suggest that the supplementation of vitamin E in these patients might not be rational.