Radan Stojanovic

Fentanyl Analogs: Structure-Activity-Relationship Study

Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Focus on Apixaban

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice.The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability.In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.

Acute Pretreatment with Chloroquine Attenuates Renal I/R Injury in Rats

Background Acute kidney injury (AKI) still remains an unresolved problem in pharmacotherapy and renal inflammation is a major factor in its development. Chloroquine, a well-known antimalarial drug, posses pleitropic effects as well: antiinflammatory, anticoagulant and vascular actions. The effects of chloroquine on renal function may involve significant increase in urine flow rate, glomerular filtration rate and sodium excretion, as well as stimulation of nitric oxide synthase. However, its role in experimental models of renal I/R injury is unknown. We aimed to analyze the acute effects of a single-dose intravenous chloroquine administered at three different times in the experimental model of I/R injury in rat. Methods Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion with saline lasting 4 hours. Chloroquine was administered in doses of 0.3 mg/kg i.v. and 3 mg/kg i.v. 30 min before ischemia, 30 min before reperfusion and 5 min before reperfusion. Selected a hemodynamic, biochemical and morphological parameters were followed in the Sham-operated animals and rats subjected to I/R injury and pretreated with saline or chloroquine. Results Chloroquine (0.3 and 3 mg/kg, i.v.) protected the I/R injured kidney in an U-shaped manner. Both doses were protective regarding biochemical and histological markers of the I/R injury (serum urea, creatinine and fractional excretion of sodium, as well as total histological score, tubular necrosis score and KIM-1 staining score) (P<0.05 vs. corresponding controls, i.e. rats subjected to I/R injury and treated with saline only). The protective effects of the lower dose of chloroquine were more profound. Time-related differences between pretreatments were not observed (P>0.05, all). Conclusion Our study shows for the first time that a single dose of chloroquine (0.3 mg/kg i.v.) could afford significant protection of the injured rat kidney.

The Role of Immunosuppressive Medications in the Pathogenesis of Hypertension and Efficacy and Safety of Antihypertensive Agents in Kidney Transplant Recipients.

The purpose of this review is to summarize current data on the role of immunosuppressants in the pathogenesis of hypertension and the efficacy and tolerability of major antihypertensive classes in kidney transplant recipients. Arterial hypertension is a common complication after kidney transplantation and a major risk factor for adverse outcome and graft rejection due to blood pressure elevation by immunosuppressive medications. Calcineurin inhibitors induce hypertension by a mechanism related to the imbalance of vasoactive substances endothelin and nitric oxide, and probably by causing overactivity of thiazide-sensitive sodium-chloride-cotransporter. Corticosteroids are well known for their hypertensive effects. The interactions of calcineurin inhibitors and mammalian target of rapamycin inhibitor sirolimus also promote hypertension. Management of arterial hypertension is a complex problem in the care of kidney transplant recipients. Target blood pressure values of <130/80 mm Hg are suggested by the National Kidney Foundation/ Kidney Disease Outcomes Quality Initiative. Calcium channel blockers may be useful in antagonizing the vasoconstrictive effects of calcineurin inhibitors. The renin-angiotensin system inhibitors seem a good option, especially in patients with proteinuria, however their effects on long-term graft and patient survival are controversial. β-Blockers could be beneficial in patients with coronary heart disease, but caution is required due to metabolic adverse effects. Thiazide diuretics could be the reasonable option for patients with glomerular filtration rate ≥30 mL/min/1.73 m2, also with caution regarding hypokalemia and glycemia. Until more evidence is provided, the choice of optimal antihypertensive therapy in kidney transplant recipients should be based on previous individual antihypertensive tolerability and efficacy, comorbidities, concomitant medications and post-transplant kidney function.

Utilization of psychiatric drugs in Serbia

Drug utilization has been defined by the World Health Organization (WHO) as the „marketing, distribution, prescription and the use of drugs in a society, with a special emphasis on the resulting medical, social, and economic consequences“ . Drug utilization studies are usually aimed at drug use-related problem detection and quantification. These studies may be quantitative (with the objective to quantify drug usage at various levels of health-care system), or qualitative (L) (which assess the appropriateness of drug utilization) 2, . Utilization of psychiatric drugs is often a subject of drug utilization studies. Increasing researchers’ interest in prescribing and utilization of psychiatric drugs is noted worldwide . It is understandable, bearing in mind that these drugs are, maybe more than other pharmacotherapeutic groups, related to different epidemiologic, social and economic variables. It is usually a high rate of prescribing of certain psychiatric drugs, as well as selfmedication (e.g. with benzodiazepines) that causes concern, as well as the consequences of such practice: development of tolerance and addiction, drug abuse, and increased treatment costs. Over the last decade in Serbia several drug utilization studies on the usage of psychiatric drugs have been conducted. These studies have addressed certain major issues: drug use patterns, prescribing behavior, gaps between guidelines and actual utilization and factors responsible for polypharmacy. Both, quantitative and qualitative aspects of psychiatric drugs use have been analysed using up-to-date methodology. Such a modern methodological approach enables comparison of the data from Serbian studies with the data from other countries, thus pointing out certain prescribers’ habits and/or patients’ preferences that are characteristic for our milieu.

Pharmacotherapy of Pain in the Older Population: The Place of Opioids.

Pain is a common symptom in older people. It is possible that pain is underreported in older persons due to an incorrect belief that it is an inevitable part of aging. Opioid analgesics are potent medications, with confirmed efficacy for the treatment of moderate to severe pain. These drugs are commonly used in older persons. However, there is insufficient evidence regarding safety of opioids in older patients. One of the reasons for this is the lack of randomized, controlled clinical trials. People of advanced age often have comorbidites and use other prescription drugs, as well as over-the-counter (OTC) compounds, thus making them more suceptible to the risk of interactions with opioids. Significant pharmacokinetic and pharmacodynamic changes that occur with advancing age increase the risk of adverse effects of opioids. There are also some discrepancies between guidelines, which recommend the use of lower doses of opioids in older patients, and the findings in the literature which suggest that pain is often undertreated in this age group. It seems that there are significant variations in the tolerability of different opioid analgesics in older people. Morphine, fentanyl, oxycodone, and buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for these patients. However, the safety and efficacy of other opioids in older patients, especially if comorbidities and polypharmacy are present, is still questionable. This review addresses the most important aspects of the use of opioids in older persons, focusing on pharmacokinetics, pharmacodynamics, adverse effects, and interactions.

Experience with developing antibiotic stewardship programmes in Serbia: potential model for other Balkan countries?

AIM Antimicrobial resistance and inappropriate use of antibiotics in children are important issues. Consequently, there is a need to develop comprehensive stewardship programs even in hospitals with limited resources starting with childrens hospitals. METHODS Retrospective observational analysis of antimicrobial utilization and resistance patterns over 5 years in a tertiary care childrens hospital in Serbia. RESULTS Cumulative antimicrobial resistance decreased but was still high, with high cumulative resistance rates among the most widely used antibiotics in the hospital. Total antibiotic use decreased from 2010 to 2014 although there was still high prescribing of reserved antibiotics. CONCLUSION Concerns with inappropriate use and high resistance rates among some antibiotics used in the hospital are being used to develop guidance on future antibiotic use in this hospital, building on the recently introduced antibiotic stewardship program, as well as encourage other hospitals in Serbia to review their policies.

Lithium – Pharmacological and Toxicological Aspects: The Current State of the Art

Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimers disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due its inhibition of glycogen synthase kinase 3 beta (GSK3β) which is included in regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc. Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well clinical studies in order to precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning pharmacological and toxicological effects of lithium.

The Effects of Nmda Antagonists On Morphine Induced Hyperthermia in Rats

Objectives NMDA receptor antagonists, are known for their anesthetic, analgesic and anti-shivering properties. This study is aimed at evaluating the effects of ketamine and magnesium sulphate on body temperature in rats, and to determine the type of interaction between them. Methods The body temperature was measured by insertion of a thermometer probe 5 cm into the colon of unrestrained male Wistar rats (200-250 g). Results Magnesium sulphate (5 and 60 mg/kg, sc) showed influence neither on baseline, nor on morphine-evoked hyperthermic response. Subanesthetic doses of ketamine (5-30 mg/kg, ip) given alone, produced significant dose-dependent reduction in both baseline colonic temperature and morphine-induced hyperthermia. Analysis of the log dose–response curves for the effects of ketamine and ketamine-magnesium sulphate combination on the baseline body temperature revealed synergistic interaction, and about 5.3 fold reduction in dosage of ketamine when the drugs were applied in fixed ratio (1:1) combinations. In addition, fixed low dose of magnesium sulphate (5 mg/kg, sc) enhanced the temperature lowering effect of ketamine (1.25-10 mg/kg, ip) on baseline body temperature and morphine-induced hyperthermia by factors of about 2.5 and 5.3, respectively. Conclusion This study is first to demonstrate the synergistic interaction between magnesium sulphate and ketamine in lowering morhine induced hyperthermia. It is possible that the synergy between ketamine and magnesium may have clinical relevance.

RAT SKELETAL MUSCLE CONTRACTILITY: THE ROLE OF BETA-ADRENOCEPTORS AND NITRIC OXIDE SYSTEM

Both beta-adrenoceptors and the nitric oxide system play a significant role in the modulation of skeletal muscle contractility. Skeletal muscle adrenoceptors mainly belong to beta2 subtype, while all three types of nitric oxide synthase may influence muscle contractility. The aim of our study was to investigate the possible interplay between beta-adrenoceptor agonists and nitric oxide system in the modulation of contractility of isolated rat hemidiaphragm. Adrenaline (0.05-1.5 mol/L) and noradrenaline (1-5 mol/L) given in a cumulative manner produced a concentration-related increase in Td. L-NAME (1, 3 and 10 mmol/L; 30 min of incubation) produced a significant, dose-dependent increase in Td of the muscle pretreated with cumulative concentrations of adrenaline (Td up to 16%). When hemidiaphragm was pretreated with noradrenaline instead of adrenaline, L-NAME (3 mmol/L) it produced a similar potentiation of Td. In conclusion, nitric oxide seems to oppose beta-adrenoceptor potentiation of diaphragm contractility, and such an interaction depends on previous adrenoceptor stimulation. Nitric oxide probably decreases beta-adrenoceptor response via cGMP-induced stimulation of phosphodiesterase 2. The interaction between substances which modulate NO system activity and cAMP levels in the skeletal muscle may be of a great clinical importance for the treatment of certain respiratory and neurological diseases.