Effect of regional vs general anesthesia on vital functions after cesarean section: a single center experience.

BACKGROUND: The aim was to determine the effect of regional anesthesia (RA) on postoperative vital functions in contrast to general endotracheal anesthesia (GEA) after the cesarean section. METHODS: Prospective cohort study included consecutive term pregnant women delivered by cesarean section (GEA, n = 284; RA, n = 249). RESULTS: Higher levels of blood pressure and heart rate, as well as lower levels of pulse oximetry were found for GEA in contrast to RA (p < 0.001). The application of RA presented less side-effects (p < 0.05). CONCLUSIONS: RA for cesarean section should be preferred when balancing the risks and benefits for the mother and fetus.

Use of Anticoagulant Therapy in Patients with Acute Myocardial Infarction and Atrial Fibrillation.

The incidence of atrial fibrillation (AF) in acute coronary syndrome (ACS) ranges from 2.3-23%. This difference in the incidence of AF is explained by the different ages of the patients in different studies and the different times of application of both reperfusion and drug therapies in acute myocardial infarction (AMI). About 6-8% of patients who underwent percutaneous intervention within AMI have an indication for oral anticoagulant therapy with vitamin K antagonists or new oral anticoagulants (NOAC).The use of oral anticoagulant therapy should be consistent with individual risk of bleeding as well as ischemic risk. Both HAS-BLED and CHA2DS2VASc scores are most commonly used for risk assessment. Except in patients with mechanical valves and antiphospholipid syndrome, NOACs have an advantage over vitamin K antagonists (VKAs). One of the advantages of NOACs is the use of fixed doses, where there is no need for successive INR controls, which increases the patient's compliance in taking these drugs. The use of triple therapy in ACS is indicated in the case of patients with AF, mechanical valves as well as venous thromboembolism. The results of the studies showed that when choosing a P2Y12 receptor blocker, less potent P2Y12 blockers such as Clopidogrel should be chosen, due to the lower risk of bleeding. It has been proven that the presence of AF within AMI is associated with a higher degree of reinfarction, more frequent stroke, high incidence of heart failure, and there is a correlation with an increased risk of sudden cardiac death. With the appearance of AF in ACS, its rapid conversion into sinus rhythm is necessary, and in the last resort, good control of heart rate in order to avoid the occurrence of adverse clinical events.

Comparison of Post-Cesarean Pain Perception of General Versus Regional Anesthesia, a Single-Center Study.

Background and Objectives: Pain during and after the procedure remains the leading concern among women undergoing cesarean section. Numerous studies have concluded that the type of anesthesia used during a cesarean section undoubtedly affects the intensity and experience of pain after the operation. Materials and Methods: This prospective cohort study was conducted at the Clinic for Gynecology and Obstetrics, Clinical Center "Dragisa Misovic-Dedinje", Belgrade, Serbia. Patients at term pregnancy (37-42 weeks of gestation) with an ASA I score who delivered under general (GEA) or regional anesthesia (RA) by cesarean section were included in the study. Following the procedure, we assessed pain using the Serbian McGill questionnaire (SF-MPQ), Visual Analogue Scale (VAS) and the pain attributes questionnaire at pre-established time intervals of 2, 12, and 24 h after the procedure. Additionally, time to patient's functional recovery was noted. We also recorded the time to the first independent mobilization, first oral intake, and lactation establishment. Results: GEA was performed for 284 deliveries while RA was performed for 249. GEA had significantly higher postoperative sensory and affective pain levels within intervals of 2, 12, and 24 h after cesarean section. GEA had significantly higher postoperative VAS pain levels. On pain attribute scale intensity, GEA had significantly higher postoperative pain levels within all intervals. Patients who received RA had a shorter time to first oral food intake, first independent mobilization, and faster lactation onset in contrast to GEA. Conclusions: The application of RA presented superior postoperative pain relief, resulting in earlier mobilization, shorter time to first oral food intake, and faster lactation onset in contrast to GEA.

Interactions between Ketamine and Magnesium for the Treatment of Pain: Current State of the Art.

BACKGROUND: Over the past three decades, NMDA-receptor antagonists have been shown to be efficient drugs for treating pain, particularly pain resistant to conventional analgesics. Emphasis will be on the old-new drugs, ketamine and magnesium, and their combination as a novel approach for treating chronic pain. METHODS: The MEDLINE database was searched via PubMed for articles that were published up to March 1, 2020, with the keywords 'ketamine', 'magnesium', and 'pain' (in the title/abstract). RESULTS: Studies in animals, as well as humans, have shown that interactions of ketamine and magnesium can be additive, antagonistic, and synergistic. These discrepancies might be due to differences in magnesium and ketamine dosage, administration times, and the chronological order of drug administration. Different kinds of pain can also be the source of divergent results. CONCLUSION: This review explains why studies performed with a combination of ketamine and magnesium have given inconsistent results. Because of the lack of efficacy of drugs available for pain, ketamine and magnesium in combination provide a novel therapeutic approach that needs to be standardized with a suitable dosing regimen, including the chronological order of drug administration.

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 the 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, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3ß) which is included in the 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 as clinical studies in order to a 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 the pharmacological and toxicological effects of lithium.

Pioglitazone attenuates kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats.

Gentamicin, belonging to the aminoglycosides, possesses the greatest nephrotoxic effect of all other antibiotics from this group. On the other hand, pioglitazone, which represents peroxisome proliferator-activated receptor γ (PPARγ) agonist recently showed antiinflamatory, antioxidative effects, amelioration of endothelial dysfunction etc. Therefore, the goal of our study was to investigate the effects of pioglitazone on kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats. These effects were observed by following values of biochemical (serum urea and creatinine) parametars, total histological kidney score, urine level of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) as well as parametars of oxidative stress (malondialdehyde, superoxide dismutase, catalase, total oxidant status, total antioxidant status, oxidative stress index and advanced oxidation protein products). It seems that pioglitazone protects the injured rat kidney in a U-shaped manner. Medium dose of pioglitazone (1 mg/kg, i.p.) was protective regarding biochemical (serum urea and creatinine), total histological score and the values of kidney injury molecule-1 (KIM-1) (P < 0.05 vs. control group, i.e. rats injected with gentamicin only). This finding could be of great importance for the wider use of aminoglycosides, with therapy that would reduce the occurrence of serious adverse effects, such as nephrotoxicity and acute renal failure.

Involvement of serotonergic and opioidergic systems in the antinociceptive effect of ketamine-magnesium sulphate combination in formalin test in rats.

BACKGROUND: Ketamine and magnesium sulphate showed synergic interaction in the tail-immersion test and additive interaction in the rat formalin test. Aim of study was to evaluate the influence of serotonergic and opioidergic system of this combination in the formalin test in rats. METHODS: Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Antagonists (naloxone and methysergide) were administrated 5 min before and magnesium sulphate 5 min after ketamine injection. Formalin (2.5%, 100 µL) was injected into the right hind paw surface (intraplantar) of rats 5 min after ketamine/magnesium combination. Data were recorded as the total time spent in pain related behavior after the injection of formalin or vehicle (0.9% NaCl). RESULTS: In the intermediate phase of the formalin test, methysergide at a dose of 0.2 mg/kg did not have any effect, but at doses of 0.5 and 1 mg/kg it had a pronociceptive effect. Methysergide (0.2, 0.5 and 1 mg/kg) inhibited the antinociceptive effect of ketamine-magnesium sulphate combination. In the intermediate phase, naloxone at a dose of 0.2 mg/kg did not have any effect, but at a dose of 3 mg/kg it produced a pronociceptive effect. Naloxone (0.2 and 3 mg/kg) antagonized the antinociceptive effect of the ketamine (5 mg/kg)-magnesium sulphate (5 mg/kg) combination. CONCLUSION: The results of the present study suggest that serotonergic and opioidergic systems are involved, at least in part, in the antinociceptive effect of the ketamine-magnesium sulphate combination in the model of inflammatory pain in rats.

Experience with developing antibiotic stewardship programs 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 children's hospitals. METHODS: Retrospective observational analysis of antimicrobial utilization and resistance patterns over 5 years in a tertiary care children's 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.

The Efficacy and Safety of Antipsychotic Medications in the Treatment of Psychosis in Patients with Parkinson's Disease.

Psychotic symptoms are present in up to 50% of patients with Parkinson's disease. These symptoms have detrimental effects on patients' and caregivers' quality of life and may predict mortality. The pathogenesis of psychotic symptoms in Parkinson's disease is complex, but the use of dopaminergic medications is one of the risk factors. The treatment of psychotic symptoms in Parkinson's disease is complicated due to the ability of antipsychotic medications to worsen motor symptoms. The efficacy of clozapine in the treatment of psychosis in patients with Parkinson's disease has been confirmed in several clinical trials; however, the adverse effects and the necessity of blood count monitoring are the reasons why the use of this drug is challenging. The studies on safety and efficacy of other antipsychotics conflicting results. The use of antipsychotics in these patients is also associated with increased mortality. Psychotic symptoms in Parkinson's disease per se are also proven predictors of mortality. Thus it is necessary to treat psychotic symptoms but the choice of an antipsychotic should be based on careful risk/benefit assessment. Pimavanserin as a novel therapeutic option with more favorable adverse effects profile is now available for this indication, but careful postmarketing monitoring is necessary to establish the true picture of this drug's long-term safety and efficacy.

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.

Prenatal diagnosis of lissencephaly: A case report.

INTRODUCTION: Lissencephaly ("smooth brain") forms a major group of brain malformations due to abnormal neuronal migration. It can cause severe intellectual and motor disability and epilepsy in children. The prenatal diagnosis of this malformation is rare. CASE REPORT: We presented a case of the prenatal diagnosis of lissencephaly. A 30-year-old pregnant woman was reffered to the hospital at the week 35 of gestation for magnetic resonance imaging (MRI after an ultrasound examination demonstrated fetal cerebral ventriculomegaly. Fetal MRI of the brain showed "smooth", agyrya cortex. The female infant was born at term with birth weight of 2,500 g and Apgar score 8, showing global developmental delay. Postnatal ultrasound and MRI confirmed classical lissencephaly. She is now 8 years old and has spastic quadriparesis, mental retardation and epilepsy. CONCLUSION: Confirmation of the ultrasound diagnosis with MRI is desirable for the prenatal diagnosis of lissencephaly.

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. ß-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.

The attitudes of medical students towards rare diseases: A cross-sectional study.

Background/Aim: Rare diseases are chronic, degenerative and may lead to permanent disability. We aimed to assess knowledge and attitudes of the 3rd and 6th year medical students towards the treatment of rare diseases in Serbia. Methods. In this cross-sectional study, two samples of students were questioned for a survey: 350/446 (78.48%) students of the 3rd year, and 242/517 (46.81%) students of the 6th year. Methods: In this cross-sectional study, two samples of students were questioned for a survey: 350/446 (78.48%) students of the 3rd year, and 242/517 (46.81%) students of the 6th year. Results: Sixth year students estimated that they were more informed on the issue analyzed than the 3rd year students (median value of 4 and 3, interquartile range of 3-5, and 1-4, respectively; p < 0.05). However, a significant percentage of participants estimated incorrectly the prevalence of rare diseases according to the European Union standards (3rd year - 42.68%, 6th year - 49.55%). Core curriculum subjects were the main source of information on rare diseases (3rd year - 63.14%; 6th year - 92.14%). Our participants agreed that the most important problems are the following: high drug prices, difficult access to drugs and lack of public information. Students found, without any differences, that community access to effective drugs for rare disease should be improved (median value - 10, interquartile range 8-10 in both groups, p < 0.05). In order to improve pharmacotherapy of rare diseases in Serbia, the participants suggested establishment of a National Plan for Rare Diseases, approval of more appropriate drugs, simplified access to appropriate medicines, and more rapid diagnostics. Conclusion: It is necessary to improve the knowledge and attitudes of medical students towards pharmacotherapy of rare diseases. [Projekat Ministarstva nauke Republike Srbije, br. 175023]

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.

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 protective effects of simvastatin in the rat model of renal ischemia-reperfusion injury: it is never too late for the pretreatment.

Acute pretreatment with a single i.v. bolus injection of simvastatin (1 mg/kg) significantly protects rat kidney injured by ischemia-reperfusion (I/R) (45 min + 6 h). We aimed to determine the optimal timing of such a pretreatment. The effects of both injections of simvastatin before ischemia and reperfusion were similar regarding total histological score. However, simvastatin injected 30 min before ischemia was 30% - 75% more effective in reduction of serum creatinine levels and interstitial edema score, while its injections 5 and 30 min before reperfusion were 25% - 60% more effective in reduction of tubular necrosis score and fractional excretion of Na+. However, the observed differences do not seem to offer significant advantage in clinical settings.

Type of electrical stimulation influences diaphragm response to adrenoceptor and calcium channel modulators: the role of extracellular and intracellular calcium events.

The influence of direct single pulse and subtetanic electrical stimulation (ES) on isolated rat hemidiaphragm response to adrenoceptor antagonists and calcium channel blockers was investigated. Muscle contractility was stimulated by cumulative micromolar noradrenaline. Noradrenaline effects on developed tension (Td) in the presence of various alpha- and beta-adrenoceptor antagonists (e.g., prazosin and ICI 118551) were qualitatively different during different types of ES. Also, intact L-voltage calcium channels were necessary for noradrenaline-induced potentiation of Td during both types of ES, while the balance between ryanodine receptors- and inositol triphosphate (IP3)-related calcium events in the muscle was influenced by the pattern of the ES.

Single-dose intravenous simvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in the rat.

The effect of acute pretreatment with a single dose of simvastatin (1 mg/kg, i.v.; 30 min before ischemia) on renal dysfunction caused by ischemia-reperfusion (I/R) injury in the rat was investigated. I/R injury was induced by clamping both renal vascular pedicles for 45 min, followed by 4 h of reperfusion with saline (2 ml/kg per hour). Simvastatin significantly improved both parameters of glomerular and tubular dysfunction (e.g., creatinine levels and fractional excretion of Na(+), respectively) and especially improved the histological score, compared to control I/R-injured rats treated with saline or 10% DMSO only.

Temporal variations at the onset of spontaneous acute aortic dissection.

There have only been a few studies of the chronobiological occurrence of acute aortic dissection (AAD), and most were international and multicentered. The aim of the present study, conducted at only one center, was to determine the most frequent daily, monthly, and seasonal occurrences of AAD. The study population included 204 patients (66.5% male) treated at our institute between January 1, 1998 and January 1, 2004. A significantly higher frequency of AAD occurred from 6:00 AM to 12:00 noon, compared with other time periods (P < 0.001). The results showed a significant circadian variation in AAD (P < 0.001) with a peak between 9:00 AM and 10:00 AM. No significant variation was found for the day of the week; however, AAD occurred most frequently on Wednesday and Monday. The frequency of AAD was found to be significantly higher during winter versus other seasons (P < 0.001). The analysis of monthly variations of the onset of AAD confirmed a peak in February (12.9%) and in January (12.3%). Similar to other cardiovascular diseases, AAD exhibits significant circadian and seasonal/monthly variations. Our findings indicate that the prevention of AAD, especially during the aforementioned vulnerable periods, is possible by adequate tailoring of the treatment of hypertension, which is the main AAD predisposing factor.