Browsing by Author "Prostran, Milica (7004009031)"

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.

Disseminated fungal infections are still rare conditions, mostly caused by Candida spp. during immunosuppression. Infection of immunocompetent individuals is uncommon. Endocarditis is a rare manifestation during candidaemia, mostly in patients with prosthetic valves. Affection of previously unaltered valves is uncommon. We presented a case of a young, previously healthy female patient with endocarditis, caused by Candida parapsilosis. The initial symptom, fever, was present four months before hospital admittance. She was febrile without other symptoms and during observation in a local hospital. After her condition deteriorated, she was transferred to the Institute for infectious and tropical diseases, Belgrade. Clinical findings on admission include petechial skin rash and moderate hepatosplenomegaly. Newly developed systolic murmur was noted, and Candida parapsilosis was isolated in multiple blood cultures. Echocardiography revealed 15 × 14 mm vegetations on the right aortic vellum. She was treated with antifungal drugs (fluconasole, liposomal amphotericin B), and the affected valve was successfully replaced. The same strain of Candida parapsilosis was isolated from the intraoperative material of the valve. There were no markers of immunosuppression or other conditions which could affect the immune system. After a prolonged period of treatment she was successfully cured, and she received a long-term intermittent suppressive fluconasole therapy for the time being. © 2013 Pelemiš et al; licensee BioMed Central Ltd.

[No abstract available]

The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED) will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II) production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation. © 2016, Indian Council of Medical Research. All rights reserved.

Backgroun/Aim. Constant production of free radicals and antioxidants (AO) in cells is a part of normal cellular function. Their imbalance might take a part in pathophysiology of many diseases, including Parkinson's disease (PD). Evaluation of the disease status, prooxidant-antioxidant balance (PAB) and antioxidants are being widely estimated. The aim of this study was to examine potential interaction between several AO variables: glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and PAB, and clinicopathologic features of patients with PD, particularly the Hoehn and Yahr (H&Y) stage. Methods. A multivariate analysis of variance (MANOVA) was conducted to analyze mean differences between clinicopathologic characteristics (gender, age at examination, duration of the disease, and the H&Y stage) and AO variables of PD patients and those of age/sex matched healthy controls. The study included 91 patients with idiopatic PD patients and 20 healthy persons. Results. The multivariate effect size was estimated at 0.269 (p < 0.001), implying that 27.0% of the variance of the dependent variables was accounted for the H&Y stage. Univariate tests showed that there were significant differences (p < 0.001) across the H&Y stage of all AO variables. The H&Y stage remained significant predictor after controlling for the second variable, the disease duration (p < 0.001, η2 = 0.249), and there were still significant differences across the H&Y stage of all variables, with effect size (η2) ranging from 0.132 (p = 0.011) (lnGSH) to the still high values of 0.535 (lnPAB), 0.627 (lnSOD) and 0.964 (lnCAT). Conclusion. The results indicate that higher level of oxidative stress in blood of PD patients is possibly related to the PD stage. Along with reduction of SOD and GSH levels, CAT activity was elevated in comparison to these values in healthy subjects. Furthermore, PAB was shifted toward oxidative stress. © 2020 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

The aim of the study was to analyse the prevalence of polypharmacy with antipsychotic drugs and analyse types of coprescribing episodes at the University Psychiatric Hospital in Serbia. A sample of 120 patients (198 hospitalisations) was analysed. The prevalence of polypharmacy was calculated as the proportion of patients receiving two or more antipsychotic drugs concomitantly for at least 28 days. Total daily antipsychotic drug load was calculated as the number of defined daily doses (DDDs) of drugs per patient per day. It was compared between patients receiving monotherapy and patients receiving polypharmacy. Statistics was performed using standard statistical methods. Monotherapy was prescribed during 32.3% hospitalisations (n = 64), while polypharmacy was noted in 67.7% (n = 134). Polypharmacy with two drugs was observed during 126 (63.6%) hospitalisations and three antipsychotics were prescribed concomitantly during 8 (4.1%) hospitalisations. Patients' characteristics were not significantly different between patients who received only monotherapy and patients receiving polypharmacy. Patients on monotherapy had significantly more prior hospitalisations than patients from the other group (t = 3.94, df= 119, p < 0.001). The prevalence of polypharmacy patient episodes (67.7%) is approximately 100% higher than the prevalence observed in developed European countries. The explanation of such prescribing habit of Serbian psychiatrists requires further investigation. The only distinguishing factor between patients receiving monotherapy and patients receiving polypharmacy is the number of prior hospitalisations. © 2007 John Wiley & Sons, Ltd.

Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term 'medical cannabis' refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory. © 2018 Vučković, Srebro, Vujović, Vučetić and Prostran.

Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term 'medical cannabis' refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory. © 2018 Vučković, Srebro, Vujović, Vučetić and Prostran.

Recent findings have demonstrated that serotonin is an important participant in the development and progression of peripheral artery diseases. Taking this into consideration, the goals of this study were to investigate the effects of serotonin on isolated Wistar rat femoral arteries in both healthy and diabetic animals, with and without artery occlusion, with a particular focus on determining the role of calcium in this process. Contraction experiments with serotonin on intact and denuded femoral artery rings, in the presence or absence of nifedipine and ouabain (both separately, or in combination), as well as Ca2+-free Krebs-Ringer bicarbonate solution were performed. The serotonin-induced results were concentration dependent, but only in healthy animals. The endothelium-dependent contraction of the femoral artery was assessed. In healthy animals, the endothelium-reliant part of contraction was dependent on the extracellular calcium, while the smooth muscle-related part was instead dependent on the intracellular calcium. In diabetic animals, both nifedipine and ouabain influenced serotonin-induced vascular effects by blocking intracellular calcium pathways. However, this was diminished after the simultaneous administration of both blockers. © 2017 John Wiley & Sons Australia, Ltd

Recent findings have demonstrated that serotonin is an important participant in the development and progression of peripheral artery diseases. Taking this into consideration, the goals of this study were to investigate the effects of serotonin on isolated Wistar rat femoral arteries in both healthy and diabetic animals, with and without artery occlusion, with a particular focus on determining the role of calcium in this process. Contraction experiments with serotonin on intact and denuded femoral artery rings, in the presence or absence of nifedipine and ouabain (both separately, or in combination), as well as Ca2+-free Krebs-Ringer bicarbonate solution were performed. The serotonin-induced results were concentration dependent, but only in healthy animals. The endothelium-dependent contraction of the femoral artery was assessed. In healthy animals, the endothelium-reliant part of contraction was dependent on the extracellular calcium, while the smooth muscle-related part was instead dependent on the intracellular calcium. In diabetic animals, both nifedipine and ouabain influenced serotonin-induced vascular effects by blocking intracellular calcium pathways. However, this was diminished after the simultaneous administration of both blockers. © 2017 John Wiley & Sons Australia, Ltd

The choice of an antiepileptic drug (AED) is usually based upon the epileptic seizure type. However, pharmacokinetic (PK) characteristics of AEDs may be valuable support in choosing the optimal therapeutic option for the individual patient. The novel (second and third generation) AEDs include: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. Although, these drugs belong to the same group, their individual PK characteristics differ. Gabapentin, unlike other new AEDs, is characterised by dose-dependent absorption, which is presumably caused by saturable L-amino acid transport system, and therefore its bioavailability ranges from 35-60%. Furthermore, gabapentin, pregabalin and vigabatrin are eliminated completely, while levetiracetam and topiramate are eliminated predominantly through the renal system. Therefore, PK variability of these individual drugs is less pronounced and more predictable in comparison to older AEDs. Their potential for drug interactions is minor, and consequently they have major clinical importance for patients with impaired hepatic function. On the other hand, felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide are eliminated via metabolic pathways, either cytochrome P (CYP) 450, or conjugation dependent transformation. Oxcarbazepine is a prodrug, and its active metabolite is licarbazepine. These drugs interact with other drugs, and disease conditions, which alter the activity of metabolic enzymes; thus these changes in PK commonly have clinical implications. Gabapentin, levetiracetam and tiagabine do not induce or inhibit hepatic metabolism enzymes. Felbamate demonstrated an inducing effect on CYP 3A4 isoenzyme, and inhibition effect on CYP 2C19 and on β-oxidation of valproic acid. Lamotrigine induces its own metabolism, and some reports imply a decrease of valproic acid levels during concomitant treatment with lamotrigine. Oxcarbazepine induces CYP 3A4, 3A5, and uridine diphosphate glucuronyl transfereases (UGT), and inhibits the metabolism of phenytoin via CYP 2C19 isoenzyme. Similar induction and inhibition characteristics are attributed to topiramate, while some studies indicate that zonisamide may have inhibition potential on phenytoin metabolism. In general, novel AEDs have linear PK, low plasma protein binding, and renal elimination, so their PK is more favorable in comparison with carbamazepine, phenobarbitone and valproic acid. This chapter gives a review of PK parameters of novel AEDs and its' variability based on age, comorbidities, concomitant therapy, and highlights the need of therapeutic drug monitoring. © 2012 Nova Science Publishers, Inc. All rights reserved.

The choice of an antiepileptic drug (AED) is usually based upon the epileptic seizure type. However, pharmacokinetic (PK) characteristics of AEDs may be valuable support in choosing the optimal therapeutic option for the individual patient. The novel (second and third generation) AEDs include: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. Although, these drugs belong to the same group, their individual PK characteristics differ. Gabapentin, unlike other new AEDs, is characterised by dose-dependent absorption, which is presumably caused by saturable L-amino acid transport system, and therefore its bioavailability ranges from 35-60%. Furthermore, gabapentin, pregabalin and vigabatrin are eliminated completely, while levetiracetam and topiramate are eliminated predominantly through the renal system. Therefore, PK variability of these individual drugs is less pronounced and more predictable in comparison to older AEDs. Their potential for drug interactions is minor, and consequently they have major clinical importance for patients with impaired hepatic function. On the other hand, felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide are eliminated via metabolic pathways, either cytochrome P (CYP) 450, or conjugation dependent transformation. Oxcarbazepine is a prodrug, and its active metabolite is licarbazepine. These drugs interact with other drugs, and disease conditions, which alter the activity of metabolic enzymes; thus these changes in PK commonly have clinical implications. Gabapentin, levetiracetam and tiagabine do not induce or inhibit hepatic metabolism enzymes. Felbamate demonstrated an inducing effect on CYP 3A4 isoenzyme, and inhibition effect on CYP 2C19 and on β-oxidation of valproic acid. Lamotrigine induces its own metabolism, and some reports imply a decrease of valproic acid levels during concomitant treatment with lamotrigine. Oxcarbazepine induces CYP 3A4, 3A5, and uridine diphosphate glucuronyl transfereases (UGT), and inhibits the metabolism of phenytoin via CYP 2C19 isoenzyme. Similar induction and inhibition characteristics are attributed to topiramate, while some studies indicate that zonisamide may have inhibition potential on phenytoin metabolism. In general, novel AEDs have linear PK, low plasma protein binding, and renal elimination, so their PK is more favorable in comparison with carbamazepine, phenobarbitone and valproic acid. This chapter gives a review of PK parameters of novel AEDs and its' variability based on age, comorbidities, concomitant therapy, and highlights the need of therapeutic drug monitoring. © 2012 Nova Science Publishers, Inc. All rights reserved.

[No abstract available]

[No abstract available]

Third degree atrioventricular (AV) heart block with severe Adams-Stokes attacks in 3 patients with Lyme borreliosis is described. All patients had similar clinical manifestations: previously healthy, they experienced syncope as an abrupt onset of the disease. Data on skin changes – erythema migrans – was subsequently obtained, although the patients did not recall being bitten by a tick. Diagnoses were based on clinical manifestations and on positive serologic test results to borrelia. Following AV block returned to sinus rhythm with normal AV conduction in all patients. © 1996 S. Karger AG, Basel.

Aim. To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Methods. Serumlevels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- And age-matched healthy children. Results. Meanvalproic acid treatment durationwas 2.80?}1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. Conclusion. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment.

Aim. To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Methods. Serumlevels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- And age-matched healthy children. Results. Meanvalproic acid treatment durationwas 2.80?}1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. Conclusion. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment.

Background: Tianeptine, a new generation antidepressant, possesses a unique mechanism of antidepressive action and has a specific pharmacokinetic profile. The aim of this study was to determine the efficacy, tolerability and safety of tianeptine in a "fragile" population of depressive patients: (1) a group of elderly patients and (2) a group with comorbid alcohol addiction. Subjects and methods: This was an open multicentric eight-week study of tianeptine efficacy, tolerability and safety including patients with mild to moderate depression (DSM-IV), age ≥55 years (group 1; n=45) or with comorbid alcohol addiction (group 2; n=32). Assessments was made with the following rating scales; MADRS, HAM-A and CGI for efficacy and DESS for tolerability. Results: After eight-week tianeptine therapy, remission (MADRS ≤12) was established in 51.1% and 84.4%patients, respectively. On day 7, the therapy led to a significant decrease of MADRS. On endpoint, there were significant differences on HAM-A, CGI-I and CGI-S scores (p<0.01). No adverse effects with frequency ≥ 10%, were registered. A lower tolerability of tianeptine was registered in a group of elderly (nausea 4.5%, leg fatigue 4.4%, irritability 2.2%, bursts of crying and sadness 2.2%), while only 3.1% depressive patients with comorbid alcohol addiction had dizziness. Conclusion: This is the first clinical study to evaluate tolerability, efficacy and safety of tianeptine in a special population of depressive patients in the region. The study showed that tianeptine had good efficacy in treatment of mild to moderate forms of depression in special populations of depressive patients (elderly population and patients with comorbid alcohol addiction). The drug was well tolerated. © Medicinska naklada.

Background: Inflammatory pain is the most commonly treated clinical pain, since it develops following trauma or surgery, and accompanies rheumatic or arthritic diseases. Tramadol is one of the most frequently used opioid analgesics in acute and chronic pain of different origin. Magnesium is a widely used dietary supplement that was recently shown to be a safe analgesic drug in different models of inflammatory pain. Aim: This study aimed to evaluate the effects of systemically or locally injected tramadol with/without systemically injected magnesium sulfate in prophylactic or therapeutic protocols of application in a rat model of somatic inflammation. Methods: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 ml, 0.5%). The antihyperalgesic/antiedematous effects of tramadol (intraperitoneally or intraplantarly injected), and tramadol-magnesium sulfate (subcutaneously injected) combinations were assessed by measuring the changes in paw withdrawal thresholds or paw volume induced by carrageenan. The drugs were administered before or after inflammation induction. Results: Systemically administered tramadol (1.25-10 mg/kg) before or after induction of inflammation reduced mechanical hyperalgesia and edema with a maximal antihyperalgesic/antiedematous effect of about 40-100%. Locally applied tramadol (0.125 mg/paw) better reduced edema (50-100%) than pain (20-50%) during 24 h. Administration of a fixed dose of tramadol (1.25 mg/kg) with different doses of magnesium led to a dose-dependent enhancement and prolongation of the analgesic effect of tramadol both in prevention and treatment of inflammatory pain. Magnesium increases the antiedematous effect of tramadol in the prevention of inflammatory edema while reducing it in treatment. Conclusion: According to results obtained in this animal model, systemic administration of low doses of tramadol and magnesium sulfate given in combination is a potent, effective and relatively safe therapeutic option for prevention and especially therapy of somatic inflammatory pain. The best result is achieved when tramadol is combined with magnesium sulfate at a dose that is equivalent to the average human recommended daily dose and when the drugs are administered when inflammation is maximally developed. Copyright © 2018 Srebro, Vučković, Milovanović, Savić Vujović and Prostran.