Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer-A Prospective Pilot Study.

BACKGROUND AND OBJECTIVES: The objective of this research was to analyze the correlation of the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), soluble programmed cell death ligand 1 (sPD-L1), and Schlafen 11 (SLFN11) with the response to first-line chemotherapy in a cohort of small cell lung cancer (SCLC) patients, and to determine their potential as predictive serum biomarkers. MATERIALS AND METHODS: A total of 60 SCLC patients were included. Blood samples were taken to determine CRP, sPD-L1, and SLFN11 levels. The first sampling was performed before the start of chemotherapy, the second after two cycles, and the third after four cycles of chemotherapy. RESULTS: The patients who died earlier during the study had NLR and SLFN11 concentrations significantly higher compared to the survivor group. In the group of survivors, after two cycles of chemotherapy, the NLR ratio decreased significantly (p < 0.01), but after four cycles, the NLR ratio increased (p < 0.05). Their serum SLFN11 concentration increased significantly (p < 0.001) after two cycles of chemotherapy, but after four cycles, the level of SLFN11 fell significantly (p < 0.01). CRP, NLR, and SLFN11 were significant predictors of patient survival according to Kaplan-Meier analysis. The combination of inflammatory parameters and SLFN11 with a cutoff value above the 75th percentile of the predicted probability was associated with significantly lower overall survival in SCLC patients (average survival of 3.6 months vs. 4.8 months). CONCLUSION: The combination of inflammatory markers and the levels of two specific proteins (sPD-L1, SLFN11) could potentially serve as a non-invasive biomarker for predicting responses to DNA-damaging therapeutic agents in SCLC.

In Vitro Antibiofilm Effect of N-Acetyl-L-cysteine/Dry Propolis Extract Combination on Bacterial Pathogens Isolated from Upper Respiratory Tract Infections.

Bacterial biofilms play an important role in the pathogenesis of chronic upper respiratory tract infections. In addition to conventional antimicrobial therapy, N-acetyl-L-cysteine (NAC) and propolis are dietary supplements that are often recommended as supportive therapy for upper respiratory tract infections. However, no data on the beneficial effect of their combination against bacterial biofilms can be found in the scientific literature. Therefore, the aim of our study was to investigate the in vitro effect of N-acetyl-L-cysteine (NAC) and dry propolis extract in fixed combinations (NAC/dry propolis extract fixed combination) on biofilm formation by bacterial species isolated from patients with chronic rhinosinusitis, chronic otitis media, and chronic adenoiditis. The prospective study included 48 adults with chronic rhinosinusitis, 29 adults with chronic otitis media, and 33 children with chronic adenoiditis. Bacteria were isolated from tissue samples obtained intraoperatively and identified using the MALDI-TOF Vitek MS System. The antimicrobial activity, synergism, and antibiofilm effect of NAC/dry propolis extract fixed combination were studied in vitro. A total of 116 different strains were isolated from the tissue samples, with staphylococci being the most frequently isolated in all patients (57.8%). MICs of the NAC/dry propolis extract fixed combination ranged from 1.25/0.125 to 20/2 mg NAC/mg propolis. A synergistic effect (FICI ≤ 0.5) was observed in 51.7% of strains. The majority of isolates from patients with chronic otitis media were moderate biofilm producers and in chronic adenoiditis they were weak biofilm producers, while the same number of isolates in patients with chronic rhinosinusitis were weak and moderate biofilm producers. Subinhibitory concentrations of the NAC/propolis combination ranging from 0.625-0.156 mg/mL to 10-2.5 mg/mL of NAC combined with 0.062-0.016 mg/mL to 1-0.25 mg/mL of propolis inhibited biofilm formation in all bacterial strains. Suprainhibitory concentrations ranging from 2.5-10 mg/mL to 40-160 mg/mL of NAC in combination with 0.25-1 mg/mL to 4-16 mg/mL of propolis completely eradicated the biofilm. In conclusion, the fixed combination of NAC and dry propolis extract has a synergistic effect on all stages of biofilm formation and eradication of the formed biofilm in bacteria isolated from upper respiratory tract infections.

Oxidative Stress and Inflammation Biomarkers in Postoperative Pain Modulation in Surgically Treated Patients with Laryngeal Cancer-Pilot Study.

(1) Background: Surgical treatment of laryngeal carcinoma includes different types of laryngectomies with neck dissection. Surgical tissue damage triggers an inflammatory response, leading to the release of pro-inflammatory molecules. This increases reactive oxygen species production and decreases antioxidant defense mechanisms, leading to postoperative oxidative stress. The aim of this study was to assess the correlation between oxidative stress (malondialdehyde, MDA; glutathione peroxidase, GPX; superoxide dismutase, SOD) and inflammation (interleukin 1, IL-1; interleukin-6, IL-6; C-reactive protein, CRP) parameters and postoperative pain management in patients surgically treated with laryngeal cancer. (2) Methods: This prospective study included 28 patients with surgically treated laryngeal cancer. Blood samples were taken for the analysis of oxidative stress and inflammation parameters before the operative treatment and after the operative treatment (1st postoperative day and 7th postoperative day). The concentrations of MDA, SOD, GPX, IL-1, IL-6, and CRP in the serum were determined by coated enzyme-linked immunosorbent assay (ELISA). The visual analog scale (VAS) was used for pain assessment. (3) Results and conclusion: There was a correlation between oxidative stress and inflammation biomarkers and postoperative pain modulation in surgically treated patients with laryngeal cancer. Age, more extensive surgery, CRP values, and use of tramadol were predictors for oxidative stress parameters.

Buffered Versus Nonbuffered Local Anesthetics and Local Pain Scores in Upper Eyelid Blepharoplasty: Randomized Controlled Trial.

PURPOSE: This split-face study aimed to see whether different types of local anesthetics or their buffered/nonbuffered combinations produce lower pain scores in upper eyelid blepharoplasty. METHODS: The study involved 288 patients, randomly divided into 9 groups: 1) 2% lidocaine with epinephrine-Lid + Epi; 2) 2% lidocaine with epinephrine and 0.5% bupivacaine (1:1)-Lid + Epi + Bupi; 3) 2% lidocaine with 0.5% bupivacaine (1:1)-Lid + Bupi; 4) 0.5% bupivacaine-Bupi; 5) 2% lidocaine-Lid; 6) 4% articaine hydrochloride with epinephrine-Art + Epi; 7) buffered 2% lidocaine/epinephrine with sodium bicarbonate (SB) in a 3:1 ratio-Lid + Epi + SB; 8) buffered 2% lidocaine with SB in a 3:1 ratio-Lid + SB; 9) buffered 4% articaine hydrochloride/epinephrine with SB in a 3:1 ratio-Art + Epi + SB. Following the injection of the first eyelid and a 5-minute period of soft pressure on the injection site, patients were asked to rate their pain level on the Wong-Baker Face Pain Rating Visual Analogue Scale. Rating of the pain level was repeated 15 and 30 minutes following anesthetic administration. RESULTS: The lowest pain scores at the first time point were observed in Lid + SB when compared with all of the other groups ( p < 0.05). At the final time point, significantly lower scores were also observed in Lid + SB, Lid + Epi + SB, and Art + Epi + SB when compared with the Lid + Epi group ( p < 0.05). CONCLUSION: These findings could help surgeons select an appropriate combination of local anesthetics, particularly in patients with lower pain threshold and tolerance because buffered combinations of local anesthetics produce significantly lower pain scores compared with nonbuffered solutions.

The Interactions of Magnesium Sulfate and Cromoglycate in a Rat Model of Orofacial Pain; The Role of Magnesium on Mast Cell Degranulation in Neuroinflammation.

Mast cell degranulation impacts the development of pain and inflammation during tissue injury. We investigated the antinociceptive effect of a combination of cromoglycate and magnesium in the orofacial model of pain and the histological profile of the effect of magnesium in orofacial pain. In male Wistar rats, formalin (1.5%, 100 µL) was injected subcutaneously into the right upper lip of rats after cromoglycate and/or magnesium. Pain was measured as the total time spent on pain-related behavior. Toluidine blue staining was used to visualize mast cells under the light microscope. In the formalin test, in phase 1, magnesium antagonized the antinociceptive effect of cromoglycate, while in phase 2, it potentiated or inhibited its effect. Magnesium significantly reduced mast cell degranulation in the acute phase by about 23% and in the second phase by about 40%. Pearson's coefficient did not show a significant correlation between mast cell degranulation and pain under treatment with magnesium. The cromoglycate-magnesium sulfate combination may prevent the development of inflammatory orofacial pain. The effect of a combination of cromoglycate-magnesium sulfate depends on the nature of the pain and the individual effects of the drugs. Magnesium reduced orofacial inflammation in the periphery, and this effect did not significantly contribute to its analgesic effect.

Magnesium Sulfate Reduces Carrageenan-Induced Rat Paw Inflammatory Edema Via Nitric Oxide Production.

Background: Magnesium is an antagonist of the N-methyl-D-aspartate receptor. This study aimed to investigate the anti-edematous effect of magnesium sulfate (MS) in different protocols of use and the possible mechanism of its action. Methods: In a rat model of carrageenan-induced paw inflammation, the anti-edematous activity of MS was assessed with a plethysmometer. The effects of the nonselective inhibitor (L-NAME), selective inhibitor of neuronal (L-NPA) and inducible (SMT) nitric oxide synthase on the effects of MS were evaluated. Results: MS administered systemically before or after inflammation reduced edema by 30% (5 mg/kg, P < .05) and 55% (30 mg/kg, P < .05). MS administered locally (.5 mg/paw, P < .05) significantly prevented the development of inflammatory edema by 60%. L-NAME, intraperitoneally administered before MS, potentiated (5 mg/kg, P < .05) or reduced (3 mg/kg, P < .05), while in the highest tested dose L-NPA (2 mg/kg, P < .01) and SMT (.015 mg/kg, P < .01) reduced the anti-edematous effect of MS. Conclusions: Magnesium is a more effective anti-edematous drug in therapy than for preventing inflammatory edema. The effect of MS is achieved after systemic and local peripheral administration and when MS is administered as a single drug in a single dose. This effect is mediated at least in part via the production of nitric oxide.

Ketamine, an Old-New Drug: Uses and Abuses.

Ketamine as an old-new drug has a variety of clinical implications. In the last 30 years, ketamine has become popular for acute use in humans. Ketamine in standard doses is principally utilized for the induction and maintenance of surgical procedures. Besides its use in anesthesia and analgesia, recent studies have shown that ketamine has found a place in the treatment of asthma, epilepsy, depression, bipolar affective disorders, alcohol and heroin addiction. Ketamine primarily functions as a noncompetitive antagonist targeting the N-methyl-D-aspartate (NMDA) receptor, but its mechanism of action is complex. It is generally regarded as safe, with low doses and short-term use typically not leading to significant adverse effects. Also, ketamine is known as a powerful psychostimulant. During the past decade, ketamine has been one of the commonly abused drugs.

Biomarkers and Predictors of Adverse Cardiovascular Events in Different Stages of Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important factor that contributes to the increase of all-cause morbidity and mortality in the group of non-communicable diseases, and it is also recognized as a strong and independent risk factor that contributes to cardiovascular disease (CVD). CVDs are a consequence of the action of a large number of risk factors among which are traditional and non-traditional. These risk factors have been the subject of a large number of studies which partially explained the unfavorable cardiovascular (CV) outcome of CKD patients. Therefore, valid studies about clinical and biohumoral predictors are of particular importance, especially in the early stages of renal disease, that is, in patients with creatinine clearance below 60 ml/min/1.73 m2 when preventive measures are most effective. Among potential predictors of adverse CV outcome are biomarkers of inflammation (Interleukin-18-IL-18), oxidative stress (ischemia-modified albumin-IMA; superoxide dismutase-SOD), acute kidney injury (kidney injury molecule-1-KIM-1; neutrophil gelatinase-associated lipocalin-NGAL), and microribonucleic acids (specific microRNA-133a). In this review, we tried to confirm the relationship between risk factors of CKD and CVD and newer, less frequently examined biomarkers with the occurrence of incidental CV events in renal patients.

Evaluation of Clinical and Genetic Determinants of Treatment OutCome In EGFR Mutation Positive Advanced Lung Adenocarcinoma.

Background: The aim of this research was to evaluate clinical and low-cost genetic determinants of treatment outcome in EGFR mutation positive advanced lung adenocarcinoma patients. Material and Methods: EGFR mutation testing and EGFR 181946C>T genotyping were performed in 101 advanced lung adenocarcinoma patients using qRT-PCR and PCR-RFLP, respectively. Progression-free survival was defined as the time from the start of TKI therapy to date of progression, and overall survival as the time from diagnosis to death from any cause. Pain level was evaluated using a Numerical Rating Scale and the Verbal Descriptor Scale. Statistical significance was considered for P < .05. Results: Patients were treated with EGFR-TKIs for a period of 1-39months (median 9), with a median PFS of 12.0 months (10.4-13.6, CI 95%), and a median OS of 19.0 months (15.1-22.7, CI 95%). The presence of pain was significantly correlated with the existence of bone (P < .001) and adrenal glands metastases (P = .029). Genetic factors did not have a direct impact on pain management but had a significant effect on the response to TKIs leading to pain alleviation. Conclusions: EGFR mutation subtype and the EGFR 181946 C>T SNP had a significant effect on the response to TKI inducing an indirect anti-dolorous effect.

Chloroquine Attenuates Oxidative Stress in Gentamicin-Induced Nephrotoxicity in Rats.

The wider application of gentamicin is limited by potential adverse effects (nephrotoxicity and ototoxicity). The goal of our study was to investigate the effects of chloroquine on biochemical and oxidative stress parameters in gentamicin-induced nephrotoxicity in rats. Animals were randomly divided into 1 of 5 groups. First was Sham group (0.9% NaCl) (n = 8); second group received gentamicin (n = 8); while third (n = 8), fourth (n = 8) and fifth group (n = 8) received gentamicin and chloroquine in a dose of 0.3, 1 and 3 mg/kg, respectively. The urea and creatinine levels were significantly lower in chloroquine treated groups in doses of 0.3 mg/kg and 1 mg/kg (P < 0.001). Total oxidant status and the oxidative stress index showed significantly lower values in all chloroquine treated groups (P < 0.001; P < 0.005). Malondialdehyde was lower in chloroquine treatment in doses of 0.3 mg/kg (P < 0.005) and 3 mg/kg (P < 0.05). Chloroquine treatment markedly reduced the level of superoxide dismutase in doses of 1 mg/kg (P < 0.01) and 3 mg/kg (P < 0.05). Our study showed that chloroquine attenuates gentamicin-induced nephrotoxicity in rats regarding biochemical and oxidative stress parameters.

Correlation of Ionized Magnesium with the Parameters of Oxidative Stress as Potential Biomarkers in Patients with Anxiety and Depression: A Pilot Study.

Background: Magnesium (Mg) is the second most abundant intracellular cation. Ionized Mg is the only active form of Mg. The concentration of ionized Mg could be a potentially novel biomarker for anxiety and depression. Aim: The aim of this study was to assess the serum concentration of ionized Mg and its correlation with biomarkers of oxidative stress and inflammation in patients with anxiety and depression. Methods: In this study included 93 respondents were divided into 3 groups: C (control group-18 respondents); A (patients with anxiety disorder, dissociative/conversion disorders and somatoform disorders-36 patients); D (patients with depression-39 patients). Clinical diagnosis was based on ICD-10 criteria. Blood samples were used for standard laboratory analysis, ionized Mg analysis, oxidative stress, and inflammatory parameters. Results: Statistical significance was recorded between healthy volunteers and patients (anxiety/depression) in ionized Mg values. In anxious patients, malondialdehyde (MDA) had a positive correlation between the parameters of oxidative stress with ionized Mg. In depressive patients, MDA had a positive correlation, and glutathione peroxidase 1 (GPX1) a negative correlation with the concentration of ionized Mg. Conclusion: Ionized Mg and its correlation with parameters of oxidative stress could be potential biomarkers in anxious and depressive patients.

Immune Cell and Biochemical Biomarkers in Advanced Laryngeal Cancer.

Objective: The aim of this study was to evaluate cell and biochemical biomarkers and establish their prognostic value in patients with advanced laryngeal cancer. Material and Methods: A prospective study included 52 patients with advanced laryngeal carcinoma surgically treated at the tertiary referral center. Tumor tissue was immunohistochemically stained for T-cell markers (CD4 and CD8), and levels of cytokines (IL-6 and IL-8) and C-reactive protein were analyzed from blood samples. Results: Overall 3-year survival (OS) of patients included in the study was 69.2% and the disease specific survival (DSS) 72.5%. Higher expression of CD4+ and CD8+ were significant prognostic factors with positive impact on both OS and DSS in univariate analysis, but not in multivariate analysis. Levels of IL-8 were a significant predictor of 3-year OS and DSS survival in patients with advanced laryngeal cancer but not levels of IL-6 and CRP values. Conclusion: Though high expression of CD4 and CD8 were demonstrated in the tumor tissue, but their prognostic role was not established. Higher values of IL-8 proved to be significant negative predictor of DSS. This could further collaborate the inclusion of combination of biomarkers in assessment of favorable treatment choice in patients with advanced laryngeal carcinoma.

Hematological parameters in EGFR-mutated advanced NSCLC patients treated with TKIs: predicting survival and toxicity.

Background: The aim of this study was to analyze the prognostic value of pre-treatment hematological parameters in EGFR-mutated non-small cell lung cancer patients treated with tyrosine-kinase inhibitors (TKIs).Patients and methods: Patients with EGFR mutations were treated with EGFR-TKIs in the first line until progression/unacceptable toxicity. Hematological parameters were derived from the absolute baseline differential counts of a complete blood count. The associations between the patients' and tumor characteristics were analyzed using Pearson Chi-Square, Fisher's exact, t-test, and Mann-Whitney tests. Cutoff values were determined using ROC curves, and correlation with survival was examined by Kaplan-Meier method and Cox regression.Results: Patients with NMR<12.62 had a longer PFS compared to patients with higher NMR values (12.0 vs. 10.0 months, p = 0.054) and a significantly longer OS (20.0 vs. 11.0 months, p = 0.010). The same parameter was confirmed as a predictors of favorable response in the patient subgroup with activating EGFR mutations. Patients with NLR>2.9 and LMR<2.5 more often presented with paronichia and diarrhea, and patients with PLR>190 more often had paronichia, diarrhea and hyperbilirubinemia.Conclusion: Low baseline value of the hematological parameter NMR has shown potential as a routine, low-cost, and minimally invasive predictor of survival in EGFR-TKI-treated NSCLC patients.

Synthesis and pharmacological evaluation of novel cis and trans 3-substituted anilidopiperidines.

BACKGROUND: 4-Anilidopiperidine class of synthetic opioid analgesics, with it's representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of µ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity. METHODS: The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl2. The antinociceptive activity of the synthesized compounds was determined by tail-immersion and formalin test. RESULTS: The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C3 of piperidine ring is designed. In addition, Hofmann rearrangement was substantially improved for the more efficient synthesis of previously published 3-substituted fentanyl analogs. The series of ten fentanyl analogs was tested in vivo for their antinociceptive activity. The most potent compound of the series was found to be cis-4, based on the determined ED50 values in tail-immersion test. CONCLUSION: Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.

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.

Pain Management After Surgical Tonsillectomy: Is There a Favorable Analgesic?

The aim of this study was to examine how ibuprofen and paracetamol prevent pain after cold-steel extracapsular tonsillectomy in children. Also, we examined the relation between age, gender, nausea, postoperative bleeding, antibiotic use, type of diet, and postoperative pain intensity and the type of administered analgesic. A prospective study was conducted on 147 children (95 males and 52 females, aged 7-17 years) who underwent tonsillectomy in the Clinical-Hospital Center "Dragisa Misovic" from January 1 to June 30, 2016. The degree of pain was measured using a visual analog scale (VAS). We did not observe any significant differences in postoperative nausea, hospitalization rate postoperative bleeding, and antibiotic use between the paracetamol and ibuprofen groups. A test of within-patient effects showed that VAS scores changed significantly during the postoperative follow-up period (P = .00), but there were no significant differences between the groups (P = .778). After 12 hours, 29.3% of the patients on paracetamol and 21.8% on ibuprofen were transferred to a soft diet; after 24 hours, 84.8% of the paracetamol group and 85.5% of the ibuprofen group were on a soft diet (χ2 test, P < .05). There was a statistically significant correlation between VAS scores measured 4 hours after the surgery and the time of transference to the soft diet (Spearman ρ test, P < .001). The transfer to soft and normal diets was not significantly different between the 2 groups as assessed by the VAS scores (Pearson χ2 test, P = .565).There is still no consensus on the most effective postoperative pain-control regiment after tonsillectomy. This study showed that satisfactory pain management was achieved equally with both paracetamol and ibuprofen.

Evaluation of Prophylactic and Therapeutic Effects of Tramadol and Tramadol Plus Magnesium Sulfate in an Acute Inflammatory Model of Pain and Edema in Rats.

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.

Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels.

BACKGROUND: In humans, orofacial pain has a high prevalence and is often difficult to treat. Magnesium is an essential element in biological a system which controls the activity of many ion channels, neurotransmitters and enzymes. Magnesium produces an antinociceptive effect in neuropathic pain, while in inflammatory pain results are not consistent. We examined the effects of magnesium sulfate using the rat orofacial formalin test, a model of trigeminal pain. METHODS: Male Wistar rats were injected with 1.5% formalin into the perinasal area, and the total time spent in pain-related behavior (face rubbing) was quantified. We also spectrophotometrically determined the concentration of magnesium and creatine kinase activity in blood serum. RESULTS: Magnesium sulfate administered subcutaneously (0.005-45mg/kg) produced significant antinociception in the second phase of the orofacial formalin test in rats at physiological serum concentration of magnesium. The effect was not dose-dependent. The maximum antinociceptive effect of magnesium sulfate was about 50% and was achieved at doses of 15 and 45mg/kg. Magnesium did not affect increase the levels of serum creatine kinase activity. CONCLUSIONS: Preemptive systemic administration of magnesium sulfate as the only drug can be used to prevent inflammatory pain in the orofacial region. Its analgesic effect is not associated with magnesium deficiency.

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.

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]