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.

Two distinct electrophysiological mechanisms underlie extensive depolarization elicited by 2,4 diaminobutyric acid in leech Retzius neurons.

Recent studies suggest that 2,4-DABA, a neurotoxic excitatory amino acid present in virtually all environments, but predominantly in aquatic ecosystems may be a risk factor for development of neurodegenerative diseases in animals and humans. Despite its neurotoxicity and potential environmental importance, mechanisms underlying the excitatory and putative excitotoxic action of 2,4-DABA in neurons are still unexplored. We previously reported on extensive two-stage membrane depolarization and functional disturbances in leech Retzius neurons induced by 2,4-DABA. Current study presents the first detailed look into the electrophysiological processes leading to this depolarization. Intracellular recordings were performed on Retzius neurons of the leech Haemopis sanguisuga using glass microelectrodes and input membrane resistance (IMR) was measured by injecting hyperpolarizing current pulses through these electrodes. Results show that the excitatory effect 2,4-DABA elicits on neurons' membrane potential is dependent on sodium ions. Depolarizing effect of 5·10-3 mol/L 2,4-DABA in sodium-free solution was significantly diminished by 91% reducing it to 3.26 ±â€¯0.62 mV and its two-stage nature was abrogated. In addition to being sodium-dependent, the depolarization of membrane potential induced by this amino acid is coupled with an increase of membrane permeability, as 2,4-DABA decreases IMR by 8.27 ±â€¯1.47 MΩ (67.60%). Since present results highlight the role of sodium ions, we investigated the role of two putative sodium-dependent mechanisms in 2,4-DABA-induced excitatory effect - activation of ionotropic glutamate receptors and the electrogenic transporter for neutral amino acids. Excitatory effect of 5·10-3 mol/L 2,4-DABA was partially blocked by 10-5 mol/L 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) a non-NMDA receptor antagonist as the first stage of membrane depolarization was significantly reduced by 2.59 ±â€¯0.98 mV (40%), whilst second stage remained unaltered. Moreover, involvement of the sodium-dependent transport system for neutral amino acids was investigated by equimolar co-application of 5·10-3 mol/L 2,4-DABA and L-alanine, a competitive inhibitor of this transporter. Although L-alanine exhibited no effect on the first stage of membrane depolarization elicited by 2,4-DABA, it substantially reduced the second stage (the overall membrane depolarization) from 39.63 ±â€¯2.22 mV to 16.28 ±â€¯2.58 mV, by 58.92%. We therefore propose that the electrophysiological effect of 2,4-DABA on Retzius neurons is mediated by two distinct mechanisms, i.e. by activation of ionotropic glutamate receptor that initiates the first stage of membrane depolarization followed by the stimulation of an electrogenic sodium-dependent neutral amino acid transporter, leading to additional influx of positive charge into the cell and the second stage of depolarization.

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.

Exploring Sirolimus Pharmacokinetic Variability Using Data Available from the Routine Clinical Care of Renal Transplant Patients - Population Pharmacokinetic Approach.

BACKGROUND: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. METHODS: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. RESULTS: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. CONCLUSIONS: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

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.

The enhancement of serotonin-induced contraction of rat femoral artery is mediated by angiotensin II release from intact endothelium.

We have performed an in vitro study on isolated intact or denuded femoral artery (FA) of healthy, diabetic, and/or rats submitted to the FA occlusion. The aim was to determine the contribution of endothelium and endothelial dysfunction (ED) on serotonin-induced action in FA. Further, the contribution of angiotensin II and cyclooxygenase products of arachidonic acid was investigated. A marker of ED, vWF was measured in animal serum. Serotonin induced contraction-dependent contraction of isolated FA, which was increased in preparations with endothelium. Pathological conditions such as endothelial denudation, nicotine-induced ED, diabetes or occlusion of FA reduced serotonin-induced contraction. Comparable reduction of serotonin-induced contraction was achieved after inhibition of AT1 receptors with losartan in isolated FA with intact endothelium. Our results demonstrate that angiotensin II contributes to the enhancement of serotonin-induced contraction of femoral arteries with intact endothelium. This increase is attenuated by endothelium removal, nicotine treatment, vascular occlusion, and/or hyperglycemia.

Calcium Channel Blockers in Restoration of Endothelial Function: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Clinical evaluation of the Endothelial Function (EF) is becoming an essential step in the quality assessment of cardiovascular risk prevention and rational pharmacotherapy of cardiovascular disorders. The existing pieces of evidence suggested that Calcium Channel Blockers (CCB) can induce positive effects on impaired EF. OBJECTIVE: To evaluate the effects of CCB on EF, we performed a meta-analysis of available data from randomized and placebo-controlled or other treatment-controlled clinical studies encompassing effects of CCB on EF, as measured by Flow-Mediated Dilation (FMD) of the brachial artery. METHODS: The relevant clinical studies were searched by systematic exploration of the appropriate databases until November 30, 2017. A random-effect model was conducted. The primary outcome was the percentage change in FMD between the baseline and the final levels in response to investigated drugs. RESULTS: Fifteen randomized clinical studies with 33 arms were identified. CCB improved FMD more pronounced than thiazide diuretics - TD (3 studies, 157 participants, WMD=2.08%, 95% CI=0.35-3.80%; P=0.02). Oppositely, ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) notably improved FMD if compared to CCB (CCB vs. ACEI: 5 studies, 533 participants, WMD = -1.62%, 95% CI = -2.74% to -0.50%; P=0.005; and CCB vs. ARB: 9 studies, 669 participants, WMD = -1.52%, 95% CI = -2.22% to -0.81%; P=0.0001). CCB effects on EF were similar to those evoked by beta blockers or placebo. CONCLUSION: CCB improved EF to a more prominent extent only if paralleled to TD, while inversely; ACEI and ARB were more effective in augmenting FMD.

Preventive treatment with dizocilpine attenuates oedema in a carrageenan model of inflammation: the interaction of glutamatergic and nitrergic signaling.

Dizocilpine is a highly selective and potent non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. It is well known that dizocilpine has different neuroprotective effects in animal models of pain, epilepsy and oedema during trauma. The search for alternative antiinflammatory drugs is ongoing. We investigated the anti-oedematous effects of dizocilpine and the probable mechanism of action in a rat model that mimics local and persistent inflammation without tissue injury or damage. Male Wistar rats were injected with 100 µL of 0.5% carrageenan to the plantar surface of the hind paw. Anti-oedematous activity was assessed in the carrageenan-induced paw inflammatory oedema test with a plethysmometer. To assess possible mechanisms of dizocilpine action, we examined the effects of the selective inhibitor of neuronal [N-ω-propyl-L-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase (NOS). Dizocilpine after systemic (0.0005, 0.005 and 0.02 mg/kg, subcutaneous (s.c.)), but not after local peripheral administration, reduced the paw inflammatory oedema. The effect is not dose dependent, and the highest decrease by about 47% at the time of maximally developed oedema was achieved with 0.005 mg/kg. Intraperitoneally (i.p.) administered L-NPA (0.5, 1 and 2 mg/kg) or SMT (0.005, 0.01 and 0.015 mg/kg) before dizocilpine abolished or reduced the anti-oedematous effect of dizocilpine by about 70-85%. An acute single dose of dizocilpine administered before inducing oedema systemically reduced the development of inflammatory oedema. The mechanism of the anti-oedematous effect includes, at least partially, an increase in nitric oxide (NO) production.

Cannabinoids and Pain: New Insights From Old Molecules.

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.

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.

Inhibition of neuronal nitric oxide synthase attenuate the hypothermic effect of ketamine-magnesium sulfate combination in rats.

Ketamine and magnesium as NMDA receptor antagonists interact synergistically to decrease body temperature in rats. The mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination has not been studied until now. The aim of this study was to examine whether nitric oxide (NO) has a role in the hypothermic effect of ketamine (10 mg/kg) and the combination of ketamine (5 mg/kg) and magnesium sulfate (5 mg/kg). The body temperature was measured by insertion of a thermometer probe 5 cm into the colon of unrestrained male Wistar rats (200-250 g). N(ω)-nitro-L-arginine methyl ester (L-NAME 2.5 and 5 mg/kg) as non-selective inhibitor of nitric oxide synthase at a dose of 5 mg/kg antagonized the effect of the ketamine-magnesium sulfate combination at 60 min (p < 0.05) and 90 min (p < 0.01). Ketamine induced hypothermia was not affected by administrating of L-NAME (2.5 and 5 mg/kg). Inhibitor of inducible nitric oxide synthase N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL 1.25 mg/kg and 2.5 mg/kg, sc) did not significantly change the hypothermic response evoked by the ketamine-magnesium sulfate combination. Inhibitor of neuronal nitric oxide synthase N-ω-Propyl-L-arginine hydrochloride (L-NPA) at a dose of 2 mg/kg antagonized the combination at 60 min when it achieved the maximum effect. The NO pathway is not involved in the hypothermic effect of ketamine. Production of NO through neuronal NO synthase, might play a role in the mechanism of the hypothermic effect of the ketamine-magnesium sulfate combination.

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.

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.

Prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation in Serbian patients with Parkinson's disease.

BACKGROUND: Biomarkers of oxidative stress are relevant in the evaluation of the disease status and prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation products (malondialdehyde and 4-hydroxynonenal) are being extensively evaluated regarding their relationship with clinical presentation and disease severity. AIM OF THE STUDY: The aim of this study was to evaluate the levels of the above-mentioned parameters in plasma of 39 men and 17 women with Parkinson's disease, originated from the Republic of Serbia and their relation to clinicopathological characteristics (gender, age at examination, duration of the disease, and Hoehn and Yahr score) and oxidative status. RESULTS: The incidence of disease was 2:1 towards males. The investigated oxidative parameters were gender and Hoehn and Yahr related. Significant association of higher Hoehn and Yahr scores was observed for malondialdehyde (p = 0.01) and prooxidant-antioxidant balance (p = 0.02). Relation between oxidant-antioxidant status was further supported by observed positive correlation between 4-hydroxynonenal (p = 0.04) and prooxidant-antioxidant balance (p = 0.03). Finally, the multivariate analysis indicated that prooxidant-antioxidant balance and malondialdehyde were partially determined by gender (10.6% and 7.6%) and Hoehn and Yahr scores (13.6% and 18.8%), while Hoehn and Yahr scores contributed to the variance of advanced oxidation protein products with 13.2%. CONCLUSION: Our results indicate the higher level of oxidative stress (oxidant-antioxidant imbalance) and possible relation of several markers with gender and disease stage in patients with Parkinson's disease. The analyzed markers could be used to specify the severity of oxidative stress; however, their potential value should be analyzed in further studies.

Toxicity evaluation of two polyoxotungstates with anti-acetylcholinesterase activity.

A toxicity evaluation of two Keggin-type heteropolytungstates, K7[Ti2PW10O40]·6H2O and K6H[SiV3W9O40]·3H2O, with different inhibitory potencies toward acetylcholinesterase activity (IC50 values of 1.04×10-6 and 4.80×10-4mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of K6H[SiV3W9O40]·3H2O. Accordingly, the toxicity of these two polyoxotungstates with anti-acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study.

Additive and antagonistic antinociceptive interactions between magnesium sulfate and ketamine in the rat formalin test.

Because ketamine and magnesium block NMDA receptor activation by distinct mechanisms of action, we hypothesized that in a model of inflammatory pain in rats the combination of ketamine and magnesium might be more effective than ketamine alone. Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Animals were injected with 100 µL of 2.5% formalin to the plantar surface of the right hind paw. Data were recorded as the total time spent in pain-related behavior after the injection of formalin or vehicle (0.9% NaCl). Ketamine and magnesium sulfate given separately reduced nocifensive behavior in the second phase of the formalin test in rats. When ketamine was applied after magnesium sulfate, the log dose-response curves for the effects of ketamine and the magnesium sulfate-ketamine combination revealed antagonistic interaction, and about 1.6 (CL 1.2-2.4) fold increment in ketamine dosage. A low dose of magnesium sulfate (5 mg/kg, subcutaneously) administered after ketamine increased the antinociceptive effect of ketamine by a factor of only 1.2 (CL 0.95-1.38), indicating an additive interaction. There was a 1.8-fold reduction in dosage of ketamine when ketamine was administered before rather than after the magnesium sulfate. The present study revealed that both ketamine and magnesium reduced pain-related behavior in the second phase of the formalin test in rats. Ketamine, when administered before or after the magnesium, provided additive or antagonistic antinociceptive interactions, respectively. Whether there will be an additive or antagonistic antinociceptive interaction between ketamine and magnesium depends on the order of drug administration.

Problems, interventions, and their outcomes during the routine work of hospital pharmacists in Bosnia and Herzegovina.

Background In the last 30 years, activities of hospital pharmacists have gone through significant changes. Pharmacists are increasingly involved in patient care. Objectives To explore drug-related and logistic problems, interventions, and their outcomes during routine everyday work of hospital pharmacists. Setting Institute for physical medicine and rehabilitation, Banja Luka, Bosnia and Herzegovina. Methods In the period of January 2013-October 2015 a prospective observational study was performed. Medical doctors, nurses, therapists, and patients addressed pharmacists, face-to-face or by telephone, with drug-related problems (DRPs) and/or logistic issues. Main outcome measure Type of DRP or logistic issue, intervention, outcome, initiator and time spent for solving the problem were documented for each consultation. Results Out of 1515 interventions, 48.8% were aimed at solving DRPs. The most common DRPs were the recommendation of a drug or dose and need for additional information about drugs. Drug price and supply were the most prevalent logistic issues. DRPs were more frequently initiated by medical doctors and required more time to solve the problem compared to logistic issues (Mann-Whitney U test, p ≤ 0.001, respectively). The acceptance rate of interventions to solve DRPs (83.7%) was lower compared to logistic issues (95.2%; p ≤ 0.001). Conclusions Hospital pharmacists were faced with an approximately equal number of DRPs and logistic issues during their routine everyday work. The overall acceptance rate of pharmacists' interventions was high, and the results of our study indicate that there is a need for more involvement of hospital pharmacists in Bosnia and Herzegovina in clinical activities. Impact on practice.