Nevena Divac

Second-generation antipsychotics and extrapyramidal adverse effects.

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability.

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT(1) antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT(1) antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg(-1)·day(-1) aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT(1) antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

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

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

Utilization of psychiatric drugs in Serbia

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

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

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

Thermomineral water promotes axonal sprouting but does not reduce glial scar formation in a mouse model of spinal cord injury

Thermomineral water from the Atomic Spa Gornja Trepča has been used for a century in the treatment of neurologic disease. The thermomineral water contains microelements, including lithium and magnesium, which show neural regeneration-promoting effects after central nervous system injury. In this study, we investigated the effects of oral intake of thermomineral water from the Atomic Spa Gornja Trepča on nerve regeneration in a 3-month-old mouse model of spinal cord injury. The mice receiving oral intake of thermomineral water showed better locomotor recovery than those without administration of thermomineral water at 8 and 12 weeks after lower thoracic spinal cord compression. At 12 weeks after injury, sprouting of catecholaminergic axons was better in mice that drank thermomineral water than in those without administration of thermomineral water, but there was no difference in glial reaction to injury between mice with and without administration of thermomineral water. These findings suggest that thermomineral water can promote the nerve regeneration but cannot reduce glial scar formation in a mouse model of spinal cord injury.

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and upon Nervous System Injury

The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer’s disease (AD). The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models.

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

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

The Effects of Nmda Antagonists On Morphine Induced Hyperthermia in Rats

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

P02-450 - Pharmacoepidemiologic studies on psychiatric drugs use in Serbia

High rate of prescribing of psychiatric drugs causes medical, social and economic consequences. This research was performed by collecting and analysing all the papers published on this matter in Serbia. In former Yugoslavia (of which Serbia was a constitutive republic), during the eighties, a study of benzodiazepines use showed a trend of the increase of their use (17,9 defined daily doses - DDDs in 1983 - 22,3 DDDs in 1988) (Macolic V et al. Benzodiazepines utilization in Yugoslavia 1983–1988. Pharmaca 1990;217–97). Similar trends continued in the nineties. In 1994 diazepam was at the first position on the list of most prescribed drugs (Miljkovic M. et al. Analysis of Drug Utilization in Serbia During the Years 1996 and 1997. Pharmacoepidemiol Drug Saf 2000;9:59–64.). The analysis of the trend of prescribing of psychiatric drugs in Serbia (2000–2004) shows the increase, with the emphasis on the use of benzodiazepines and antidepressants (Divac N. et al. Trends in consumption of psychiatric drugs in Serbia and Montenegro 2000–2004. Pharmacoepidemiol Drug Saf. 2006;15:835–8.). There are also positive, qualitative changes in the prescribing practice: the increase of the use of SSRI antidepressants and atypical antipsychotics. Specific prescribing habits were noticed: the common practice of polypharmacy in the treatment of psychoses (Divac N. et al. Antipsychotic polypharmacy at the University Psychiatric Hospital in Serbia. Pharmacoepidemiol Drug Saf. 2007;16:1250–1.). Pharmacoepidemiologic methods have found its place in Serbian science. The methodology used in these studies is mostly up-to-date. Main limitation of these studies is the lack of databases.