Sandra Vezmar

Biochemical and Clinical Aspects of Methotrexate Neurotoxicity

Acute, subacute and chronic neurotoxicity have been observed after the administration of high-dose and/or intrathecal methotrexate (MTX). Acute toxicity is usually transient without permanent damage. Subacute and chronic toxicity are associated with changes in the brain and/or the spinal cord which may be progressive and even lead to coma and death in severe cases. It is believed that MTX can induce direct toxic effects to the CNS by damaging the neuronal tissue. Moreover, MTX interferes with the metabolic pathways of folates, excitatory amino acids, homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, adenosine and biopterins, inducing biochemical alterations which have been associated with neurotoxic symptoms. It has been suggested that acute toxicity is partly mediated by adenosine, whereas homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, excitatory amino acids and biopterins may play an important role in the development of subacute and chronic toxicity. A better understanding of the pathogenesis of MTX neurotoxicity would offer the possibility of developing new therapeutic strategies for its treatment or prevention.

Methotrexate-Associated Alterations of the Folate and Methyl-Transfer Pathway in the CSF of ALL Patients With and Without Symptoms of Neurotoxicity

Severe neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.

Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate.

OBJECTIVE Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. MATERIAL AND METHODS CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. RESULTS After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. CONCLUSIONS In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.

Getting the balance right: Established and emerging therapies for major depressive disorders

Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

Are local clinical guidelines useful in promoting rational use of antibiotic prophylaxis in caesarean delivery

Objectives To identify changes in prescribing patterns of antibiotic prophylaxis in Caesarean delivery after introduction of local clinical guidelines. To identify changes in outcomes of prescribing antibiotics following the implementation of local clinical guidelines on antibiotic prophylaxis. Setting University of Belgrade, Medical School, Clinic of Gynaecology and Obstetrics “Narodni front” Belgrade, Serbia. Method A quantitative retrospective analysis of antibiotic use before (January–June 2005), and following (January–June 2006) implementation of guidelines on antibiotic prophylaxis in two wards. Patients who underwent Caesarean section prior to (261) and following (281) introduction of local guidelines, participated in this study. Main outcome measures Drug utilization cost presented as the number of DDD/100 bed days/eur, the average duration of hospital stay, number of wound infections. Results There was a significant change in prescribing patterns of antibiotic prophylaxis in Caesarean section following introduction of local guidelines. The use of ceftriaxone, amikacin and metronidazole decreased (57.47% vs. 11.74%; 9.19% vs. 4.27%; 61.69% vs. 46.26%, respectively). On the other hand, the use of “older” antibiotics such as gentamicin, cefuroxime, cefazolin and ampicillin increased (14.56% vs. 29.18%; 9.2% vs. 17.44%; 9.58% vs. 45.2% and 0% vs. 3.9%, respectively). DDD/100 bed days/eur analysis revealed a 47% decrease of total cost for prophylactic antibiotic treatment in Caesarean section following local guideline implementation. In contrast, rate of wound infections and duration of hospital stay were not significantly different in both groups. Conclusion In an attempt to ensure cost-effective prophylactic use of antibiotics in Caesarean delivery, local clinical guidelines were introduced. They resulted in changes in prescribing patterns of antibiotics. There was a significant decrease in use of ‘third’ generation of cephalosporin’s whereas the use of “older” antibiotics with proven efficacy and safety increased. In contrast, there was no significant change in treatment outcomes such as wound infection and average hospital stay.

Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity

Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity Intrathecal and/or high-dose intravenous administration of methotrexate (MTX) in the treatment of malignancies such as acute lymphoblastic leukaemia (ALL) has been associated with cases of mild to severe neurotoxicity. The pathogenic mechanism of neurotoxicity is not clear, possibly MTX-associated biochemical alterations of the folate and methyl-transfer metabolic pathways play an important role. We report a case of an adult patient treated for ALL relapse with signs of chronic leukoencephalopathy associated with MTX administration. In order to assess alterations in the folate and methyl-transfer pathway we determined 5-methyltetrahydrofolate (5-methyl-THF), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in the cerebrospinal fluid (CSF) of the patient. Three CSF samples were obtained by lumbar punction within a four-month period. Concentrations of the metabolites were measured using validated bioanalytical methods based on HPLC with UV and fluorescence detection. The results showed two-fold lower 5-methyl-THF levels (29.3-31.8 nmol/L) in all obtained samples compared to reference values. SAM concentrations were even more than five-fold lower in two samples (5-34.2 nmol/L). SAH concentrations were in the range 7.5-14.3 nmol/L. Our patient had pronounced alterations in the folate and methyltransfer pathway which indicate that MTX-associated biochemical alterations of these pathways may play an important role in the development of leukoencephalopathy. Biohemijske Promene Povezane SA Primenom Metotreksata Kod Pacijenta SA Hroničnom Neurotoksičnosti Primena metotreksata (MTX) u visokim dozama i/ili intratekalno u terapiji malignih oboljenja poput akutne limfoblastične leukemije (ALL) povezana je sa pojavom blagih ili teških oblika neurotoksičnosti. Patogeneza neurotoksičnosti nije u potpunosti razjašnjena, ali se važna uloga pripisuje biohemijskim promenama folatnog i metiltransfernog metaboličkog puta za koje se smatra da su uzrokovane dejstvom MTX. Opisujemo slučaj odrasle pacijentkinje na terapiji recidiva ALL sa simptomima hronične leukoencefalopatije najverovatnije uzrokovane primenom MTX. U cilju procene folatnog i metil-transfernog puta u cerebrospinalnoj tečnosti (CST) pacijentkinje merene su koncentracije 5-metiltetrahidrofolata (5-metil-THF), S-adenozilmetionina (SAM) i S-adenozilhomocisteina (SAH). Tri uzorka CST su dobijena lumbalnom punkcijom u periodu od četiri meseca. Koncentracije su merene pomoću validiranih bioanalitičkih metoda zasnovanih na primeni HPLC sa ultraljubičastom i fluorescentnom detekcijom. Rezultati su pokazali dvostruko sniženje koncentracije 5-metil-THF (29.3-31.8 nmol/L) u poređenju sa referentnim vrednostima u svim uzorcima, dok su koncentracije SAM bile pet puta manje u dva uzorka (5-34.2 nmol/L). Koncentracije SAH su bile u rasponu 7.5-14.3 nmol/L. Naša pacijentkinja je imala izražene promene u folatnom i metil-transfernom metaboličkom putu koje ukazuju na to da biohemijske promene ovih metaboličkih puteva za koje se smatra da su uzrokovane dejstvom MTX mogu igrati važnu ulogu u razvoju leukoencefalopatije.

Are COX-2 inhibitors preferable to combined NSAID and PPI in countries with moderate health service expenditures?

RATIONALE In developed countries, cyclooxygenase 2 (COX-2) inhibitors were shown to be less costly than the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) in treatment of patients with high risk of serious gastrointestinal (GI) adverse effects. It is questionable if such results apply to developing countries where health service costs are lower and there is high discrepancy between generic and patent protected drug prices. We analysed the direct cost of treatment with generic NSAIDs in combination with PPIs versus branded COX-2 inhibitors in patients with high risk of serious GI adverse effects from the perspective of the public health service in Serbia. METHODS Total cost of treatment of serious GI complications and the use of NSAID+PPI versus COX-2 inhibitors were calculated. A model for estimation of cost of treatment of NSAID+PPI versus COX-2 inhibitors which included the probability of developing serious GI adverse effects was developed. RESULTS Total cost of treatment of serious GI adverse effects resulted in an average of

Itraconazole prophylaxis in pediatric cancer patients receiving conventional chemotherapy or autologous stem cell transplants.

814/patient. Considering the relative risk of such adverse effects for patients with four or more risk factors, the least costly treatment over 6 months was the use of celecoxib (

Pharmacokinetics and Efficacy of Fluvoxamine and Amitriptyline in Depression

487). Compared with diclofenac+omeprazole, cost savings were estimated at

Methotrexate-associated neurotoxicity is not only insufficient leucovorin rescue

59 and