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 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 $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 ($487). Compared with diclofenac+omeprazole, cost savings were estimated at $59 and $22 per patient with celecoxib and etoricoxib, respectively. CONCLUSION: Cost savings may be achieved by using COX-2 inhibitors in patients at high risk of GI adverse effects even in countries with moderate health care service expenditures. Such possibility requires further investigation.

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.

Pharmacokinetics and efficacy of fluvoxamine and amitriptyline in depression.

Although often necessary for obtaining remission following major depressive disorder, combined antidepressant treatment is frequently associated with drug interactions and enhanced adverse drug effects. We investigated pharmacokinetic interactions following combined fluvoxamine and amitriptyline treatment and their impact on therapeutic efficacy and tolerability. Twenty-two inpatients with major depression [Hamilton Depression Scale (HAM-D) rating > or =18] were treated with either amitriptyline (75 mg/day), fluvoxamine (100 mg/day) or both. Blood samples, for determination of amitriptyline, its major metabolite nortritpyline, and fluvoxamine, were obtained after single dose administration and in steady-state. Therapeutic efficacy was evaluated using HAM-D and adverse drug effects were evaluated using the clinical global impression scale. Following combined treatment, steady-state plasma levels of nortriptyline were significantly decreased compared to monotherapy. HAM-D scores after two-week treatment showed that there was a better response to combined treatment. There was no significant difference in severity of adverse effects among groups. We observed a pharmacokinetic interaction between fluvoxamine and amitritpyline resulting in impaired metabolism of the later. However, no significant impact of the interaction on treatment safety was observed. Moreover, concomitant use of amitriptyline at 75 mg/day and fluvoxamine at 100 mg/day was well tolerated with a more prompt and stronger onset of clinical response compared to monotherapy in patients with major depression.

Methotrexate-associated alterations of the folate and methyl-transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity.

BACKGROUND: 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. PROCEDURE: MTX, 5-methyltetrahydrofolate, calcium folinate, S-adenosylmethionine, and S-adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high-dose MTX (5 g/m(2)) followed by calcium folinate rescue (3 x 15 mg/m(2)) and/or intrathecal (8-12 mg) MTX. Two patients developed subacute MTX-associated neurotoxicity. CSF was obtained by lumbal puncture 1-3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection. RESULTS: In non-toxic patients, CSF concentrations of 5-methyltetrahydrofolate and S-adenosylmethionine were in the normal range 2 weeks after administration of high-dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5-methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S-adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5-methyltetrahydrofolate and S-adenosylmethionine during or following toxicity. S-adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non-toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion. CONCLUSION: Intrathecal MTX without folinate rescue as well as MTX-associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl-transfer pathway.

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

GOAL OF WORK: During the renovation works at our institution, the incidence density for invasive aspergillosis (IA) increased from <0.5 to 0.99/1,000 inpatient days in 2001. As a direct response to this increased environmental risk, itraconazole (ITC) was administered for primary prophylaxis in pediatric cancer patients for whom a particular high risk of IA was anticipated due to prolonged severe neutropenia (>10 days), autologous stem cell transplantation, acute myeloblastic leukemia or relapsed acute lymphoblastic leukemia, or high-dose steroids >3 weeks. MATERIALS AND METHODS: In this open-label, prospective observational study, ITC was given in ITC solution or capsule. Trough concentrations were measured in plasma with high-performance liquid chromatography after at least 7 days of treatment. Doses were adjusted to target plasma trough ITC concentrations > or =0.5 mg/l. RESULTS: From 2001 to 2005, 39 pediatric cancer patients received 44 prophylactic ITC cycles; 102 trough plasma concentrations were measured after oral administration. Plasma target concentrations >0.5 mg/l were achieved with both formulations. A median dose of 8 mg kg(-1) day(-1) (3.5-16.0 mg kg(-1) day(-1)) was necessary in pediatric oncology patients. The bioavailability of the liquid formulation was significantly lower when the solution was given by a feeding tube. Adverse effects (gastrointestinal, elevated transaminases, and one hemolysis) which led to the cessation of the ITC prophylaxis were reported in 11% of all courses. No breakthrough infection was seen in this pediatric population. CONCLUSION: Oral ITC offers a feasible and inexpensive option for antifungal prophylaxis in selected pediatric cancer patients. Drug monitoring and meticulous consideration of possible interactions and adverse effects are mandatory.

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.