In vitro effects of antidepressants and mood-stabilizing drugs on cell energy metabolism.

The evaluation of drug-induced mitochondrial impairment may be important in drug development as well as in the comprehension of molecular mechanisms of the therapeutic and adverse effects of drugs. The primary aim of this study was to investigate the effects of four drugs for treatment of depression (bupropion, fluoxetine, amitriptyline, and imipramine) and five drugs for bipolar disorder treatment (lithium, valproate, valpromide, lamotrigine, and carbamazepine) on cell energy metabolism. The in vitro effects of the selected psychopharmaca were measured in isolated pig brain mitochondria; the activities of citrate synthase (CS) and electron transport chain (ETC) complexes (I, II + III, and IV) and mitochondrial respiration rates linked to complex I and complex II were measured. Complex I was significantly inhibited by lithium, carbamazepine, fluoxetine, amitriptyline, and imipramine. The activity of complex IV was decreased after exposure to carbamazepine. The activities of complex II + III and CS were not affected by any tested drug. Complex I-linked respiration was significantly inhibited by bupropion, fluoxetine, amitriptyline, imipramine, valpromide, carbamazepine, and lamotrigine. Significant inhibition of complex II-linked respiration was observed after mitochondria were exposed to amitriptyline, fluoxetine, and carbamazepine. Our outcomes confirm the need to investigate the effects of drugs on both the total respiration rate and the activities of individual enzymes of the ETC to reveal the risk of adverse effects as well as to understand the molecular mechanisms leading to drug-induced changes in the respiratory rate. Our approach can be further replicated to study the mechanisms of action of newly developed drugs.

Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance.

BACKGROUND: The precision of the population pharmacokinetic model used in therapeutic drug monitoring (TDM) is essential for successful dosage optimisation. OBJECTIVE: To evaluate the predictive performance of pharmacokinetic models used in our hospital and to evaluate the possible impact of demographic characteristics or renal function on TDM accuracy. METHODS: We compared a posteriori an adjusted concentration-time curve profile based on the first measured drug concentration with the second measured drug concentration. Linear regression models were used to compare predicted and observed drug serum concentrations, and to evaluate potential relationships between predictive performance and patients´ demographic/clinical features. Predictive performance of TDM was expressed using accuracy, precision, sensitivity and specificity. RESULTS: One hundred and fifty-two patients were enrolled in the study. All pharmacokinetic models showed good predictive performance expressed by the coefficient of determination (r2) of 0.5642, 0.7263, 0.9001 and 0.9454 for continuous vancomycin, intermittent vancomycin, amikacin and gentamicin, respectively. Accuracy was 93.3%, 91.2%, 113.9% and 130.9% for continuous vancomycin, intermittent vancomycin, amikacin and gentamicin, respectively. Demographic characteristics or renal functions had no substantial impact on the accuracy of TDM. CONCLUSION: We found the predictive performance of both aminoglycosides and vancomycin pharmacokinetic models to be satisfactory.

In vitro effects of antipsychotics on mitochondrial respiration.

Assessment of drug-induced mitochondrial dysfunctions is important in drug development as well as in the understanding of molecular mechanism of therapeutic or adverse effects of drugs. The aim of this study was to investigate the effects of three typical antipsychotics (APs) and seven atypical APs on mitochondrial bioenergetics. The effects of selected APs on citrate synthase, electron transport chain complexes (ETC), and mitochondrial complex I- or complex II-linked respiratory rate were measured using mitochondria isolated from pig brain. Complex I activity was decreased by chlorpromazine, haloperidol, zotepine, aripiprazole, quetiapine, risperidone, and clozapine. Complex II + III was significantly inhibited by zotepine, aripiprazole, quetiapine, and risperidone. Complex IV was inhibited by zotepine, chlorpromazine, and levomepromazine. Mitochondrial respiratory rate was significantly inhibited by all tested APs, except for olanzapine. Typical APs did not exhibit greater efficacy in altering mitochondrial function compared to atypical APs except for complex I inhibition by chlorpromazine and haloperidol. A comparison of the effects of APs on individual respiratory complexes and on the overall mitochondrial respiration has shown that mitochondrial functions may not fully reflect the disruption of complexes of ETC, which indicates AP-induced modulation of other mitochondrial proteins. Due to the complicated processes associated with mitochondrial activity, it is necessary to measure not only the effect of the drug on individual mitochondrial enzymes but also the respiration rate of the mitochondria or a similar complex process. The experimental approach used in the study can be applied to mitochondrial toxicity testing of newly developed drugs.

Estimation of once-daily amikacin dose in critically ill adults.

This study aimed at investigating variables affecting amikacin pharmacokinetics in order to propose optimal initial dosing in critically ill adult patients treated with once-daily amikacin regimen. Amikacin pharmacokinetics was calculated based on plasma concentrations using one compartmental analysis. Relationships between pharmacokinetic parameters and demographic/clinical data were explored in linear regression models. Simulated dose and dosing intervals were derived from body size descriptors and estimated creatinine clearances for each patient. Amikacin volume of distribution best correlated with body surface area, while amikacin clearance was best predicted by CKD-EPI creatinine clearance. Our study suggests that dose of 517 mg per m2 of body surface area leads to amikacin levels most approaching target peak concentration. Dosing interval calculated as 228.7 × e-3.08× CKD-EPI creatinine clearance (mL s-1) + 15.84 most closely approximated optimal dosing intervals based on individual pharmacokinetics. The dosing nomogram based on CKD-EPI creatinine clearance was designed.

Importance of vancomycin loading doses in intermittent infusion regimens.

PURPOSE: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to explore the real frequency of loading dose use and to evaluate the impact of loading dose for the achievement of vancomycin PK/PD target in adult patients treated with intermittent vancomycin. As a secondary aim we determined optimal vancomycin loading dose based on individual pharmacokinetic calculations. METHODS: Vancomycin pharmacokinetic models were computed using two-compartmental analysis. Based on these models AUC24 were calculated. Unpaired t-test was used to compare AUC24 achieved in patients treated with and without vancomycin loading dose. RESULTS: Vancomycin loading dose was administered only in 17.8% patients. Volume of distribution and clearance median values (interquartile range) for vancomycin in whole study population (n = 45) were 0.69 (0.55-0.87) L/kg and 0.0304 (0.0217-0.0501) L/h/kg, respectively. The AUC24 was significantly higher in patients taking loading dose compared with the group without loading dose: mean (SD) AUC24 was 496 (101) vs. 341 (77) mg h/L. Proportion of patients reaching PK/PD goal was 87.5% and 24.3% with and without loading dose administration, respectively. Considering individual pharmacokinetic parameters optimal vancomycin loading dose was 27.5 mg/kg of body weight. CONCLUSIONS: Loading dose administration plays crucial part in rapid attainment of vancomycin PK/PD target in adult patient treated with intermittent vancomycin, although it is not frequently used in clinical practise. The optimal loading dose of 25-30 mg/kg of body weight should be routinely administered to adult patients treated with intermittent vancomycin.

Newly Developed Drugs for Alzheimer's Disease in Relation to Energy Metabolism, Cholinergic and Monoaminergic Neurotransmission.

Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.

Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy.

Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions.

Biological hypotheses and biomarkers of bipolar disorder.

The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state.