Teresa Maria de Jesus Ponte Carvalho

Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity.

AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n= 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P ≤ 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 µg ml(-1) h), (-)-ASOX by 358% (0.14 vs. 0.50 µg ml(-1) h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 µg ml(-1) h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 µg ml(-1) h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

Simultaneous analysis of tramadol, O-desmethyltramadol, and N-desmethyltramadol enantiomers in rat plasma by high-performance liquid chromatography-tandem mass spectrometry: application to pharmacokinetics.

Tramadol (T) is available as a racemic mixture of (+)-trans-T and (-)-trans-T. The main metabolic pathways are O-demethylation and N-demethylation, producing trans-O-desmethyltramadol (M1) and trans-N-desmethyltramadol (M2) enantiomers, respectively. The analgesic effect of T is related to the opioid activity of (+)-trans-T and (+)-M1 and to the monoaminergic action of (+/-)-trans-T. This is the first study using tandem mass spectrometry as a detection system for the simultaneous analysis of trans-T, M1, and M2 enantiomers. The analytes were resolved on a Chiralpak® AD column using hexane:ethanol (95.5:4.5, v/v) plus 0.1% diethylamine as the mobile phase. The quantitation limits were 0.5 ng/ml for trans-T and M1 and 0.1 ng/ml for M2. The method developed and validated here was applied to a pharmacokinetic study in rats. Male Wistar rats (n=6 at each time point) received a single oral dose of 20 mg/kg racemic trans-T. Blood samples were collected up to 12 h after drug administration. The kinetic disposition of trans-T and M2 was enantioselective (AUC((+))/((-)) ratio=4.16 and 6.36, respectively). The direction and extent of enantioselectivity in the pharmacokinetics of trans-T and M2 in rats were comparable to data previously reported for healthy volunteers, suggesting that rats are a suitable model for enantioselective studies of trans-T pharmacokinetics.

Increased parameters of oxidative stress and its relation to transfusion iron overload in patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are group of stem cell disorders characterised by peripheral cytopaenias and a variable risk of progression to acute myeloid leukaemia. Most patients have anaemia and many develop transfusion dependence and iron overload (IOL), considered to be a negative independent prognostic factor associated with a higher risk of leukemic transformation and shorter survival.1 Iron pool is regarded as an important regulator of the production of reactive oxygen species (ROS). The excessive production of ROS and reactive nitrogen species causes lipid peroxidation, which can suppress self-renewal, the number of haematopoietic stem cells and directly induce DNA damage and genomic instability.2 However, the role of iron-mediated oxidative stress in the physiopathology of MDS remains uncertain. The present study aimed to evaluate plasma nitrite (NO2 −) and plasma malonaldehyde, secondary product of lipid peroxidation, in patients with MDS and correlate them with IOL due to transfusion dependence in MDS patients. Consecutive adult patients with MDS with and without IOL, followed at the University Hospital of the Federal University of Ceara, Brazil, were enrolled. The study was approved by the local ethics committee (licence 150/2009). They were classified according to the presence or absence of IOL defined as serum ferritin of 1000 ng/ml or …

Study of the safety of methylphenidate: Focus on nephrotoxicity aspects.

AIMS Methylphenidate (MPD) is increasingly prescribed for the treatment of Attention Deficit Hyperactivity Disorder and there are concerns about its appropriate use. Furthermore, little is known about the potential nephrotoxicity in patients using MPD. This study aimed to investigate the safety of MPD, with focus on the possible effects of this drug on renal function. MAIN METHODS We investigated the effects of MPD on renal perfusion system and renal tubular cells through in vivo and in vitro experimental models. KEY FINDINGS In the in vivo experiments, 24 h and 48 h after MPD administration, urea, creatinine, creatinine clearance, and the fractional excretion of sodium and potassium were not changed. In the isolated kidney perfusion, MPD significantly reduced urinary flow, glomerular filtration rate and the percentage of tubular sodium transport. However, the perfusion pressure, renal vascular resistance and the percentage of tubular potassium transport were unchanged in this system. In the canine renal epithelial cell line MDCK culture, MPD was not cytotoxic and, in histopathological analysis, MPD did not promote alterations. SIGNIFICANCE Our findings suggest a possible nephrotoxic effect of MPD, since it altered renal function by reducing the glomerular activity, urinary flow and sodium transport. These effects need to be further investigated in order to minimize potential harms associated with the use of MPD.

Methemoglobin measure in adult patients with sickle-cell anemia: influence of hydroxyurea therapy

Introduction: Hemoglobin S (HbS) is unstable hemoglobin that easily oxidizes, causing methemoglobin (MetHb) increased production in patients with sickle-cell anemia (SCA). Objectives: To determine MetHb levels and the influence of hydroxyurea (HU) therapy on this marker in patients with SCA. Materials and methods: Blood samples from 53 patients with SCA at the steady-state, with and without HU therapy, and 30 healthy individuals were collected to evaluate MetHb levels. The MetHb measurement was performed by spectrophotometry. Complete blood count, HU measurements, and fetal hemoglobin (HbF) and HbS concentrations were taken from medical records. Results: MetHb levels were statically higher in patients with SCA when compared to control group (p < 0.001). There was no statistical difference in MetHb level between SCA patients, either using or not HU. We obtained a positive correlation between MetHb measurements and HbS concentration (r = 0.2557; p = 0.0323). Conclusion: HbS presence favored hemoglobin breaking down, and consequently increased MetHb production. Treatment with HU, however, did not influence the levels of this marker.

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

Sickle cell anemia (SCA) is a recessively inherited disease characterized by chronic hemolytic anemia, chronic inflammation, and acute episodes of hemolysis. Hydroxyurea (HU) is widely used to increase the levels of fetal hemoglobin (HbF). The objective of this study was to standardize and validate a method for the quantification of HU in human plasma by using ultra high performance liquid chromatography (UPLC) in order to determine the plasma HU levels in adult patients with SCA who had been treated with HU. We used an analytical reverse phase column (Nucleosil C18) with a mobile phase consisting of acetonitrile/water (16.7/83.3). The retention times of HU, urea, and methylurea were 6.7, 7.7, and 11.4 min, respectively. All parameters of the validation process were defined. To determine the precision and accuracy of quality controls, HU in plasma was used at concentrations of 100, 740, and 1600 µM, with methylurea as the internal standard. Linearity was assessed in the range of 50-1600 µM HU in plasma, obtaining a correlation coefficient of 0.99. The method was accurate and precise and can be used for the quantitative determination of HU for therapeutic monitoring of patients with SCA treated with HU.