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

center dot Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide. WHAT THIS STUDY ADDS center dot The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel. 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 mu g ml-1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mu g ml-1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mu g 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 mu g 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.

Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers

center dot Citalopram (CITA) pharmacokinetics are enantioselective in healthy volunteers and the metabolism of (+)-(S)-CITA to (+)-(S)-DCITA is dependent on CYP2C19. Omeprazole is a potent CYP2C19 inhibitor. WHAT THIS STUDY ADDS center dot This study indicates that omeprazole induces a loss of enantioselectivity in the CITA pharmacokinetics because of the selective inhibition of (+)-(S)-CITA metabolism. AIM The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (-)-(R)-CITA enantiomers in healthy volunteers. METHODS In a cross-over study, healthy volunteers (n = 9) phenotyped as extensive metabolizers of CYP2C19 and CYP2D6 and with an oral midazolam clearance ranging from 10.9 to 149.3 ml min-1 kg-1 received a single dose of racemic CITA (20 mg orally) in combination or not with omeprazole (20 mg day-1 for 18 days). Serial blood samples were collected up to 240 h after CITA administration. CITA and demethylcitalopram (DCITA) enantiomers were analyzed by LC-MS/MS using a Chiralcel (R) OD-R column. RESULTS The kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (-)-(R)-CITA [AUC S : R ratio of 0.53 (95% CI 0.41, 0.66) for CITA and 1.08 (95% CI 0.80, 1.76) for DCITA] than (+)-(S)-CITA. Racemic CITA administration to healthy volunteers in combination with omeprazole showed a loss of enantioselectivity in CITA pharmacokinetics with an increase of approximately 120% in plasma (+)-(S)-CITA concentrations [AUC S : R ratio of 0.95 (95% CI 0.72, 1.10) for CITA and 0.95 (95% CI 0.44, 1.72) for DCITA]. CONCLUSIONS The administration of multiple doses of omeprazole preferentially inhibited (+)-(S)-CITA metabolism in healthy volunteers. Although omeprazole increased plasma concentrations of (+)-(S)-CITA by approximately 120%, it is difficult to evaluate the clinical outcome because the range of plasma CITA concentrations related to maximum efficacy and minimum risk of adverse effects has not been established.

Role of NFKB2 on the early myeloid differentiation of CD34+ hematopoietic stem/progenitor cells

To better understand the early events regulating lineage-specific hematopoietic differentiation, we analyzed the transcriptional profiles of CD34+ human hematopoietic stem and progenitor cells (HSPCs) subjected to differentiation stimulus. CD34+ cells were cultured for 12 and 40 h in liquid cultures with supplemented media favoring myeloid or erythroid commitment. Serial analysis of gene expression (SAGE) was employed to generate four independent libraries. By analyzing the differentially expressed regulated transcripts between the un-stimulated and the stimulated CD34+ cells, we observed a set of genes that was initially up-regulated at 12 h but were then down-regulated at 40 h, exclusively after myeloid stimulus. Among those we found transcripts for NFKB2, RELB, IL1B, LTB, LTBR, TNFRSF4, TGFB1, and IKBKA. Also, the inhibitor NFKBIA (IKBA) was more expressed at 12 h. All those transcripts code for signaling proteins of the nuclear factor kappaB pathway. NFKB2 is a subunit of the NF-kappa B transcription factor that with RELB mediates the non-canonical NF-kappa B pathway. Interference RNA (RNAi) against NFKB1, NFKB2 and control RNAi were transfected into bone marrow CD34+HSPC. The percentage and the size of the myeloid colonies derived from the CD34+ cells decreased after inhibition of NFKB2. Altogether, our results indicate that NFKB2 gene has a role in the early commitment of CD34+HSPC towards the myeloid lineage. (C) 2010 International Society of Differentiation. Published by Elsevier Ltd. All rights reserved.

Monitoring of protein catabolism in neonates and young infants post-cardiac surgery

Aims: To evaluate cell catabolism by balance of nitrogen and phosphate, and creatinine excretion in children post-cardiac surgery; to establish protein and energy requirements to minimize catabolism; and to assess nutritional therapy by following these parameters and serial anthropometric measurements. Methods: A prospective observational study of children with congenital heart disease undergoing cardiac surgery. Blood samples and 24-h urine collections were obtained postoperatively for creatinine measurement and nitrogen and phosphate balance. Anthropometric measurements (weight, mid-arm muscle circumference and triceps skinfold thickness) were obtained preoperatively and at paediatric intensive care unit and hospital discharge. Results: Eleven children were studied for 3-10 postoperative days. Anabolism was associated with higher protein and energy intakes compared to catabolism (1.1 vs. 0.1 g/kg/day and 54 vs. 17 kcal/kg/day, respectively). On days with anabolism, phosphate balance was greater compared with that on days with catabolism. Daily creatinine excretion did not correlate with protein balance. Anthropometric measurements did not change significantly over time. Conclusions: Children with congenital heart disease undergoing cardiac surgery achieved anabolism with > 55 kcal/kg/day and > 1 g/kg/day of protein. Balance of phosphate was useful to monitor cell breakdown. Anthropometric measurements were not valuable to evaluate nutritional therapy in this population.

SAGE analysis demonstrates increased expression of TOSO contributing to Fas-mediated resistance in CLL

To identify novel genes involved in the molecular pathogenesis of chronic lymphocytic leukemia (CLL) we performed a serial analysis of gene expression (SAGE) in CLL cells, and compared this with healthy B cells (nCD19(+)). We found a high level of similarity among CLL subtypes, but a comparison of CLL versus nCD19(+) libraries revealed 55 genes that were over-represented and 49 genes that were down-regulated in CLL. A gene ontology analysis revealed that TOSO, which plays a functional role upstream of Fas extrinsic apoptosis pathway, was over-expressed in CLL cells. This finding was confirmed by real-time reverse transcription-polymerase chain reaction in 78 CLL and 12 nCD19(+) cases (P <.001). We validated expression using flow cytometry and tissue microarray and demonstrated a 5.6-fold increase of TOSO protein in circulating CLL cells (P =.013) and lymph nodes (P =.006). Our SAGE results have demonstrated that TOSO is a novel overexpressed antiapoptotic gene in CLL.

Short-Term Effects of Hydroxyethylstarch Resuscitation on Systemic and Regional Hemodynamics and Metabolism in a Brain-Dead Canine Model

Background. Hydroxyethylstarch (HES) is a synthetic polymer of glucose that has been suggested for therapeutic use in long-term plasma expansion. The aim of this study was to test the hypothesis that the infusion of a small volume of HES may provide benefits in systemic and regional hemodynamics and metabolism in a brain-dead canine model compared with large volume crystalloid resuscitation. Methods. Fourteen mongrel dogs were subjected to a brain-death protocol by consecutive insufflations of a balloon catheter in the epidural space. One hour after induction of brain-death, the animals were randomly assigned to two groups: NS (0.9% NaCl, 33mL/kg), and HES (6% HES 450/0.7, 17mL/Kg). Systemic and regional hemodynamics were evaluated using Swan-Ganz, ultrasonic flowprobes, and arterial catheters. Serial blood samples were collected for blood gas, electrolyte, and serum chemistry analysis. Systemic, hepatic, and splanchnic O(2)-derived variables were also calculated. Results. Epidural balloon insufflations induced a significant increase in mean arterial pressure, cardiac output (MAP and CO, respectively), regional blood flow, and systemic vascular resistance. Following the hyperdynamic phase, severe hypotension with normalization of systemic and regional blood flow was observed. Fluid resuscitation induced a prompt increase in MAP, CO, and portal vein blood flow, and a significant reduction in systemic and pulmonary vascular resistance. There were no differences between groups in metabolic indices, liver function tests (LFTs), or renal function tests. HES was more effective than NS in restoring cardiac performance in the first 2h after fluid resuscitation (P < 0.05). Both tested solutions partially and temporarily restored systemic and regional oxygen delivery. Conclusion. Small volumes of 6% HES 450/0.7 improved cardiovascular performance and provided the same regional hemodynamic and metabolic benefits of large volumes of isotonic crystalloid solutions. (C) 2011 Elsevier Inc. All rights reserved.

Histometric Study of Alveolar Bone in Rats Submitted to Ethanol During Lactation

The present work studied the adverse effects of maternal exposure of rats to alcohol during lactation, on the development of their offspring. Histometric evaluation by karyometry and of the alveolar bone at the level of the first upper molar of the sucking was perfomed. Two groups of animals, one coming from mothers exposed to drinking water containing 20% ethanol during the total lactation period and the other of controls coming from mothers receiving only alcohol-free drinking water during this period. On the 21 first day of lactation the young of each group were aleatorily selected and following anesthesia, their heads severed; after histological treatment, serial 6 mu m sections on the frontal plane at the molar level, stained with hematoxilin and eosin, were obtained. The experimental results produced, suggest that sucking from ethanol-treated mothers, show retarded post-natal growth, their alveolar bones presenting scarce, little calcified trabeculae, and a more abundant bone marrow compared to controls.

The Developing Left Superior Cervical Ganglion of Pacas (Agouti Paca)

In this study the main question investigated was the number and size of both binucleate and mononucleate superior cervical ganglion (SCG) neurons and, whether post-natal development would affect these parameters. Twenty left SCGs from 20 male pacas were used. Four different ages were investigated, that is newborn (4 days), young (45 days), adult (2 years), and aged animals (7 years). By using design-based stereo-logical methods, that is the Cavalieri principle and a physical disector combined with serial sectioning, the total volume of ganglion and total number of mononucleate and binucleate neurons were estimated. Furthermore, the mean perikaryal (somal) volume of mononucleate and binucleate neurons was estimated using the vertical nucleator. The main findings of this study were a 154% increase in the SCG volume, a 95% increase in the total number of mononucleate SCG neurons and a 50% increase in the total volume of SCG neurons. In conclusion, apart from neuron number, different adaptive mechanisms may coexist in the autonomic nervous system to guarantee a functional homeostasis during ageing, which is not always associated with neuron losses. Anat Rec, 292:966-975, 2009. (C) 2009 Wiley-Liss, Inc.

Expression analysis of matrix metalloproteinase-9 in epithelialized and nonepithelialized apical periodontitis lesions

Objective. The objective of this study was to determine the expression of matrix metalloproteinase-9 (MMP-9) in apical periodontitis lesions. Study design. Nineteen epithelialized and 18 nonepithelialized apical periodontitis lesions were collected after periapical surgery. After histological processing, serial sectioning, H&E staining, and microscopic analysis, 10 epithelialized and 10 nonepithelialized lesions were selected for immunohistochemical analysis for MMP-9 and CD 68. At least one third of each specimen collected was frozen at -70 degrees C for further mRNA isolation and reverse transcription into cDNA for real-time-PCR procedures. Geometric averaging of multiple housekeeping genes normalized MMP-9 mRNA expression level. Results. Polymorphonuclear neutrophils, macrophages and lymphocytes presented MMP-9 positive immunostaining in both types of lesions. When present, epithelial cells were also stained. The number and the ratio of MMP-9(+)/total cells were greater in nonepithelialized than epithelialized lesions (P = .0001) presenting a positive correlation to CD68(+)/total cells (P = .045). Both types of lesions presented increased MMP-9 expression (P < .0001) when compared to healthy periapical ligaments. However, no significant differences were observed for MMP-9 mRNA expression between ephithelized and nonephithelized lesions. Conclusion. The present data suggest the participation of several inflammatory cells, mainly CD68(+) cells, in the MMP-9 expression in apical periodontitis lesions. MMP-9 could be actively enrolled in the extracellular matrix degradation in apical periodontitis lesions. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; 107: 127-132)

Effects of the pendulum appliance, cervical headgear, and 2 premolar extractions followed by fixed appliances in patients with Class II malocclusion

Introduction: In this retrospective study, we compared the cephalometric effects, the dental-arch changes, and the efficiency of Class II treatment with the pendulum appliance, cervical headgear, or extraction of 2 maxillary premolars, all associated with fixed appliance therapy. Methods: The sample of 82 patients with Class II malocclusion was divided into 3 groups: group 1 patients (n = 22; treatment time, 3.8 years) were treated with the pendulum appliance and fixed orthodontic appliances. Group 2 patients (n = 30; treatment time, 3.2 years) were treated with cervical headgear followed by fixed appliances; group 3 patients (n = 30; treatment time, 2.1 years) were treated with 2 maxillary premolar extractions and fixed appliances. The average starting ages of the groups ranged from 13.2 to 13.8 years. Data were obtained from serial cephalometric measurements and dental casts. The dental casts were analyzed with the treatment priority index. The treatment efficiency index was also used. Results: The 3 treatment protocols produced similar cephalometric effects, especially skeletally. Comparisons among the 2 distalizing appliances (pendulum and cervical headgear) and extraction of 2 maxillary premolars for Class II treatment showed changes primarily in the maxillary dentoalveolar component and dental relationships. The facial profile was similar after treatment, except for slightly more retrusion of the upper lip in the extraction patients. The treatment priority index demonstrated that occlusal outcomes also were similar among the groups. The treatment efficiency index had higher values for the extraction group. Conclusions: The effects of treatment with the pendulum appliance or cervical headgear and extraction of 2 maxillary premolars associated with fixed appliances were similar from both occlusal and cephalometric standpoints. Class II treatment with extraction of maxillary teeth was more efficient because of the shorter treatment time. Differences in maxillary incisor retraction should be noted, but these differences might have been due to greater maxillary dentoalveolar protrusion in the extraction group before treatment. (Am J Orthod Dentofacial Orthop 2009;136:833-42)