Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in Trypanosoma cruzi, an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease TcPAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from Escherichia coli as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against T. cruzi epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake.

[This corrects the article on p. 693 in vol. 8, PMID: 29046637.].

Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both in vivo and in vitro. In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.

Quantitative multicomponent analysis is considered an analytical goal to save time and cost in analysis. Hence, this work aimed to provide sensitive and selective UV-spectrophotometric, chemometric manipulation, and ultra-performance LC (UPLC) methods for the determination of well-known coformulated antiemetics used in pregnancy, namely pyridoxine HCl (PYR), meclozine HCl, and cyclizine. The developed UV-spectrophotometric methods are dual wavelength in ratio spectra and first derivative of the ratio spectra with which PYR was determined selectively at 290.8 nm, whereas the other drugs in a ternary mixture were determined from their ratio spectra using a spectrum of PYR as a divisor in 0.1 M HCl. An ecofriendly partial least-squares regression chemometric method was applied to raw UV absorbance data for the determination of the ternary mixture in a 218-355 nm range using a three-factor, three-level design with water as the green solvent. A gradient UPLC method was developed and successfully resolved the ternary mixture within 5 min. Different ratios of water (adjusted to pH 3 with phosphoric acid) and methanol were delivered at 0.5 mL/min as the mobile phase into a Hypersil Gold C18 column (50 × 2.1 mm, 1.9 µm). The developed methods were successfully applied to different pharmaceutical formulations containing the aforementioned drugs and validated according to the International Conference on Harmonization guidelines. The results obtained were reproducible and reliable and can be applied for routine analysis and QC in laboratories.

In this paper, three rapid, simple, accurate and precise spectrophotometric methods were developed for the determination of meclizine hydrochloride in the presence of pyridoxine hydrochloride without previous separation. The methods under study are dual wavelength (DWL), ratio difference (RD) and continuous wavelet transform (CWT). On the other hand, pyridoxine hydrochloride (PYH) was determined directly at 291nm. The methods obey Beer's law in the range of (5-50μg/mL) for both compounds. All the methods were validated according to the ICH guidelines where the accuracy was found to be 98.29, 99.59, 100.42 and 100.62% for DWL, RD, CWT and PYH; respectively. Moreover the precision of the methods were calculated in terms of %RSD and it was found to be 0.545, 0.372, 1.287 and 0.759 for DWL, RD,CWT and PYH; respectively. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of pyridoxine hydrochloride and meclizine hydrochloride in quality-control laboratories.

Accurate and precise TLC-densitometric and HPLC-diode-array detector (DAD) methods have been developed and validated to resolve two binary mixtures containing pyridoxine hydrochloride (PYH) with either cyclizine hydrochloride (CYH) or meclizine hydrochloride (MEH). In the developed TLC-densitometric method, chromatographic separation of the three studied drugs was carried out on silica gel 60 F254 plates using a developing system containing methylene chloride + acetone + methanol (7 + 1 + 0.5, v/v/v) scanning separated bands at 220 nm. Beer-Lambert law was obeyed in the ranges of 0.2-5, 0.2-4, and 0.2-4 µg/band for PYH, CYH, and MEH, respectively. On the other hand, the developed HPLC-DAD method depended on chromatographic separation on a Zorbax Eclipse C18 column using methanol-KH2PO4 (0.05 M; 90 + 10, v/v; pH 5, with H3PO4 and KOH) as the mobile phase, a flow rate of 1 mL/min, and UV scanning at 220 nm. A linear relationship was obtained between the integrated peak area and the concentration in the ranges of 10-50, 10-50, and 7-50 µg/mL for PYH, CYH, and MEH, respectively. The proposed methods were successfully applied for the determination of the cited drugs in their pharmaceutical formulations. Statistical comparison with the reported methods using Student's t- and F-tests found there were no significant differences between the proposed and reported methods for accuracy and precision.

Sialorrhea in children with cerebral palsy (CP) results in aspiration, decreased social integration, and poor quality of life. Management options include transdermal anticholinergics such as the scopolamine patch. A controlled clinical trial has proven botulinum toxin (BTX) injections into the salivary glands are an effective alternative to transdermal anticholinergics with a safer side effect profile. Multiple studies of the injections in diverse populations demonstrate reduction in saliva production with improvement in quality of life and decrease in hospitalization-associated costs. The authors describe a 15-year-old boy with spastic quadriplegic CP who developed emesis, nausea, and lethargy 1 day after the first injection of botulinum toxin A (BTX-A) to his salivary glands for sialorrhea management. The authors ascribed his symptoms to scopolamine withdrawal. Given the lack of exposure in the medical literature, there is minimal awareness of the withdrawal syndrome from transdermal scopolamine in children with or without CP, resulting in delayed diagnosis and potential complications. Treatment of the withdrawal syndrome has been successful with meclizine though safety and efficacy has not been established in children younger than 12 despite frequent clinical and over-the-counter use. Prompt diagnosis of the transdermal scopolamine withdrawal syndrome can result in quicker treatment and a shorter hospital stay.

This study describes a specific, precise, sensitive and accurate method for simultaneous determination of hydroxyzine, loratadine, terfenadine, rupatadine and their main active metabolites cetirizine, desloratadine and fexofenadine, in serum and urine using meclizine as an internal standard. Solid-phase extraction method for sample clean-up and preconcentration of analytes was carried out using Phenomenex Strata-X-C and Strata X polymeric cartridges. Chromatographic analysis was performed on a Phenomenex cyano (150 × 4.6 mm i.d., 5 μm) analytical column. A D-optimal mixture design methodology was used to evaluate the effect of changes in mobile phase compositions on dependent variables and optimization of the response of interest. The mixture design experiments were performed and results were analyzed. The region of ideal mobile phase composition consisting of acetonitrile-methanol-ammonium acetate buffer (40 mm; pH 3.8 adjusted with acetic acid): 18:36:46% v/v/v was identified by a graphical optimization technique using an overlay plot. While using this optimized condition all analytes were baseline resolved in <10 min. Solvent mixtures were delivered at 1.5 mL/min flow rate and analytes peaks were detected at 222 nm. The proposed bioanalytical method was validated according to US Food and Drug Administration guidelines. The proposed method was sensitive with detection limits of 0.06-0.15 μg/mL in serum and urine samples. Relative standard deviation for inter- and intra-day precision data was found to be <7%. The proposed method may find application in the determination of selected antihistaminic drugs in biological fluids.