- Galleria mellonella larvae allow the discrimination of toxic and non-toxic chemicals. [Journal Article]
- CChemosphere 2018 Feb 06; 198:469-472
- The acute toxicities of 19 chemicals were assessed using G. mellonella larvae. The results obtained were compared against LD50 values derived from in vitro cytotoxicity tests and against in vivo acut...
The acute toxicities of 19 chemicals were assessed using G. mellonella larvae. The results obtained were compared against LD50 values derived from in vitro cytotoxicity tests and against in vivo acute oral LD50 values. In general, cell culture systems overestimated the toxicity of chemicals, especially low toxicity chemicals. In contrast, toxicity testing in G. mellonella larvae was found to be a reliable predictor for low toxicity chemicals. For the 9 chemicals tested which were assigned to Globally Harmonised System (GHS) category 5, the toxicity measured in G. mellonella larvae was consistent with their GHS categorisation but cytotoxicity measured in 3T3 or NHK cells predicted 4 out of 9 chemicals as having low toxicity. A more robust assessment of the likely toxicity of chemicals in mammals could be made by taking into account their toxicities in both cell cultures and in G. mellonella larvae.
- Effects of antihistamines on the H295R steroidogenesis - Autocrine up-regulation following 3β-HSD inhibition. [Journal Article]
- TVToxicol In Vitro 2018 Feb 01; 48:302-309
- Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive ...
Millions of people of all ages suffer from allergies worldwide and as a consequence antihistamines are among the most commonly prescribed pharmaceuticals in the world. We investigated the disruptive effects of three antihistamines, promethazine (PMZ), cetirizine (CET) and fexofenadine (FEX) on the H295R steroidogenesis. A multi-steroid LC-MS/MS method was used to quantify 13 steroid hormones in the steroidogenesis. In addition, real-time RT-PCR was used to determine if exposure to antihistamines altered gene expression in the cell line. When exposing the H295R cells to PMZ and CET, significant increases in Δ5-steroids and significant decreases in Δ4-steroids were observed, indicating an inhibition of 3β-hydroxysteroid dehydrogenase (3β-HSD). A sequential decrease in corticosteroids, androgens and estrogens were also observed. Overall, FEX had no effect on the steroidogenesis even though minor effects were observed at the highest concentrations. Real-time RT-PCR showed that PMZ resulted in significant up-regulation of 3β-HSD and 17β-HSD, whereas CET only resulted in up-regulation of 3β-HSD. This indicated that the decrease in steroids downstream from 3β-HSD following PMZ and CT exposure induced a compensatory autocrine response in 3β-HSD gene expression. The effects on the steroidogenesis were observed at concentrations 30-50 times higher than the therapeutic plasma concentrations. However, antihistamines are lipophilic and may accumulate in adrenals and gonads. Thus, disruptive effects of PMZ and CET on human steroidogenesis cannot be excluded.
- Reductions in Corpus Callosum Volume Partially Mediate Effects of Prenatal Alcohol Exposure on IQ. [Journal Article]
- FNFront Neuroanat 2017; 11:132
- Disproportionate volume reductions in the basal ganglia, corpus callosum (CC) and hippocampus have been reported in children with prenatal alcohol exposure (PAE). However, few studies have investigat...
Disproportionate volume reductions in the basal ganglia, corpus callosum (CC) and hippocampus have been reported in children with prenatal alcohol exposure (PAE). However, few studies have investigated these reductions in high prevalence communities, such as the Western Cape Province of South Africa, and only one study made use of manual tracing, the gold standard of volumetric analysis. The present study examined the effects of PAE on subcortical neuroanatomy using manual tracing and the relation of volumetric reductions in these regions to IQ and performance on the California Verbal Learning Test-Children's Version (CVLT-C), a list learning task sensitive to PAE. High-resolution T1-weighted images were acquired, using a sequence optimized for morphometric neuroanatomical analysis, on a Siemens 3T Allegra MRI scanner from 71 right-handed, 9- to 11-year-old children [9 fetal alcohol syndrome (FAS), 19 partial FAS (PFAS), 24 non-syndromal heavily exposed (HE) and 19 non-exposed controls]. Frequency of maternal drinking was ascertained prospectively during pregnancy using timeline follow-back interviews. PAE was examined in relation to volumes of the CC and left and right caudate nuclei, nucleus accumbens and hippocampi. All structures were manually traced using Multitracer. Higher levels of PAE were associated with reductions in CC volume after adjustment for TIV. Although the effect of PAE on CC was confounded with smoking and lead exposure, additional analyses showed that it was not accounted for by these exposures. Amongst dysmorphic children, smaller CC was associated with poorer IQ and CVLT-C scores and statistically mediated the effect of PAE on IQ. In addition, higher levels of PAE were associated with bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after control for TIV, child sex and age, socioeconomic status, maternal smoking during pregnancy, and childhood lead exposure. These data confirm previous findings showing that PAE is associated with decreases in subcortical volumes and is the first study to show that decreases in callosal volume may play a role in fetal alcohol-related impairment in cognitive function seen in childhood.
- Inhibition of hepatic apolipoprotein A-I gene expression by histamine. [Journal Article]
- EJEur J Pharmacol 2018 Mar 15; 823:49-57
- In a recent high throughput analysis to identify drugs that alter hepatic apolipoprotein A-I (apo A-I) expression, histamine receptor one (H1) antagonists emerged as potential apo A-1 inducing drugs....
In a recent high throughput analysis to identify drugs that alter hepatic apolipoprotein A-I (apo A-I) expression, histamine receptor one (H1) antagonists emerged as potential apo A-1 inducing drugs. Thus the present study was undertaken to identify some of the underlying molecular mechanisms of the effect of antihistaminic drugs on apo AI production. Apo A-I levels were measured by enzyme immunoassay and Western blots. Apo A-I mRNA levels were measured by reverse transcription real-time PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA as the internal control. The effects of histamine and antihistamines on apo A-I gene were determined by transient transfection of plasmids containing the apo A-I gene promoter. Histamine repressed while (H1) receptor antagonist azelastine increased apo A-I protein and mRNA levels within 48 h in a dose-dependent manner. Azelastine and histamine increased and suppressed, respectively, apo A-I gene promoter activity through a peroxisome proliferator activated receptor α response element. Treatment of HepG2 cells with other H1receptor antagonists including fexofenadine, cetirizine, and diphenhydramine increased apo A-I levels in a dose-dependent manner while treatment with H2receptor antagonists including cimetidine, famotidine, and ranitidine had no effect. We conclude that H1receptor signaling is a novel pathway of apo A1 gene expression and therefore could be an important therapeutic target for enhancing de-novo apo A-1 synthesis.
- First-in-human implantation of a novel self-expanding supra-annular transcatheter heart valve for transcatheter aortic valve implantation inside a small degenerated aortic surgical bioprosthesis. [Case Reports]
- CCCatheter Cardiovasc Interv 2018 Jan 23
- With next-generation valves such as the ALLEGRA valve from NewValve Technologies (NVT), Hechingen Germany, there is a very likely treatment expansion for patients with aortic valve disease. Besides t...
With next-generation valves such as the ALLEGRA valve from NewValve Technologies (NVT), Hechingen Germany, there is a very likely treatment expansion for patients with aortic valve disease. Besides treatment of native valvular aortic stenosis with the ALLEGRA valve, the special implant mechanism seems to be an appealing concept for patients with degenerated surgical bioprostheses. We report the first case of a transfemoral implantation in small degenerated surgical bioprosthesis of a 76-year-old woman.
- Curcumin as an In Vivo Selective Intestinal Breast Cancer Resistance Protein Inhibitor in Cynomolgus Monkeys. [Journal Article]
- DMDrug Metab Dispos 2018 Jan 22
- To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observa...
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selectiveBCRP inhibition, in addition to several well-known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole. Oral area under the plasma concentration-time curve (AUC) and bioavailability of well-known BCRP (sulfasalazine and rosuvastatin), P-glycoprotein (fexofenadine, aliskiren, and talinolol), and cytochrome P450 (CYP)3A (midazolam) substrates were investigated in the presence and absence of inhibitors. Oral exposures of sulfasalazine and rosuvastatin were markedly elevated by curcumin with minimal changes in systemic clearance, whereas pharmacokinetic alterations after fexofenadine, aliskiren, and talinolol oral exposure were limited. Curcumin increased oral midazolam exposure without affecting systemic clearance, presumably due to partial inhibition of intestinal CYP3A. Lapatinib increased the oral AUC for sulfasalazine to a greater extent than curcumin did, whereas pantoprazole had a smaller effect. However, lapatinib also exerted significant effects on fexofenadine, failed to selectively discriminate between BCRP and P-glycoprotein inhibition, and had an effect on oral midazolam exposure comparable with that of curcumin. Thus, pharmacokinetic evaluation in monkeys demonstrated that pretreatment with curcumin as an in vivo selective BCRP inhibitor was more appropriate than pretreatment with lapatinib and pantoprazole for the assessment of the impact of BCRP on gastrointestinal absorption in non-rodent models.
- Organic anion transporting polypeptide 1a4 is responsible for the hepatic uptake of cardiac glycosides in mice. [Journal Article]
- DMDrug Metab Dispos 2018 Jan 18
- Among organic anion transporting polypeptide (Oatp) family transporters expressed in the rodent liver, such as Oatp1a1, Oatp1a4, Oatp1b2, and Oatp2b1, Oatp1a4 has a unique character to recognize neut...
Among organic anion transporting polypeptide (Oatp) family transporters expressed in the rodent liver, such as Oatp1a1, Oatp1a4, Oatp1b2, and Oatp2b1, Oatp1a4 has a unique character to recognize neutral cardiac glycosides as substrate in addition to organic anions. The relative contribution of Oatp1a4 to the substrate uptake into hepatocytes has not been clarified. In this study, we investigated the importance of Oatp1a4 in the hepatic uptake of its substrate drugs using Slco1a4-/-mice. The hepatic mRNA expression of Slco1a4 was decreased significantly in Slco1a4-/-mice, whereas no differences were seen in other hepatic transporters between wild-type and Slco1a4-/-mice. We determined the plasma concentrations, and liver-to-plasma ratio of Oatp1a4 substrates including ouabain, digoxin, BQ-123, fexofenadine, rosuvastatin, pravastatin, nafcillin, and telmisartan, after continuous intravenous infusion. The plasma concentrations of ouabain and rosuvastatin were 2.1 and 1.7-fold higher in Slco1a4-/-mice, and the liver-to-plasma concentration ratios of ouabain and digoxin were 13.4 and 4.3-fold lower in Slco1a4-/-mice, respectively. Furthermore, the biliary clearance of ouabain and digoxin with regard to plasma concentration were 21.9 and 4.1-fold lower in Slco1a4-/-mice, respectively, accompanied with a marked reduction in their liver-to-plasma ratios, whereas the systemic clearance of ouabain, but not digoxin, was reduced significantly in Slco1a4-/-mice. These results suggest that Oatp1a4 plays a major role in the hepatic accumulation of cardiac glycosides in mice.
- Preparation of β-cyclodextrin-gold nanoparticles modified open tubular column for capillary electrochromatographic separation of chiral drugs. [Journal Article]
- EElectrophoresis 2018 Jan 10
- In this paper, β-cyclodextrin (β-CD) modified gold nanoparticles (AuNPs) coated open tubular column (OT column) was prepared for capillary electrochromatography. The open tubular column was construct...
In this paper, β-cyclodextrin (β-CD) modified gold nanoparticles (AuNPs) coated open tubular column (OT column) was prepared for capillary electrochromatography. The open tubular column was constructed through self-assembly of gold nanoparticles on 3-mercaptopropyl-trimethoxysilane (MPTMS) prederivatized capillary and subsequent modification of thiols β-cyclodextrin (SH-β-CD). Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and ultraviolet visible spectroscopy were carried out to characterize the prepared open tubular column and synthesized gold nanoparticles. By comparing different coating times of gold nanoparticles and thiols β-cyclodextrin, we got the optimal conditions for preparing the open tubular column. Also, the separation parameters were optimized including buffer pH, buffer concentration and applied voltage. Separation effectiveness of open tubular column was verified by the separation of four pairs of drug enantiomers including bifonazole, fexofenadine, omeprazole and lansoprazole, and satisfactory separation results were achieved for these analytes studied. In addition, the column showed good stability and repeatability. The relative standard deviation values less than 5% were obtained through intra-day, inter-day, and column-to-column investigations.
- Sorption of citalopram, irbesartan and fexofenadine in soils: Estimation of sorption coefficients from soil properties. [Journal Article]
- CChemosphere 2018; 195:615-623
- The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic,...
The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic, and citalopram cationic and neutral), in seven different soils was studied. The measured sorption isotherms were described by Freundlich equations, and the sorption coefficients, KF(for the fixed n exponent for each compound), were related to the soil properties to derive relationships for estimating the sorption coefficients from the soil properties (i.e., pedotransfer rules). The largest sorption was obtained for citalopram (average KFvalue for n = 1 was 1838 cm3 g-1) followed by fexofenadine (KF = 35.1 cm3/nμg1-1/ng-1, n = 1.19) and irbesartan (KF = 3.96 cm3/nμg1-1/ng-1, n = 1.10). The behavior of citalopram (CIT) in soils was different than the behaviors of irbesartan (IRB) and fexofenadine (FEX). Different trends were documented according to the correlation coefficients between the KFvalues for different compounds (RIRB,FEX = 0.895, p-value<0.01; RIRB,CIT = -0.835, p-value<0.05; RFEX,CIT = -0.759, p-value<0.05) and by the reverse relationships between the KFvalues and soil properties in the pedotransfer functions. While the KFvalue for citalopram was positively related to base cation saturation (BCS) or sorption complex saturation (SCS) and negatively correlated to the organic carbon content (Cox), the KFvalues of irbesartan and fexofenadine were negatively related to BCS, SCS or the clay content and positively related to Cox. The best estimates were obtained by combining BCS and Cox for citalopram (R2 = 93.4), SCS and Cox for irbesartan (R2 = 96.3), and clay content and Cox for fexofenadine (R2 = 82.9).
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- Mast Cell Activation Syndrome. [Journal Article]
- SSkinmed 2017; 15(6):477-479
- A 51-year-old woman with a history of asthma and Hashimoto's thyroiditis presented to the dermatology service with a chief complaint of "itchy bumpy rashes" that persisted beyond 24 hours. She noted ...
A 51-year-old woman with a history of asthma and Hashimoto's thyroiditis presented to the dermatology service with a chief complaint of "itchy bumpy rashes" that persisted beyond 24 hours. She noted that, 3 days prior to the onset of urticaria, a pyrroloquinoline quinone supplement had been started. The urticaria was accompanied by variable episodes of transient facial swelling and difficulty breathing. The patient noted that exposure to fish, nuts, and nonsteroidal anti-inflammatory drugs triggered facial swelling. Other reported findings included a 5-year history of diarrhea, sense of memory deterioration, concentration difficulties, and clinical manifestations of anomic aphasia. Although her allergy testing was "negative," she had been given the diagnoses of lactose intolerance and gastroesophageal reflux disease. Laboratory studies on initial presentation were significant for a positive history of antithyroperoxidase antibodies and elevated total complement activity. Medications included budesonide/formoterol, fluticasone/salmeterol, levothyroxine, albuterol, and fexofenadine 180 mg twice daily. Although her "rash" had initially responded to fexofenadine, it soon became refractory to treatment. Her family history was significant only for thyroid disease.