The pharmacokinetics of 38% silver diamine fluoride in healthy children with dental caries: a quasi-experimental study.

PURPOSE: Silver diamine fluoride (SDF) is a medication used for the arrestment of dental caries. This study aims to determine the pharmacokinetics (PK) of silver and fluoride following SDF application in healthy children with dental caries. METHODS: A total of 15 subjects, aged 4 to 10 years, with at least one cavity on a primary tooth, were recruited for this study. Urine samples were collected at baseline, first 24 h (F1) and second 24 h (F2) after SDF treatment for analysis of silver and fluoride content. Hair samples were also collected at baseline and at 7, 14, 30, 60, 75, and 90 days after SDF treatment to analyze silver content. RESULTS: Participants with under or over-collection of urine, or failure to provide urine collection were excluded for fluoride analysis. As a result, eight subjects' urine samples were eligible for fluoride analysis. Significant correlations were observed between baseline urinary fluoride levels and F1/F2 levels. Pairwise comparisons from Friedman's test showed significant differences between baseline and F1 fluoride levels. For silver analysis, 15 subjects were studied. F1 urinary silver levels were higher than baseline and F2 levels. Subsequent to SDF treatment, hair silver levels displayed fluctuations around the baseline. None of the participants reported adverse effects, and all caries teeth ceased progression within 30 days. CONCLUSIONS: The urinary fluoride levels after SDF treatment, although higher, were not clinically significant. Urinary and hair silver levels were negligible. Therefore, SDF appears safe to be used among children.

Effects of CYP3A5 Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Renal Transplant Recipients.

BACKGROUND: The aim of this study was to compare the within-patient variability trough levels (Co), dose-adjusted Co, and dose requirements of Prograf and Advograf with CYP3A5 polymorphisms in Malaysia renal transplant recipients. METHODS: Stable post-renal transplantation patients switched from Prograf to Advograf were retrospectively identified from University Malaya Medical Centre (n = 28). Co and concomitant tacrolimus dose 6 months preconversion and postconversion were examined. CYP3A5 was genotyped using reverse transcriptase polymerase chain reaction. Wilcoxon signed rank test and Mann-Whitney U test were used to compare Co and dose between formulations and according to genotypes. RESULTS: There was a significant difference in the whole-blood tacrolimus Co between the 2 groups (6.16 ± 1.74 ng/mL vs 4.90 ± 1.06 ng/mL; P = .0001). The mean daily maintenance dose of Prograf was 3.9 ± 2.0 mg/kg (0.06 mg/kg/d), which was reduced to 3.3 ± 1.7 mg/d (0.04 mg/kg/d) with Advograf (P = .01). The mean maintenance dose of tacrolimus required for those with CYP3A5*1/*1 (high-expressive) was significantly higher than those with CYP3A5*1/*3 (intermediate-expressive) and CYP3A5*3/*3 (low-expressive) (P < .01) for both formulations. Comparing those with CYP3A5*1/*1, the average dose-adjusted Co was significantly higher in patients with CYP3A5*3/*3 with Advograf (P < .05). CONCLUSIONS: The requirement for daily maintenance dose was higher in those with CYP3A5*1/*1 variants in both tacrolimus formulations in the Malaysian patients. Furthermore, those with CYP3A5*3/*3 demonstrated significantly higher dose-adjusted Co with Advograf.

Analysis of melamine migration from melamine food contact articles.

Migration of melamine has been determined for 41 types of retail melamine-ware products in Malaysia. This study was initiated by the Ministry of Health, Malaysia, in the midst of public anxiety on the possibility of melamine leaching into foods that come into contact with the melamine-ware. Thus, the objective of this study was to investigate the level of melamine migration in melamine utensils available on the market. Samples of melamine tableware, including cups and plates, forks and spoons, tumblers, bowls, etc., were collected from various retail outlets. Following the test guidelines for melamine migration set by the European Committee for Standardisation (CEN 2004) with some modifications, the samples were exposed to two types of food simulants (3% acetic acid and distilled water) at three test conditions (25°C (room temperature), 70 and 100°C) for 30 min. Melamine analysis was carried out using LC-MS/MS with a HILIC column and mobile phase consisting of ammonium acetate/formic acid (0.05%) in water and ammonium acetate/formic acid (0.05%) in acetonitrile (95 : 5, v/v). The limit of quantification (LOQ) was 5 ng/ml. Melamine migration was detected from all samples. For the articles tested with distilled water, melamine migration were [median (interquartile range)] 22.2 (32.6), 49.3 (50.9), 84.9 (89.9) ng/ml at room temperature (25°C), 70 and 100°C, respectively. In 3% acetic acid, melamine migration was 31.5 (35.7), 81.5 (76.2), 122.0 (126.7) ng/ml at room temperature (25°C), 70 and 100°C, respectively. This study suggests that excessive heat and acidity may directly affect melamine migration from melamine-ware products. However the results showed that melamine migration in the tested items were well below the specific migration limit (SML) of 30 mg/kg (30,000 ng/ml) set out in European Commission Directive 2002/72/EC.

Comparative bioavailability study of two salbutamol tablets in healthy adult volunteers.

This study was carried out to compare the rate and extent of absorption of a generic salbutamol in oral dosage form (Brethmol, 4 mg) with the proprietary equivalent product (Ventolin, 4 mg), in healthy adult subjects, under fasting conditions. The study was a single dose, randomized, two way crossover study with a four-week washout period. It involved 22 healthy volunteers who received a single dose (4 mg) of the test and the reference products after an overnight fast of at least 10 hours. Blood samples were collected at pre-dose and a serial of 14 samples were collected from each of the subject from 1 h until 48 h post-dose. Plasma concentrations of salbutamol were analyzed using GCMS method. The mean AUC(0-yen) values were 91.26 and 96.45 h.ng/ml for reference and test product, respectively. The mean C(max) values were 12.26 and 12.38 ng/ml and the mean t(max) values were 2.80 and 2.33 hours for reference and test product, respectively. Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC(0-yen) and the C(max) for the test and reference products were contained within the bioequivalence limit (80 - 125%) (C(max): 89.8 - 110.5% and AUC(0-yen): 91.6 - 121.5%). There was no statistically significant difference for the t(max) between the test and reference formulations (p = 0.30). The test formulation was found to be bioequivalent to the reference formulation with regard to AUC(0-yen) and C(max). There was no statistically significant difference in Brethmol and Ventolin t(max). In conclusion, Brethmol and Ventolin are bioequivalent in healthy subjects.

Correcting endogenous concentrations of testosterone influences bioequivalence and shows the superiority of TDS(R)-testosterone versus Androgel(R).

AIM: Circulating concentrations of endogenous compounds such as testosterone, complicate the analysis of pharmacokinetic parameters when these compounds are administered exogenously. This study examines the influence of three correction methods of accounting for endogenous concentrations on the determination of bioequivalence between two testosterone formulations. METHODS: 12 healthy males received 50 mg TDS-testosterone, TDS-placebo, and 50 mg Androgel in a randomized placebo controlled study. Three correction methods (1,2 and 3) to remove the influence of endogenous testosterone from the exogenous blood concentrations data were carried out before the calculation of the AUC and Cmax. The relative bioavailabilities between two treatments were then performed for the AUC and Cmax for all the corrected and uncorrected data. Correction 4 was performed on the AUC and the Cmax values and the average values were calculated for both active treatments. RESULTS: The relative bioavailability comparison of the AUC and Cmax, showed that the TDS-testosterone and Androgel was bioequivalent by using uncorrected data (CI: 93 - 120%; AUC0-12 and 88 - 117%; Cmax). However, they were not bioequivalent when using all the corrections data ((Corr. 1; CI: 52 - 106%; AUC0-12 and 50 - 258%; Cmax), (Corr. 2; CI: 71 - 655%; AUC0-12 and 87 - 286%; Cmax), (Corr. 3; CI: 67 - 315%; AUC0-12 and 88 - 157%; Cmax)). TDS-testosterone also showed the higher AUC0-12 and Cmax compared to Androgel for uncorrected and all the Corrections 1, 2, 3 and 4. CONCLUSIONS: Different results obtained in the relative bioavailability between TDS-testosterone and Androgel for uncorrected data and corrected data, suggests that correcting endogenous concentrations is important for the proper determination of bioequivalent for endogenous compounds such as testosterone.

Validation and application of capillary electrophoresis for the analysis of lidocaine in a skin tape stripping study.

A fast and simple capillary zone electrophoresis method was developed and validated for the determination of lidocaine in skin using tape samples. Separation was performed in a 350 mm (265 mm to window) x 50 microm i.d. fused silica capillary using a background electrolyte of phosphoric acid-Tris pH 2.5. The extraction of lidocaine from tape samples was achieved using methanol, which was diluted to 50% with water before injection. Procaine was the internal standard. The migration times for procaine and lidocaine were 2.9 and 3.2 min, respectively. The limit of quantification for lidocaine was 50 microg, with signal to noise ratio greater than 10. The calibration curve was linear from 50 to 1000 microg with r(2) greater than 0.99. The CV for both within- and between-assay imprecision and the percentage of inaccuracy for the quality control samples including lower and upper limits of quantitation were 97%. The accuracy and selectivity of this method allowed the measurement of lidocaine in tape samples obtained from a skin tape stripping study of local anesthetics in healthy subjects.

Validation of high-performance liquid chromatographic-mass spectrometric method for the analysis of lidocaine in human plasma.

A sensitive and simple liquid chromatography-tandem mass spectrometry method is developed and validated for the determination of lidocaine in human plasma. Bupivacaine is used as an internal standard, and the plasma extraction is performed by a simple liquid-liquid extraction. The limit of quantitation (LOQ) is 0.5 ng/mL with a signal-to-noise ratio greater than 5. The calibration curve is linear from 0.5 to 250 ng/mL with an r2 greater than 0.99. The coefficients of variation for within- and between-assay imprecision, including LOQ, are < or = 13% and < or = 8%, respectively. The percentage of inaccuracy for within- and between-assay, including LOQ, are < or = 9% and < or = 5%, respectively. The absolute recovery of lidocaine and bupivacaine are greater than 84% and 82%, respectively. The higher sensitivity and accuracy of this method allow the measurement of low concentrations of lidocaine in plasma from a clinical study of topically applied lidocaine in healthy subjects.

Pharmacokinetics of a new testosterone transdermal delivery system, TDS-testosterone in healthy males.

AIMS: The Transdermal Delivery System (TDS) is a liquid formulation that can be applied to the skin via a metered pump spray to deliver drug to the systemic circulation. The aims of this study were to assess the ability of the TDS preparation to deliver testosterone systemically, and to characterize the pharmacokinetic profiles of the hormone in healthy males. METHODS: An open label, comparative, randomized placebo controlled study involving three treatments and three periods with a minimum of a 1 week washout period was conducted. Twelve healthy males received 50 mg TDS-testosterone, TDS-placebo, and 50 mg of a commercially available topical testosterone preparation (Androgel, 1% topical testosterone gel). RESULTS: The mean AUC(0,12 h) was higher following application of TDS-testosterone (61.8 ng ml-1 h), compared with Androgel (57.7 ng ml-1 h) and TDS-placebo (50.7 ng ml-1 h. The mean Cmax (0,12 h) was similar for TDS-testosterone (6.6 ng ml-1) and Androgel (6.5 ng ml-1) and these values were higher than those for TDS-placebo (5.7 ng ml-1). Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC(0,12 h) and the Cmax (0,12 h) between TDS-testosterone and Androgel, were contained within the bioequivalence limit (80, 125%) (Cmax 89.2, 112.3% and AUC 93.5, 120.5%). Serum testosterone concentrations were lower following TDS-Placebo and were not bioequivalent either to the gel or spray. CONCLUSIONS: The TDS preparation was shown to deliver testosterone systemically to humans and the concentrations of the hormone in the 12 h following TDS administration were bioequivalent to an existing topical delivery gel.

Study of a combined percutaneous local anaesthetic and the TDS system for venepuncture.

Transdermal Delivery System (TDS) is a liquid formulation which can be applied to the skin via a metered pump spray to deliver drug across skin. This placebo controlled, double blind trial compared anaesthetic properties of two TDS systems (TDS alpha and TDS beta) with placebo. The active and placebo treatments were applied to the dorsum of the hands, bilaterally and simultaneously for 5 min on 100 healthy volunteers. Following cannulation, pain perception was measured using the verbal rating score (VRS) and visual analogue score (VAS). Lidocaine plasma levels were assessed at 0 and 2 h. The VRS and VAS results show that TDS beta significantly decreased pain score compared to placebo (p < 0.02). Blood lidocaine at 2 h post application was also higher for TDS beta than for TDS alpha, suggesting that a 5 min application of TDS beta was effective in delivering local anaesthetic and accelerating the onset of skin anaesthesia prior to venous cannulation in adults.