Assessment of groundwater pollution in Tokyo using PPCPs as sewage markers.

While the occurrence of pharmaceuticals and personal care products (PPCPs) in groundwater has typically been reported in bank filtration sites, irrigated fields, septic tanks, and sewage disposal practices, fewer studies have been conducted in highly urbanized areas, where infiltration of treated or untreated sewage is not supposed to be a source of groundwater recharge. Furthermore, little is known about the occurrence of various kinds of PPCPs in relation to microbial indicators in groundwater from different types of aquifers. Thus, we examined the city-wide occurrence of selected PPCPs (diethyltoluamide, crotamiton, ethenzamide, propyphenazone, carbamazepine, and caffeine) and E. coli in 50 groundwaters from unconfined aquifers (<30 m in depth) and confined aquifers (up to 500 m in depth) in Tokyo, where unintended groundwater contamination could take place due to decrepit sewer networks. PPCPs were detected in unconfined aquifers and springs (23/34 samples, 68%), and in confined aquifers (7/16 samples, 44%). Compared with published results for sewage influents, concentrations of PPCPs, excluding caffeine, were generally 1-2 orders of magnitude lower, while in some samples concentrations were quite comparable. The high occurrence rate of PPCPs, even in confined aquifers, indicated that such aquifers are not always protected from pollution by sewage near the land surface. Among the PPCPs analyzed, carbamazepine and crotamiton were most frequently detected, which would appear to be owing to their high persistence, combined with the high concentration of crotamiton in sewage. Crotamiton was detected in all four E. coli-positive groundwaters, and thus may potentially serve as a precautionary indicator of E. coli contamination. Using carbamazepine as a sewage marker, we estimated that 0.8%-1.7% of the dry-weather flow of sewage was leaking out into the unconfined aquifers.

Development of a multicommuted flow-through optosensor for the determination of a ternary pharmaceutical mixture.

The combination of multicommutation and flow-through multioptosensing is presented in this work as a powerful strategy for the routine analysis of active principles in pharmaceuticals. By coupling methodologies, the selectivity and sensitivity of optosensors is maintained, while the use of the multicommutation approach provides additional advantages, such as low reagent consumption, low waste generation and reduced human supervision. The potential of this integration is enhanced when implemented with multiwavelength detection mode. An UV sensor is here developed for the simultaneous determination of three widely used active principles: salicylamide, caffeine and propyphenazone. The measuring wavelengths were 276 nm for caffeine and propyphenazone, and 302 nm for salicylamide. The five three-way solenoid valves used in the system are controlled by Java-written home-made software. The sensor is based on the on-line selective retention of two of the three analytes on a precolumn placed just before the sensing zone and filled with the same solid support than the flow-through cell (C(18) silica gel). This approach allows the sequential arrival of the analytes to the sensing zone, so allowing their determination with only one sample injection. So, the use of C(18) placed, in both the precolumn and the flow-cell combines the advantages of the increase of sensitivity and selectivity in the detection solid zone with the additional increase of the selectivity in the precolumn. The sensor was applied to the determination of the analytes in several pharmaceutical preparation of the Spanish Pharmacopoeia, obtaining satisfactory results.

Molecular Ionization-Desorption Analysis Source (MIDAS) for Mass Spectrometry: Thin-Layer Chromatography.

Molecular ionization-desorption analysis source (MIDAS), which is a desorption atmospheric pressure chemical ionization (DAPCI) type source, for mass spectrometry has been developed as a multi-functional platform for the direct sampling of surfaces. In this article, its utility for the analysis of thin-layer chromatography (TLC) plates is highlighted. Amino acids, which are difficult to visualize without staining reagents or charring, were detected and identified directly from a TLC plate. To demonstrate the full potential of MIDAS, all active ingredients from an analgesic tablet, separated on a TLC plate, were successfully detected using both positive and negative ion modes. The identity of each of the compounds was confirmed from their mass spectra and compared against standards. Post separation, the chemical signal (blue permanent marker) as reference marks placed at the origin and solvent front were used to calculate retention factor (Rf) values from the resulting ion chromatogram. The quantitative capabilities of the device were exhibited by scanning caffeine spots on a TLC plate of increasing sample amount. A linear curve based on peak are, R2 = 0.994, was generated for seven spots ranging from 50 to 1000 ng of caffeine per spot.

Simultaneous spectrophotometric determination of paracetamol and salicylamide in human serum and pharmaceutical formulations by a differential kinetic method.

A rapid, simple, and sensitive differential kinetic method is presented for the determinations of acetaminophen (also known as paracetamol) and salicylamide. The method is based on their oxidation reaction by Fe3+ ion in the presence of 1, 10-phenanthroline as indicator. The reactions can be monitored spectrophotometrically by measuring the increase in the absorbance of the solution at 510 nm. Two times were selected one in which only paracetamol is oxidized by Fe3+ ion and the other in which both drugs are oxidized by Fe3+ ion. The data were evaluated by the proportional equations method. The method allowed the simultaneous determination of paracetamol and salicylamide at concentrations between 0.5-20 and 1-40 microg/mL with relative standard deviations of 3.47 and 2.58%, respectively. The method was applied to the simultaneous determination of paracetamol and salicylamide in human serum and pharmaceutical formulations.

Reference region modeling approaches for amphetamine challenge studies with [11C]FLB 457 and PET.

Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [(11)C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [(11)C]FLB 457 dopamine D2/D3 binding. Six healthy tobacco smokers were imaged with [(11)C]FLB 457 at baseline and at 3 hours after amphetamine (0.4 to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [(11)C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [(11)C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [(11)C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2.

Determination of salicylamide and five metabolites in biological fluids by high-performance liquid chromatography.

Two high-performance liquid chromatographic (HPLC) assay procedures were developed for the determination of salicylamide and its metabolites in serum, urine, and saliva. One method involves reverse-phase ion-pair chromatography and UV detection, and is used to determine salicylamide, salicylamide glucuronide, and salicylamide sulfate. The other method, with a different mobile phase and without the ion-pairing reagent, is used to determine gentisamide (the hydroxylated metabolite of salicylamide), gentisamide glucuronide, and gentisamide sulfate. The assays are performed by direct injection of the sample after protein precipitation with ethanol containing the internal standard. Increased sensitivity for the determination of low concentrations of salicylamide is obtained by organic extraction of this drug from serum or saliva. Calibration curves for the conjugates of salicylamide and gentisamide were obtained, in the absence of authentic standards, by partial enzymatic hydrolysis, using the decrease of the conjugate peaks and the concomitant increase of free salicylamide or gentisamide concentrations to determine peak area ratio-concentration relationships. Application of the HPLC assay procedures to the determination of salicylamide excretion products in the urine of three normal human subjects resulted in 98.6% (range:97.1-100.1%) recovery of a 1-g oral dose of the drug. All five metabolites of salicylamide were found in urine, but only salicylamide glucuronide, salicylamide sulfate, and gentisamide glucuronide were found consistently and in appreciable quantities. Salicylamide and all of its metabolites except gentisamide sulfate were found in human and rat serum, and unconjugated salicylamide as well as gentisamide were found in human saliva.

Rapid spectrophotometric determination of salicylamide in analgesic tablets.

An independent, simple, and rapid procedure is suggested for the routine analysis of salicylamide in analgesic tablets containing acetaminophen, phenobarbital, caffeine, codeine phosphate, prednisone, ascorbic acid, and chloroquine phosphate. The method does not require the preliminary separation of salicylamide from other constituents by the time-consuming solvent extraction technique or by chromatography prior to determination. The absorbance was linear for investigated concentrations of salicylamide from 0 to 4.0 mg/100 ml of solution at 308 nm.

Differentiating nonaqueous titration of aspirin, acetaminophen, and salicylamide mixtures.

Mixtures containing aspirin, acetaminophen, and salicylamide were assayed potentiometrically by nonaqueous titration. The difference in pKa values for these weak acids was sufficient to permit successful differentiation. The titrant was tetrabutylammonium hydroxide, and the titration solvent was dimethylformamide. The procedure was applied to commercial dosage forms.

Simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide by high-pressure liquid chromatography.

A method for the simultaneous quantitation of acetaminophen, aspirin, caffeine, codeine phosphate, phenacetin, and salicylamide was developed. The method is based on reversed-phase high-pressure liquid chromatography with a mobile phase buffered with phosphate (pH 2.3). The procedure not only separated these six active ingredients but also salicylic acid, the major decomposition product of aspirin. The method gave excellent results for three commercial products and a synthetic mixture containing four active ingredients. Lowering the pH increased the retention time of some weak acids and decreased that of some weak bases. Only these changes in the retention times made the separation possible.

Spectrofluorometric determination of acetylsalicylic acid, salicylamide, and salicyclic acid as an impurity in pharmaceutical preparations.

Spectrofluorometry, either direct or in combination with a separation technique, provides a sensitive and accurate method for the determination of certain extent fluorescent analgesic drugs and the determination of impurities in many combination preparations. A critical examination of the UV spectra of common analgesics and related compounds indicates that the fluorescence inner filter effect should be negligible below 10(-5) M and that selective excitation and emission wavelengths should minimize interference from other fluorescent species. Fluorometric procedures are presented for the determination of salicylamide, acetylsalicylic acid, and salicylic acid, as an impurity, in preparations containing salicylamide, acetylsalicylic acid, acetaminophen, caffeine, and phenacetin as major constituents. Inner filtering is the limiting factor only for the direct and indirect determination of salicylamide and the direct determination of acetylsalicylic acid. Results of fluorometric determinations compare favorably with other reference methods. Salicylic acid is determined in the 10(-7) M concentration range after separation from salicylamide, acetaminophen, and caffeine.

Simultaneous GLC analysis of salicylamide, phenylpropanolamine hydrochloride, caffeine, chlorpheniramine maleate, phenylephrine hydrochloride, and pyrilamine maleate in capsule preparations.

A GLC method is described for the quantitative determination of salicylamide, phenylpropanolamine hydrochloride, caffeine, chlorpheniramine maleate, phenylephrine hydrochloride, and pyrilamine maleate. The sample was dissolved in ethanol, and an aliquot of the solution was brought to dryness and treated with 0.1 ml of 4-(dimethyl-amino)pyridine in pyridine-acetic anhydride (1:1). The components were isolated and measured by applying 1 microliter of the reaction mixture to a chromatograph equipped with a flame-ionization detector and fitted with 8% OV-101 glass columns. The accuracy was good. Dicyclohexylphthalate was used as the internal standard.

Quantitative analysis of tribromsalan in blood and urine.

Tribromsalan can be quantitatively measured in whole blood and urine by a technique involving extraction with ethyl acetate, treatment with silica gel, separation by TLC, and quantitative measurement by fluorescent spectrophotometry. This method has a sensitivity down to 125 ng (25 ppb in 5.0 ml of sample) of free tribromsalan and shows an average 90% recovery of tribromsalan in blood and urine with standard deviations of 9.7 and 7.4%, respectively.

Stability of salicylamide-caffeine complex at different temperatures and its thermodynamic parameters.

The stability constants for formation of complexes of salicylamide with caffeine have been measured between 15 and 45degrees, by means of the solubility method. There was a linear solubility increase at all temperatures but phase diagrams indicated that at 15 and 25degrees an additional phase was formed which was found to be an insoluble 1 : 1 complex. The enthalpies and entropies of interactions were evaluated. They indicate that the interaction is exothermic and enthalpy controlled.

The dissolution mechanism in a system undergoing complexation: salicylamide in caffeine solution.

The dissolution rate of compressed salicylamide discs has been measured in water and in caffeine solutions of increasing concentration at 15, 25, 37 and 45 degrees in an apparatus rotating at 48 rev min-1 or more. Dissolution rate profiles showed breaks indicative of a shift in the mechanism of dissolution from interfacial towards transport control. The shifts occurred at higher caffeine concentrations on increasing the agitation rate or temperature. The dependencies of dissolution rates on agitation rates typified the intermediate type of dissolution and Arrhenius plots indicated that interfacial and transport processes participated in salicylamide dissolution.

Crystallographic, theoretical and molecular modelling studies on the conformations of the salicylamide, raclopride, a selective dopamine-D2 antagonist.

The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamid e (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (less than 4.0 kcal mol-1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.

FT-IR and NMR spectroscopic studies of salicylic acid derivatives. I. Gentisamide -- a metabolite of salicylamide.

Gentisamide (GAM, 2,5-dihydroxybenzamide), a minor first-pass metabolite of salicylamide (SAM, 2-hydroxybenzamide), was studied using FT-IR, 1D and 2D homo- and heteronuclear 1H and 13C NMR spectroscopy. GAM was isolated from human urine eight hours after oral administration of SAM. FT-IR, 1H and 13C NMR spectra unequivocally confirmed the chemical structure of GAM through chemical and substituent shifts, coupling constants and connectivities in COSY, NOESY, HETCOR and HBMC spectra. From NOESY spectra of GAM in DMSO-d6, it was concluded that the amide protons are oriented toward the ortho-proton at C-6. Obtained results indicate that the presence of the additional phenol group at C-5 in GAM favours the formation of intramolecular hydrogen bonding of the O...HO type between C2-OH proton and oxygen atom of the amide group.

Effect of certain additives on the diffusion characteristics through a cellophane membrane of acetylsalicylic acid, salicylamide and phenacetin. Part 1: Effect of certain surface active agents.

The diffusion rate (D. R.) of certain ionic and non-ionic surfactant concentrations through a standard cellophane membrane was studied. D. R. of acetylsalicylic acid significantly increased in the presence of 0.1% w/v Brij 35, Tween 20 or 40 respectively. The other tested surfactants slightly increased D. R. of acetylsalicylic acid, while that of salicylamide increased in presence of 0.1% w/v of either Tween 20, 40, 60 or 80; Myrj 52 or 59; Brij 58; benzalkonium chloride, cetrimide or sodium lauryl sulphate. The highest D. R. of phenacetin was observed in presence of either 0.01% w/v Tween 20 or 0.001% w/v Brij 35.

Availability studies on acetylsalicylic acid, salicylamide and phenacetin at different pH values.

The optimum partitioning rate of acetylsalicylic acid has been attained at pH = 4 and minimum partitioning rate was found to be at pH = 8. The maximum partitioning rate of salicylamide was observed at pH = 5 and the smallest one was found at pH = 6 or 8. At pH = 3 a maximum amount of phenacetin was found in the aqueous phase, while at pH = 6 a maximum amount was found in the octanolic layer. The maximum partitioning rate was found at pH = 6 and lowest one was observed at pH = 3. The gastrointestinal absorption of acetylsalicylic acid, salicylamide and phenacetin was significantly increased, as reflected by the urinary excretion data in presence of solid buffer components at pH values of 4,5 and 6 respectively.

[Use of a densitometric method for analysis of active substances in the drugs. XVI. Multicomponent drugs containing ascorbic acid]. / Zastosowanie pomiarów densytometrycznych do oznaczania skladników czynnych w lekach.

A densitometric method for the determination of active substances in Ascofer, Fenquil, Rutinoscorbin and Scorbolamid after separation of their components by means of TLC-has been elaborated. Usefulness of the method was checked by comparison of the obtained results with those afforded by means of reference methods.

[A fatal case due to intoxication with seven drugs detected by GC-MS and TDx methods].

A twenty-year-old woman was suspected to ingest large amounts of 4 kinds of over-the-counter analgesic and antipyretic drugs, and was found dead. Drugs and poisons were screened by TOXI-LAB drug detection system in the serum and urine, and analyzed by GC-MS and TDx system in the blood, urine, organ tissues and contents of stomach and small intestine. The concentrations (microgram/g) of bromisovalum, apronalide, ibuprofen, ethenzamide, acetaminophen and caffeine in the heart blood were 36.5, 7.58, 43.1, 16.9, 1.22 and 177, respectively. Salicylic acid concentration in the serum was 82.1 micrograms/ml. The concentrations of bromisovalum and caffeine are high enough to be lethal levels. Neither fatal pathological findings nor traumatic wounds were seen. The overdose of both bromisovalum and caffeine and synergistic, additive or combined effects of other 5 drugs above are considered to be her cause of death.