Solubility in binary solvent systems. IV. Prediction of naphthalene solubilities using the UNIFAC group contribution model

This work extends the UNIFAC group contribution method of solid-liquid equilibria to binary solvent mixtures, and compares its predictions to experimental solubilities for naphthalene in 16 different solvent mixtures. Deviations between experimental and calculated values are of the order of 10–20% for most solvent systems, and are comparable in magnitude to deviations noted in the pure solvents. The ability of the UNIFAC model to provide reasonable estimates of naphthalene solubilities based only on heat of fusion data and group contribution parameters suggests that the model may be useful in the area of drug design.     

Diagnosis of hypothyroidism: a comparison of statistical techniques.

From replies to a postal questionnaire used in a radioactive iodine follow-up scheme patients had to be classified as either "suspected hypothyroid" or "euthyroid." A comparisons has been made of the effectiveness of published statistical techniques in making this classification. Two main conclusions emerged. Firstly, all except one of the methods identified an acceptable proportion of the hypothyroid patients, and, secondly, the results given by these methods were remarkably similar. Thus the simplest, which required only a count of the number of symptoms present, was selected for use.     

Solubility in binary solvent systems. 6. Prediction of naphthalene and biphenyl solubilities based on the Wilson model

Solubilities have been determined at 30, 35 and 40° C for biphenyl in carbon tetrachloride, cyelohexane, n-hexane, n-heptane and n-octane, and tor naphthalene in benzene, cyclohexane, toluene, ethylbenzene, carbon tetrachloride and n-hexane. Results of these measurements, combined with published data at 25 °C, are used to calculate the Wilson interaction parameters and to predict the solubilities of naphthalene and biphenyl in binary solvent mixtures. The Wilson model predicts the binary solvent solubilities to within an average deviation of 2.2%, using as input data the solubilities in the pure solvents.     

Arsenic health risk assessment in drinking water and source apportionment using multivariate statistical techniques in Kohistan region,northern Pakistan

The present study was conducted in Kohistan region, where mafic and ultramafic rocks (Kohistan island arc and Indus suture zone) and metasedimentary rocks (Indian plate) are exposed. Water samples were collected from the springs, streams and Indus river and analyzed for physical parameters, anions, cations and arsenic (As³⁺, As⁵⁺ and arsenic total). The water quality in Kohistan region was evaluated by comparing the physio-chemical parameters with permissible limits set by Pakistan environmental protection agency and world health organization. Most of the studied parameters were found within their respective permissible limits. However in some samples, the iron and arsenic concentrations exceeded their permissible limits. For health risk assessment of arsenic, the average daily dose, hazards quotient (HQ) and cancer risk were calculated by using statistical formulas. The values of HQ were found >1 in the samples collected from Jabba, Dubair, while HQ values were <1 in rest of the samples. This level of contamination should have low chronic risk and medium cancer risk when compared with US EPA guidelines. Furthermore, the inter-dependence of physio-chemical parameters and pollution load was also calculated by using multivariate statistical techniques like one-way ANOVA, correlation analysis, regression analysis, cluster analysis and principle component analysis.     

The solubilities of the lower testosterone esters

The solubilities of the formate to valerate esters of testosterone have been determined in water and several organic solvents. The aqueous solubilities decrease logarithmically as the homologous series is ascended, but the acetate is less soluble than anticipated in the organic solvents. The variation in solubility from ester to ester can be predicted in the organic solvents from thermodynamic data, and is a reflection of the differences in melting point. The melting point differences are explained from the space group dimensions and the area of α to α face contact in the crystals.     

Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity

Quercetin is an equally good inhibitor of xanthine oxidase (type O, oxygen-reducing enzyme) and xanthine dehydrogenase (type D, NAD+-reducing enzyme) activity of a preparation of the xanthine-oxidizing enzyme partially purified from rat liver. The inhibition seems competitive with the oxidase form and non-competitive (mixed-type) with the dehydrogenase form of the enzyme. These inhibitory properties should be referred to the flavonoid structure of quercetin rather than to its antioxidant power. The antioxidant properties of quercetin and its inhibitory effect on the xanthine-oxidizing enzyme are discussed with reference to hyperuricemic and ischemic states.     

Prediction of precipitation-induced phlebitis: a statistical validation of an in vitro model

To avoid phlebitis, new intravenous (IV) parenterals are often screened by injection into animals. This method is not only expensive and time consuming, it is also detrimental to the animals. An alternate method, focusing on precipitation as the cause, uses an in vitro dynamic injection model that requires less money and time and reduces the need for live models. Validation of the dynamic injection apparatus, for predicting mechanical phlebitis, is established. Twenty-one currently marketed IV products were injected into isotonic Sorenson's phosphate buffer flowing at 5 mL/min. The resulting opacities, produced by precipitation, are measured in an ultraviolet flow cell. These opacity data, coupled with literature reports on phlebitis occurrence, were used to generate a logistic regression that indicates the probability of phlebitis given an opacity value measured by the apparatus. Regression results are supported by a receiver operator characteristic curve that establishes the most ideal cut-off opacity value. This opacity value provides the highest combined sensitivity (statistical power) and specificity while minimizing false-positive and false-negative results. Both analyses show that an opacity value of 0.003 best delineates phlebitic and nonphlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93), and negative predictive value (0.78) indicate the model's predictive accuracy and reliability. These results support the use of the dynamic model in place of animals for preliminary phlebitis testing of new IV injectables.     

Supplementing pharmaceutical analysis techniques using radiotracers

Radiolabeled compounds can be used for alleviating the degradation pathways and mass balance of drug products in the solid formulation, because it provides a very sensitive and specific method of locating and measuring particular compounds. The present study utilizes this methodology on levormeloxifene-a partial oestrogen receptor agonist-in the solid dosage form. It demonstrates how radiotracers can be used as a supplement to conventional analytical methods to investigate the degradation pathways and mass balance of drug substances as well as how they can be useful to cross validate the traditional analytical methods developed for the determination of uniformity of content, assay, and purity. To decrease the study time, pilot studies-in which the product was stored at high pressures of molecular oxygen and elevated temperatures-were performed. Conditions mimicking the degradation processes taking place under standard storage conditions of the drug substance were found, and these super-enhanced stress conditions were applied. The study time was thereby dramatically decreased. The produced degradation products were studied by liquid chromatography with mass spectrometric detection. The most important degradation pathway was ascribed to the oxidation of the pyrrolidine nitrogen atom in levormeloxifene to an N-oxide derivative of the drug substance.     

Bioanalytical applications using supercritical fluid techniques

The bioanalytical applications of supercritical fluid techniques, such as supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC), are of increasing interest. The main role of these techniques is in the sample preparation and separation of biologically active compounds, particularly drugs and their metabolites, as well as endogenous compounds. An insight is given into the different types of extracting fluids and modifiers, detectors, stationary phases, mobile phases and collection strategies. A critical discussion is presented on the existing state of the art concerning the applications of SFC and SFE with a specific focus on its advantages and limitations in the bioanalytical field. New developments and the possibilities for routine work in the near future are also covered.     

Theophylline-like properties of xanthine analogs

Theophylline and other methylxanthines display a large number of biological effects, some of which are clinically important. The effects of these compounds are commonly ascribed to an inhibition of cyclic AMP breakdown. However, it becomes actually evident that another mechanism, namely adenosine receptor antagonism, could be responsible for certain methylxanthine effects. It could be of interest to find new compounds displaying only one of these mechanisms, either phosphodiesterase inhibition or adenosine receptor antagonism. We have studied several synthetic imidazol[1,2a]pyrazines, some of which display theophylline-like pharmacological properties at lower doses than theophylline. We showed that some of these compounds inhibited mitogen-induced [3H]-thymidine uptake by human lymphocytes, which is consistent with increases in cyclic AMP levels: the most efficient compounds were those which were better phosphodiesterase inhibitors than theophylline and poorer adenosine receptor antagonists.     

Physiological roles of xanthine oxidoreductase

Xanthine oxidoreductase (XOR) is a major protein component of the milk fat globule membrane (MFGM) surrounding fat droplets in milk and its enzymology is well characterised. The enzyme is widely distributed in mammalian tissues and is generally accepted to be a key enzyme of purine catabolism. It catalyses the oxidation of a wide range of substrates and can pass electrons to molecular oxygen, generating reactive oxygen species (ROS); similar reduction of nitrite yields reactive nitrogen species (RNS). While XOR has been implicated in ischemia-reperfusion injury, its involvement in normal physiological processes has been less studied. It is argued here that XOR-derived ROS and RNS play a role in innate immunity, specifically in the inflammatory response and in anti-microbial defense of the gastrointestinal tract. XOR-derived species could also be involved in signalling. Additionally, XOR is likely to play a part in metabolism of xenobiotics and has recently been shown to mediate the secretion of milk fat globules. The human enzyme has only relatively recently been characterized. The enzyme purified from breast milk shows very low enzymatic activity, and it is suggested that human XOR has evolved so as to be regulated by an exceptional range of pre- and posttranslational mechanisms.     

Drug derivatives of xanthine]

The data on the pharmacological effects of xanthines and their use in pharmacotherapy, particularly, in regulation of cellular hemostasis to correct disorders of microcirculation are summarized. The possible mechanisms of hemostasis regulation by xanthines and the most promising ways of search for new antiaggregation drugs in this series are considered.     

Effect of anti-inflammatory drugs on xanthine oxidase and xanthine oxidase induced depolymerization of hyaluronic acid

The inhibitory effect of various anti-inflammatory drugs on the xanthine oxidase derived depolymerization of hyaluronic acid was studied. The depolymerization was assayed by repeated viscosity measurements. By using a low xanthine oxidase activity, the decrease in viscosity with time followed first order reaction kinetics and was therefore suitable for kinetic analysis. The xanthine oxidase activity was monitored by assay of O2-consumption with a Clark-electrode and by assay of urate production. We present evidence that salicylic, acetylsalicylic, gentisic and azodisalicylic acid and sulfasalazine inhibit the production of oxygen-derived free radicals by xanthine oxidase. We found that sulfapyridine, 5-aminosalicylic acid, allopurinol, mannitol, glucuronic acid and N-acetylglucosamine in addition to the earlier studied drugs, paracetamol, ibuprofen, benoxaprofen and gentisic acid exert their effect via scavenging of free radicals. These drugs had very little effect on the enzyme activity.