Thermodynamic modeling of activity coefficient and prediction of solubility: Part 2. Semipredictive or semiempirical models

The solubility of stearic acid, ranitidine hydrochloride, and stavudine were predicted in selected organic solvents. The experimental solubility data of stearic acid and ranitidine hydrochloride were reported in previous work of the authors and stavudine's solubility was measured in this work. Equilibrium aqueous solubility of crystalline stauvudine was determined at controlled temperatures by stirring and filtration, with spectrophotometric quantification. The new model developed in Part 11 of this communication was modified as a semipredictive model with two adjustable parameters. Predicting the solubility data with the NRTL model using just one experimental point resulted in a big error while the modified new model and the UNIQUAC model showed much smaller errors. A new method was proposed in this work for predicting the solubility data of all polymorphs of a given compound using the experimental solubility data of one of the polymorphs of the same chemical compound. Although in general, the UNIQUAC model predictions were marginally superior, the new model is simpler and does not require the molecular parameters such as Van der Waals area and volume. The solubility prediction in a mixture of solvents using the NRTL and UNIQUAC models was also discussed.     

Ameliorative effect of Alpinia officinarum Hance extract on nonylphenol-induced reproductive toxicity in male rats

Nonylphenol (NP), an endocrine-disrupting chemical, interferes with reproductive function and induces oxidative stress in different organs, including the testis and prostate. Alpinia officinarum Hance (ALP), a plant species of the Zingiberaceae family, has proven antioxidant properties. This study aimed to evaluate the effect of the alcoholic extract of ALP treatment on NP-induced reproductive toxicity and oxidative stress in male rats using biochemical and histopathological biomarkers. Our experimental groups were defined as follows: oil treatment (control), NP 10 mg/kg, ALP 10 mg/kg (ALP HD), NP + ALP 5 mg/kg (NP + ALP LD) and NP + ALP 10 mg/kg (NP + ALP HD). NP administration caused significant cytotoxicity and a significant increase in oxidative stress prostate-specific antigen (PSA) levels accompanied by a significant reduction in testosterone levels. The relative weight of the testis of both NP + ALP LD and NP + ALP HD groups was significantly decreased compared to the control group. Histopathological evaluations revealed destructive effects in testis and prostate tissue samples. In conclusion, ALP administration improved cytotoxicity, oxidative stress, testosterone and PSA levels, and testis and prostate tissue destructive effects induced by the NP in male rats.     

Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.     

Effects of Diets Containing Fish Oil and Vitamin E on Rheumatoid Arthritis

Animal, tissue culture, and human studies have evaluated the effects of fish oil supplementation in patients with rheumatoid arthritis (RA) over the last two decades. These studies have clearly shown potentially beneficial changes in cytokine and eicosanoid metabolism. The overall clinical improvement, however, has been only moderate. European clinical trials have shown significant pain reduction in patients with RA treated with vitamin E. A recent animal study in RA-prone mice evaluated the effects of vitamin E in addition to omega-3 and omega-6 fatty acids on cytokine and eicosanoid production. The authors suggest that vitamin E might have an additional positive effect on autoimmune disease by decreasing proinflammatory cytokines and lipid mediators. Is this information ultimately important in terms of dietary advice for patients with RA? Are further clinical trials indicated? The following article will present a brief critical review.     

The effect of piperine on midazolam plasma concentration in healthy volunteers,a research on the CYP3A-involving metabolism

Some studies showed that piperine (the alkaloid of piper nigrum) can change the activities of microsomal enzymes. Midazolam concentration is applied as a probe to determine the CYP3A enzyme activity. This study was done to determine piperine pretreatment role on midazolam plasma concentration.Twenty healthy volunteers (14 men and 6 women) received oral dose of piperine (15 mg) or placebo for three days as pretreatment and midazolam (10 mg) on fourth day of study and the blood samples were taken at 0.5, 2.5 and 5 h after midazolam administration. The midazolam plasma levels were assayed using HPLC method (C18 analytical column, 75:25 methanol:water as mobile phase, UV detector at 242 nm wavelength and diazepam as internal standard). Data were fit in a “one-compartment PK model” using P-Pharm 1.5 software and analyzed under statistical tests.The mean ±SD of the age and body mass index were 24.3 ± 1.83 years (range: 21–28 years) and 23.46± 2.85, respectively. The duration of sedation in piperine receiving group was greater that the placebo group (188±59 vs. 102±43 min, p<0.0001). Half-life and clearance of midazolam were higher in piperine pretreatment group compared to placebo [1.88±0.03 vs. 1.71± 0.04 h (p<0.0001) and 33.62 ± 0.4 vs. 37.09 ± 1.07 ml/min (p<0.0001), respectively].According to the results, piperine can significantly increases half-life and decreases clearance of midazolam compared to placebo. It is suggested that piperine can demonstrate those effects by inhibition CYP3A4 enzyme activity in liver microsomal system.     

Expression of mRNA for the gap‐junctional protein connexin43 in human colonic tissue is variable in response to β‐carotene supplementation

Increased expression of the gap‐junctional protein connexin43 (Cx43) is reported to be increased in mouse and human dermal fibroblasts in vitro in response to β‐carotene treatment. In the present study, we determined the level of Cx43 mRNA expression in colonic mucosa from normal subjects and subjects with a prior history of colonic polyps or cancer before and after three months of administration of a placebo or β‐carotene. RNA was reverse transcribed and used in a polymerase chain reaction assay employing primers selected from the human Cx43 gene sequence. Cx43 mRNA expression was normalized on the basis of β₂‐microglobulin mRNA expression. The β‐carotene concentration in colonic mucosa, as well as serum and diet, was also determined to establish a correlation between Cx43 expression and β‐carotene concentration. In an initial analysis of samples collected from 10 subjects before supplementation, the quantity of Cx43 mRNA was variable and did not correlate with β‐carotene intake or the concentration of β‐carotene in tissue or serum. In samples collected at zero and three months from eight subjects who were controls or received a placebo, there was no correlation between Cx43 mRNA level and tissue or serum β‐carotene concentration. In samples collected from subjects before and after three months of β‐carotene supplementation, there was a significant increase in tissue and serum β‐carotene concentration in all subjects and an increase in Cx43 mRNA expression after supplementation relative to baseline in four of six samples. The high variability in Cx43 expression indicates that induction of Cx43 mRNA expression is not solely dependent on the concentration of β‐carotene in diet, serum, or tissue. However, the results from subjects supplemented with β‐carotene suggest that induced expression may occur in colonic tissue of some individuals.