Pharmacokinetics, hepatic biotransformation and biliary and urinary excretion of bromosulfophthalein (BSP) in an experimental liver disease mimicking biliary cirrhosis

We studied the hepatic handling of bromosulfophthalein in healthy rabbits with hepatic coccidiosis 28 days after an experimental infection with sporulated oocysts of Eimeria stiedai, an experimental model of liver disease histopathologically resembling primary biliary cirrhosis in man. A pharmacokinetic study of the results was performed following a multicompartmental model with 7 transfer constants to describe the physiological disposition of the dye. The study showed that the plasma disappearance, distribution volume (Vi), hepatic biotransformation and the biliary and urinary elimination of conjugated (BSPc) and unconjugated (BSPu) bromosulfophthalein were markedly altered. Whereas Vi and urinary excretion of the dye were significantly increased, the hepatic clearance, biotransformation and biliary excretion of BSPc and BSPu were drastically reduced in infected rabbits. Satisfactory agreement was obtained between the experimental and estimated data, particularly those relating to biotransformation clearance and biliary and urinary excretion of the dye. These results demonstrate that severe liver disease in rabbits with histopathological liver alterations resembling several hepatic dysfunctions in man markedly reduce hepatic uptake, metabolism and biliary excretion of a xenobiotic such as BSP.     

Susceptibility to endometrial cancer: influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P-450 (CYP1A1) loci.

A case-control study was designed to identify associations between polymorphisms at p53, cytochrome P-450 (CYP1A1) and glutathione-S-transferases and endometrial cancer susceptibility. Among all polymorphisms analysed, an insertional variant in p53 (P53PIN3) and two polymorphisms in the 3''-end and exon 7 of CYP1A1 showed significant association with enhanced endometrial cancer risk.     

Nitrate administration to enhance the detection of myocardial viability by technetium-99m tetrofosmin single-photon emission tomography

A comparison was performed between technetium-99m tetrofosmin myocardial perfusion tomography at baseline and after nitrate administration, using a 2-day protocol, and rest-reinjection thallium-201 single-photon emission tomography (SPET) studies in order to assess whether nitrates enhance the detection of viable myocardium with^99mTc-tetrofosmin. Fifteen patients with coronary artery disease, previous myocardial infarction and a left ventricular ejection fraction <40% underwent²⁰¹T1 rest-injection and^99mTc-tetrofosmin. baseline-postnitroglycerin (0.4 mg sublingually) SPET studies, within 48 h. Tomograms based on the three spatial planes were divided into 15 segments and regional tracer uptake was quantitatively analysed. Viability was defined as presence of tracer uptake >50% of peak activity on baseline studies or after reversibility. The percentage of peak activity of^99mTc-tetrofosmin at baseline correlated with that of 201T1 (r=0.82,P <0.001). On baseline^99mTc-tetrofosmin studies, 73 of the 225 segments that were analysed had <50% of peal. activity. Fifteen percent of these segments showed reversibility after nitrate administration, with an increase in^99mTc-tetrofosmin uptake from 40%±9% to 57%±9% of peak activity (P=0.003). All reversible segments after nitrate administration had viability criteria on²⁰¹Tl studies, but 20 segments that were non-viable on^99mTc-tetrofosmin. studies were viable on²⁰¹Tl studies. Using a threshold value of >40% of peak activity, only seven segments remained non-viable on^99mTc-tetrofosmin studies. Overall agreement between^99mTc-tetrofosmin with nitrates and²⁰¹Tl-reinjection regarding the presence of myocardial viability was 90%. Detection of myocardial viability with^99mTc-tetrofosmin. was enhanced after nitrate administration, correlating with viability criteria observed on thallium studies.     

Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma

BACKGROUND: Regular use of inhaled corticosteroids (ICSs) can improve asthma symptoms and prevent exacerbations. However, overall adherence is poor among patients with asthma. Objective To estimate the proportion of poor asthma-related outcomes attributable to ICS nonadherence. METHODS: We retrospectively identified 405 adults age 18 to 50 years who had asthma and were members of a large health maintenance organization in southeast Michigan between January 1, 1999, and December 31, 2001. Adherence indices were calculated by using medical records and pharmacy claims. The main outcomes were the number of asthma-related outpatient visits, emergency department visits, and hospitalizations, as well as the frequency of oral steroid use. RESULTS: Overall adherence to ICS was approximately 50%. Adherence to ICS was significantly and negatively correlated with the number of emergency department visits (correlation coefficient [ R ] = -0.159), the number of fills of an oral steroid ( R = -0.179), and the total days' supply of oral steroid ( R = -0.154). After adjusting for potential confounders, including the prescribed amount of ICS, each 25% increase in the proportion of time without ICS medication resulted in a doubling of the rate of asthma-related hospitalization (relative rate, 2.01; 95% CI, 1.06-3.79). During the study period, there were 80 asthma-related hospitalizations; an estimated 32 hospitalizations would have occurred were there no gaps in medication use (60% reduction). CONCLUSIONS: Adherence to ICS is poor among adult patients with asthma and is correlated with several poor asthma-related outcomes. Less than perfect adherence to ICS appears to account for the majority of asthma-related hospitalizations.     

Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation

BACKGROUND: Histologic and immunohistologic features of nasal polyps (NP) are similar to those observed in asthma, thus suggesting a similar immunopathology. OBJECTIVE: The primary objective of this study was to further understand the anti-inflammatory and immunoregulatory effects of locally delivered corticosteroids. To this end, the effect of intranasal budesonide on the expression of specific cytokines, lymphocyte subsets, and epithelial remodeling in this model of airway tissue inflammation were studied. METHODS: We used immunohistochemical techniques to examine nasal mucosae (NM) from healthy individuals and nasal polyp (NP) tissues from patients with nasal polyposis obtained before and after intranasal budesonide treatment. RESULTS: First, the density of CD8(+) cells was markedly increased in NP tissues after intranasal budesonide treatment from 16.1 +/- 8.4 (M +/- SEM) per mm(2) to 39.9 +/- 24.1. Second, the density of cells immunoreactive for IL-4, IL-5, IFN-gamma, IL-12, and TGF-beta in NP was significantly greater than in control NM tissues. The density of IL-4(+) and IL-5(+) cells in NP tissues significantly decreased after budesonide treatment from 40 +/- 12 to 17.8 +/- 8 and from 19.3 +/- 11 to 10.4 +/- 7, respectively. In contrast, the density of IFN-gamma(+) and IL-12(+) cells remained unchanged. In addition, we found that the density of TGF-beta(+) cells significantly increased after intranasal budesonide from 18 +/- 5 to 41 +/- 9. Third, damage to the entire length of the NP epithelium was quantified using a grading system. The epithelium of untreated NP was substantially damaged; remarkable epithelial restitution with no apparent changes in stromal collagen deposition was observed after intranasal budesonide treatment. CONCLUSIONS: These findings demonstrate that intranasal budesonide induced an increase in CD8 population and a selective regulatory effect on tissue cytokine expression. Furthermore, intranasal budesonide promoted epithelial remodeling. We hypothesize that these immunoregulatory and remodeling effects elicited by steroids might be, at least in part, mediated by the induction of TGF-beta.     

Biliary lipid secretion in the regenerating liver of the rat.

The effect of two-thirds hepatectomy on biliary lipid secretion was studied in fasted rats. Bile acids, cholesterol and phospholipids were determined in the bile of rats with biliary drainage. Bile acid and phospholipid concentrations were not significantly modified during liver regeneration but there was a significant decrease in cholesterol concentrations in bile at 12 h after hepatectomy, with a gradual return to normal values. The molar percentage of cholesterol and the calculated lithogenic index of bile were also significantly decreased by 12 h. The biliary secretion of bile acids and phospholipids, expressed per gram of liver, showed a tendency to increase regeneration, but cholesterol secretion was significantly decreased from 12 to 48 h following liver resection. Some possibilities to explain the uncoupling between cholesterol secretion and bile acid secretion are discussed.