Anti-inflammatory effects of simvastatin in nonsteroidal anti-inflammatory drugs-induced small bowel injury.

Small bowel injury can occur as the result of a multifaceted process that includes increased acid secretion, generation of reactive oxygen species, and cyclooxygenase inhibition. However, no effective medication for small bowel ulceration is available. Simvastatin is an important lipid-lowering agent with anti-inflammatory activity. We aimed to validate the effects of simvastatin in vitro and in vivo. In presence or absence of simvastatin, IEC-6 small bowel cell line with 50 ng/ml of tumor nectosis factor α (TNF-α) was investigated by western blotting, qRT-PCR, and DCF-DA assay. In addition, an in vivo study of nonsteroidal anti-inflammatory drugs (NSAID)-induced small bowel inflammation was performed using 7-week-old specific-pathogen-free (SPF) male C57BL/6 mice. Simvastatin treatment reduced the mRNA levels of interleukin-6 and interleukin-8 by approximately 50% in TNF-α-stimulated IEC-6 cells. Treatment with a combination of 50 ng/ml TNF-α and µM simvastatin decreased activation of Akt, IκBα, and nuclear factor-κB p65 level in IEC-6 cells. By DCF-DA staining, intracellular reactive oxygen species (ROS) production was increased in TNF-α-stimulated cells, and treatment with simvastatin decreased the level of ROS. In addition, in vivo mouse model of NSAID-induced small bowel inflammation, the administration of simvastatin reduced the number of small bowel hemorrhagic lesions and the level of ROS production as determined by gross examination and 8-hydroxydeoxyguanosine immunohistochemistry of small bowel tissue, respectively. Simvastatin reduced NSAID-induced injuries by both suppression of ROS generation and modulation of inflammatory cytokines in vitro and in vivo. Therefore, simvastatin, an HMG-CoA reductase inhibitor, has potential as a prophylactic and therapeutic agent for NSAID-induced small bowel injury.

Prognostic significance of glycaemic control in patients with HBV and HCV-related cirrhosis and diabetes mellitus.

AIMS: Diabetes mellitus (DM) is frequently observed in patients with cirrhosis, particularly that due to hepatitis C virus (HCV) infection. However, no studies have focused on the clinical significance of glycaemic control in cirrhotic patients because of their short life expectancy and poor hepatic function. The aim of this study was to evaluate the prognostic impact of glycaemic control in patients with hepatitis B virus (HBV) and HCV-related cirrhosis and DM. METHODS: A total of 434 patients with HCV-related (HCV group, n = 88) or HBV-related (HBV group, n = 346) cirrhosis were studied retrospectively. We determined the prevalence of DM and treatment methods for hyperglycaemia and status of glycaemic control, and the patients' outcome. RESULTS: The prevalence of DM was 43.2% (38/88) in the HCV group and 19.7% (68/346) in the HBV group. Patients in the HCV group were older with a female preponderance. DM was detected before the diagnosis of cirrhosis or simultaneously in 92% and 79% in the HCV and HBV groups, respectively. Most patients were treated with insulin or oral hypoglycaemic agents. However, blood glucose levels were maintained within the normal range in 34.2% of the HCV group and in 23.5% of the HBV group. Forty-six patients died during the observation period in both groups. Hepatic failure was the most common cause of death, and sepsis and variceal bleeding were more frequent in the HCV group than in the HBV group. Multivariate analysis showed that Child-Pugh class was the most important factor for survival in both groups. In the HCV group, the status of glycaemic control was a significant independent factor of survival (P = 0.018). In the HBV group, age and the development of spontaneous bacterial peritonitis were significant. CONCLUSION: DM is more frequent in patients with HCV-related cirrhosis than in patients with HBV. Strict control of blood glucose levels could improve survival in HCV patients. A precise assessment of the risks and benefits of glycaemic control is required to reduce the mortality and morbidity of patients with cirrhosis and DM.

Dose uniformity of ophthalmic suspensions.

PURPOSE: To quantify the rate of redispersion of three commercially available ophthalmic preparations as well as the drug content of single drops during the course of emptying a full container of suspension eyedrops. SETTING: Department of Ophthalmology, University of Köln, and Department of Pharmaceutical Technology, University of Bonn, Germany. METHODS: In a computer-controlled test apparatus used to simulate the shaking and dropping behavior of humans under strictly reproducible conditions, we studied the rate of redispersion of three ophthalmic suspensions: 50 mg indomethacin, 50 mg prednisolone-21-acetate, and 50 mg dexamethasone in 5 mL of aqueous fluid. The degree of shaking intensity essential for the redispersion of the ophthalmic suspensions was quantified in healthy persons and patients by an acceleration sensor. RESULTS: The mean dose delivered and the coefficient of variation of prednisolone were satisfactory. However, only 25% of the dexamethasone was available for administration; the rest remained in the bottle as a cake of sediment. Also, the variability of the drug content between drops was unacceptably high. The mean dose of indomethacin was adequate, but the between-drop variability was excessive. CONCLUSION: The dose uniformity of suspension eyedrops depends on their homogeneity immediately before administration. Among the formulation factors studied, particle size appears to be the most important. The various redispersion rates of the three drugs underline their clinical profile.

[Dosage problems in suspension eyedrops]. / Dosierungsprobleme bei Suspensions-Augentropfen.

PURPOSE: In opthalmic suspensions, the mean dose and the uniformity of amounts administered in single drops depend upon the redispersibility of drug particles by shaking. The present article is a contribution to the development of the experimental and theoretical basis for a reproducible test, by which the dose uniformity of suspension eyedrops can be assessed under therapeutically relevant conditions. The requirement that suspension eyedrops and similar dosage forms should be redispersable after sedimentation upon storage is stated in the monographs on eyedrops of the German Pharmacopoeia and can be found in similar contexts in other pharmacopoeias. Until now, however, no corresponding test method has been specified. METHODS: Shaking profiles were recorded in 31 subjects and 27 patients using an acceleration sensor. They were compared with the acceleration profile of a computer-controlled pneumatic shaker and sampler. Both frequency and intensity of the shaking action were quantified by Fourier analysis of the acceleration profiles. The drug content of single drops of Isopto-dex (0.1% dexamethasone), Chibro-Amuno 3 (1% indomethacin), and Inflanefran-forte (1% prednisolone acetate) was assessed exhaustively in four 5-ml specimens of each ophthalmic suspension using the apparatus. The dose uniformity of single drops of suspension eyedrops was measured by UV-spectrophotometry for the entire contents of bottles. Four samples per day were drawn after six shaking cycles for approximately 4 weeks with three intervals of 4 h during daytime and 1 interval of 12 h during the night. RESULTS: The shaking intensity of patients was lower than that of healthy subjects, while the frequency was similar for both groups. The intensity of the apparatus corresponds to the 67th percentile of the patients and to the 18th percentile of the healthy subjects. It was sufficiently close to the central values of both distributions to allow comparisons. for Isopto-dex, the mean drug content of 9.5 microns per drop amounted to only 25% of the value expected after complete redispersion, with a coefficient of variation (CV) of 23%. The mean value for Chibro-Amuno 3 was 93% of the expected quantity of indomethacin with a CV of 34%, while the mean content of Inflanefran-forte drops was 95% of the labelled dose with a CV as low as 9%. CONCLUSION: The drug content of single drops of ophthalmic suspensions can be studied under well-defined and reproducible conditions by means of a computer-controlled pneumatic shaking and sampling apparatus. Under the conditions prevailing in this study, the solidified sediment of Isopto-dex was incompletely redispersed, so that doses were significantly too low. A variable dosing pattern with acceptable mean was observed for Chibro-Amuno 3, while the results for Inflanefran-forte were fully satisfactory.