Simvastatin-tacrolimus and simvastatin-cyclosporin interactions in rats

The effect of simvastatin (SV)-tacrolimus (TL) and simvastatin-cyclosporin (CyA) interactions on creatine phosphokinase levels and renal and hepatic function were investigated in rats. Animals were divided into seven groups; (1) SV (150 mg kg⁻¹ oral) alone, (2) SV+TL (150 mg kg⁻¹ oral+0.5 mg kg⁻¹ intraperitoneal (i.p.)), (3) TL (0.5 mg kg⁻¹ i.p.) alone, (4) SV+CyA (150 mg kg⁻¹ oral+10 mg kg⁻¹ oral), (5) CyA (10 mg kg⁻¹ oral) alone, (6) control vehicle for oral administration, and (7) control vehicle for i.p. administration. A marked reduction in body weight and mortality was observed in the (SV+CyA) and (SV+TL) groups. Plasma creatine kinase levels in the (SV), (TL), (SV+CyA) and (SV+TL) groups, 7 days postadministration, were significantly higher compared with those before administration (p <0.05). The plasma urea nitrogen levels in the (TL), (SV+CyA) and (SV+TL) groups after 7 days of administration were significantly higher than those of the controls. In addition, a marked increase in the plasma levels of alanine and aspartate amino transferases were observed in the (SV+CyA) groups. © 1998 John Wiley & Sons, Ltd.     

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E(2) (PGE(2)), thromboxane A(2) and prostacyclin (PGI(2)) production. Accumulating evidence suggests that the inhibition of PGE(2) production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE(2), selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE(2) receptors have been identified. The antipyretic action of blunted PGE(2) production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP(3)) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP(1) pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP(2) or EP(4) agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP(1) or EP(3) receptors. Moreover, EP(2) receptor-deficient mice had salt-sensitive hypertension and EP(4) receptor blockade moderated salt and water excretion and both EP(2) and EP(4) agonists had renoprotective effects. This suggests that strategies to maintain activation of EP(2) and EP(4) receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP(2) and EP(4) receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.     

Prostaglandin E1 improves survival rate after 95% hepatectomy in rats

BACKGROUND/AIM: Prostaglandin E1 (PGE1) has a wide-ranging effect on cytoprotection. Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study, we examined the effect of a nontoxic HSP-inducer, PGE1, on acute liver failure after 95% hepatectomy in rats. METHODS: PGE1 or vehicle was intravenously administered to rats 30 min before and during hepatectomy. RESULTS: Nine of 30 rats pretreated with PGE1 survived, whereas all 20 rats pretreated with vehicle died within 96 h after operation. During the 24-h postoperative period, PGE1 significantly suppressed the release of alanine aminotransferase and elevation of hyaluronic acid. Histological examination showed that the vacuolized hepatocytes and round hepatocytes with pyknotic nuclei are frequently seen in rats pretreated with vehicle, whereas active regeneration is seen in rats pretreated with PGE1. During the first 24 h after surgery, HSP70 induction was absent in the residual livers of vehicle-treated rats. In contrast, PGE1 stimulated the HSP accumulation within 24 h, and viable hepatocytes contained abundant HSP70 in their nuclei. CONCLUSION: Our results suggest that PGE1 may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 production in the residual liver.     

Measurement of melatonin in body fluids: Standards, protocols and procedures

Background and Purpose  

The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6-sulfatoxymelatonin (a6MTs) in urine, is a defining feature of suprachiasmatic nucleus (SCN) function, the body’s endogenous oscillatory pacemaker. The primary objective of this review is to ascertain the clinical benefits and limitations of current methodologies employed for detection and quantification of melatonin in biological fluids and tissues.     

A case of paraspinal arteriovenous fistula in the lumbar spinal body assessed with time resolved three‐dimensional phase contrast MRI

A 93‐year‐old female with a paraspinal arteriovenous fistula (AVF) occurred within the lumbar spinal vertebral body was assessed with time resolved three‐dimensional (3D) phase‐contrast MRI (4D‐Flow) on 1.5 Tesla MR scanner (GE Healthcare). The 3D vector field, streamlines, and pathlines analyses demonstrated uni‐directional flow from the aorta to the large vascular cavity in the lumbar vertebral body by means of the lumbar artery as well as dilated paravertebral veins as drainers, which confirmed AVF, not aortic pseudoaneurysm. The 4D‐Flow also showed an added value in planned endovascular surgery concerning localization of the precise shunting point and the shunting volume quantification. J. Magn. Reson. Imaging 2012;36:1231–1233. © 2012 Wiley Periodicals, Inc.