Effects of bromocriptine on hepatic cytochrome P-450 monooxygenase system

We have evaluated the in vitro effects of bromocriptine (Br), on the hepatic cytochrome P-450 monooxygenase system of rats pretreated with saline phenobarbitone (PB) and beta-naphthoflavone (BNF). Br inhibited ethoxyresorufin O-dealkylase (EROD) activity in liver microsomes of rats pretreated with saline and PB but not in BNF pretreated animals. Maximum inhibition of EROD activity by Br in the microsomes of saline and PB pretreated rats were 50%-60% of the control. In contrast, a dual effect was observed on aminopyrine N-demethylase activity (APD) by Br in microsomes of saline, PB and BNF pretreated rats. At a low concentration (25 microM), Br inhibited the activity of APD to a similar extent in all pretreatment groups; however, with higher concentrations of Br (50 microM to 300 microM), enhancement of APD activity was observed. Br (300 microM) increased the APD activity to 2-3 times the control level in microsomes of rats pretreated with saline, PB or BNF. Spectral studies revealed a Type II binding of Br to cytochrome P-450 from microsomes of saline and PB pretreated rats. A reverse type I binding was observed for BNF induced microsomes. In addition, Br also enhanced NADPH cytochrome c (P-450) reductase activity to a similar extent in all pretreatment groups. These results suggest that the inhibition of EROD activity may be due to direct binding by Br to certain isozymes of cytochrome P-450 and that the enhancing effect of Br on APD activity may be in part due to the activation of the NADPH cytochrome c reductase component of the cytochrome P-450 monooxygenase system.     

Calciphylaxis – a topical overview

'Calciphylaxis', a calcification syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60-80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcification and the finding of mural calcification affecting small arteries and arterioles on histopathology help to confirm the diagnosis of this entity which generally has a poor prognosis. A high index of suspicion and an active multidisciplinary management approach, with rigorous attention to wound care and prevention of sepsis, are vital in the management of these patients. In this overview, we discuss the pathophysiology, clinical features and associations, risk factors, diagnosis and management issues relating to calciphylaxis.     

The Sigma-trial protocol: a prospective double-blind multi-centre comparison of laparoscopic versus open elective sigmoid resection in patients with symptomatic diverticulitis

Backround  

Diverticulosis is a common disease in the western society with an incidence of 33–66%. 10–25% of these patients will develop diverticulitis. In order to prevent a high-risk acute operation it is advised to perform elective sigmoid resection after two episodes of diverticulitis in the elderly patient or after one episode in the younger (< 50 years) patient. Open sigmoid resection is still the gold standard, but laparoscopic colon resections seem to have certain advantages over open procedures. On the other hand, a double blind investigation has never been performed. The Sigma-trial is designed to evaluate the presumed advantages of laparoscopic over open sigmoid resections in patients with symptomatic diverticulitis.     

Induction and depression of cytochrome P-450-dependent mixed-function oxidase by a cloned consensus alpha-interferon (IFN-alpha CON1) in the hamster

A novel analogue of human alpha-interferon (IFN-alpha CON1) was tested for its ability to modify the hepatic cytochrome P-450-dependent mixed-function oxidase system in the hamster. This cloned interferon was derived by selecting the most frequently observed amino acid sequences at each position in the known human alpha-interferon subtypes. IFN-alpha CON1 had a biphasic effect on cytochrome P-450 and related drug biotransformation in the hamster causing an initial increase followed by a significant depression. IFN-alpha CON1 also had a biphasic effect on cytochrome P-450 in the lung, adrenal and spleen but only a depressant effect in the kidney. This effect was not due to morphological damage and followed the species specificity for this type of interferon. Both the increase and the decrease in cytochrome P-450 could be prevented by the administration of the protein synthesis inhibitor puromycin. Various isozymes of cytochrome P-450 induced by phenobarbital, beta-napthaflavone and clofibrate were also depressed by this interferon. The results presented in this report suggest that IFN-alpha CON1 interferon will likely depress drug biotransformation in humans because the antiviral effects and the "anti-cytochrome P-450" effect of interferons cannot be separated, and this interferon has antiviral properties in both hamster and human cells. Clinically relevant drug interactions may be common during the concomitant use of this interferon and other drugs that are metabolized by cytochrome P-450.