Prevention of bacterial infection and sepsis in acute severe pancreatitis.

Between 1984 and 1986 six patients with acute respiratory failure (requiring ventilation for at least 3 days) complicating acute pancreatitis were managed on the intensive care unit (median ventilation period 6 days; range 3-41 days). Between 1987 and 1989 nine similar patients were managed (median ventilation period 35 days, range 4-69 days), and a regimen of enteral tobramycin, polymyxin and amphotericin to selectively decontaminate the digestive tract (SDD) was introduced. Five of six patients treated before 1987 had serious infections (three Gram-negative, one fungal), compared with only one of nine patients treated with SDD (P < 0.05). Clinical signs of sepsis were evident for 62% of the pre-SDD period, compared with 39% of the period during SDD therapy (P < 0.001). Systemic antibiotic prescribing was reduced in the SDD group; however, mortality remained unaffected with only two patients surviving pre-SDD and three during SDD treatment. SDD reduces infection rates and sepsis in patients with acute pancreatitis and may help to improve the prognosis of this life-threatening condition.     

Induction of Leydig cell adenomas by ammonium perfluorooctanoate: a possible endocrine-related mechanism.

Ammonium perfluorooctanoate (C8) produced an increased incidence of Leydig cell adenomas in Crl:CD BR (CD) rats fed 300 ppm for 2 years. A hormonal (nongenotoxic) mechanism was examined since C8 was negative in short-term tests for genotoxicity. Adult male CD rats were gavaged with either 0, 1, 10, 25, or 50 mg/kg C8 for 14 days. In addition, a control group was pair-fed to the 50 mg/kg C8 group. A dose-dependent decrease in body and relative accessory sex organ (ASO) weights was seen, with the relative ASO weights of the 50 mg/kg group significantly less than those of the pair-fed control. Serum estradiol levels were elevated in the 10, 25, and 50 mg/kg C8-treated animals. Estradiol levels in the 50 mg/kg C8 group were 2.7-fold greater than those in the pair-fed control. The increase in serum estradiol levels occurred at the same dose levels as the increase in hepatic beta-oxidation activity. A statistically significant downward trend with dose was seen in serum testosterone levels when compared with the ad libitum control. However, when the 50 mg/kg C8-treated rats were compared with their pair-fed control, no significant differences were seen. Challenge experiments, which can identify the presence and location of a lesion in an endocrine axis, were undertaken to clarify the significance of this downward trend in serum testosterone following C8 exposure. In the challenge experiments, adult CD rats were gavaged with either 0 or 50 mg/kg C8 for 14 days. One hour before termination, rats received either a human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH), or naloxone challenge. Following hCG challenge, serum testosterone levels in the 50 mg/kg C8 were significantly decreased (50%) from those in the ad libitum controls. Similar decreases, although not significant, were seen in serum testosterone following GnRH and naloxone challenge. The challenge experiments suggest that the decrease in serum testosterone following C8 exposure is due to a lesion at the level of the testis. In addition, progesterone, 17 alpha-hydroxyprogesterone, and androstenedione were examined in the 50 mg/kg C8-treated males following hCG challenge. A 60% decrease was observed in androstenedione levels in the C8-treated animals from those in the ad libitum controls; no other differences were seen. These data suggest that the decrease in serum testosterone following hCG challenge may be due to a decrease in the conversion of 17 alpha-hydroxyprogesterone to androstenedione. The observed effects described above can be attributed to the elevated serum estradiol levels.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhibition and metabolite complexation of rat hepatic microsomal cytochrome P450 by tricyclic antidepressants.

Administration of imipramine (IMIP) and other tricyclic antidepressants to humans and experimental animals has been associated with inhibition of hepatic cytochrome P450 (P450)-mediated drug oxidation. This study investigated the capacity of several structurally related tricyclic antidepressants to inhibit microsomal P450 activity in vitro. It was found that IMIP, desipramine (DES), amitriptyline (AMIT) and nortriptyline (NOR) were poor inhibitors of P450 activity unless they were preincubated with microsomes and NADPH prior to transfer to flasks containing substrate. Thus, subsequent experiments characterized the time-dependent intensification of inhibition produced by the drugs. Preincubation of the N-methylaminoalkyl agents DES and NOR (200 microM) with NADPH-supplemented microsomes for 30 min led to an approximate 30% decrease in spectrally apparent P450 content; the N,N-dimethylaminoalkyl drugs IMIP and AMIT did not significantly decrease apparent P450 content. Analysis of optical difference spectra of microsomes during NADPH-mediated metabolism of these drugs revealed a prominent increase in absorbance at 454 nm with DES and NOR but not IMIP or AMIT. Monospecific antibodies to the male-specific P450 2C11 and, to a lesser extent, P450 3A2 were effective in preventing the formation of the DES metabolite 454 nm-Soret peak. In addition, the 454 nm absorbance was not produced by the incubation of DES with NADPH-fortified hepatic microsomes from adult female or immature male rats. Studies with the steroid substrate testosterone, which undergoes P450-specific positional hydroxylation, indicated that P450 2C11-mediated 2 alpha- and 16 alpha-hydroxylation were most susceptible to the time-dependent intensification of inhibition produced by DES (8.5 and 7.0 min preincubation required for loss of 50% activity, respectively) and NOR (4.0 and 4.0 min for loss of 50% of both activities). The 6 beta- (P450 3A2) and 7 alpha-hydroxylase (P450 2A1) pathways were somewhat less susceptible to inhibition than 2 alpha- and 16 alpha-hydroxylation. These findings suggest that DES and NOR form a metabolite intermediate (MI)-complex, characterized by a Soret region absorbance maximum near 454 nm in the optical difference spectrum, with microsomal P450 in male rat liver in vitro. Studies with the steroid substrate testosterone as well as immunoinhibition experiments are consistent with the proposition that this MI complex forms principally with the male-specific enzymes P450 2C11 and 3A2. Although a human orthologue of P450 2C11 has not yet been identified, P450s of the 3A subfamily are quantitatively important enzymes in human liver. MI complexation of such enzymes could be a feasible underlying mechanism for certain clinically important drug interactions involving tricyclic antidepressants.     

Sleep disorders in women: clinical evidence and treatment strategies.

Sleep disorders are more prevalent in women than in men. Sex hormones modulate sleep-wake behaviors and mood and may contribute to heightened risk across the life cycle of women. Sleep disorders may have a unique expression in women, emerging throughout their reproductive life cycle. These conditions require careful treatment strategy to manage medical, hormonal, and behavioral contributing factors to poor sleep efficiency and impaired quality of life. This review focuses on clinical evidence for sleep disorders in women and discusses existing evidence of risk factors and treatment options for insomnia and sleep-disordered breathing in women.     

Ethics roundtable debate: Patients and surrogates want 'everything done' – what does 'everything' mean?

Highly complex and specialized care plans sometimes overwhelm the comprehension of patients and families. Many optimistic surrogates of critically ill patients err on the side of desiring that everything be done but with a nebulous idea of what 'everything' entails. Physicians must work closely to educate surrogates as to the benefits versus the risks of treatment. Our roundtable experts ponder the question of whether providers possess the authority to interpret unilaterally the nature of requests for everything.