Biomedical subjects

P V Desmond

Publications and source records attributed to P V Desmond.

At least 19 recordsLinked to original sources

PubMed2005

Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.

BACKGROUND: Chronic hepatitis B infection (CHB) is a major health problem in Australia and worldwide. CHB is associated with significant long-term morbidity and mortality. Well tolerated treatment is now available, however the development of resistance is common and the optimal timing of treatment is yet to be determined. Identifying the factors that influence the natural history of CHB may help determine which patients need treatment and when to start it. OBJECTIVE: To determine the demographics, clinical features and virological profile of Australian patients infected with CHB and the influence of these factors on disease activity and severity. STUDY DESIGN: Review of prospectively collected demographic, clinical and virological features of all patients positive for hepatitis B surface antigen (HBsAg) for more than 6 months who were referred to St. Vincent's Hospital liver clinics. Age, sex and ethnicity were correlated with hepatitis B e antigen status (HBeAg), HBV replication status (ALT and HBV DNA), genotype and liver histology. RESULTS: 703 chronic hepatitis B surface antigen positive patients were identified. The patients were predominantly male with an average age of 44. Eighty two percent of patients were born overseas, primarily from Asian (65%) and Mediterranean countries (14%). Two thirds (426) had an elevated ALT (median 79) at presentation. HBeAg was positive in 37%. Active viral replication, defined as abnormal ALT or positive HBVDNA, was present in 74%, 48% of whom were HBeAg negative. In a subset of 103 patients genotyped, 8% had genotype A, 29% B, 41% C and 22% D. Genotype correlated with ethnicity; patients infected with genotypes A were predominantly Caucasian, B and C were Asian, and D were Mediterranean. Of 296 (42%) patients who underwent liver biopsy, 76 (27%) had advanced fibrosis. Advanced fibrosis was associated with increasing age and Mediterranean ethnicity. CONCLUSION AND RECOMMENDATIONS: Perinatal or early childhood transmission is predominant mode of infection in Australia. Two thirds of this cohort had active replication and were at increased risk of developing cirrhosis and/or hepatoma. Advanced disease was associated with age and ethnicity. HBeAg negative CHB accounts for almost half of all those with active viral replication. This parallels the rise in this form of CHB in Asia and the Mediterranean basin. Screening should be offered to people born in, or with parents born in areas of high endemnicity. To detect the development of active disease, patients with positive HBsAg but normal ALT should have liver function tests done 6 monthly and those with elevated ALT should be referred for consideration of therapy, irrespective of HBeAg status.

Antiviral Agents↗

PubMed2003

Prospective assessment of the diagnostic and therapeutic impact of small-bowel push enteroscopy.

BACKGROUND AND STUDY AIMS: Although the reported diagnostic yield of push enteroscopy has been substantial in previous studies, its clinical impact has never been prospectively evaluated. The primary aim of this study was to prospectively determine the diagnostic and therapeutic impact of enteroscopy. In addition, the yield of new and clinically important findings was prospectively assessed. PATIENTS AND METHODS: Consecutive patients referred for enteroscopy were studied. The referring clinician completed a form indicating the working diagnosis, degree of diagnostic certainty, and the management plan had enteroscopy been unavailable. Diagnostic certainty was indicated on a scale of 1 = very unlikely (1 - 9 %) to 6 = certain (100 %). Following enteroscopy, the referring doctor completed another form indicating these features in the light of the enteroscopic findings. RESULTS: The study group comprised 77 patients referred for 79 push enteroscopies. There was a change in working diagnosis or management plan as a result of enteroscopy in 39/77 (51 %) patients. The working diagnosis and the management plan changed in 29/77 (38 %) and 34/77 (44 %), respectively, and the diagnostic certainty changed in a further 29 patients (38 %). There were clinically significant small-bowel findings in 16 (20 %) and new upper gastrointestinal findings in 16 (20 %), giving an overall diagnostic yield of 40 %. CONCLUSIONS: Enteroscopy has a significant impact on clinicians' working diagnoses and management plans.

Adult↗

PubMed2001

Use of an overtube for enteroscopy--does it increase depth of insertion? A prospective study of enteroscopy with and without an overtube.

BACKGROUND AND STUDY AIMS: Although a stiffening overtube is commonly used with push enteroscopy, in the belief that this will allow increased insertion into the small intestine, there is no prospective data to support this view. The aim of this study is to prospectively study the depth of insertion into the small intestine at enteroscopy with and without an overtube. PATIENTS AND METHODS: A total of 38 patients referred for enteroscopy were prospectively studied. Alternate enteroscopies were performed with or without an overtube; therefore 19 patients had enteroscopy with and 19 without an overtube. The groups were well matched for age, sex, indication, use of fluoroscopy, and dedicated anesthetic assistance. Depth of insertion was assessed by advancing the enteroscope as far as possible, then straightening the enteroscope until the tip began withdrawing. The difference between the straightened insertion depth and the distance from the incisors to the pylorus was recorded as the insertion depth beyond the pylorus. This was considered the major end point. Statistical analysis was performed using the Mann-Whitney test for nonparametric data. RESULTS: The median straightened total insertion depth from the incisors was greater when enteroscopy was performed with an overtube compared with enteroscopy without an overtube (125 cm vs. 110 cm, P=0.05). The median straightened insertion depth beyond the pylorus was significantly greater with overtube use (70 cm vs. 50 cm, P = 0.01). No significant difference between the groups was observed in terms of the likelihood of significant findings at enteroscopy. CONCLUSIONS: Use of an overtube for push enteroscopy results in significantly deeper insertion into the small intestine. Although a larger study would be needed to demonstrate an increase in diagnostic yield and to confirm the safety of overtube use, this study does provide the first objective evidence of an advantage in terms of insertion depth.

Adult↗

PubMed2001

Investigation of potential iatrogenic transmission of hepatitis C in Victoria, Australia.

OBJECTIVE: To determine the level of exposure to medical and surgical procedures among Australian-born patients whose mode of acquisition of the hepatitis C virus (HCV) is unknown. METHOD: Place and time of study: Melbourne, Australia, 1998-2000. DESIGN: Retrospective case series. INSTRUMENT: Structured questionnaire administered by one interviewer. SETTING: Referral centre for hepatitis C in a tertiary teaching hospital. PARTICIPANTS: Australian-born individuals persistently HCV antibody (anti-HCV) positive on at least two second-generation commercial assays. MAIN OUTCOME MEASURES: Demographic and self-reported exposure data. RESULTS: Of 135 anti-HCV positive individuals with no known mode of transmission, 54 (40%) individuals fulfilled all the entry criteria and agreed to participate. Of the 54 cases, 53 had at least one medical/surgical procedure and/or invasive dental work; 46 (85%) had dental extractions, 19 (35.2%) had complex dental work, e.g. root canal, 44 (82%) had an operation requiring general anaesthesia, 41 (75.9%) had a procedure requiring local anaesthetic, and a number of endoscopic procedures were reported: gastroscopy (n=3), colonoscopy (n=3), laparoscopy (n=4), arthroscopy (n=5), cystoscopy (n=2). CONCLUSION: We have documented exposure to medica/surgical procedures among HCV patients with no previously recognised mode of transmission. IMPLICATIONS: The findings of this study have important public health implications for current cleaning, disinfection and sterilisation procedures and protocols (or lack of these) as well as for the policies and guidelines relating to the re-use of medical equipment such as multi-dose vials, suturing material and anaesthetic circuits.

Cross Infection↗

PubMed2001

Changes in hepatitis C-related liver disease in a large clinic population.

BACKGROUND: Hepatitis C virus (HCV) infection is a significant problem in the Australian community. Over the past few years, the number of patients with diagnosed hepatitis C has increased greatly. The aims of the present study were to define the clinical features of a large group of patients with chronic HCV infection and to examine changes occurring in the referral base and epidemiological characteristics of this group since analysis of the first 342 patients in 1994. METHODS: The study included 1,546 consecutive anti-HCV-positive patients who had been referred to St Vincent's Hospital from January 1990 to June 1998. Clinical and laboratory data were collected on all patients. RESULTS: Referrals from general practitioners increased from 31% to 70% of all patients between 1990-1993 and 1994-1998. A history of injecting drug use (IDU) was present in 64% of the patients. While 89% of the IDU group was Australasian born, 49% of those in the sporadic group were born overseas. Cirrhosis was found in 18% of biopsied patients. Age, infection duration, age at infection, Mediterranean or Asian origin and a history of transfusion or lack of HCV risk factors were associated with cirrhosis on univariate analysis. Patient age was the only independent predictor of cirrhosis. CONCLUSION: The majority of patients with HCV are diagnosed in general practice. A risk factor for infection is identified in 82% of patients. While our reported prevalence of cirrhosis may be an overestimate of that in the overall HCV community, the ultimate disease burden is likely to be significant.

Adult↗

PubMed2000

Alcohol up-regulates UDP-glucuronosyltransferase mRNA expression in rat liver and in primary rat hepatocyte culture.

The interactions between alcohol and cytochrome P-450 enzymes have been well investigated. However, the data regarding the effect of alcohol on the regulation of UDP-glucuronosyltranferase (UGT) activity are less clear. The aim of the present study was to determine the role of alcohol in the regulation of UGT mRNA expression by using whole animal and primary cultured hepatocytes. Chronic ethanol feeding of rats significantly increased the expression of liver UGT1A1 mRNA to 177% of control. The mRNA levels for UGT1A5, UGT2B1 and UGT2B3 were also enhanced, but did not reach statistical significance. In cultured hepatocytes, treatment with either ethanol or isopentanol significantly increased the expression of UGT1A1, UGT1A5, UGT2B1, and UGT2B3 mRNAs, but to different degrees. The induction of UGT1A1 and UGT2B1 mRNAs by ethanol or isopentanol was time-dependent and maximal changes occurred at 48 h. The expression of UGT1A6 mRNA was not significantly modified by either ethanol or isopentanol. In conclusion, ethanol and isopentanol have direct roles in the regulation of UGT.

Animals↗

PubMed2000

Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat.

BACKGROUND AND AIMS: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes. METHODS AND RESULTS: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin. The induction of UGT1A1 and UGT1A5 by bilirubin was concentration and time dependent. Treatment with chenodeoxycholic acid, cholic acid, deoxycholic acid, hyodeoxycholic acid and lithocholic acid at a concentration of 100 micromol/L for 48 h significantly enhanced the mRNA expression of UGT2B1, a UGT isoform responsible for the glucuronidation of bile acids. The UGT2B3 mRNA level was also increased by hyodeoxycholic acid. The regulation of UGT2B1 mRNA by chenodeoxycholic acid and hyodeoxycholic acid was dose and time dependent. CONCLUSION: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.

Animals↗

PubMed2000

Cost-effectiveness analysis of lamivudine for the treatment of chronic hepatitis B.

OBJECTIVE: To estimate the short term and long term cost effectiveness, from a healthcare perspective, associated with the introduction of lamivudine for chronic hepatitis B. DESIGN: The analysis used a 2-step modelling approach. A decision tree was used to estimate clinical outcomes and costs after 1 year. The 1-year results were then extrapolated to 70 years using a Markov model. PATIENTS: The study population comprised hypothetical cohorts of patients with chronic hepatitis B, representative of those likely to receive treatment in clinical practice in Australia. MAIN OUTCOME MEASURES AND RESULTS: In the short term, more patients sero-converted when lamivudine was available, with an incremental cost-effectiveness ratio of 3341 Australian dollars ($A) per additional seroconversion. In the long term, the introduction of lamivudine increased life expectancy by 3.9 years [3.2 quality-adjusted life-years (QALYs)] compared with when interferon-alpha was the only treatment, or 4.6 years (3.8 QALYs) compared with no treatment. There were reductions in lifetime risk of developing compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma of 5, 11 and 11%, respectively, when lamivudine was available. The incremental cost of having lamivudine available, as opposed to interferon-alpha only, was $A633 per year of life saved or $A735 per QALY. CONCLUSION: The introduction of lamivudine is expected to reduce and delay the progression of chronic hepatitis B, increasing the life expectancy and quality of life of patients for a small overall increase in healthcare costs.

Antiviral Agents↗

PubMed1999

The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes.

PURPOSE: To investigate the direct effects of sex hormones, growth hormone, thyroid hormones and dexamethasone on the regulation of UDP-glucuronosyltransferase (UGT). METHODS: Rat hepatocytes were cultured on matrigel and treated with various hormones. Northern blot analysis was carried out using cDNA probes to family 1 and family 2 isoforms. RESULTS: Treatment with 10(-5) M testosterone increased the mRNA levels of UGT 2B1 by 29% and UGT2B3 by 32%. Incubation of growth hormone (10 mU) with hepatocytes suppressed the expression of UGT2B1 and UGT2B3 by 17% and 38%, respectively. T3 administration resulted in a time and dose-dependent effect on the expression of UGT 1 isoforms, with increased UGT1A6 by 70%, and decreased UGT1A1 by 38% and UGT1A5 by 35%. All UGT isoforms except UGT 1A6 studied in this assay were up-regulated by dexamethasone, but to different degrees. The regulation of UGT1A1 and UGT2B1 by dexamethasone was dose and time dependent, and the induction of dexamethasone in the expression of UGT1A1 and UGT2B1 was blocked by cycloheximide but not dichloro-1-D-ribofuranosylbenzimidazole. CONCLUSIONS: This study demonstrates that multiple hormones take part in the regulation of UGT mRNA expression in the rat and individual genes can be differentially modulated.

Animals↗

PubMed1999

Imaging of the normal and abnormal pancreaticobiliary system with single-shot MR cholangiopancreatography: a pictorial review.

Magnetic resonance cholangiopancreatography (MRCP) is a rapidly evolving non-invasive imaging modality that produces images of the pancreatic duct and biliary tree without the need for intravenous or oral contrast. The images are equivalent to those from endoscopic retrograde cholangiopancreatography (ERCP), but the non-invasive acquisition avoids the morbidity and mortality associated with diagnostic ERCP. Magnetic resonance cholangiopancreatography is indicated in patients who require only a diagnostic ERCP, who fail an ERCP or who are unable to undergo ERCP due to altered post-surgical anatomy. Other evolving indications include triaging of patients with obstructive jaundice into percutaneous or endoscopic management drainage pathways depending on the site, length and nature of the duct obstruction, thereby potentially decreasing the number of failed or unsuccessful ERCP. Pre-operative identification of anomalous biliary anatomy and choledocholithiasis prior to laparoscopic cholecystectomy promise to modify the pre-operative and operative management of the patient in order to minimize the risk of duct injury and unnecessary intra-operative dissection and cholangiography. The advantages of the technique include its non-invasiveness, the absence of contrast administration, its relative operator independence and the ability to evaluate both sides of an obstructed duct, thereby accurately evaluating stricture morphology and length. The disadvantages of MRCP compared to ERCP include its lack of an immediate therapeutic solution to duct obstruction, procedural cost, unit availability and the inability to evaluate patients with pacemakers or ferromagnetic implants.

Bile Duct Diseases↗

PubMed1999

Severity of liver disease in hepatitis C infection contracted through injecting drug use.

BACKGROUND: Injecting drug use (IDU) is currently the most common route of hepatitis C virus (HCV) transmission in Australia and many other Western countries. Most reports on the natural history of HCV have examined populations that included patients from all risk groups, but it is possible that this increasingly important subgroup is different. AIMS: To assess the severity of liver disease in individuals who acquired HCV through IDU. METHODS: Three hundred and forty-six patients with confirmed HCV infection and a history of IDU, who had had a liver biopsy performed were recruited from a liver clinic. Demographic data, liver function tests and hepatitis B serology were obtained on all patients. A detailed drug use history and HCV viral studies were also available in a subgroup of 142 patients. RESULTS: Mean age of the group was 34 years and 73% were male. Mean duration of HCV infection was 14.6 years. Forty one per cent were infected with genotype 3a, 19% - 1a, 17% - 1 (nonsubtypable), 14% - 1b and 4% - 2b. Cirrhosis was present in 12% of patients. Patients with cirrhosis (38 years) were older than those with chronic hepatitis (34 years; p=0.0003) and had a longer duration of infection (17.2 vs 14.3 years; p=0.003). On multivariate analysis, however, patient age was the only factor independently associated with cirrhosis (odds ratio 4.2; 95% confidence interval 1.4-12.6). CONCLUSION: While cirrhosis is less common in this group than in other HCV infected populations, its prevalence may increase as these patients are followed over a longer period of time.

Adult↗

PubMed1998

Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.

In patients with chronic hepatitis C, alcohol consumption has been proposed as a risk factor for the progression of liver disease; however, evidence for this remains conflicting. Two hundred thirty-four anti-hepatitis C virus (HCV)-positive patients who had a liver biopsy performed within the past 24 months were studied. Demographic data and information on risk factors were recorded. A detailed lifetime alcohol consumption history was obtained. Viral studies included HCV viral titer and HCV genotype. Mean age (+/- SEM) of the group was 40.8 +/- 0.7 years. One hundred sixty-six (71%) were male. A risk factor for HCV infection was found in 195 patients (86%). Genotype distribution was: 1b: 22%; 1a: 15%; 1(nonsubtypable): 15%; 3a: 34%; and 2: 7%. Fifty (21%) patients had cirrhosis. Patients with cirrhosis were older (51.6 +/- 1.8 years) than those with chronic hepatitis (37.6 +/- 0.6 years; P = .0001), were infected at an older age (25.9 +/- 2.0 vs. 20.9 +/- 0.6 years; P = .001), and had a longer duration of infection (20.5 +/- 1.3 vs. 16.2 +/- 0.5 years; P = .0008). Patients with cirrhosis had a greater total lifetime alcohol consumption (288,765 +/- 58,115 g) than those with chronic hepatitis (189,941 +/- 15,453 g; P = .018). Cirrhotic patients also had greater total alcohol consumption during the period of infection with HCV (240,962 +/- 63,756 g vs. 146,510 +/- 12,862 g; P = .02). On multivariate analysis, subject age and total alcohol consumption were independently associated with the presence of cirrhosis. Total lifetime alcohol consumption is a risk factor for the progression of liver disease caused by HCV.

Adult↗

PubMed1998

Regulation of uridine diphosphate glucuronosyltransferase during the acute-phase response.

The acute-phase response is associated with profound effects on oxidative drug metabolism. However, the effects on glucuronidation are poorly characterized. The aim of the present study was to determine the role of mediators of the acute-phase response in the regulation of hepatic uridine diphosphate glucuronosyltransferase (UGT) expression. Family 1 and family 2 UGT isoforms were studied in turpentine-injected rats and in primary hepatocyte cultures exposed to cytokines and/or dexamethasone. In the in vivo model, glucuronidation of p-nitrophenol was unaffected, while testosterone glucuronidation was reduced to 65% of control (P<0.01). In contrast, the mRNA level of UGT1*1 (which metabolizes bilirubin, not phenols) was depressed to 16% of control (P<0.002), while the mRNA level of UGT2B3 (which metabolizes testosterone) was reduced to 53% (P<0.05). In primary hepatocyte culture, dexamethasone treatment resulted in a 3.4-fold induction of UGT1*1 mRNA levels (P<0.001) but only a 1.5-fold induction of UGT2B3 (P=0.1). Interleukin-6 in the presence of dexamethasone resulted in a marked dose-dependent suppression of both UGT1*1 and UGT2B3, although to different degrees. Interleukin-1 had no effect on UGT mRNA levels. Thus, inflammatory mediators, such as cytokines and glucocorticoids, may be important determinants of both oxidative and conjugative drug metabolism by the liver.

Acute-Phase Reaction↗

PubMed1997

Sex hormones differentially regulate isoforms of UDP-glucuronosyltransferase.

PURPOSE: To investigate the role of sex hormones in the regulation of UDP-glucuronosyltransferase (UGT). METHODS: We examined liver from adult, prepubertal, gonadectomised and gonadectomised plus hormone replaced rats of both sexes. Immunohistochemistry and immunoblots were performed using a polyclonal UGT antibody to a number of family 1 and family 2 UGT isoforms. Northern blot analysis was performed utilising cDNA probes to family 1 and family 2 isoforms. RESULTS: Immunohistochemistry demonstrated variations in intensity and distribution of staining in the hormonally manipulated rats. Immunoblots showed variations in individual band intensity between rat groups. Immunoblots using a more specific antibody (anti-17 beta-hydroxysteroid UGT, which recognises UGT2B3 and UGT2B2) demonstrated marked differences between male and female rats and significant alterations after gonadectomy and testosterone replacement in the male rats. In northern analysis, UGT2B3 and 2B1 mRNA were significantly higher in adult males than females, and in prepubertal males compared to prepubertal females. In male rats, gonadectomy resulted in a 45-53% reduction in UGT2B3 and 2B1 levels respectively, which increased significantly with testosterone treatment to greater than normal adult levels. No change in UGT2B3 or 2B1 occurred after gonadectomy in females. In contrast, UGT1*1 mRNA tended to be higher in adult female and prepubertal female rats than in their male counterparts. In females, gonadectomy resulted in significant up-regulation of UGT1*1, while gonadectomy plus oestradiol treatment resulted in markedly reduced levels. UGT1*1 mRNA was not significantly altered by gonadectomy in males. CONCLUSIONS: This study demonstrates the differential effects of sex hormones on the expression of isoforms from the two phylogenetically distinct UGT families.

Animals↗

PubMed1996

UDP-glucuronosyltransferase in Gilbert's syndrome.

The diagnosis of Gilbert's syndrome, a condition characterised by mild jaundice related to chronic unconjugated hyperbilirubinemia, is often presumptive and the pathogenesis is incompletely understood. It would be of interest to develop an immunohistochemical staining method to confirm a diagnosis of Gilbert's syndrome. To this end liver tissues from ten patients with a presumed diagnosis of Gilbert's syndrome and six normal controls were examined by immunohistochemistry with polyclonal antibodies raised to UDP-glucuronosyltransferase (UGT). All subjects had normal liver biopsies by hemotoxylin and eosin staining. In normal human liver specific staining for UGT was seen diffusely in all hepatocytes of the hepatic lobule with zone 3 accentuation. There was a reduction of immunostaining throughout the hepatic lobule in all specimens from patients with Gilbert's syndrome and faint residual staining was seen in zone 3. This thus proved a useful method to confirm a clinical diagnosis of Gilbert's syndrome. Raising monospecific antibodies to UGT may give an insight into polypmorphisms of phase II drug metabolism. Bosma et al.* have recently provided evidence from in vitro studies that subjects with Gilbert's syndrome have a putative defect in the promoter region of the gene encoding UDP-glucuronosyltransferase 1, resulting in reduced transcription. These studies have yet to be confirmed from human biopsy specimens and the possibility of second mutations in intronic sequences affecting the stability of UDP-glucuronosyltransferase 1 m RNA are being explored. *Bosma PJ, Chowdhury JR, Bakker C et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333: 1171-5.

Adult↗

PubMed1996

UDP glucuronosyltransferase in the cirrhotic rat liver.

In patients with cirrhosis, the elimination of drugs metabolized by glucuronidation is relatively preserved, in comparison with the metabolism of drugs by oxidation. This study explores this phenomenon at a molecular level. In cirrhotic rat livers the content of UDP-glucuronosyltransferase (UGT) was examined by immunohistochemistry and immunoblotting using three antibodies: (i) a polyclonal antibody directed against a broad number of UGT isoforms from both family 1 and family 2; (ii) a family 2-specific antibody; and a (iii) family 1-specific antibody. The steady state mRNA level of UGT of a family 2 isoform was also detected by northern blot analysis. The results demonstrate normal or increased UGT protein by immunohistochemistry and immunoblot in cirrhotic livers compared with controls. This was accompanied by increased steady state mRNA encoding the UGT isoform UGT2B1. In contrast, an isoform of cytochrome P450 (CYP2C11) was reduced markedly in both immunohistochemical staining and immunoblot analysis. These results suggest that in cirrhosis there is a comparative increase or at least a maintenance of UGT enzyme content and that this most likely occurs at a pretranslational level.

Animals↗

PubMed1996

UDP-glucuronosyltransferase in the regenerating rat liver.

In both acute and chronic liver disease in man, elimination of drugs metabolized by the cytochrome P450 (CYP) enzymes is impaired. In contrast, those drugs metabolized by UDP-glucuronosyltransferase (UGT) have a relatively normal elimination. Studies in rats with experimentally induced liver injury also show this relative preservation of glucuronidation. In liver disease, a number of factors, including inflammation, fibrosis and regeneration, may be associated with this differential effect on drug metabolism. Partial hepatectomy provides a model in which to isolate the effects of liver regeneration on drug metabolism. Partial hepatectomy or sham operation was performed in 24 male Sprague-Dawley rats and three rats from each group were studied at days 1, 2, 4 and 6. Comparison between CYP and UGT was made at the protein level using immunohistochemistry and immunoblotting probed with a polyclonal antibody to UGT, identifying both family 1 and family 2 isoforms, and an antibody to the CYP isoform CYP2C11. Steady state messenger RNA levels of four isoforms of UGT were assessed by northern blot analysis. By both immunohistochemistry and immunoblotting, the level of CYP protein decreased from day 2 to 6 after hepatectomy. In contrast, the UGT protein level was not altered by partial hepatectomy. Northern blot analysis of UGT isoforms demonstrated differential regulation of isoforms from the two major families. The UGT family 1 isoforms were initially markedly depressed following partial hepatectomy and then steadily rose over 6 days to greater than the level in controls. In contrast, there was an apparent increase in UGT2B1 mRNA (not significant) on day 2, while UGT2B3 mRNA was maintained over the six days. These results demonstrate that during hepatic regeneration the protein content of total UGT is normal, while CYP2C11 protein is markedly reduced. Northern blot analysis suggests that individual isoforms of UGT are differentially regulated during the regeneration process.

Animals↗

PubMed1996

Preventing endoscopic retrograde cholangiopancreatography related sepsis: a randomized controlled trial comparing two antibiotic regimes.

Current antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP) is not standardized and may be inadequate. We aimed to evaluate the efficacy of 3 days of additional oral antibiotics in the prevention of ERCP-related sepsis. One hundred and fifty-six patients were randomized prospectively to receive either intravenous ticarcillin and clavulinic acid (Timentin; SmithKline Beecham, Dandenong, Victoria, Australia), pre-ERCP (group I) or Timentin and 3 days of oral amoxycillin and clavulinic acid (Augmentin; SmithKline Beecham, Dandenong, Victoria, Australia), group II). Blood cultures were taken 30 min after the procedure. The occurrence of sepsis, defined as a temperature over 38 degrees C, occurring in the first 7 days was recorded and the risk factors for the development of sepsis were evaluated. Four patients had significant positive blood cultures despite the prior administration of Timentin. Sepsis occurred in 10% of group I patients, but only 3% of group II patients (relative risk 3.30; 95% confidence intervals 0.74-14.8). The performance of sphincterotomy and the presence of common bile duct stones were significant risk factors for the development of sepsis. We would recommend 3 days of additional oral Augmentin after a single dose of intravenous antibiotics in patients at increased risk of sepsis, which would include those with bile duct stones and/or those undergoing a therapeutic procedure.

Amoxicillin↗