Hepatic metabolism of neurotensin.

Neurotensin is released from the intestinal mucosa into the portal circulation and, to exert a systemic effect, it must traverse the liver intact. We examined the potential role of the liver in neurotensin clearance using the isolated perfused rat liver model. With N-terminal and C-terminal directed RIAs and HPLC, we demonstrated rapid metabolism of intact neurotensin to inactive N-terminal fragments in the isolated rat liver system. The disappearance half-lives of C-terminal and N-terminal immunoreactivity were 20.4 +/- 6.0 min and 82.7 +/- 7.7 min, respectively, (P less than 0.002). To assess whether this neurotensin disappearance might be due to metabolism within the perfusate itself by a peptidase released from liver, we further incubated neurotensin in perfusate previously circulated through liver. A rapid and progressive breakdown of intact neurotensin to N-terminal fragments was again shown. These data demonstrate that a substantial proportion of the hepatic clearance of neurotensin is attributable to release of a peptidase by the liver into the circulation.

Intracellular binding is an important determinant of the avid hepatic uptake of the high clearance drug omeprazole.

The contribution of intracellular storage to hepatic uptake of the high clearance drug, omeprazole, was examined in the recirculating isolated perfused rat liver preparation. Following injection of [3H]omeprazole (7.5 microCi, 5 mg) into the portal vein over 1 min, livers were perfused for 5 min (N = 3) or 30 min (N = 3) and then homogenized at 4 degrees and fractionated by differential centrifugation. Radiolabelled omeprazole and metabolites were determined by scintillation counting of fractions of eluant from HPLC. Seventy per cent of drug had been taken up by the liver at 5 min and 85% at 30 min, with unchanged drug representing 43 and 7.4%, respectively, of drug taken up. At both times, 70-75% of intracellular unchanged drug and the major metabolites were located in the cytosol, and the cytosol:perfusate concentration ratio was approximately 10:1. Mitochondrial, lysosomal and microsomal fractions contained relatively little drug. Extensive cytosolic binding of omeprazole therefore contributes substantially to the initial avid hepatic first-pass uptake of this drug.

Gastric acid secretory capacity falls after repeated within-day pentagastrin testing in fed subjects.

Between-day pentagastrin testing yields highly reproducible stimulated gastric acid output values, but little is known of the reproducibility of repeated within-day pentagastrin tests. We have performed three pentagastrin tests within the 1 day in nine healthy subjects. Within-day tests were 6 hours apart; the first followed an overnight fast and the second and third were both 4 hours after a substantial meal. A further test was performed the following morning, again after an overnight fast, which allowed comparison of within-day and between-day testing. In the second and third within-day tests there was a marked decrease of stimulated gastric acid output, with both maximal and peak acid output decreased to approximately half of the value of the first test (P less than 0.01). By contrast there were no significant differences in the acid output values obtained in between-day tests (both following an overnight fast). Possible mechanisms for the decreased output on repeated within-day testing include alterations in the sensitivity of the gastrin receptor, or some neurohumoral influence secondary to the preceding meal. Future studies of the duration of action of drugs affecting acid secretion may need to take account of these findings.

Hepatic metabolism of vasoactive intestinal polypeptide (VIP) in the rat.

Vasoactive intestinal polypeptide (VIP) is released into the portal circulation by a meal stimulus, but is rapidly cleared from plasma. Although it is known to bind to receptors on liver cells, the role of the liver in the clearance of VIP is not clearly defined. We therefore studied the disappearance of VIP in recirculating and in single pass isolated perfused rat liver (IPRL) preparations. Disappearance of added VIP was rapid in recirculating IPRL experiments with a half life of ca. 30 min. In single-pass steady-state studies in which livers were perfused at 16 ml/min for 30 min, clearance of VIP was complete (16 ml/min) at concentrations of 500 fmol/ml, but clearance fell to 3 and 1 ml/min at perfusate concentrations of 8 and 40 pmol/ml respectively. Further experiments to evaluate whether VIP was disappearing in perfusate itself demonstrated substantial metabolism of VIP in perfusate which had previously been circulated through a liver for 90 min. The products of metabolism were identical to those found in the IPRL. We conclude that VIP is rapidly cleared as it passes through the isolated perfused rat liver model with a significant proportion of clearance attributable to release of a peptidase from the liver into the perfusate.

The hospital of the future--planning for change.

This paper describes the hospital planning model developed by the North Eastern Metropolitan Region of the Health Department Victoria to forecast acute public hospital bed-day requirements in the Region. Three age-specific variables: population; separation rate; and length of stay have been used to estimate the level of demand for hospital services. The model also delineates services delivered on a same day or long stay basis. The application of the model to three local government areas demonstrates the importance of population growth and ageing on the type and level of hospital services required and the implications thereof for service delivery and the physical configuration of hospitals.

Suitability of casemix classification for output funding of blood services in Victoria. Victorian Blood Users Group.

OBJECTIVE: To study the suitability of diagnosis-related groups (DRGs) to quantify blood use in order to fund hospitals directly for fresh blood components. DESIGN: (i) Retrospective empirical analysis of hospital inpatient separation data, matching DRG classification with blood usage. (ii) Prediction of blood usage based on actual DRGs and comparison with actual blood products issued from the blood service. SETTING: Eight large public hospitals, April 1994-March 1995, the Department of Human Services and the Australian Red Cross Blood Service in Victoria, 1994-1997. MAIN OUTCOME MEASURES: Requirement for transfusion according to DRG; quantity of blood or blood products transfused; and statistical reliability of measuring blood component usage by DRG. RESULTS: A match between patient records and transfusion records for 287,117 patient separations showed that the patients had received 51,115 units of red cells, 30,451 units of platelet concentrates, 9043 units of fresh frozen plasma and 1273 units of cryoprecipitate. Ten per cent of DRGs (527) accounted for over 70% of blood product usage. The numbers of DRGs in which blood products were used for at least 30 separations (with a relative SEM [for units of blood used per separations using blood] of up to 20% at a 95% confidence level) were 56 for red cells, 8 for platelets and 4 for fresh frozen plasma. Estimates of red cell usage calculated from actual DRGs for three consecutive years (1994-1997) showed that DRGs predicted aggregate issues of red cells by the Red Cross Blood Service (ratio of actual red cells issued to red cell usage estimates were 1.036 for 1994-95, 0.994 for 1995-96, and 1.021 for 1996-97, respectively). CONCLUSION: DRGs are moderately good predictors of blood product usage, and could be used to allocate funds for blood products to hospitals instead of to the blood service. However, DRG data are not designed to manage blood issue policies, because DRGs do not represent single diagnoses or procedures and some are surrogate descriptions of procedures.

Extraction of neurotensin by the liver.

1. Neurotensin is released from the intestine into the portal circulation and to exert a systemic effect it must traverse the liver intact. 2. The role of the liver in neurotensin clearance was examined using the isolated perfused rat liver preparation. Two concentrations of neurotensin were used to determine the extraction capacity of the liver. 3. Approximately 10% of the added neurotensin (with either dose) was extracted in a single pass through the liver. This extraction rate was low when compared to previous studies with cholecystokinin (60% extraction in a single pass) and vasoactive intestinal peptide (100%). 4. It is concluded that there is a small but high capacity for direct extraction of neurotensin. This low direct extraction percentage supports our previous contention that the major influence of the liver on the metabolism of neurotensin is by the release of neurotensin degrading peptidases into the circulation.

Changes in bed resources and admission patterns in acute public hospitals in Victoria, 1987-1995.

OBJECTIVE: To describe changes in admission patterns, bed resources and hospital use in acute public hospitals and their relationship with early readmissions and interhospital transfers in Victoria between 1987 and 1995. DESIGN: Descriptive study of longitudinal trends using data from the Victorian inpatient Minimum Database and the Acute Health Services Branch of the Department of Human Services, Victoria. SETTING: State of Victoria. MAIN OUTCOME MEASURES: Acute public hospital beds and hospital separations per 1000 population; separation type (same-day or longer); mean length of stay; interhospital transfers; and readmissions to the same hospital within 28 days. RESULTS: Between 1987-88 and 1994-95, public hospital beds in Victoria decreased from 3.2 to 2.8/1000 population, and mean length of hospital stay decreased from 6.4 to 4.2 days. There was a significant direct correlation between number of beds/1000 and length of stay (r = 0.90; 95% confidence interval [CI], 0.52-0.98). Bed occupancy remained constant at 80%. Over the same period, same-day admissions increased from 22% to 42% of hospital separations, interhospital transfers increased from 2.7% to 4% of separations, and readmissions to the same hospital within 28 days for any reason increased from 12.4% to 15% of separations (21% increase). Beds/1000 were inversely correlated with interhospital transfers (r = -0.83; 95% CI, -0.31 to -0.97), while readmission rates were inversely correlated with beds/1000 (r = -0.89; 95% CI, -0.98 to -0.50) and length of hospital stay (r = -0.95; 95% CI, -0.99 to -0.74). CONCLUSIONS: There were significant changes in the patterns of use of public hospitals between 1987 and 1995, possibly reflecting technological advances and changes in clinical practice, as well as policy to improve efficiency. Early readmission rates may be a useful proxy measure of potentially avoidable adverse outcomes.

Relapse of duodenal ulceration after healing with omeprazole.

The subsequent recurrence rate after duodenal ulcers were healed with omeprazole, 10 mg or 30 mg a day, was documented during a 12-month period in 55 patients. Endoscopy was performed if patients developed symptomatic recurrence; those patients who remained symptom-free at 12 months were also requested to undergo endoscopy to assess the incidence of asymptomatic recurrence. The proportion with symptomatic recurrence during the year was 56%. The median times (life-table analysis) to relapse were 50 and 39 weeks in the group that was treated initially with 30 mg and 10 mg of omeprazole, respectively, although this trend to slower relapse in the higher-dose group was not statistically significant. Five asymptomatic ulcers were detected in 11 asymptomatic subjects who agreed to a final endoscopy. The over-all recurrence rate was similar to previously-reported recurrence rates after the cessation of histamine H2-receptor antagonist drugs.

Effect of 'weekend therapy' with omeprazole on basal and stimulated acid secretion and fasting plasma gastrin in duodenal ulcer patients.

The effect of intermittent dosage with omeprazole on basal and pentagastrin stimulated gastric acid secretion and fasting plasma gastrin was assessed in eight duodenal ulcer subjects who were in remission. Omeprazole (20 mg daily) was given for a three day 'weekend' each week for two months. Twenty four hours after the first and eighth weekend, basal and peak acid output were still markedly suppressed (greater than 50%) compared with pretreatment. After the treatment free four days, however (just before the eighth weekend), peak acid output had returned to pretreatment values; basal acid output was still somewhat reduced (mean 3.6 mmol/l) but the difference from baseline was not statistically significant. Fasting plasma gastrin concentration increased slightly but significantly, from a baseline median of 17 pmol/l to 25 and 31 pmol/l respectively, 24 hours after the first and eighth weekends. All but two values (of 16) remained within the reference range. Before the fourth and eighth weekends, and again at 12 days and three months after treatment, gastrin values were not significantly different from baseline. Thus a 'weekend therapy' regimen with this long acting antisecretory compound produces substantial acid suppression, but for only part of the week, with modest and reversible changes in fasting plasma gastrin. It should therefore be suitable for efficacy testing for prevention of recurrence of peptic ulcer or reflux oesophagitis.