Gastric A-cell function in normal dogs

Glucagon release from the gastric fundus and pancreas were compared in normal dogs by measuring glucagon in plasma from a major gastroepiploic vein, the superior pancreaticoduodenal vein, and the inferior vena cava. In 32 dogs in the basal state, gastric vein glucagon averaged 97 +/- 40 pg/ml, not significantly different from the 93 +/- 41 pg/ml level in the vena cava. Pancreaticoduodenal vein glucagon averaged 250 +/- 32 pg/ml (P less than 0.001). Intravenous arginine infused in four dogs caused a rise in mean gastric vein glucagon to 210 +/- 33 pg/ml within 3 min, and glucagon remained between 53 and 98 pg/ml above the vena caval level thereafter. In the gastric vein, the rise in glucagon was significantly greater than in the vena cava at 3, 5, and 10 min (P less than 0.05), but was far less than in the pancreaticoduodenal vein where glucagon rose to 1,295 +/- 379 pg/ml at 1.5 min. Evidence of modest gastric glucagon release was observed after the intragastric instillation of arginine, but not during insulin or phloridzin-induced hypoglycemia. It was concluded that in normal dogs under the circumstances studied, the gastric fundus is not a major source of circulating glucagon.     

Drinking in sodium-depleted rats with bile duct, vena cava or portal vein obstruction

The authors investigated whether a depletion of sodium with furosemide enhanced the water and 0.3 M NaCl intakes of rats with experimental cholestasis, portal hypertension or congestive heart failure. These were induced, respectively, by bile duct ligation (BDL), portal vein constriction or vena cava constriction. BDL alone increased daily saline intake. In BDL rats, but not in sham-ligated controls, experience with a prior depletion of sodium enhanced the 2-h saline intake and the retention of water and sodium after a subsequent depletion. Chronic cava constriction, but not portal constriction, enhanced sodium intake and retention after sodium depletion during a 2-h test and enhanced water intake overnight after the test. The results suggest that the ingestion of sodium by BDL and cava-constricted rats may share a common mechanism.     

Angiomyolipomatous hamartoma of the tongue

To examine the role of the liver in lipopolysaccharide (LPS)-induced hypophagia, we investigated the effect of hepatic portal and vena cava infusions (1 mL/30 min) of LPS (100 microg/kg of body weight) on feeding in rats. LPS infusion significantly reduced food intake when administered via either the hepatic portal vein or the vena cava. Both the magnitude and time course of this hypophagia were similar regardless of the infusion route. As in previous experiments of ours in which LPS was administered by intraperitoneal (i.p.) injection, LPS reduced food intake by decreasing meal frequency, without affecting meal size or duration. The results suggest that peripherally administered LPS does not act primarily in the liver to reduce food intake.     

Differential contribution of angiotensinergic and cholinergic receptors in the hypothalamic paraventricular nucleus to osmotically induced AVP release

We studied the involvement of periventricular and hypothalamic angiotensinergic and cholinergic pathways in osmotically induced arginine vasopressin (AVP) release into the blood. In conscious Wistar rats, i.c.v. injections of 0.2, 0.3 and 0.6 M hyperosmolar saline (5 microl) resulted in concentration-dependent increases in AVP release (5.2 +/- 1.5, 10.6 +/- 2.2 and 18.0 +/- 2.2 pg/ml, respectively, vs. 2.0 +/- 0.1 in controls). The two lower saline concentrations did not affect arterial blood pressure (non-pressure-associated AVP release), whereas 0.6 M saline induced increase in blood pressure (pressure-associated AVP release). In the first set of experiments, periventricular angiotensin AT1, muscarinic or nicotinic receptors were blocked by i.c.v. administration of losartan (10 nmol), atropine (100 nmol) or hexamethonium (100 nmol), respectively, before i.c.v. hyperosmolar saline injections. Losartan significantly reduced the 0.2 M and 0.3 M, but not the 0.6 M, saline-induced increase in AVP release. The 0. 3 M saline-induced AVP release was blocked by atropine and hexamethonium, whereas the 0.6 M saline-induced AVP release was blocked by atropine only. In the second set of experiments, losartan (4 nmol), atropine (200 nmol) or hexamethonium (200 nmol) was injected bilaterally into the paraventricular nucleus before i.c.v. hyperosmolar saline injections. Losartan reduced 0.3 M and potentiated 0.6 M saline-induced AVP release. On the other hand, atropine and hexamethonium significantly reduced both 0.3 and 0.6 M saline-induced AVP release. We conclude that afferents arising from periventricular osmosensitive neurons to the hypothalamic paraventricular nucleus, which are involved in non-pressure-associated osmotically induced AVP release, are both angiotensinergic and cholinergic, whereas those mediating pressure-associated AVP release are cholinergic in nature.     

Mammalian base excision repair and DNA polymerase beta

OBJECTIVE: To describe six dogs with congenital abnormalities involving the portal vein, caudal vena cava, or both. ANIMALS: Six client-owned dogs with congenital interruption of the portal vein or the caudal vena cava, or both. METHODS: Portal vein and caudal vena cava anatomy was evaluated by contrast radiography and visualization at surgery. Vascular casts or plastinated specimens were obtained in three animals. RESULTS: Portal blood shunted into the caudal vena cava in four dogs and the left hepatic vein in one. Two of these five dogs also had interruption of the caudal vena cava with continuation as azygous vein, as did an additional dog, in which the portal vein was normally formed. Portal vein interruption was present in 5 of 74 (6.8%) dogs with congenital portosystemic shunts evaluated at the Veterinary Teaching Hospital during the study period. CONCLUSIONS: Serious malformations of the abdominal veins were present in more than 1 in 20 dogs with single congenital portosystemic shunts. CLINICAL RELEVANCE: Veterinarians involved in diagnosis and surgery for portosystemic shunts should be aware of these potential malformations, and portal vein continuity should be evaluated in all dogs before attempting shunt attenuation.     

Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep

Experimental data suggest that elevated FFA levels play a leading role in the impaired GH secretion in obesity and may therefore contribute to the maintenance of overweight. GH has a direct lipolytic effect on adipose tissue; in turn, FFA elevation markedly reduces GH secretion. This suggests the existence of a classical endocrine feedback loop between FFA and GH secretion. However, the FFA mechanism of action is not yet understood. The involvement of somatostatin (SRIH) is controversial, and in vitro experiments suggest a direct effect of FFA on the pituitary. In sheep it is possible to collect hypophysial portal blood and quantify SRIH secretion in hypophysial portal blood under physiological conscious and unstressed conditions. In this study we determined the effects of FFA (Intralipid and heparin) infusion on peripheral GH and portal SRIH levels in intact rams chronically implanted with perihypophysial cannula and in rams actively immunized against SRIH to further determine SRIH-mediated FFA effects on GH axis. Immediately after initiation of Intralipid infusion, we observed a marked increase in the FFA concentration (2160 +/- 200 vs. 295 +/- 28 nmol/ml; P < 0.01) as well as a significant decrease in basal GH secretion (1.8 +/- 0.1 vs. 2.5 +/- 0.3 ng/ml; P < 0.05) and a drastic reduction of the GH response to i.v. GH-releasing hormone injection (4.8 +/- 0.7 ng/ml in FFA group vs. 35.8 +/- 9.7 ng/ml in saline group; P < 0.01). No change in plasma insulin-like growth factor I levels was observed. During the first 2 h of infusion, the GH decrease observed was concomitant with a significant increase in portal SRIH levels (22.1 +/- .2 vs. 13 +/- 1.6 pg/ml; P < 0.01). In rams actively immunized against SRIH, the effect of FFA on basal GH secretion was biphasic. During the first 90 min of infusion, the decrease in GH induced by FFA was significantly blunted in rams actively immunized against SRIH (57 +/- 9% for immunized rams vs. 23.5 +/- 2.5% for control rams). This corresponds to the period of increased SRIH portal levels. After this first 90-min period, no difference was seen between control and immunized rams. Our results show that FFA exert their inhibitory action on the GH axis at both pituitary and hypothalamic levels, the latter mainly during the first 90 min, through increased SRIH secretion.     

Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity

Since it is unclear whether methotrexate and cytarabine are synergistic or antagonistic in the treatment of acute lymphoblastic leukemia, the Pediatric Oncology Group studied the prognostic significance of a potential interaction between these agents. RBC methotrexate concentrations were compared from 140 patients at lower risk of relapse randomized to two treatment groups: one receiving six methotrexate infusions with overlapping cytarabine; the other, six methotrexate infusions alone. Samples from 248 patients from all risk groups were studied to determine whether patients with extremely low RBC methotrexate concentrations had inferior outcomes. Among low-risk patients studied 3 weeks after the sixth infusion, median RBC methotrexate concentrations were 0.13 nmol/ml RBCs (n = 71) for the methotrexate-only group and 0.02 nmol/ml RBCs (n = 69) for the methotrexate/cytarabine-treated low-risk patients, P < 0.001 by the two-sided Wilcoxon test. For low- and high-risk patients receiving methotrexate/cytarabine infusions, event-free survival at 1 and 3 years after RBC sampling was 97 +/- 2% and 90 +/- 3% for patients with concentrations greater than the median, and 88 +/- 3% and 78 +/- 4% for those with concentrations at or below the median. Log rank comparisons of event-free survival in the first year and overall yielded P = 0.005 and P = 0.04, respectively. Cytarabine altered methotrexate pharmacology when the drugs were infused together. Patients whose levels were extremely low had an adverse prognosis. Although this study could not assess efficacy of the methotrexate/cytarabine combination, it appears that concurrent administration is not optimal.     

Orthotopic transplantation of a partial hepatic autograft in dogs

The purpose of this study was to investigate the availability of an orthotopic transplantation of partial hepatic autograft in dogs as a means of surgical training. Male mongrel dogs weighting 10-15 kg were used. The left lobe of the liver was harvested while preserving the left branches of the portal vein, hepatic artery and bile duct, and the left hepatic vein. The remnant liver was removed while preserving the inferior vena cava using a veno-venous bypass. Orthotopic transplantation of the autograft was performed while anastomosing the left hepatic vein to the inferior vena cava, portal and arterial reconstruction, and external biliary drainage. Thirteen out of 29 dogs survived more than 48 h after transplantation. However, 6 out of 13 dogs were sacrificed after developing bile peritonitis due to a dislodgement of the biliary catheter, and only two dogs were able to survive for 7 days after transplantation. The arterial ketone body ratio recovered to 1.0 within 1 h after reperfusion, and the ratio of the dogs that survived for more than 48 h remained above 1.0 until sacrifice. Orthotopic transplantation of a partial hepatic autograft is a useful and simple procedure to train surgeons for partial liver transplantation.     

Brain scanning with the Anger multiplane tomographic scanner as a second examination evaluation by the ROC method

The disposition kinetics and systemic availability of ketamine, a dissociative anaesthetic agent, was studied in normal domestic cats. A similar dose (25 mg/kg) of ketamine hydrochloride was administered by the i.v. and i.m. routes; drug concentrations in plasma were measured by a gas-liquid chromatographic procedure. A rapid distribution phase (t1/2 (alpha) = 3 min) was followed by a slower first-order elimination phase. The half-life of the drug (66.9 +/- 24.1 min) was independent of the route of parenteral administration. Absorption from i.m. site of administration was rapid, with peak plasma level at 10 min, and ca. 92 per cent of the dose was available systemically. Extent of plasma protein binding, measured in vitro at 5 and 20 mug/ml by equilibrium dialysis technique, was 53 per cent and independent of ketamine concentration. Simulated plasma and tissue level curves, which were generated by an analogue computer programmed with the individual rate constants of the two-compartment open model, showed that 10 and 15 per cent of the dose were present in the central and peripheral compartments, respectively, at 90 min after i.v. administration of the drug. Peak tissue level of 42 per cent of the dose was reached at 12 to 15 min. Parenteral administration of ketamine, at the dosage rate studied, quickly produced an immobilizing effect of variable duration (0.75 to 1.75 hr) in normal cats.     

Pharmacokinetics and clinical effects of cefozopran in pediatric patients

An investigation was made into pharmacokinetics and clinical effects of the newly-developed cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), in pediatric patients. In 26 patients in whom pharmacokinetics were investigated, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by i.v. injection were 21.3 +/- 10.0 (mean +/- standard deviation), 51.0 +/- 9.9 and 68.3 +/- 0.7 micrograms/ml, respectively. Serum concentrations at 6 hours after administration were 2.9 +/- 1.7, 2.3 +/- 0.9 and 4.6 +/- 2.6 micrograms/ml, with the levels roughly above MIC90s for dominating pathogenic bacteria being maintained until 6 hours after treatment. Urine concentrations were in the range between 200 and 560 micrograms/ml at 4 to 6 hours after dosing. Cumulative urine excretion accounted for 70 to 80% of dose. In 11 patients in whom pharmacokinetic investigations were performed, peak serum concentrations of CZOP administered at doses of 10, 20 and 40 mg/kg by 30-min. i. v. drip infusion were 37.1, 66.3 +/- 25.5 and 95.7 +/- 8.9 micrograms/ml, respectively. Serum concentrations at 6 hours after dosing were 1.6, 2.3 +/- 0.8 and 3.0 +/- 0.4 micrograms/ml, respectively, with the levels above MIC90s for dominating pathogenic bacteria also being maintained until 6 hours after administration. Urine concentrations were 190 micrograms/ml or more until 8 hours after dosing and the cumulative urinary excretion accounted for 50 to 70% of dose. In 9 patients with meningitis in whom CZOP penetration into cerebrospinal fluid was investigated, concentrations in the fluid of the compound i.v. injected at doses from 40 to 53 mg/kg were in the range between 1.6 and 43.4 micrograms/ml exceeding MICs for pathogenic bacteria at 1 to 1.5 hours after dosing. In all of the 38 patients in whom pharmacokinetic investigations and clinical evaluations were performed, CZOP was good to excellent (excellent in 22 patients and good in 16 patients). Also in bacteriological evaluations, all of the 31 strains of investigated pathogenic bacteria were eradicated. The clinical efficacy rates for the 335 subjects for clinical evaluations were 97.0% (195/201) for patients in whom pathogenic bacteria were detected (group A), and 95.5% (128/134) for patients in whom no pathogenic bacteria were detected (group B). In bacteriological evaluations, the eradication rates of Gram-positive and Gram-negative bacteria were 96.3% (77/80) and 94.5% (155/164), respectively, with the eradication rate in total being 95.1% (232/244). Safety investigations were performed in 364 patients. Adverse reactions were reported in 11 patients (3.0%), including diarrhea (aqueous stool and soft stool) in 7 patients (1.9%) and drug rash (rash, eruption and wheal) in 4 patients (1.1%). Abnormal laboratory test values were noted in 54 patients, including eosinophilia in 20 patients (6.3%) and elevated GPT in 20 patients (6.3%). The adverse reactions and abnormal laboratory test values were not serious, disappearing or improving during the continued treatment period or as a result of discontinuation of the treatment. Serum and urine concentrations of CZOP, when administered by i.v. injection and 30-min, i.v. drip infusion at doses of 10, 20 and 40 mg/kg, were higher than the MICs for pathogenic bacteria until 6 hours after dosing. The drug also showed favorable penetration into cerebrospinal fluid. It was therefore considered that CZOP was a highly useful drug for the treatment of pediatric infections with sufficient bacteriological and clinical efficacy when administered at a dose of 40 to 80 mg/kg three to four times daily.     

The effect of systemic venous drainage of the pancreas on insulin sensitivity in dogs

To assess the metabolic consequences of the diversion of the pancreatic venous drainage to the systemic circulation, the pancreaticoduodenal and gastrosplenic veins were anastomosed to the inferior vena cava in nine normal dogs. This procedure maintained the integrity of the entire pancreas while shunting the hormonal output of the pancreas to the periphery. The metabolic effects were assessed from the sensitivity to insulin during a euglycemic hyperinsulinemic glucose clamp using an insulin infusion of 800 microU/kg per min. The studies were controlled by their duplication in seven dogs identically treated but with the pancreatic veins reanastomosed to the portal vein. No differences in systemic insulin levels or insulin sensitivity before and after surgery were seen under these circumstances. After diversion, however, basal insulin levels rose from 4.5 +/- 1.0 to 11.5 +/- 2.5 microU/ml. Basal glucose metabolic clearance rate (MCR) rose to 3.0 +/- 0.4 from 2.0 +/- 0.3 ml/kg per min. On insulin infusion, maximal stimulation of MCR within the 2-h infusion period was to 15.2 +/- 2.5 ml/kg per min preoperatively and to 7.2 +/- 0.8 ml/kg per min after diversion. Using ratios of MCR-to-insulin concentration as an index of insulin sensitivity, it was demonstrated that this index decreased by at least 50% after diversion. These data imply that portal venous drainage of the pancreas is an important factor in the determination of peripheral insulin sensitivity.     

Vascular reconstruction using left renal vein graft in advanced hepatobiliary malignancy

BACKGROUND/AIMS: In surgical resection for advanced hepatobiliary malignancies involving the portal vein and inferior vena cava, vascular reconstruction is usually required. We utilized left renal vein grafts for vascular reconstruction in cases of these malignancies, and their clinical significance is evaluated in this study. METHODOLOGY: Left renal vein grafts were utilized for reconstruction of the portal vein in four patients and patch repair of the inferior vena cava was performed in two patients with advanced hepatobiliary malignancies. All six patients underwent hepatic resection with vascular resection and reconstruction. Postoperative renal function and graft patency were assessed. RESULTS: Transient slight renal disturbances appeared in some patients, but there was no severe renal dysfunction requiring specific therapy. Graft patency was maintained during the follow-up period in all patients. CONCLUSION: The use of left renal vein grafts as autovein grafts seems appropriate in cases involving reconstruction of the portal vein and in those involving patch repair of the inferior vena cava defect in surgical resection for advanced hepatobiliary malignancies.     

Effects of vena caval banding in experimentally induced multiple portosystemic shunts in dogs

Effects of vena caval banding on portal venous and vena caval hemodynamics were examined in 6 control dogs and in 10 dogs that had undergone attenuation (banding) of the abdominal part of the caudal vena cava and had dimethylnitrosamine-induced multiple portosystemic shunts (PSS). Additionally, indocyanine green (ICG) extraction and clearance after infusion to steady state were used to calculate hepatic plasma flow in these dogs. Sixteen dogs were randomly assigned to 2 groups: control (n = 6) or diseased (n = 10). Diseased dogs were administered dimethylnitrosamine (2 mg/kg, PO, twice weekly) until multiple PSS developed, as assessed by results of clinical laboratory tests, ultrasonography, and hepatic scintigraphy. Shunts were confirmed visually at celiotomy and by contrast portography. Venous pressures (caudal vena caval, portal, and hepatic) were recorded before and after vena caval banding for up to 7 days in dogs from both groups. Peritoneal cavity pressures were recorded in all dogs after closure of the body wall. To determine ICG extraction and clearance, a bolus injection of ICG (0.5 mg/kg, i.v.) was administered, followed by steady-state infusion of 0.097 mg/min. Extractions and clearances of ICG were measured, and from these, hepatic plasma flow rates were determined immediately before and after banding and at 6 hours, 48 hours, and 7 days after banding. The gradient (caudal vena caval pressure within 1 to 2 mm of Hg of portal pressure) between caudal vena cava and portal venous pressures established at banding was maintained after the first hour in both groups. Caudal vena cava pressures established at banding were maintained throughout the study, with the exception of the first hour in diseased dogs. Extraction ratios were higher in control dogs at all times, except at 48 hours. Clearance was higher in control dogs at all times. Hepatic plasma flow did not differ between groups, except immediately after banding, when flow was greater in diseased dogs, and differences were not found over time in either group. This study indicated that vena caval banding in this model of experimentally induced multiple PSS increases and maintains caudal vena cava pressure, relative to portal venous pressure (after the first hour) for 7 days, and that calculated hepatic plasma flow is not persistently improved by vena caval banding.     

Heterotopic liver transplantation in rats: effect of intrahepatic islet isografts and split portal blood flow on liver integrity after auxiliary liver isotransplantation

BACKGROUND: Auxiliary heterotopic liver grafts atrophy in the absence of portal venous inflow; evidence suggests that an islet-derived hepatotrophic factor may exist in the portal drainage. Here we examine the effects of intrahepatic islet isografts in maintaining hepatocyte integrity in Wistar Furth rats with one of several types of arterialized auxiliary liver isografts. METHODS: In type 1 procedures the auxiliary liver was interposed into the recipient infrarenal vena cava and perfused through the graft portal vein with caval blood. In type 2 procedures the donor infrahepatic vena cava was anastomosed end-to-side to the recipient vena cava and the recipient portal vein was diverted to the graft portal vein. Both types of auxiliary grafts were arterialized; bile duct drainage was through the duodenum. Syngeneic islets were isolated and embolized into the portal veins of one half of the donor type 1 or native type 2 livers (1500 to 1700 islets). Finally, we performed six type 3 procedures in which a type 2 procedure was performed except that the portal blood flow was split so that the portal vein receiving the splenic, gastric, pancreatic, and duodenal drainage supplied the native liver and that the common mesenteric vein supplied the auxiliary graft with equivalent portal blood flow. Atrophy in heterotopic and native livers were compared for the three models after 3 months. RESULTS: Intrahepatic islets in type 1 auxiliary liver isografts without portal venous inflow did not prevent graft atrophy. Conversely, native livers deprived of portal venous inflow in our type 2 procedures, regardless of the presence of intrahepatic islet isografts, atrophied relative to auxiliary liver grafts in which portal venous inflow was provided by diverting the recipient's portal vein to the graft. In type 3 recipients atrophy was greater in the native livers than in the grafts. CONCLUSIONS: The results of our study suggest that islet-derived factors are not sufficient to prevent hepatocellular atrophy in auxiliary rat liver transplantation models and that a potent hepatotrophic factor may exist in the venous drainage of the bowel distal to the duodenum.     

pR plasmid replication provides evidence that single-stranded DNA induces the SOS system in vivo

The aim of this study was to quantitate factors affecting the initial "peak" of the pulmonary artery (PA) drug concentrations after i.v. bolus drug administration, which is a determinant of the subsequent drug uptake into both the lungs and other well-perfused organs. Indocyanine green (ICG) was used as a marker drug in anaesthetized (1.5% halothane) sheep prepared with an inferior vena cava injection catheter and a large-gauge pulmonary artery blood sampling catheter. For three ranges of cardiac output, 2.5-mg doses of ICG were injected in the following combinations: 10 ml injected over 1, 5 or 10 s; 5 or 25 ml injected over 1 s. On-line PA ICG concentrations were recorded for approximately 60 s using a densitometer. The mean maximum PA ICG concentrations (2-8 mg litre-1), the mean times at which they occurred (7-18 s after injection) and the time lags before ICG was detected in the PA (4-9 s), were inversely related to cardiac output, but linearly related to the time over which the injection was made. The area under the curve of the peak was related inversely to cardiac output only, while the aspect ratio of the peak was related inversely to the time over which the injection was made only. The injectate volume had no effect on any of the measured values. We conclude that, in some circumstances, the rate of injection of drugs with narrow margins of safety should be tailored to the cardiac output of an individual.     

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.     

The importance of assessing the morphofunctional state of the liver in the diagnosis of fatal alcoholic intoxication

The morphology and function of the liver was studied by pathomorphological, gas chromatographic, and histochemical analysis in 108 forensic medical expert evaluations of alcohol poisoning, coronary disease, alcohol cardiomyopathy, craniocerebral injury, and mechanical asphyxia. Ethanol concentrations in the blood collected from various parts of the venous system varied: in 69% of cases the level of ethanol was higher in the inferior vena cava than in the portal vein. Histochemical analysis of ethanol-oxidizing enzymatic systems together with pathomorphological findings and alcohol measurements in various parts of the venous system help assess the morphology and function of the liver, define the thanatogenesis, and draw objective expert conclusion on the cause of death.     

An estimate of the rate of direct drug diffusion from the surface of heart and kidney--implications for their representation as compartments

In many regional pharmacokinetic experiments and models, the anatomical boundaries of the heart and kidney are intrinsically assumed to be barriers for drug diffusion such that these organs can be represented as one or more compartments. To test this, an experimental preparation was developed in which the heart and kidney of anaesthetized sheep were surrounded with 0.9% saline. The rate of drug diffusion from the surface of the organs into the saline was examined during constant-rate i.v. drug infusions. It was found that the maximum clearances of lidocaine and procainamide into the pericardial saline were 10.3-11.6 and 0.6-2.1 ml min-1 respectively, and the values for the kidney were 0.3-0.6, 0.1-1.0 and 0.4-1.3 ml min-1, for lidocaine, procainamide, and meperidine respectively. These corresponded to calculated times of 4-481 min to reach the steady-state saline concentration depending on the drug and the organ. The steady-state ratio of the saline concentrations over the arterial blood drug concentrations usually ranged from 0.5-1.0. It is concluded that drugs can rapidly enter regions of low or no perfusion surrounding these organs, and that the concept of treating the heart and kidney as compartments may not be valid in certain 'worst-case' situations.     

Effects of canrenoate potassium, an aldosterone antagonist on portal hemodynamics in patients with compensated liver cirrhosis

BACKGROUND/AIMS: Long-term administration of spironolactone is reported to reduce portal pressure in cirrhotic patients. We examined the effects of acute administration of canrenoate potassium, an aldosterone antagonist, on portal hemodynamics in compensated cirrhotic patients using noninvasive duplex Doppler ultrasonography. MATERIALS AND METHODS: Baseline values were obtained in the fasting state, and then 200mg of canrenoate potassium in 10ml of saline solution was intravenously administered to 22 patients, whereas 10ml of saline solution was administered as a placebo to 8 patients. RESULTS: The portal cross-sectional area, portal blood velocity and portal blood flow decreased by 5.3 +/- 9.2, 10.4 +/- 8.7% and 13.0 +/- 12.4%, respectively at the nadir 60min after administration and these decreases persisted until 120min. Placebo did not affect these parameters of portal hemodynamics. Eleven responders, who had a more than 10% drop in portal blood flow 60min after administration, had significantly higher levels of plasma aldosterone than 8 non responders who had less than 10% drop. The reduction rate of portal blood flow was closely correlated with plasma aldosterone level. CONCLUSIONS: These findings suggest that aldosterone antagonist directly causes a reduction in portal blood flow, probably through inhibition of aldosterone-induced vasoconstrictive action.     

Role of the liver and gut in systemic diphenhydramine clearance in adult nonpregnant sheep

We investigated the contribution of the liver and gut to systemic diphenhydramine (DPHM) clearance in adult nonpregnant sheep in two separate studies. In the first study, a simultaneous 50-mg bolus each of DPHM and its deuterium-labeled analog ([2H10]DPHM) was administered to five sheep via the femoral (i.v.) and the portal venous (p.v.) routes in a randomized manner. Arterial plasma concentrations of DPHM, [2H10]DPHM, and their deaminated metabolites, DPMA (diphenylmethoxyacetic acid) and [2H10]DPMA, were measured using gas chromatography-mass spectrometry. The hepatic first-pass extraction of DPHM after p.v. administration was 94.2 +/- 3.7%. However, the area under the plasma concentration versus time profile of the metabolite after i.v. dosing was only 32.5 +/- 14.0% relative to that after p.v. administration. Thus, only approximately 32.5% of the i.v. dose is metabolized in the liver and a significant extrahepatic systemic clearance component is evident. Using the calculated total hepatic blood flow values, it was found that 98.6 +/- 9.2% of the i.v. dose eventually was delivered to the "hepatoportal" system. Because the drug delivered to the hepatoportal system is almost completely eliminated in a single pass (hepatic extraction approximately 94%), this indicates a lack of any significant pulmonary drug uptake. Also, because only approximately 32.5% of the i.v. dose is metabolized in liver, the gut is most likely responsible for the clearance of the remainder. This gut contribution to systemic DPHM clearance was confirmed in a separate direct study in four sheep where the steady-state DPHM gut extraction ratio was 49.0 +/- 3.0%. Thus, gut accounts for a significant proportion (>/=50%) of DPHM systemic clearance in sheep in spite of a very high hepatic drug extraction efficiency.