Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg-1 h-1 into six volunteers to study its pharmacokinetics and effects on pentagastrin-stimulated gastric acid secretion (100 ng kg-1 h-1). The concentration of oxyntomodulin in plasma measured with a cross-reacting glucagon assay increased from 37 +/- 5 to 106 +/- 17 and 301 +/- 40 pmol l-1, respectively. The metabolic clearance rate was 5.2 +/- 0.7 ml kg-1 min-1 and the half-life in plasma was 12 +/- 1 min. Oxyntomodulin reduced the pentagastrin-stimulated acid secretion by 20 +/- 9% during the low-rate infusion (P less than 0.05) and by 76 +/- 10% during the high-rate infusion (P less than 0.05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C-peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.     

Atrial natriuretic peptide: evidence of action as a natriuretic hormone at physiological plasma concentrations in man

The administration of exogenous atrial natriuretic peptide (ANP) causes a natriuresis and diuresis in man, but this has, to date, only been demonstrated at plasma ANP concentrations within the high pathological or pharmacological ranges. Evidence that ANP acts physiologically requires the demonstration of a natriuretic effect when it is infused to recreate plasma concentrations similar to those observed after physiological stimuli. We infused human alpha-ANP (1-28) at a calculated rate of 1.2 pmol min-1 kg-1 for 3 h into seven water-loaded normal subjects, achieving plasma ANP concentrations within the upper part of the physiological range. The subjects' resting plasma ANP concentration increased from 3.8 +/- 1.5 to 20.9 +/- 1.9 pmol/l. The infusion of ANP caused a 60% increase of mean urinary sodium excretion from 111 +/- 18 to 182 +/- 30 mumol/min (P less than 0.001) and a 28% increase of mean water excretion from 10.8 +/- 0.8 to 13.8 +/- 1.6 ml/min (P less than 0.01). The infusion suppressed mean plasma renin activity from 1.55 +/- 0.10 to 1.17 +/- 0.06 pmol of ANG I h-1 ml-1 (P less than 0.001). Mean plasma aldosterone concentration (242 +/- 16 basally and 215 +/- 15 pmol/l at the end of ANP infusion) did not change significantly. Pulse rate and blood pressure were unchanged throughout the study. No significant change in any of the variables mentioned above occurred during the infusion of the vehicle alone on a separate study day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.     

The effect of captopril on blood pressure and angiotensins I, II and III in sodium-depleted dogs: problems associated with the measurement of angiotensin II after inhibition of converting enzyme

1. Changes in arterial blood pressure, blood angiotensin I, plasma angiotensin II and plasma angiotensin III were measured in conscious sodium-depleted dogs after infusion of captopril, an orally active inhibitor of converting enzyme. 2. Angiotensins II and III were measured after chromatography to remove angiotensin I, which increased in concentration after inhibition of converting enzyme and which interfered in the direct assay for angiotensin II. 3. Infusion of captopril at 20, 200, 2000 and 6000 microgram h-1 kg-1, each for 3 h, produced a rapid fall in blood pressure and in concentration of angiotensin II. Angiotensin II was undetectable at 6000 microgram h-1 kg-1 (mean pre-infusion value for all samples was 39 +/- SD 15 pmol/1, n = 14). 4. The percentage fall in blood pressure correlated with the percentage fall in plasma angiotensin II (r = 0.65, P < 0.001). 5. These results suggest that the initial fall in blood pressure may be mediated in part by the suppression of angiotensin II. 6. Blood angiotensin I concentration rose with each rate of infusion of drug to a maximum 16-fold increase at 6000 microgram h-1 kg-1 (26-416 pmol/l). The rise in angiotensin I was inversely related to the fall in angiotensin II (r = 0.68, P < 0.001).     

Atrial natriuretic peptide inhibits fluid intake in hyperosmolar subjects.

1. The effect of atrial natriuretic peptide on osmotically stimulated thirst appreciation and consequent fluid intake was investigated in healthy man. 2. Six seated male subjects were studied on two occasions: synthetic alpha-human atrial natriuretic peptide (99-126) (2 pmol min-1 kg-1) or placebo (saline, 150 mmol/l NaCl) was infused intravenously for 105 min; 30 min after the start of atrial natriuretic peptide/placebo infusion, hypertonic saline (855 mmol/l NaCl) was infused (0.06 ml min-1 kg-1) for 60 min. Subjects were then allowed free access to water for the next 2 h; infusion of atrial natriuretic peptide/placebo continued for the first 15 min of the drinking period. 3. The plasma atrial natriuretic peptide concentration did not alter significantly during infusion of hypertonic saline and placebo; it rose to a steady state of 12.7 +/- 1.1 pmol/l (mean +/- SEM) during the infusion of atrial natriuretic peptide and hypertonic saline, and remained at this level during the first 15 min of the drinking period. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, similar increases in plasma osmolality (P less than 0.001) and plasma vasopressin concentration (P less than 0.005) occurred. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, thirst increased significantly over the time course of both studies (P less than 0.01), but the effect of atrial natriuretic peptide infusion compared with placebo infusion was to significantly decrease thirst at 60 min. 4. Drinking rapidly abolished thirst and vasopressin secretion before changes in plasma osmolality occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Intraduodenal Administration of HCl and Glucose on Circulating Immunoreactive Secretin and Insulin Concentrations

A new radioimmunoassay for secretin was used to investigate (a) serum secretin responses to intraduodenally infused HCl and glucose, (b) the metabolic half-life and the volume of distribution of exogenous secretin and (c) the effect of endogenously released secretin on insulin secretion in 25 anesthetized dogs. Portal and femoral venous blood samples were taken simultaneously before, during, and after intraduodenal infusion of HCl (21 meq/30 min) and glucose (131 ml/30 min). Control experiments were performed with intraduodenal infusion of saline.Mean portal venous immunoreactive secretin concentration of six dogs rose from 313 muU/ml before to 1,060 muU/ml 10 min after initiation of the intestinal acidification (P < 0.005). Femoral venous immunoreactive secretin concentration rose from 220 muU/ml before to 567 muU/ml 15 min after intestinal acidification (P < 0.01). Secretin concentrations remained elevated during the remainder of the infusion.In the same six dogs mean portal venous immunoreactive insulin concentration rose from 38 muU/ml before to 62 muU/ml at the end of the infusion (P < 0.05). Peripheral immunoreactive insulin, glucose, and free fatty acid concentrations, however, did not change significantly.Pancreatic exocrine function was studied in four dogs. The rise in secretin concentration was followed promptly by a highly significant increase in exocrine pancreatic flow rate and bicarbonate secretion, indicating biological activity of the circulating immunoreactive secretin.The effect of intraduodenal infusion of glucose on immunoreactive secretin concentration was studied in 12 dogs. Glucose in concentrations ranging from 2.5% to 10% had no detectable influence on portal or peripheral secretin concentration. Infusion of 50% glucose caused a slight decline in secretin concentration.The metabolic clearance rate, half-life of disappearance, and volume of distribution of exogenous secretin was studied in three dogs by the constant infusion technic. The metabolic clearance rate was 730+/-34 ml/min, volume of distribution was 17.4+/-0.8% of body weight, and the half-life of disappearance was 2.8+/-0.1 min. It could be calculated that 1.38 U/kg-h(-1) of endogenous secretin was released into the peripheral circulation during the steady state period of the HCl infusion experiments.The data indicated that immunoreactive secretin was released rapidly after intestinal acidification, continued to be secreted throughout the duration of HCl infusion, and was promptly distributed in the extracellular compartment. Furthermore, they suggested that endogenously released secretin could stimulate insulin secretion. The HCl-mediated insulinogenic effect of immunoreactive secretin, however, was too weak to influence peripheral immunoreactive insulin, glucose, and free fatty acid concentrations.The failure of intraduodenal glucose to stimulate secretin release suggests that secretin is not the insulin-stimulatory factor released from the gastrointestinal tract in response to glucose.     

The independent effect of ketone bodies on forearm glucose metabolism in normal man.

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 mumol kg-1 min-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg-1 min-1) and insulin (0.01 U kg-1 h-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg-1 h-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 +/- 14 and +49 +/- 21 [mean +/- SEM] nmol 100 ml forearm [FA]-1 min-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulinaemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 +/- 4 mumol/l to a plateau of 450 +/- 30 mumol/l, while control levels declined from baseline (ketone body vs control; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pancreatic polypeptide on motilin and circulating metabolites in man

Pancreatic polypeptide was infused intravenously in healthy fasting subjects at 1 pmol kg-1 (n = 7) and 4 pmol kg-1 min-1 (n = 10) producing plasma PP concentrations of 223 +/- 37 pmol/l (mean +/- SEM) and 891 +/- 64 pmol/l respectively. These levels are similar to and four-fold higher than those seen after a normal mixed breakfast in healthy young adults. In a separate study five healthy subjects ingested a small breakfast during infusion of PP on different days at 1 pmol kg-1 min-1 and 2 pmol kg-1 min-1 respectively. PP at 1 pmol kg-1 min-1 caused a marked reduction in fasting plasma motilin concentrations to 20% of the basal level (p less than 0.001). There were, however, no significant changes in plasma concentrations of insulin, glucagon, gastrin, secretin, enteroglucagon, gastric inhibitory peptide or neurotensin. Despite previous reports possibly implicating PP in metabolism, there were no significant effects on blood levels of glucose, alanine lactate, 3-hydroxybutyrate, glycerol or non-esterified fatty acids, either in the fasting state or after the ingestion of food. Although it seems unlikely that PP is a major hormonal regulator of intermediary metabolism in man, its ability to suppress motilin at physiological concentrations suggests the possibility of an indirect influence on digestive motor function.     

Role of renal arterial pressure in the regulation of extracellular volume in conscious dogs.

1. This study in conscious dogs examined the quantitative effects of a reduction in the renal arterial pressure on the renal homeostatic responses to an acute extracellular fluid volume expansion. 2. Seven female beagle dogs were chronically instrumented with two aortic catheters, one central venous catheter and a suprarenal aortic cuff, and were kept under standardized conditions on a constant high dietary sodium intake (14.5 mmol of Na+ day-1 kg-1 body weight). 3. After a 60 min control period, 0.9% (w/v) NaCl was infused at a rate of 1 ml min-1 kg-1 body weight for 60 min (infusion period). Two different protocols were applied during the infusion period: renal arterial pressure was maintained at 102 +/- 1 mmHg by means of a servo-feedback control circuit (RAP-sc, 14 experiments) or was left free (RAP-f, 14 experiments). 4. During the infusion period, in the RAP-sc protocol as well as in the RAP-f protocol, the mean arterial pressure increased by 10 mmHg, the heart rate increased by 20 beats/min, the central venous pressure increased by 4 cmH2O and the glomerular filtration rate (control 5.1 +/- 0.3 ml min-1 kg-1 body weight, mean +/- SEM) increased by 1 ml min-1 kg-1. 5. Plasma renin activity [control 0.85 +/- 0.15 (RAP-f) and 1.08 +/- 0.23 (RAP-sc) pmol of angiotensin I h-1 ml-1] decreased similarly in both protocols.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide: an endogenous factor enhancing sodium excretion in man

For many years experimental evidence has suggested the existence of a circulating factor able to enhance sodium excretion. Very recently peptides with natriuretic activity in experimental animals have been isolated from mammalian and human cardiac tissue. In order to determine whether this natriuretic activity has relevance to man we have studied the effects of an infusion of alpha-human atrial natriuretic peptide (alpha-h-ANP) in normal subjects. Sodium excretion trebled (P = less than 0.005) during the infusion of a calculated dose of 15 pmol of alpha-h-ANP min-1 kg-1 and there was an accompanying diuresis; radioimmunoassay of plasma alpha-h-ANP during the natriuresis indicated a mean peak incremental concentration of 203 +/- 78 (SEM) pmol/l. The infusion of a calculated dose of 1.5 pmol min-1 kg-1 did not affect sodium excretion. There were no haemodynamic changes and no side effects were noted.     

Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretin and cholecystokinin levels.

Pancreatic trypsin output and plasma secretin and cholecystokinin (CCK) levels were measured in five healthy volunteers to investigate the mechanisms involved in regulating postprandial pancreatic secretion. The pancreas was stimulated by a liquid test meal or by either intravenous secretin (1-82 pmol/kg-1 per h-1) or caerulein, a CCK analogue (2.3-37 pmol/kg-1 per h-1), or by a combination of secretin and caerulein. Pancreatic secretion was assessed by a marker perfusion technique (polyethylene glycol [PEG 4000]), plasma secretin, and CCK by specific radioimmunoassays. Increasing doses of secretin produced increasing bicarbonate output (P less than 0.01), whereas trypsin was not stimulated over basal. Graded caerulein produced a stepwise increase in trypsin and bicarbonate output (P less than 0.01). Potentiation occurred for bicarbonate secretion between secretin and caerulein, but not for trypsin output. Postprandial trypsin secretion averaged 29.1 IU/min-1 over 150 min (equal to 55% of maximal response to caerulein). The peak trypsin response amounted to 90% of maximal caerulein. Significant increases of plasma secretion (P less than 0.05) and CCK (P less than 0.01) were observed after the meal. Comparison of enzyme and CCK responses to the testmeal or to exogenous caerulein suggested that the amount of CCK released after the meal could account for the postprandial trypsin secretion. We conclude that (a) the postprandial enzyme response in man is submaximal in comparison to maximal exogenous hormone stimulation; (b) CCK is a major stimulatory mechanism of postprandial trypsin secretion, whereas secretin is not involved; and (c) Potentiation of enzyme secretion is not a regulatory mechanism of the postprandial secretory response.     

Regulation of gastric acid secretion by neurotensin in man. Evidence against a hormonal role.

The present study was designed to evaluate neurotensin as a hormonal regulator of gastric acid secretion in man. After a fat-rich meal, the strongest known stimulus of neurotensin release, plasma neurotensin-like immunoreactivity (NTLI) was elevated from 7.6 +/- 1.9 to 15.5 +/- 2.5 pM. Plasma NTLI was measured with antiserum L170, which requires the biologically active carboxyl-terminal hexapeptide of the neurotensin molecule for recognition and does not crossreact significantly with any known natural catabolite in human plasma. Intravenous infusion of neurotensin at 25 pmol X kg-1 h-1 resulted in a plasma level of 14.7 +/- 2.1 pM, similar to the maximal physiological level observed after the fat-rich meal. Intravenous infusion of neurotensin at 25 pmol X kg-1 h-1 during 2 h, however, failed to significantly inhibit peptone meal-stimulated gastric acid secretion measured by intragastric titration. The 2-h acid output to peptone was 40.8 +/- 6.2 and 41.3 +/- 6.9 mmol during the vehicle and the neurotensin infusion, respectively. Intravenous infusion of neurotensin at 100 or 400 pmol X kg-1 h-1 did not affect acid output, whereas at 1,600 pmol X kg-1 h-1, which resulted in a plasma neurotensin concentration of 725 +/- 80 pM, significantly reduced peptone meal-stimulated gastric acid secretion. The neurotensin-induced inhibition of acid output was independent of the hormone gastrin. The present results provide evidence against a hormonal role for neurotensin in the regulation of meal-stimulated gastric acid secretion in man.     

Metabolic clearance rate of arginine vasopressin in severe chronic renal failure.

1. The metabolic clearance rate of arginine vasopressin was determined using a constant infusion technique in normal subjects and patients with chronic renal failure immediately before commencing dialysis. Endogenous arginine vasopressin was suppressed in all subjects before the infusion with a water load. 2. Plasma arginine vasopressin concentrations were determined using a sensitive and specific radioimmunoassay after Florisil extraction. The detection limit of the assay was 0.3 pmol/l, and intra- and inter-assay coefficients of variation at 2 pmol/l were 9.7% and 15.3%, respectively. 3. In normal subjects, the metabolic clearance rate was determined at two infusion rates producing steady-state concentrations of arginine vasopressin of 1.3 and 4.4 pmol/l. In the patients with renal failure, a single infusion rate was used, producing a steady-state concentration of 1.5 pmol/l. 4. At comparable plasma arginine vasopressin concentrations, metabolic clearance rate was significantly reduced in patients with renal failure (normal 1168 +/- 235 ml/min versus renal failure 584 +/- 169 ml/min; means +/- SD; P < 0.001). 5. Free water clearance was significantly reduced in normal subjects during the arginine vasopressin infusion from 8.19 +/- 2.61 to -1.41 +/- 0.51 ml/min (P < 0.001), but was unchanged in the patients with renal failure after attaining comparable plasma arginine vasopressin concentrations. 6. In normal subjects there was a small but significant fall in metabolic clearance rate at the higher steady-state arginine vasopressin concentration (1168 +/- 235 ml/min at 1.3 pmol/l versus 1059 +/- 269 ml/min at 4.4 pmol/l; P = 0.016).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of midazolam versus propofol for short-term sedation following coronary artery bypass grafting

Midazolam and propofol were compared in an open randomized study for postoperative sedation during 12 h of mechanical ventilation in 40 patients following coronary artery bypass grafting. After an intravenous loading dose of midazolam (50 micrograms.kg-1) or propofol (500 micrograms.kg-1), a titrated continuous infusion was administered of midazolam (mean dose 38.1 micrograms.kg-1.h-1 (SEM 2.6)) or propofol (mean dose 909 micrograms.kg-1.h-1 (SEM 100)) together with a narcotic analgesic infusion. During mechanical ventilation midazolam and propofol produced a similar quality of sedation, but recovery (midazolam 66 min (SEM 16); propofol 24 min (SEM 7)) and weaning from the ventilator (midazolam 243 min (SEM 44); propofol 154 min (SEM 33)) where faster with propofol. In the 2 groups administration of an intravenous loading dose caused a significant decrease in mean arterial pressure but hemodynamic tolerance during maintenance infusion was good.     

PHARMACOKINETICS OF INTRAVENOUS CAFFEINE IN CRITICALLY ILL PATIENTS

The pharmacokinetics of intravenous caffeine used to measure liver function were evaluated in 20 critically ill patients. Each patient received a single dose of 3.0 mg/kg of caffeine benzoate as a 30-min i.v. infusion. Caffeine serum concentrations were analysed by an enzyme-multiplied immunoassay technique (EMIT). Caffeine pharmacokinetics fitted an open one-compartment model. The mean value for the half-life (t1/2) was 9.46 +/- 4.32 h, the volume of distribution was 0.55 +/- 0.13 l/kg, and the plasma clearance (Cl) was 0.85 +/- 0.44 ml/min/kg. The pharmacokinetics parameters of caffeine in critically ill patients compared with normal volunteers were characterized by a reduction in plasma clearance and prolongation in plasma half-life, whereas the volume of distribution remained unchanged.     

Pharmacokinetics and dose proportionality of cefpimizole in normal humans after intramuscular administration.

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were evaluated after intramuscular administration of single doses (dose range, 100 to 1,000 mg) and multiple doses (dose range, 500 to 2,000 mg) given b.i.d. for 6 or 11 days. The kinetics after intramuscular administration correspond to a one-compartment model with first-order input. The apparent volume of distribution of the absorbed dose averaged 18.6 +/- 3.4 (standard deviation) liters for 58 individuals; the absorption-phase and elimination-phase rate constants averaged 2.53 +/- 1.16 h-1 (half-life, 0.27 h) and 0.338 +/- 0.041 h-1 (half-life, 2.05 h), respectively; and the mean residence time was 3.43 +/- 0.43 h. The total body clearance of the absorbed dose after single-dose intramuscular administration was 102 +/- 13 ml/min. The primary route of elimination was renal with 73 to 83% of the administered dose excreted in the urine as unchanged drug. Renal clearance averaged 81 +/- 13 ml/min. Dose proportionality was obtained from area under the plasma curve, concentration maximum in plasma, and cumulative urinary excretion levels. Multiple-dose evaluation of intramuscular administration of cefpimizole indicated no apparent change in the absorption or elimination phases after b.i.d. dosing for 6 or 11 days. The kinetic parameters determined from multiple-dose plasma and urine levels were in close agreement with the same parameters calculated from single-dose results. No apparent accumulation of cefpimizole occurred, and nondetectable levels of drug were observed in the 24-h plasma and 24- to 48-h urine specimen after administration of the last dose. The kinetics of cefpimizole after intramuscular administration were similar to the kinetics obtained after intravenous infusion.     

Pharmacokinetics and metabolism of 14C-tinidazole in humans

Following intravenous infusion of 800 mg of 14C-tinidazole during 30 min to two human subjects, a mean of 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose during five days: 12% of the dose was excreted in the faeces, indicating the possible involvement of biliary excretion and other secretory processes in the disposition of tinidazole. At 6 min after the end of the infusion, the mean plasma tinidazole concentration was 12 mg/l. Tinidazole was a major component in 0-120 h urine (about 32% of urinary 14C): the major metabolite in the 0-12 h urine examined was ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone (about 30% urinary 14C), the product of hydroxylation and nitro-group migration. These compounds were also present in the faeces. A minor urinary metabolite was 2-hydroxymethyltinidazole (about 9% urinary 14C), which was also present in plasma. The mean pharmacokinetic parameters obtained for tinidazole were similar to those reported in the literature; total clearance 51 ml/min, renal clearance 10 ml/min, volume of distribution 501 and half-life 11.6 h.     

Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man.

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h-1 kg-1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 +/- 0.20 versus 0.67 +/- 0.10 mmol/l), plasma nonesterified fatty acid (395 +/- 13 versus 51 +/- 1 mumol/l), blood glycerol (152 +/- 2 versus 11 +/- 1 mumol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64-104) versus 4 (3-5) mumol/l] were all significantly higher (all P less than 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 +/- 0.07 versus 0.27 +/- 0.08 mg min-1 kg-1, P less than 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 +/- 0.77 to 6.17 +/- 0.71 mg min-1 kg-1, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal haemodynamic, hormonal and excretory effects of low-dose atrial natriuretic factor infusion in renal transplant recipients.

1. In experimental studies, activation of renal sympathetic nerves attenuates the natriuretic response to atrial natriuretic factor. We therefore investigated the response to low-dose infusion of atrial natriuretic factor in renal transplant recipients. 2. Eight male cyclosporin-treated renal transplant recipients received human-alpha atrial natriuretic factor (1-28) at a dose of 1.2 pmol min-1 kg-1 or placebo for 2 h in a placebo-controlled, randomized, cross-over study. The plasma atrial natriuretic factor concentration rose from 18.5 to 49.2 pmol/l in association with an immediate natriuresis (a rise of 49.1 mumol/min in the first 30 min, P less than 0.05; peaking at a 61% increase from baseline, P less than 0.01), diuresis (from 3.37 to 7.46 ml/min) and a threefold rise in urinary cyclic GMP excretion. 3. In response to infusion of atrial natriuretic factor, the packed cell volume rose by 4.2% (P less than 0.001) and the filtration fraction by 5% (from 22 to 27%, P less than 0.05), but there was no significant change in renal plasma flow, glomerular filtration rate or mean arterial blood pressure. Likewise, the plasma catecholamine concentrations, plasma renin activity and serum erythropoietin concentration remained unchanged. 4. The sensitivity of the renal allograft to plasma atrial natriuretic factor concentrations in the high physiological range suggests a role for endogenous atrial natriuretic factor in the modulation of graft function. Furthermore, the immediate natriuretic response to atrial natriuretic factor in the effectively denervated transplant kidney, in contrast to the delayed response seen in normal subjects, may imply that sympathetic nerves have an inhibitory effect on the renal response to atrial natriuretic factor in normal man.(ABSTRACT TRUNCATED AT 250 WORDS)