Influence of food intake on electrocardiograms of healthy male volunteers.

OBJECTIVE: To study the influence of food intake on electrocardiogram (ECG) variables (heart rate, QT-, QTc-, PR-intervals, QRS-time) and morphological alterations of the T-waves in 12 healthy male volunteers. METHODS: The study was of open, three-period crossover design. On each occasion, all subjects fasted from midnight. During two of the study periods, the subjects were given a standardised meal at 1.5 h and 5.5 h after the baseline assessments, respectively, whereas, during the third period, they remained fasting for the entire study period of about 9 h. ECG and blood pressure were recorded at baseline and thereafter every hour for 8 h. RESULTS: No ECG changes were observed following the fasting condition, whereas a clear change in ECG and an increased heart rate were recorded in response to the meal intake during the other two periods. The most prominent ECG effect was the change in the size and shape of the T-waves, which were described as flattened to biphasic and, occasionally, negative. These alterations were most pronounced in the precordial leads V4 to V6 in the ECG recording immediately following the meal intake, with a gradual return to baseline conditions over 4-5 h. Moreover, a transient increase of supine systolic blood pressure was also recorded in response to the meal intake. CONCLUSIONS: The intake of a meal can cause clear and consistent ECG changes in healthy male subjects, comprising increases in heart rate as well as alterations in the size and shape of the T-waves (flattened to biphasic and, occasionally, negative). Also, a post-meal increase in the supine systolic blood pressure was recorded.

Determinants of furosemide delivery to its site of action.

We have investigated the pharmacokinetic determinants of delivery of furosemide to its site of action in the renal tubules in patients and healthy volunteers. The bioavailability of furosemide is low and variable. Patients with renal disease may also have a low renal extraction of furosemide. In clinically relevant concentrations the free fraction of furosemide is inversely proportional to the plasma albumin concentration. A change in the free fraction of furosemide will change Clr, Clnr, and Vd in the same direction and that will cause minimal changes in the excretion rate of furosemide and its t1/2. A change in RBF will change the secretory clearance of furosemide to the same proportion and consequently also the excretion rate and its t1/2.

Acute tolerance to furosemide. Pretreatment with captopril or prazosin does not influence diuresis and natriuresis.

To investigate whether the development of acute tolerance to furosemide in human subjects could be prevented or delayed by angiotensin converting enzyme inhibition or alpha 1-receptor blockade, a study was conducted on healthy volunteers. The protocol on the experimental days was identical except for pre-treatment with placebo, captopril or prazosin. During continuous furosemide infusion with urinary furosemide excretion at a constant rate, the subjects became progressively dehydrated, with a maximal decrease in plasma volume of 9-11%. The diuretic/natriuretic response to furosemide was similar in the three protocols. Acute tolerance to diuresis developed earlier than that to natriuresis, again with no differences between the protocols. Not until the plasma volume had decreased by 9% did the natriuresis diminish significantly. In the placebo and captopril protocols acute tolerance was caused mainly by a decreased glomerular filtration rate, and in the prazosin protocol mainly by increased tubular reabsorption. It is concluded that neither ACE inhibition nor alpha 1-receptor blockade prevented or delayed the acute tolerance to furosemide. The results suggest that acute tolerance to furosemide can be induced through different but complementary homeostatic mechanisms in the kidney.

Conjunctival oxygen tension is influenced by plasma and blood volume, and flow through the external carotid artery.

An investigation of the feasibility and validity of measurement of the conjunctival oxygen tension as a monitor of peripheral circulation, blood and extracellular fluid volume and cerebral circulation was carried out in 7 healthy volunteers and 5 unconscious critical care patients with proven total cerebral infarction. The healthy volunteers were subjected to changes in hydration achieved by the administration of furosemide and subsequent rehydration by administration of normal saline. Conjunctival oxygen tension was found to be a sensitive indicator of changes in the degree of hydration presumably by its ability to detect changes in peripheral circulation depending upon circulating blood and extracellular fluid volume. A drawback is that other stimuli of the sympatho-adrenergic system such as temperature and pain, interfere with measurement in the conscious volunteer. In patients with presumed total brain infarction the conjunctival PO2 cannot be used as a reliable monitor of cerebral blood flow because of varying perfusion of the palpebral conjunctiva from the external carotid artery in the occasional patient.

Tolerability of remoxipride in the long term treatment of schizophrenia. An overview.

506 patients with schizophrenia, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria, were included in a long term treatment programme with remoxipride, a selective dopamine (D2)-receptor antagonist. This overview includes pooled data from all patients who have been treated long term with remoxipride in clinical trials, focusing on patients treated for more than 6 months (n = 283). Remoxipride was administered in daily doses of 75 to 600mg. The assessment tools were Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Simpson and Angus scale, Abnormal Involuntary Movements Scale (AIMS) for abnormal involuntary movements, adverse events/symptoms using a 26-item checklist, clinical chemistry, and haematology and cardiovascular investigations. The majority of patients had a long duration of illness (median 11 years). 67% of patients (340/506) withdrew from treatment before 12 months and 44% (223/506) stopped treatment before 6 months. The median BPRS total score decreased during the first 3 months from 23 to 12, and this level of improvement was maintained throughout the 12-month period. Treatment-emergent adverse events reported by more than 5% of the patients were insomnia, tiredness, drowsiness and tremor in the group treated for 6 to 12 months. No symptoms, including checklist extrapyramidal symptoms (EPS), were reported by more than 5% of patients treated for 12 months. Low frequencies of EPS according to the Simpson and Angus scale were seen in patients treated for more than 6 months (n = 147). A small but statistically significant reduction of the mean total AIMS score from baseline to last rating was observed. There were infrequent changes in heart rate, resting diastolic blood pressure and electrocardiogram (ECG). Clinical chemistry and haematology data showed no evidence of clinically significant changes over time during the 12 months of treatment. Among 506 patients, 7 suicides and 7 suicide attempts occurred during the study period. Other serious adverse events were abnormal liver function test (2 cases), gastrointestinal, urinary retention, status epilepticus (psychotic polydipsia), granulocytopenia (1 each) and myocardial infarction (5 cases). Remoxipride is of potential value as a drug which is both effective and well tolerated in the long term management of patients with schizophrenia.

Changes in renal clearance of furosemide due to changes in renal blood flow and plasma albumin concentration.

We have shown that, within therapeutic plasma concentrations, the unbound fraction of furosemide changes in direct proportion to the reciprocal of the plasma albumin concentration (correlation coefficient 0.99). Changes in the albumin concentration were produced by ultrafiltration of human plasma using a haemofiltration filter. Thus, we propose that, when studying changes in the pharmacokinetics of a highly protein bound drug, calculated changes in the unbound fraction offer an alternative to actual measurement of the unbound concentration, which is often difficult. Nine healthy volunteers receiving a continuous furosemide infusion were studied in normovolaemia and after dehydration (-1.4 kg), with and without pretreatment with an angiotensin converting enzyme inhibitor (captopril) or an a1-adrenoceptor blocking agent (prazosin). Significantly larger changes in the renal clearance of furosemide were found that could be explained by changes in the unbound fraction. Following dehydration, the unbound fraction of furosemide was decreased by about 5%, while its renal clearance fell by 27%, 33% and 13% after pretreatment with placebo, captopril and prazosin, respectively. The secretory clearance of the unbound furosemide changed substantially and in parallel with changes in the renal blood flow. It is suggested that changes in the renal clearance and excretion of furosemide and its t1/2 are much more dependent on changes in renal blood flow than on changes in its unbound fraction.

Improvement of renal preservation by adding lidoflazine to University of Wisconsin solution. An experimental study in the rat.

The purpose of this study was to investigate the possibility of improving the organ preservation properties of the University of Wisconsin (UW) solution by adding the calcium entry blocker lidoflazine. We also investigated the possibility of decreasing the cold ischemia and reperfusion damage by pretreatment with lidoflazine of the donor and/or recipient. The protective effects of lidoflazine treatment were estimated by measuring the amount of trapped erythrocytes in the rat renal medulla after 48 h of cold storage, subsequent transplantation, and 20 min of reperfusion. Lidoflazine (20 mg/liter) added to the UW solution decreased the amount of erythrocyte trapping from 14.8 +/- 3.1% in controls to 8.6 +/- 1.7% (P less than 0.01). The flow rate of the flush-out solution during the harvesting procedure was also significantly (P less than 0.01) increased when lidoflazine was included in the UW solution (1.10 +/- 0.21 ml/min vs 0.75 +/- 0.22 ml/min). Administration of lidoflazine (0.28 mg/kg body wt) to the donor and/or the recipient did not further reduce the postischemia/reperfusion damage as estimated by the degree of erythrocyte trapping. In conclusion, the results indicate that the preservation properties of the UW solution can be significantly improved by adding lidoflazine to the solution.

Pharmacokinetics of recombinant human superoxide dismutase in healthy volunteers.

We studied the pharmacokinetics and effects of recombinant human superoxide dismutase (rhSOD) in 32 normal human volunteers after intravenous bolus doses from 1 mg/kg to 45 mg/kg in a single-blind, placebo-controlled, crossover design. The drug was well tolerated. Neither cardiovascular nor renal function, such as the echocardiographically determined cardiac index, insulin or para-aminohippurate clearance, or the urinary excretion of beta 2-microglobulin or N-acetylglucosaminidase, was affected. Pharmacokinetic analysis by use of noncompartmental methods showed an overall half-life of rhSOD to be about 4 hours for doses from 3 mg/kg to 45 mg/kg. The peak concentrations ranged from 24 to 837 mg/L, and urinary excretion increased from 3% to 57% of total dose after single intravenous bolus administrations of the drug from 1 mg/kg to 45 mg/kg. The mean renal clearance of rhSOD initially increased with dose then plateaued at the highest dose, whereas the nonrenal clearance decreased with dose to a plateau; total clearance remained essentially constant. The progressive increase in renal clearance may be explained by saturation of the tubular reabsorption and degradation of the protein, a mechanism previously described in animal models.

Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients.

The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg.6 h-1. While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml min; P less than 0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P less than 0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors. Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients. In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.

Enhanced local production of complement components in the small intestines of patients with Crohn's disease.

There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum. The mean (+/- SEM) jejunal-fluid C4 concentration was 2.0 +/- 0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7 +/- 0.1 mg per liter; P less than 0.001). The mean C3 concentration was 1.0 +/- 0.1 mg per liter in the patients and 0.7 +/- 0.1 mg per liter in the controls (P less than 0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid:serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due to at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4). We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages.

The jejunal secretion of histamine is increased in active Crohn's disease.

Previous studies of mast-cell density and histamine content in biopsy specimens in patients with Crohn's disease have yielded conflicting results. In this in vivo study we have measured the jejunal secretion rate of histamine in patients with Crohn's disease (n = 15) of the terminal small bowel and in healthy controls (n = 24). The secretion studies were performed using a recently developed segmental jejunal perfusion system with a two-balloon, six-channel small tube. The histamine secretion rate was 152 +/- 29 (SEM) ng/cm small intestine per h in patients with Crohn's disease, which meant a significant increase (p less than 0.01) compared with the secretion rate in controls (71 +/- 11 ng/cm per h). Moreover, the secretion of histamine was related to the disease activity. Patients with active disease (n = 8) (i.e., Crohn's disease activity index greater than 150) had a mean histamine secretion rate of 193 +/- 47 ng/cm per h, while patients with inactive disease (Crohn's disease activity index less than 150) had a secretion rate not significantly increased compared with controls (105 +/- 24 ng/cm per h). The present data indicate increased mast-cell involvement of the small intestine in active Crohn's disease of the distal ileum. This finding might reflect the systemic nature of the disease process.

Signs of increased leakage over the jejunal mucosa during gliadin challenge of patients with coeliac disease.

Intestinal secretion rates of albumin, hyaluronan, and beta 2-microglobulin (beta 2-micro) were determined under basal conditions and after gliadin challenge of coeliac patients and healthy controls by the use of a jejunal perfusion technique. A new tube system was used where a jejunal segment is isolated between balloons and then perfused with a balanced salt solution. Under basal conditions the secretion rate of albumin was similar in the patients and controls while the secretion rate of the glycosaminoglycan hyaluronan, a high molecular weight connective tissue component, was increased more than two times in coeliac patients. Beta 2-micro was secreted in on average three-fold rates in coeliacs compared with controls. All three substances were secreted at a higher rate in patients with active disease than in those with inactive disease defined by morphological damage in small bowel biopsies. The concentrations in jejunal perfusion fluids relative to serum levels in the coeliac patients were for albumin 0.0007, beta 2-micro 0.10, and for hyaluronan 1.94. Challenge with a single dose of gliadin into the jejunal segment gave within 60 min a significant, about two-fold, increase of the secretion rates of all three measured substances. The appearance of hyaluronan could reflect a gliadin induced mucosal oedema with an enhanced leakage from the interstitial/lymph fluid, rich in this glycosaminoglycan. The observed parallel increases in the jejunal secretion of albumin and beta 2-micro after gliadin challenge are best explained by a similar mechanism.

Challenge with gliadin induces eosinophil and mast cell activation in the jejunum of patients with celiac disease.

PURPOSE: The aim of this study was to clarify the role of eosinophils and mast cells in the small bowel in celiac disease. PATIENTS AND METHODS: Patients with celiac disease (n = 10) were investigated by perfusion of a closed jejunal segment. The concentrations of certain granule constituents from eosinophils, eosinophil cationic protein (ECP), and from mast cells/basophils, histamine, were measured and the jejunal secretion rates of these cellular markers were calculated. RESULTS: Compared with findings in healthy control subjects (n = 14), increased secretion rates were observed under basal conditions in patients with histopathologically active celiac disease. Gliadin, administered by perfusion to the jejunal segment, induced a fourfold increase in ECP secretion and a twofold increase of histamine secretion in patients with celiac disease (n = 7), but did not influence the secretion rates of these substances in healthy controls (n = 3). The secretion rate of ECP started to increase 20 minutes after challenge of the perfused segment with gliadin and reached maximum levels 40 minutes later. The secretion rate of histamine started to increase 40 minutes after gliadin administration. Concurrently with these inflammatory events, the secretion of albumin was doubled as a sign of increased mucosal leakage. CONCLUSION: These data indicate that eosinophils and mast cells are both involved in the early gliadin-induced reactions of the small intestine, and suggest that these cells are effector cells participating in the celiac lesion of the mucosa.

Tissue distribution of 125I-labelled carbonic anhydrase isozymes I, II and III in the rat.

Carbonic anhydrase (CA) isozymes CA I and CA II were isolated from rat erythrocytes, and CA III from rat skeletal muscle. They were purified to homogeneity and labelled with 125I using the Bolton-Hunter method. The tissue distribution of these [125I]CA isozymes was studied in rats with whole-body autoradiography at various times after an intravenous injection. The distribution pattern showed a remarkable organ specificity. CA I and CA III were to a great extent localized to the renal cortex. This is compatible with renal uptake, secondary to glomerular filtration, of these isozymes. This would be expected from the renal handling of proteins with the following characteristics: molecular weight of 29,000; iso-electric points, pI, around 7.2 and 6.5 respectively. However, CA II of similar molecular shape and size, with a pI of 6.8, remained in the blood and was preferentially localized to the liver. Further studies are needed to clarify why such similar proteins are targeted to different organs.

A new technique for segmental jejunal perfusion in man.

A multichannel tube with two occluding balloons was developed for measurements of the secretion of different endogenous substances into a defined segment of the small intestine. The tube was inserted under fluoroscopic guidance with the aid of a guide wire and was in position in the proximal jejunum after 45-90 min. The overall success rate of the complete procedure was 90%. The system prevented contamination of the perfusate from gastric and pancreatic secretion. Major dilution of the intestinal secretion was avoided due to high recovery of the perfusion fluid. The jejunal secretion rates of high and low molecular weight substances, i.e., albumin, beta 2-microglobulin, hyaluronan, and histamine, were tested. The recovery of the effluent fluid and the volume marker 14C-PEG 4000 exceeded 95% and was also stable over the perfusion period. The mean secretion rates in 23 healthy controls of albumin (635 micrograms/cm/h), beta 2-microglobulin (0.87 microgram/cm/h), hyaluronan (1061 ng/cm/h), and histamine (70 ng/cm/h) were also stable during the perfusion period. Ten healthy controls were studied under steady state conditions for 3 h. The concentrations in jejunal perfusion fluid relative to serum levels were for albumin 0.06%, indicating the degree of passive leakage from the plasma compartment to the intestinal lumen. The appearance of the low-molecular weight protein beta 2-microglobulin in perfusion fluid was on average 3% of its circulating levels, suggesting that the concentrative transport from plasma is dependent on the molecular size. The jejunal fluid concentrations of histamine and hyaluronan exceeded their respective concentrations in plasma, indicating that local intestinal secretion/synthesis is mainly responsible for their appearance in jejunal fluid. In summary, the technique is simple, rapid, atraumatic, safe, and reproducible and, potentially, can accurately reflect biochemical processes in the small intestine.

The effect of type of preservation solution and hemodilution of the recipient on postischemic erythrocyte trapping in kidney grafts. An experimental study in the rat.

The role of recipient hemodilution for postischemic renal medullary red cell trapping was investigated after different periods of cold storage in a conventional cold storage solution (Sacks'). At all cold storage times investigated (4, 12, 24, and 48 hr) medullary red cell trapping was reduced by isovolemic hemodilution, with about 50% reduction of recipient hematocrit. Trapping was also reduced when a modification of a new preservation solution (University of Wisconsin solution [UW]) was used and compared with flush-out and storage in a standard preservation solution (Sacks'). The combination of hemodilution and preservation in modified UW solution had additional capacity to reduce medullary red cell trapping. Thus, even after 48 hr of cold storage, only a moderate trapping was observed. The results also indicate that measurements of medullary red cell trapping offers an accurate method of grading postischemic renal damage.