Probabilistic assessment of the cumulative dietary acute exposure of the population of Denmark to organophosphorus and carbamate pesticides.

Organophosphorus and carbamate pesticides are acetylcholinesterase-inhibiting pesticides and as such have a common mode of action. We assessed the cumulative acute exposure of the population of Denmark to 25 organophosphorus and carbamate pesticide residues from the consumption of fruit, vegetables and cereals. The probabilistic approach was used in the assessments. Residue data obtained from the Danish monitoring programme carried out in the period 2004-2007, which included 6704 samples of fruit, vegetables and cereals, were used in the calculations. Food consumption data were obtained from the nationwide dietary survey conducted in 2000-2002. Contributions from 43 commodities were included in the calculations. We used the relative potency factor (RPF) approach to normalize the toxicity of the various organophosphorus and carbamate pesticides to the two index compounds chlorpyriphos and methamidophos. RPF values derived from the literature were used in the calculations. We calculated the cumulative acute exposure to 1.8% and 0.8% of the acute reference dose (ARfD) of 100 microg kg(-1) body weight (bw) day(-1) of chlorpyrifos as an index compound at the 99.9th percentile (P99.5) for children and adults, respectively. When we used methamidophos as the index compound, the cumulative acute intakes were calculated to 31.3% and 13.8% of the ARfD of 3 microg kg(-1) bw day(-1) at P99.9 for children and adults, respectively. With both index compounds, the greatest contributor to the cumulative acute exposure was apple. The results show that there is no cumulative acute risk for Danish consumers to acetylcholinesterase-inhibiting pesticides.

Dietary exposure assessment of Danish consumers to dithiocarbamate residues in food: a comparison of the deterministic and probabilistic approach.

Probabilistic and deterministic estimates of the acute and chronic exposure of the Danish populations to dithiocarbamate residues were performed. The Monte Carlo Risk Assessment programme (MCRA 4.0) was used for the probabilistic risk assessment. Food consumption data were obtained from the nationwide dietary survey conducted in 2000--02. Residue data for 5721 samples from the monitoring programme conducted in the period 1998--2003 were used for dithiocarbamates, which had been determined as carbon disulphide. Contributions from 26 commodities were included in the calculations. Using the probabilistic approach, the daily acute intakes at the 99.9% percentile for adults and children were 11.2 and 28.2 microg kg(-1) body weight day(-1), representing 5.6% and 14.1% of the ARfD for maneb, respectively. When comparing the point estimate approach with the probabilistic approach, the outcome of the point estimate calculations was generally higher or comparable with the outcome of the probabilistic approach at the 99.9 percentile (consumers only). The chronic exposures for adults and children were 0.35 and 0.76 microg kg(-1) body weight day(-1) at the 99.9 percentile, representing 0.7% and 1.5%, respectively, of the acceptable daily intake for mancozeb and maneb at 50 microg kg(-1) body weight.

Divergent cardiac response to exercise in essential hypertension vs. normotension and the effect of enalapril.

The aims of this study were to examine (1) the cardiac response to exercise in essential hypertension and (2) the effect of long-term enalapril treatment on cardiac reserve. Ten normotensive control subjects and 15 patients with moderate, essential hypertension underwent radionuclide ventriculography during graded, supine exercise (0 W-50 W-100 W). The hypertensive patients were studied during monotherapy using hydrochlorothiazide and 3 and 12 months after supplementation with enalapril 10-40 mg o.d. During exercise, the control subjects demonstrated a 17% increase in left ventricular ejection fraction (LVEF) mediated by a 30% decrease in end-systolic volume, a small increase in stroke volume and a minor biphasic (increase-decrease) change in end-diastolic volume. In the hypertensive patients, both the end-diastolic and the end-systolic volume increased substantially with no increase in LVEF, although stroke volume increased by 33%. Long-term therapy with enalapril induced only a minor change towards a more normal pattern of cardiac response to exercise. The hypertensive patients increased their stroke volume during exercise by recruiting preload reserve instead of increasing contractility. Long-term treatment with enalapril had little, if any, effect on this abnormal cardiac response.

Changes in left and right ventricular performance and volumes in seven-year survivors of acute myocardial infarction.

We describe the spontaneous long-term changes in right (RV) and left (LV) ventricular performance during a 7-year period after acute myocardial infarction (AMI). Radionuclide ventriculography was performed in the second week after AMI in 201 patients. RV and LV ejection fractions, and LV end-diastolic and end-systolic volumes were determined. A follow-up after 7 years was performed in 55 survivors. Of these, 16 patients were also examined after 1 year. During the 7-year follow-up period, LV ejection fraction decreased from 0.49 to 0.45 (p < 0.01). LV end-diastolic volume increased from 161 to 210 ml (30%) (p < 0.01), and LV end-systolic volume from 83 to 123 ml (48%) (p < 0.01). In patients without recurrent AMI, coronary artery bypass grafting surgery, or angiotensin-converting enzyme inhibitor therapy (n = 37) during follow-up, no change in average LV ejection fraction was observed. Nevertheless, this subgroup had substantial increases in LV end-diastolic volume, from 157 to 190 ml (21%) (p = 0.002) and in LV end-systolic volume, from 80 to 105 ml (31%) (p < 0.001). In a subgroup of patients also reinvestigated after 1 year (n = 16), there was a 15% increase in LV end-diastolic volume the first year after AMI with an additional 10% increase in LV end-diastolic volume between years 1 and 7. Corresponding figures for LV end-systolic volume were 20% and 12%, respectively. Hardly any association was apparent between LV ejection fraction, LV end-diastolic volume, and LV stroke volume at discharge for subsequent LV dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations.

Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean +/- S.D.) values following single dose administration of Cardil and Cardizem were 678.4 +/- 321.5 and 948.6 +/- 580.6 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 +/- 2.0 and 6.0 +/- 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean +/- S.D.) values in steady state of Cardil and Cardizem were 880.1 +/- 399.8 and 1056.8 +/- 509.8 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).

Multiple oral administration of a ketoprofen-dextran ester prodrug in pigs: assessment of gastrointestinal bioavailability by deconvolution.

Deconvolution has been applied to estimate the in vivo dissolution/release process of ketoprofen from a ketoprofen-dextran ester prodrug in pigs. The prodrug was given to three pigs at intervals of 12 hr and in seven doses corresponding to 4 mg ketoprofen/kg body weight. Frequent blood sampling was carried out at the first, third, and seventh intervals. Plasma steady-state concentrations of ketoprofen following the prodrug administration were between 2 and 4 micrograms/ml. The reference consisted of a single p.o. dose of parent ketoprofen (4 mg/kg body weight). For each pig the response following the multiple dosing was deconvolved with the reference response using an algebraic deconvolution procedure adopted from the literature. The obtained cumulated in vivo dissolution/release profiles revealed similar release rates for the three pigs and similar extents of release (59, 70, and 65%). The mean in vivo dissolution/release times (MDT) were calculated to be 5.4, 6.1, and 5.7 hr, respectively. In conclusion, following administration of the dextran prodrug the plasma concentration curves and the dissolution/release profiles are uniform, with small interindividual variations.

Left-ventricular performance, volumes, and catecholamine responses during anaesthesia induction--monitoring by combined radionuclide cardiography and right heart catheterization.

Sequential radionuclide imaging and continuous recording of arterial and right heart pressures were carried out during anaesthesia with midazolam 0.2 mg kg-1, pancuronium 0.15 mg kg-1 and fentanyl 10 micrograms kg-1 in eight patients with normal cardiopulmonary status scheduled for craniotomy. The aim was to examine how a stress-free anaesthetic induction tailored to protect against the hypertension and tachycardia provoked by laryngoscopy and intubation influenced left-ventricular performance, left-ventricular loading conditions and plasma catecholamine concentrations. During the 20-min study period no significant changes were observed in heart rate, left-ventricular ejection fraction, ratio of peak systolic pressure to left-ventricular end-systolic volume, pulmonary capillary wedge pressure, left-ventricular end-systolic volume, cardiac output, dopamine and noradrenaline concentrations. Except for a minor increase in mean arterial pressure after laryngoscopy and intubation, mean arterial pressure decreased 24%, left-ventricular end-diastolic volume decreased 15%, and left-ventricular stroke volume decreased 21%. Central venous pressure increased by 75% but there was no parallel increase in pulmonary wedge pressure, which in turn did not reflect the alterations in ventricular end-diastolic volume. Plasma adrenaline concentrations decreased significantly (66%). The chosen induction regimen preserved global left-ventricular pump function during laryngoscopy and intubation without any activation of the sympathetic nervous system. Central venous and pulmonary wedge pressures were unreliable in the assessment of ventricular preload during induction of general anaesthesia.

Left ventricular peak filling rate, heart failure and 1-year survival in patients with acute myocardial infarction.

Radionuclide left ventricular (LV) peak filling rate (PFR) was determined in 185 survivors of acute myocardial infarction (AMI) and expressed in units of (1) end-diastolic volume per second (EDV s-1). (2) stroke volume per second (SV s-1), or (3) actual millilitres of blood filled into the left ventricle per second (ml s-1). The purpose of the study was to assess the interrelationship between the three expressions of PFR, and to analyse their significance with regard to signs of congestive heart failure and 1-year survival in patients with AMI. PFR EDV s-1, PFR SV s-1 and PFR ml s-1 had a poor relationship to each other, were all influenced by LV volumes and ejection fraction, and supplied contradictory information with regard to LV filling in patients with heart failure. None of the three expressions of LV peak filling rate had an association to heart failure that was independent of LV volume and ejection fraction. A low PFR EDV s-1 in contrast to a high PFR SV s-1 was associated with a high 1-year cardiac mortality, suggesting that these 'normalized' indices of LV peak filling rate signalled LV size and stroke volume rather than actual LV filling behaviour. No association was present between PFR ml s-1 and 1-year mortality. We conclude that the clinical use of radionuclide LV PFR in patients with AMI may lead to spurious results, unless the influence of LV size and ejection fraction is taken into consideration.

Bioavailability of ketoprofen from orally administered ketoprofen-dextran ester prodrugs in the pig.

The bioavailability of ketoprofen after oral administration of aqueous solutions of various ketoprofen-dextran ester prodrugs in pigs was assessed. Conjugates derived from dextran fractions in the molecular weight range 10,000-500,000 were employed. Compared to the administration of an oral solution of an equivalent dose of parent ketoprofen, the average absorption fractions for the different prodrugs ranged from 100 to 67%. Relatively small inter-individual variation of ketoprofen bioavailability was observed. Apparently, the molecular size of the employed dextran transport group only has a minor influence on the pharmacokinetic parameters. The ketoprofen plasma profiles for all the administered prodrugs exhibited a characteristic lag time of ketoprofen appearance in the blood (2-3 h). Quite similar results were obtained from identical experiments carried out in the pig, employing naproxen-dextran esters. Thus, the present study adds support to a more versatile application of the dextran ester prodrug approach to providing selective colon delivery of drugs possessing a carboxylic acid functional group.

Stability of ketoprofen-dextran ester prodrugs in homogenates of various segments of the pig GI tract.

Initial velocities of ketoprofen formation from ketoprofen-dextran ester prodrugs incubated in homogenates of various segments of the pig GI-tract were determined. Enzyme-mediated drug release was found in caecum and colon homogenates with their contents, whereas release rates in the stomach, duodenum, jejunum and ileum homogenates were comparable to those determined in pure buffer solutions of identical pH. In colon homogenates adjusted to various pH values between 6.0 and 7.9, little variation in release rates was observed. However, the contribution of enzyme-catalyzed drug regeneration to the overall initial velocity of ketoprofen formation increased significantly as a function of decreasing pH. The presence of several antibiotics and betamethasone in colon homogenates did not affect the drug activation process, whereas the addition of various enzyme inhibitors slowed down the ketoprofen release rates. During incubation in colon homogenates the average molecular weight of the dextran esters decreased. The drug release may therefore involve an initial fragmentation of the drug-liganded dextran chains carried out by dextranases secreted from the microflora which reside in the pig's large bowel.

Left ventricular volumes in the recovery phase after myocardial infarction: relation to infarct location, left ventricular function and one-year cardiac mortality.

Absolute left ventricular volumes, normalized to body surface area, were determined by a count-based radionuclide technique in 189 patients with myocardial infarction (MI). All examinations were performed in the second week after MI. Fifty-three percent of the patients had an increased end-diastolic volume index (EDVI) and 72% an increased end-systolic volume index (ESVI). Patients with anterior MI had the same median EDVI as patients with inferoposterior MI, but significantly higher median ESVI and significantly lower median stroke volume index (SVI). SVI was subnormal in 19% of the 189 patients and left ventricular ejection fraction (LVEF) was subnormal in 67%. A non-linear, inverse relationship was present between EDVI and LVEF and between ESVI and LVEF, but LVEF varied greatly for any degree of ventricular dilatation. During a 1-year follow-up period, death from cardiac causes occurred in 29 patients. A strong relationship was present between the degree of ventricular dilatation and 1-year mortality, as well as between the degree of SVI or LVEF reduction and 1-year mortality but, next to clinical heart failure, LVEF was the single most powerful predictor of cardiac death, and various combinations of EDVI, ESVI and SVI did not add more prognostic information to that obtained by heart failure than did LVEF.

Symptoms and signs of heart failure in patients with myocardial infarction: reproducibility and relationship to chest X-ray, radionuclide ventriculography and right heart catheterization.

102 patients with myocardial infarction (MI) were examined by three clinicians, who independently recorded the following symptoms and signs: dyspnoea, a displaced apex beat, S3-gallop, rales, neck vein distension, hepatomegaly, and dependent oedema. Chest X-ray, radionuclide ventriculography, and (in 40 patients) right heart catheterization were carried out immediately after the physical examination. The clinicians frequently disagreed as to the presence of physical signs of heart failure in individuals. Moreover, these signs were of limited value in identifying patients with pulmonary vascular congestion on chest X-ray, reduced left or right radionuclide ventricular ejection fractions, enlarged ventricular volumes or haemodynamic evidence of ventricular dysfunction. We conclude that clinicians frequently disagree in the recognition of physical signs of heart failure, and that these signs have an unpredictable relationship to radiographic, radionuclide and haemodynamic measures of ventricular performance in patients with MI. Nevertheless, physical signs are useful in identifying patients with high risk of cardiac death.

Right and left ventricular ejection fractions: relation to one-year prognosis in acute myocardial infarction.

Right and left ventricular ejection fractions (RVEF and LVEF) were measured by radionuclide angiography in 423 patients with acute myocardial infarction (AMI). All investigations were performed at hospital discharge. Of 304 patients with first AMI, 26% had normal ejection fractions, 10% had a decrease in RVEF only, 46% a decrease in LVEF only, and 18% decrease in both RVEF and LVEF. Death from cardiac causes occurred in 52 patients in a one-year follow-up period. A reduced RVEF at hospital discharge had little, if any, relation to one-year mortality. In contrast, there was an inverse curvilinear relationship between LVEF and one-year cardiac mortality.

Gas-producing infections after lower-limb amputation because of ischemia.

During the period 1972-1982, 22 patients with gas-producing infections after lower-limb amputation because of ischemia were reviewed. In 16 cases bacteria of the genus Clostridium could be cultured. Treatment consisted of hyperbaric oxygen, surgical debridement, and antibiotics. The incubation period was 1-11 days after the primary amputation, and the duration of the infection 2-31 days, significantly lower among 14 patients with diabetes mellitus. There was no difference in the course of clostridial and nonclostridial infections. No deaths were attributable to gas-forming infection.

The prophylactic effect of 5-aminosalicylic acid and salazosulphapyridine on degraded-carrageenan-induced colitis in guinea pigs.

Experimental colitis was induced in guinea pigs by administration of 5% degraded carrageenan for 5 days. The prophylactic effect of a slow-release preparation of 5-aminosalicylic acid (5-ASA; 13 mg/100 g/day) was compared with approximately equimolar amounts of salazosulphapyridine (SASP; 26 mg/100 g/day) and placebo. Treatment was started 2 days before initiation of carrageenan administration. The drugs were administered through a chronic gastric fistula. At the end of the study concentrations of 5-ASA and acetylated 5-ASA (Ac-5-ASA) in cecal contents and in plasma were determined. In the placebo group, all guinea pigs developed many small punctiform ulcerations in the cecum (median, 30/cm2). In the 5-ASA group no protective effect was demonstrated, since the number of ulcerations was 37/cm2. The difference is not statistically significant. However, the SASP group presented significantly fewer ulcerations (4/cm2). The concentrations of 5-ASA and/or its acetylated metabolite were several times higher in the cecum content and twice as high in plasma in the SASP group, indicating a difference in the absorption patterns of 5-ASA and the two drugs. These results and the etiological difference between the human ulcerative colitis and the carrageenan model may account for the lack of prophylactic effect of the slow-release 5-ASA in this experiment.

Preoperative starvation and blood glucose concentrations in children undergoing inpatient and outpatient anaesthesia.

Blood glucose concentrations were measured in 82 children undergoing inpatient anaesthesia and in 46 children undergoing anaesthesia as outpatients. The children were aged between 6 months and 9 yr. Outpatients were fasted from bedtime, while inpatients were randomly allocated to two groups. In group A the children were fasted from bedtime, whereas in group B the children were fed 6 h before anaesthesia. There was no difference in mean blood glucose concentration between the fasted inpatients and outpatients nor between children younger than, or older than, 4 years of age. A blood glucose concentration of less than 40 mg dl-1 was found in only one of the fasted children (1%). The mean blood glucose concentration was greater in group B than A, but only significantly so for children older than 4 yr. It is concluded that to minimize the risks of hypoglycaemia and inhalation of vomit on induction of anaesthesia children older than 6 months should be fasted overnight and operated on in the morning.