Sten Rasmussen

5-Aminosalicylic acid in patients with an ileo-rectal anastomosis: A comparison of the fate of sulfasalazine and Pentasa

SummaryThe pharmacokinetics of 5-aminosalicylic acid (5-ASA) from sulphasalazine (SASP) and the slow-release 5-ASA preparation Pentasa was investigated in a cross-over study in 9 otherwise healthy patients with an ileo-rectal anastomosis. The 24-hour recoveries of the drugs were 90.5% and 84.7%, respectively. The median release of 5-ASA from SASP was 50% and from Pentasa 75%. Equal amounts of 5-ASA (18.0% vs 17.9%) were found in the faeces, and a significantly larger amount (4.4% vs 28.9%) of the metaboliteN-acetyl-5-aminosalicylic acid (ac-5-ASA) was found in faeces following Pentasa. A larger amount of 5-ASA was absorbed and subsequently excreted in the urine, mainly as the metabolite (2.5% vs 20.5%) from Pentasa. This confirms previous results in ileostomized patients treated with Pentasa. The present findings also demonstrate that bacterial azo-reduction of SASP in patients with ileorectal anastomosis may be an adequate way to deliver 5-ASA in this type of patient. Both treatments may be used in these patients during a flare up of ulcerative colitis, but randomized studies are needed.

Reproducibility of determination of right ventricular ejection fraction by radionuclide imaging: assessment by the statistical method of variance components.

SummaryConfidence limits for single and repeat measurements of right ventricular ejection fraction (RVEF) were established by means of a model based on the statistical method of variance components. A total of 80 subjects (age 23 to 74 years) were examined by two radionuclide methods 1) gated first-pass (fp) technique performed in a standard 30° right anterior oblique projection, and 2) multigated equilibrium imaging (muga) in an individual left anterior oblique view, applying with both methods separate end-diastolic and endsystolic ventricular regions of interest.Values obtained by fp technique were clearly higher than those measured by the muga approach, and the correlation between them was only fair: RVEFmuga = 0.48 RVEFfp + 0.13; r = 0.73; SEE = 0.08. The 95% confidence limits for a single measurement were with the fp technique: ‘true’ RVEF = measured RVEF ±6 EF-units compared to ±16 units with the muga method. At repeat determination within an interval of four weeks, the minimal changes in measured RVEF that were statistically significant at the 5% level were with the fp technique ±8 units with the same observer on both occasions and ±9 units with different observers. Corresponding figures with the muga method were ±16 and ±22 units, respectively. The minimal changes in a subjects ‘true’ RVEF necessary to produce a significant change in measured RVEF were with fp technique ±14 units for the same observer and ±17 units for different observers, compared to ±30 and ±41 units with the muga method.In conclusion, the variability with the muga approach was far greater than with the fp technique and the consequent reproducibility so poor as to preclude meaningful measurement of RVEF by the muga method.

The renin-angiotensin system during converting enzyme inhibition with captopril in patients with severe treatment-resistant hypertension.

Abstract. The effect of captopril on blood pressure (BP) and various components of the renin‐angiotensin system was assessed in ten severely hypertensive patients. Captopril acutely reduced the BP with a maximum decrease of 23% at 90–120 min.

Acute effects of smoking on left ventricular function and neuro-humoral responses in patients with known or suspected ischaemic heart disease

Systolic left ventricular function was examined by radionuclide ventriculography in 12 habitual smokers with known or suspected ischaemic heart disease, aged 33–69 years, before, during, and after smoking of two cigarettes in a row and was repeated on a non‐smoking control day. Plasma concentrations of adrenaline, noradrenaline, renin, and angiotensin II were determined on the smoking day, before and immediately after smoking. During smoking, there were significant increases in heart rate (+27%), rate‐pressure product (+23%), and cardiac output (+14%) in the face of a significant increase in left ventricular end‐systolic volume (+5%) and significant decreases in ejection fraction (−6%) and stroke volume (−8%). Blood pressure was virtually unchanged, and total peripheral resistance remained constant. Plasma adrenaline increased by 100%, renin decreased by 21%, and noradrenaline and angiotensin II did not change. The humoral changes were not correlated to changes in any of the haemodynamic variables. Areas of myocardial hypokinesis emerged or widened during smoking in 11 of 12 patients. Thus, in patients with known or suspected ischaemic heart disease, smoking was associated with an acute decrease in systolic ventricular function and development of widespread hypokinesis despite adrenaline stimulation.

Converting enzyme inhibition: a novel concept in drug therapy of hypertension

The development of the new drug Captopril (Capoten@) presents a number of unique features. The aim of the manufacturers was to create a molecule capable of inhibiting the enzyme responsible for conversion of the largely inactive decapeptide angiotensin I to the highly active vasopressor peptide angiotensin 11. In this way it should be possible to neutralize one of the most powerful pressor systems in the organism: the renin-angiotensin system [I] . This premeditated design, as carried out in a very professional way, is certainly attractive in an intellectual sense. Any keen observer of the pharmaceutical industry will note the sharp contrast to unimaginative production of new molecules with subsequent pharmacologic testing of the possible therapeutic potential [ 2 ] . In this day and age characterized by an inordinate interest in so-called natural products, it is appropriate to note that the story of Captopril started out by the demonstration of a ‘bradykinin potentiating factor’ in samples of poison from the viper Bothrops jararaca of South America. This factor turned out to be a mixture of peptides with bradykinin potentiating and converting enzyme inhibitory activities [3]. After isolation and subsequent synthesis of several peptides, including the nonapeptide converting enzyme inhibitor teprotide, a lot of information on converting enzyme was obtained. This knowledge was important as a basis for the development of the orally active converting enzyme inhibitor Captopril, which was designed as a specific active site binding agent. Admittedly, the term converting enzyme is singularly uninformative. A qualification is often made by using the term angiotensin converting enzyme. This enzyme is found in many locations such as the plasma, the brush border of the proximal renal tubules, and the endothelial cells of several vascular beds. The abundance of converting enzyme in endothelial caveolae of the pulmonary vascular system is probably of particular importance [4]. The pulmonary converting enzyme activates angiotensin I by conversion to angiotensin I1 and, at the same time, the enzyme inactivates bradykinin. In an operational sense, the lung functions as an endocrine organ, as i t were, since a potent vasoconstrictor hormone is added to the blood perfusing the lung whereas a possible content of bradykinin in mixed venous blood will be metabolized during pulmonary transit.

Dose-response relationship in normal subjects of prenalterol, a beta-adrenergic agonist with positive inotropic and resistance lowering effects

SummaryThe acute haemodynamic effects of increasing doses of parenterally administered prenalterol — a beta-adrenergic stimulating drug — were assessed in normal subjects by means of radionuclide ventriculography. Prenalterol induced dose-related increases in the left ventricular ejection fraction and the systolic pressure end-systolic volume ratio. Left ventricular end-systolic and end-diastolic volumes decreased to the same extent accounting for an unchanged stroke volume. Cardiac output increased due to a rise in the heart rate. Systolic blood pressure increased, whereas diastolic and mean blood pressure remained unchanged. Calculated total peripheral resistance decreased significantly. The maximum effect of prenalterol on cardiac performance occurred with a dose of 18 to 36 µg/kg. Plasma concentrations of prenalterol showed large interindividual variations. In conclusion, prenalterol improves the pump function of the normal heart and causes a fall in peripheral vascular resistance, implying a reduction of the load on the heart. These effects may prove beneficial in the treatment of acute heart failure.

Deterioration of Renal Function During Angiotensin Converting Enzyme Inhibition in Hypertensive Patients with a Poorly Functioning Solitary Kidney

During treatment with the angiotensin converting enzyme inhibitor, Captopril, glomerular filtration rate (GFR) decreased in three unilaterally nephrectomized hypertensive patients with a poorly functioning remaining kidney. The fall in GFR was not related to changes in the blood pressure, and was reversed when Captopril was stopped. In a fourth nephrectomized patient the initially normal GFR was not affected by captopril. These observations point to a functional reduction in GFR due to a withdrawal of an intrarenal action of angiotensin II. Maintenance of GFR may become critically dependent on a functioning renin-angiotensin system when renal perfusion pressure is reduced to a certain degree. Inhibition of angiotensin II formation may lead to a decrease in GFR in patients with renal hypertension and pre-existing renal insufficiency.

Contrasting Effects of the Renin–Angiotensin System on Renal Function Disclosed During Converting Enzyme Inhibition in Patients with Renal Hypertension

In three unilaterally nephrectomized patients with a poorly functioning remaining kidney, a reversible decrease of glomerular filtration rate (GFR) was observed during treatment with captopril. Only modest decreases in blood pressure occurred. In four patients with various forms of malignant hypertension and impairment of renal function, GFR remained unchanged or even increased when the blood pressure was reduced by captopril. All patients had increased plasma concentrations of renin and angiotensin II prior to captopril. We hypothesize that an activation of the renin-angiotensin system in hypertensive patients with reduced GFR may either reflect a compensatory mechanism aiming at maintaining renal function, or imply an excessive angiotensin-mediated vasoconstriction causing a decrease in renal function. The use of angiotensin converting enzyme inhibitors may be damaging for renal function in the first situation and beneficial in the second.