Biomedical subjects
Publications and source records attributed to L Hansson.
In six normal subjects treatment with 4 mg nedocromil sodium failed to alter the cough and bronchoconstriction induced by inhaled capsaicin. Because nedocromil has previously been shown to inhibit reflex bronchoconstriction provoked by inhaled sulphur dioxide and inhaled bradykinin, the results suggest that inhaled capsaicin acts on different nerve fibres.
Aggregating platelets release serotonin, which induces contraction of most vascular smooth muscle by activation of S2-serotoninergic receptors. Serotonin released in the circulation may contribute to the increase in peripheral resistance of hypertension as the responsiveness of blood vessels from hypertensive animals and humans to the vasoconstrictor action of the monoamine is augmented. The data obtained with the new antihypertensive agent ketanserin may favor that interpretation. Ketanserin is a selective S2-serotoninergic antagonist with additional alpha 1-adrenergic blocking properties. In humans, it has a terminal half-life of 12 to 25 hours and is eliminated predominantly by the liver. The hemodynamic profile of ketanserin is that of a vasodilator drug with actions on both resistance and capacitance vessels. On short-term intravenous administration, it lowers blood pressure in hypertensive patients with minimal reflex changes in cardiovascular function. When given orally long term to hypertensive patients, ketanserin causes a sustained reduction in arterial blood pressure, comparable to that obtained with either beta-adrenergic blockers or diuretics. Several studies have shown a greater efficacy in older (greater than 60 years of age) than in younger patients independent of starting pressure. Side effects mainly consist of dizziness, somnolence, and dry mouth, but they are usually not severe. The mechanism underlying the antihypertensive effect of ketanserin is unclear. It cannot be attributed to either S2-serotoninergic or alpha 1-adrenergic blockade alone, but an interaction between the two effects appears to be required.
Treatment of elevated arterial pressure has been shown to reduce hypertension-induced mortality and morbidity in severe as well as in milder forms of hypertension, but results are suboptimal, and treated hypertensive patients still have significantly higher cardiovascular morbidity and mortality than comparable normotensive subjects. In particular, the risk of coronary heart disease has been little affected by antihypertensive treatment. There may be several explanations for these less than ideal results of antihypertensive treatment; for example, that blood pressure has not been brought down to strictly normotensive levels or that several of the commonly used antihypertensive agents increase serum lipoprotein concentrations, which to a certain extent may offset the intended therapeutic effect. To improve results of antihypertensive treatment it appears desirable (1) to lower blood pressure to strictly normotensive levels, (2) to use antihypertensive agents, e.g. ACE inhibitors, which do not negatively affect serum lipoproteins, (3) to supplement antihypertensive therapy with active lipid-lowering therapies in selected patients. Such means should have a positive effect on reducing the risk of coronary heart disease.
Combined action drugs is a term applied to describe antihypertensive agents which lower blood pressure by interference with more than one physiological mechanism contributing to the genesis and maintenance of hypertension. In this group numerous compounds have been developed which have an antagonistic effect on beta-adrenoceptors and at the same time achieve other effects, for example vasodilatation, usually through an antagonistic effect at alpha-adrenoceptor sites. In view of the multifactorial aetiology of essential hypertension, it is logical to try to reduce the elevated arterial pressure in this condition by interfering with more than one mechanism. It seems to be important that a vasodilating component is present, since the hallmark of established essential hypertension is increased total peripheral resistance. Thus, a combined action drug with a vasodilating component will lower blood pressure and at the same time maintain organ perfusion. A beta-adrenoceptor blocking component is also desirable in view of the proven secondary prevention against coronary heart disease obtained with beta-blockers and the proposed primary preventive effect attributable to beta-blockade. Finally, since the combination of beta-blockade and vasodilatation (e.g. due to peripheral alpha 1-blockade) usually does not induce metabolic disturbances, agents of this kind are not likely to elevate serum lipoproteins. Thus, this paper will briefly review the use of the combined action drug carvedilol in the treatment of hypertension.
A digestion procedure involving nitric acid, magnesium nitrate hexahydrate, and hydrochloric acid suffices for selenium determinations in whole blood, serum, and urine by molecular fluorescence spectrometry. To test the accuracy of the method we compared the results with those from hydride-generation atomic absorption spectrometry, and we also analyzed reference materials.
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Preliminary results of a randomized, double-blind, placebo-controlled trial of PN 200-110 (isradipine) are reported. The study involves 5 centers and 61 patients with essential hypertension. Either PN 200-110 or placebo was added to an ongoing daily regimen of 10 mg of pindolol to determine if this agent would enhance the effect of the beta-adrenoreceptor blocking agent. PN 200-110 was given twice daily, starting with a dose of 2.5 mg or 5 mg, which could be doubled after 4 weeks. The average final dose was 6.3 mg given twice daily. Supine blood pressure was significantly reduced from a mean of 162/103 mm Hg to 144/88 mm Hg (p less than 0.001) in the patients who received the combination therapy. Heart rate did not change significantly. In 3 patients therapy was withdrawn, 1 during placebo and 2 during active treatment, owing to definite or suspected side effects.
Factors influencing treatment outcome and patient satisfaction in a short-term psychiatric treatment programme were analysed using a path analysis method. The programme used two models of treatment planning, one with and one without active participation of the patient in formulating a written treatment contract. A causal structural model, which explained 23% of the variance in the model, was used in the final analysis. The results indicated a positive relationship between a cooperation contract procedure and the level of expectations of improvement as well as high ratings of the importance of the patients own effort in treatment. The level of expectations of improvement were related to the symptom level at discharge and global improvement during treatment, indicating a better treatment outcome for the patients of the cooperation contract group, while the importance of own effort was not related to treatment outcome. Symptoms at discharge were mainly determined by symptoms at admission and global improvement, and also by expectations of improvement, initial psychic status and social background. The explained variance was 63%. Satisfaction with treatment was mainly determined by global improvement, symptoms at discharge and expectations of improvement. The explained variance was 60%. It is concluded that attention to patient expectations of improvement viewed as an important intermediate variable, is related to a an improvement in treatment outcome.
The impact of antihypertensive drugs has been considerable over the last few decades. Hypertension-associated mortality and morbidity have decreased significantly following the introduction of potent and useful antihypertensive drugs. Against this background, it is disturbing that three recent large-scale studies have shown that morbidity and mortality in treated hypertensive patients are markedly higher than in comparable normotensive subjects. It is conceivable that these findings can be explained to some extent by the fact that the elevated arterial pressure quite frequently is not lowered to strictly normotensive levels. Another aspect of the impact of antihypertensive drugs is that they frequently affect the mood and well-being of the patient. In the early days of antihypertensive therapy, the interference of drugs with the quality of life was considerable. With the drugs available today, negative effects on well-being are much rarer, although still extant. Thus, there is still room for improvement of antihypertensive drugs both in this respect and, more importantly, in achieving a further lowering of hypertension-induced cardiovascular morbidity and mortality.
Similar neurological disturbances and metabolic alterations have been observed in liver insufficiency and in bacterial sepsis. In both liver failure and sepsis an altered neurotransmitter profile in the central nervous system (CNS) has been implicated in the pathogenesis of encephalopathic symptoms. It has been suggested that equivalent disturbances in brain neurotransmitters, especially serotonin, play a role in the encephalopathy accompanying sepsis and liver failure. The objective of this study was to compare the CNS serotonin metabolism in rats with an end-to-side portacaval shunt (PCS) with that found in rats with 12 or 24 hr of intraabdominal sepsis. The metabolism of CNS serotonin was estimated after inhibition of two enzymes acting in the 5-hydroxyindole synthetic pathway (decarboxylase and monoamine oxidase). The 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined in different regions of the CNS, thereby permitting evaluation of the synthetic activity of the serotonin neurotransmitter system. As previously reported, a marked increase in CNS serotonin synthetic rate was noted following PCS. In contrast, and in contradistinction to several recent reports, no major changes in the CNS serotonin synthesis rate were present following 12 or 24 hr of sepsis. CNS levels of the serotonin metabolite 5-HIAA were elevated in both sepsis and PCS rats. These data indicate that sepsis and liver failure have different effects upon serotonin metabolism in the CNS and suggest that differing pathogenetic mechanisms may underlie the encephalopathy clinically associated with these conditions.
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Structural vascular changes in the precapillary arterioles are a cardinal feature of established hypertension, and have been described in several vascular beds. In brief, the wall:lumen ratio becomes increased due to hypertrophy of the vascular smooth muscle cells. This results in a reduction of the inner radius in the precapillary vessels, which causes a structurally based vascular hyperreactivity and accentuates the increase in systemic vascular resistance, another hallmark of established hypertension. Much interest has been devoted to the possibility of obtaining a regression of these structural vascular changes. Previously, the emphasis was on obtaining a fall in blood pressure, but more recently additional factors have also been considered, in particular the so-called trophic factors. In this context the calcium antagonists of the dihydropyridine type appear to be of particular interest, since these are markedly effective in lowering elevated arterial pressure, while at the same time they do not cause reflex-mediated elevations of trophic factors during long-term treatment. Few clinical data are yet available to show whether calcium antagonists can cause a regression of structural vascular changes, but some recent animal work suggests that they are clearly useful in this respect.
Cardiovascular morbidity and mortality is higher in treated hypertensive patients than in normotensive subjects of the same age, sex and from the same populations. A possible and logical explanation for this could be that arterial pressure in treated hypertensive patients usually is significantly higher than in matched normotensive subjects. For these reasons it would appear logical to identify a therapeutic goal in the treatment of hypertension: to obtain normotensive blood pressure levels. In order to obtain this goal, combined treatment with more than one antihypertensive drug would appear to be required. Therapeutic combinations consisting of an ACE-inhibitor plus a diuretic or an ACE-inhibitor plus a calcium antagonist constitute two examples of antihypertensive drug combinations that would appear to offer potent antihypertensive efficacy and good tolerability.
1. In almost all forms of established hypertension the increase in blood pressure can be attributed to increased total peripheral vascular resistance. 2. beta-adrenoceptor blocking compounds, which are frequently used as first-line therapy in hypertension, may compromise blood flow to vital organs in view of the fact that they reduce cardiac output both acutely and during long-term treatment. 3. beta-adrenoceptor blocking agents with a marked intrinsic sympathomimetic activity (ISA) such as pindolol differ in this respect by lowering arterial pressure without lowering cardiac output while causing a reduction in total peripheral resistance. 4. Direct vascular effects of beta-adrenoceptor blockers with marked ISA could contribute to the normalisation of hypertension-induced structural arteriolar changes. The effect appears to be dissociated from the effect caused by the lowering of blood pressure per se.
The differentiating power of two individually related measures of outcome, target complaints and psychiatrists' evaluation of individually defined treatment objectives, were studied in two models of treatment planning, one with and one without active patient participation. Target complaints were measured at admission, after 5 days and at discharge. Treatment objectives were initially defined in written treatment contracts and evaluated at discharge. These measures were compared with patients' self-reported symptoms as well as with independently rated clinical symptoms at admission and discharge. Both target complaints and psychiatrists' evaluations measured improvement during treatment. The differentiating power between the two experimental conditions was, however, much weaker than that of the symptom rating scales. The psychiatrists' evaluations were strongly influenced by state at discharge and only to a minor extent by changes during treatment. It is concluded that symptom rating scales are superior to individualized measures of outcome in studies on a general psychiatric ward, possibly because the patients are fairly homogenous concerning anxiety.
The relations between mean and maximum fall in arterial oxygen saturation (SaO2) during sleep, hypoxaemia during moderate and maximum exercise, and lung mechanics were studied in 16 patients with interstitial lung disease. Mean and minimum SaO2 during sleep were significantly related to each other and to daytime oxygenation but not to lung mechanics. Although the maximum fall in SaO2 during sleep was similar to the fall during maximum exercise (a level seldom achieved during normal daily activities), profound hypoxaemic episodes during sleep were rare and brief and therefore contributed little to the mean SaO2. The fall in mean SaO2 during sleep was not significant and was considerably less than during moderate exercise (average 0.5 v an estimated 4.5%, p less than 0.05). It is therefore concluded that in patients with interstitial lung disease oxygen desaturation during sleep is mild and less severe than hypoxaemia during exercise.
In hypertensive patients, morbidity and mortality from the malignant phase, stroke, left ventricular failure, coronary disease and progressive renal failure are closely linked to the level of blood pressure. This relationship between blood pressure and risk can be demonstrated also when blood pressure is lowered with antihypertensive agents. Thus, it appears that the treated blood pressure level is a much stronger indicator of prognosis than is the initial untreated value. However, in the last 2 years, 3 large scale studies have shown that morbidity and mortality in treated hypertensive patients are still considerably higher than expected and significantly greater than in comparable normotensive subjects or control populations. There could be several explanations for these disturbing findings. One is that long-standing hypertension may cause irreversible cardiovascular changes that continue to put such individuals at risk, even after their blood pressure has been brought under control. Another possibility is that the pharmacological agents used in the treatment of hypertension may have some partially adverse effects in addition to their beneficial action on blood pressure. For example, drug-induced changes in serum lipids or of serum electrolytes could somewhat offset the advantages from blood pressure reduction. Furthermore, less than optimal control of elevated blood pressure could be a factor. It is worth noting that consistent arterial pressure reduction has been achieved in only a fraction of treated patients in the large scale intervention trials.(ABSTRACT TRUNCATED AT 250 WORDS)