Fecal incontinence and radiation dose on anal sphincter in patients with locally advanced rectal cancer (LARC) treated with preoperative chemoradiotherapy: a retrospective, single-institutional study

Background. The objective of the study is to determine the correlations among the variables of dose and the sphincter function (SF) in patients with locally advanced rectal cancer treated with preoperative capecitabine/radiotherapy followed by low anterior resection (LAR) + TME. Methods. We retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 2 years free from disease. We re-contoured the anal sphincters (AS) of patients with the help of the radiologist. SF was assessed with the Wexner scale (0-20 points, being punctuation inversely proportional to annal sphincter functionality). All questionnaires were filled out between January 2010 and December 2012. Dosimetric parameters that have been studied include V20, V30, V40, V50, mean dose (Dmean), minimum dose (Dmin), D90 (dose received by 90% of the sphincter) and D98. Statistical analysis. The correlations among the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF relating to maximum doses to the sphincter were assessed by the Mann-Whitney test. Results. Mean Wexner score was 5.5 points higher in those patients with V20 > 0 compared to those for which V20 = 0 (p = 0.008). In a multivariate regression model, results suggest that the effect of V20 on poor anal sphincter control is independent of the effect of distance, with an adjusted OR of 3.42. Conclusions. In order to improve the SF in rectal cancer treated with preoperative radiotherapy/capecitabine followed by conservative surgery, the maximum radiation dose to the AS should be limited, when possible, to <20 Gy (AU)

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Fecal incontinence and radiation dose on anal sphincter in patients with locally advanced rectal cancer (LARC) treated with preoperative chemoradiotherapy: a retrospective, single-institutional study.

BACKGROUND: The objective of the study is to determine the correlations among the variables of dose and the sphincter function (SF) in patients with locally advanced rectal cancer treated with preoperative capecitabine/radiotherapy followed by low anterior resection (LAR) + TME. METHODS: We retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 2 years free from disease. We re-contoured the anal sphincters (AS) of patients with the help of the radiologist. SF was assessed with the Wexner scale (0-20 points, being punctuation inversely proportional to annal sphincter functionality). All questionnaires were filled out between January 2010 and December 2012. Dosimetric parameters that have been studied include V 20, V 30, V 40, V 50, mean dose (D mean), minimum dose (D min), D 90 (dose received by 90% of the sphincter) and D 98. STATISTICAL ANALYSIS: The correlations among the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF relating to maximum doses to the sphincter were assessed by the Mann-Whitney test. RESULTS: Mean Wexner score was 5.5 points higher in those patients with V 20 > 0 compared to those for which V 20 = 0 (p = 0.008). In a multivariate regression model, results suggest that the effect of V 20 on poor anal sphincter control is independent of the effect of distance, with an adjusted OR of 3.42. CONCLUSIONS: In order to improve the SF in rectal cancer treated with preoperative radiotherapy/capecitabine followed by conservative surgery, the maximum radiation dose to the AS should be limited, when possible, to <20 Gy.

Influence of different treatment techniques and clinical factors over the intrafraction variation on lung stereotactic body radiotherapy

Purpose: In the present study we compared three different Stereotactic body radiation therapy (SBRT) treatment delivery techniques in terms of treatment time (TT) and their relation with intrafraction variation (IFV). Besides that, we analyzed if different clinical factors could have an influence on IFV. Finally, we appreciated the soundness of our margins. Materials and methods: Forty-five patients undergoing SBRT for stage I lung cancer or lung metastases up to 5 cm were included in the study. All underwent 4DCT scan to create an internal target volume (ITV) and a 5 mm margin was added to establish the planning target volume (PTV). Cone-beam CTs (CBCTs) were acquired before and after each treatment to quantify the IFV. Three different treatment delivery techniques were employed: fixed fields (FF), dynamically collimated arcs (AA) or a combination of both (FA). We studied if TT was different among these modalities of SBRT and whether TT and IFV were correlated. Clinical data related to patients and tumors were recorded as potential influential factors over the IFV. Results: A total of 52 lesions and 147 fractions were analyzed. Mean IFV for x-, y- and z-axis were 1 ± 1.16 mm, 1.29 ± 1.38 mm and 1.17 ± 1.08 mm, respectively. Displacements were encompassed by the 5 mm margin in 96.1 % of fractions. TT was significantly longer in FF therapy (24.76 ± 5.4 min), when compared with AA (15.30 ± 3.68 min) or FA (17.79 ± 3.52 min) (p < 0.001). Unexpectedly, IFV did not change significantly between them (p = 0.471). Age (p = 0.003) and left vs. right location (p = 0.005) were related to 3D shift ≥2 mm. In the multivariate analysis only age showed a significant impact on the IFV (OR = 1.07, p = 0.007). Conclusions: The choice of AA, FF or FA does not impact on IFV although FF treatment takes significantly longer treatment time. Our immobilization device offers enough accuracy and the 5 mm margin may be considered acceptable as it accounts for more than 95 % of tumor shifts. Age is the only clinical factor that influenced IFV significantly in our analysis

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Influence of different treatment techniques and clinical factors over the intrafraction variation on lung stereotactic body radiotherapy.

PURPOSE: In the present study we compared three different Stereotactic body radiation therapy (SBRT) treatment delivery techniques in terms of treatment time (TT) and their relation with intrafraction variation (IFV). Besides that, we analyzed if different clinical factors could have an influence on IFV. Finally, we appreciated the soundness of our margins. MATERIALS AND METHODS: Forty-five patients undergoing SBRT for stage I lung cancer or lung metastases up to 5 cm were included in the study. All underwent 4DCT scan to create an internal target volume (ITV) and a 5 mm margin was added to establish the planning target volume (PTV). Cone-beam CTs (CBCTs) were acquired before and after each treatment to quantify the IFV. Three different treatment delivery techniques were employed: fixed fields (FF), dynamically collimated arcs (AA) or a combination of both (FA). We studied if TT was different among these modalities of SBRT and whether TT and IFV were correlated. Clinical data related to patients and tumors were recorded as potential influential factors over the IFV. RESULTS: A total of 52 lesions and 147 fractions were analyzed. Mean IFV for x-, y- and z-axis were 1 ± 1.16 mm, 1.29 ± 1.38 mm and 1.17 ± 1.08 mm, respectively. Displacements were encompassed by the 5 mm margin in 96.1 % of fractions. TT was significantly longer in FF therapy (24.76 ± 5.4 min), when compared with AA (15.30 ± 3.68 min) or FA (17.79 ± 3.52 min) (p < 0.001). Unexpectedly, IFV did not change significantly between them (p = 0.471). Age (p = 0.003) and left vs. right location (p = 0.005) were related to 3D shift ≥2 mm. In the multivariate analysis only age showed a significant impact on the IFV (OR = 1.07, p = 0.007). CONCLUSIONS: The choice of AA, FF or FA does not impact on IFV although FF treatment takes significantly longer treatment time. Our immobilization device offers enough accuracy and the 5 mm margin may be considered acceptable as it accounts for more than 95 % of tumor shifts. Age is the only clinical factor that influenced IFV significantly in our analysis.

Impact of initial FDG PET/CT in the management plan of patients with locally advanced head and neck cancer

Objective. To determine the impact of initial FDG PET/CT staging on clinical stage and the management plan in patients with locally advanced head and neck cancer (LAHNC). Materials and methods. We retrospectively reviewed the records of 72 consecutive patients (2007–2010) staged with PET/CT and conventional CT with tumours of hypopharynx/larynx (26 patients, 36 %), oral cavity (17 patients, 24 %), oropharynx (16 patients, 22 %), nasopharynx (12 patients, 17 %), and others (2 %). The impact of PET/CT on management plans was considered high when PET/CT changed the planned treatment modality or treatment intent, and intramodality changes were considered as minor changes with low impact. Results. FDG PET/CT changed the stage in 27 patients and had high impact on the management plan in 12 % of patients (detection of distant metastases in 6 patients and stage II in 2 patients). Intramodality changes were more frequent: FDG PET/CT altered the TNM stage in 18/72 (25 %) of patients, upstaging N stage in 90 % of patients with low impact. Conclusions. Initial FDG PET/CT staging not only improves stage but also affects the management plan in LAHNC patients (AU)

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Impact of initial FDG PET/CT in the management plan of patients with locally advanced head and neck cancer.

OBJECTIVE: To determine the impact of initial FDG PET/CT staging on clinical stage and the management plan in patients with locally advanced head and neck cancer (LAHNC). MATERIALS AND METHODS: We retrospectively reviewed the records of 72 consecutive patients (2007-2010) staged with PET/CT and conventional CT with tumours of hypopharynx/larynx (26 patients, 36 %), oral cavity (17 patients, 24 %), oropharynx (16 patients, 22 %), nasopharynx (12 patients, 17 %), and others (2 %). The impact of PET/CT on management plans was considered high when PET/CT changed the planned treatment modality or treatment intent, and intramodality changes were considered as minor changes with low impact. RESULTS: FDG PET/CT changed the stage in 27 patients and had high impact on the management plan in 12 % of patients (detection of distant metastases in 6 patients and stage II in 2 patients). Intramodality changes were more frequent: FDG PET/CT altered the TNM stage in 18/72 (25 %) of patients, upstaging N stage in 90 % of patients with low impact. CONCLUSIONS: Initial FDG PET/CT staging not only improves stage but also affects the management plan in LAHNC patients.

[Adipocytokines: implications in the prognosis and drug treatment of cardiovascular diseases]. / Adipocitocinas: implicaciones en el pronóstico y tratamiento farmacológico de patología cardiovascular.

Adipocytokines, fat tissue derived factors with regulatory properties, are involved in the pathophysiology of atheromatous and metabolic illnesses such as: ischemic heart disease, insulin resistance, obesity, dyslipidemia and diabetes mellitus. Enlargement of visceral adipose tissue depots determines a worse evolution for those complaints. Drugs as angiotensin converting enzyme inhibitors (ACEI), thiazolidinediones (glitazones) or angiotensin-II receptor antagonists, generally associated with the adequate hypolipidemic (statins, fibrates) or antiobesity (orlistat, sibutramine, rimonabant) medication, would increase those adipocytokines with anti-inflammatory and insulin-sensitizing properties (i.e. adiponectin or visfatin), while reducing pro-inflammatory and thrombogenic cytokines (as leptin, tumor necrosis factor [TNF]-alpha, plasminogen activator inhibitor 1 [PAI-1]). Thus, these pharmacologic therapeutic approaches would have a beneficial effect in order to diminish morbidity-mortality and improve the prognosis of patients with said diseases, all of them related to high cardiovascular risk.

Amine oxidase substrates for impaired glucose tolerance correction.

Amine oxidases are widely distributed from microorganisms to vertebrates and produce hydrogen peroxide plus aldehyde when catabolizing endogenous or xenobiotic amines. Novel roles have been attributed to several members of the amine oxidase families, which cannot be anymore considered as simple amine scavengers. Semicarbazide-sensitive amine oxidase (SSAO) is abundantly expressed in mammalian endothelial, smooth muscle, and fat cells, and plays a role in lymphocyte adhesion to vascular wall, arterial fiber elastic maturation, and glucose transport, respectively. This latter role was studied in detail and the perspectives of insulin-like actions of amine oxidase substrates are discussed in the present review. Independent studies have demonstrated that SSAO substrates and monoamine oxidase substrates mimic diverse insulin effects in adipocytes: glucose transport activation, lipogenesis stimulation and lipolysis inhibition. These substrates also stimulate in vitro adipogenesis. Acute in vivo administration of amine oxidase substrates improves glucose tolerance in rats, mice and rabbits, while chronic treatments with benzylamine plus vanadate exert an antihyperglycaemic effect in diabetic rats. Dietary supplementations with methylamine, benzylamine or tyramine have been proven to influence metabolic control in rodents by increasing glucose tolerance or decreasing lipid mobilisation, without noticeable changes in the plasma markers of lipid peroxidation or protein glycation, despite adverse effects on vasculature. Thus, the ingested amines are not totally metabolized at the intestinal level and can act on adipose and vascular tissues. In regard with this influence on metabolic control, more attention must be paid to the composition or supplementation in amines in foods and nutraceutics.

Effects of verapamil and elgodipine on isoprenaline-induced metabolic responses in rabbits.

Verapamil (0.17 microg kg(-1) min(-1) intravenous, i.v.) but not elgodipine (35 ng kg(-1) min(-1)) modestly enhanced the weak blood glucose increase induced by the i.v. infusion of isoprenaline (0.3 microg kg(-1) min(-1)) in conscious rabbits. However, elgodipine but not verapamil suppressed the increase in circulating insulin evoked by the agonist. Both drugs enhanced the rise in plasma lactate mediated by isoprenaline but only elgodipine potentiated the lipolytic effect of the agonist. In isolated islets elgodipine (10(-6) M) blocked forskolin (10(-6) M)-induced insulin release. However, in rabbit adipocytes elgodipine potentiated both glycerol release and cAMP accumulation induced by isoprenaline (10(-8)-10(-6) M). Excess K(+) (40-60 mM) did not alter basal lipolysis or the response to isoprenaline in either rabbit or mouse adipocytes. Therefore, Ca2+ influx through L-type Ca2+ channels does not seem to play a significant role in the lipolytic effect of isoprenaline. Metabolic alterations found with Ca2+ channel antagonists were of minor intensity and probably devoid of pathological implications.

Inhibition of protein synthesis sequentially impairs distinct steps of stimulus-secretion coupling in pancreatic beta cells.

Proteins with a short half-life are potential sites of pancreatic ss cell dysfunction under pathophysiological conditions. In this study, mouse islets were used to establish which step in the regulation of insulin secretion is most sensitive to inhibition of protein synthesis by 10 microM cycloheximide (CHX). Although islet protein synthesis was inhibited approximately 95% after 1 h, the inhibition of insulin secretion was delayed and progressive. After long (18-20 h) CHX-treatment, the strong (80%) inhibition of glucose-, tolbutamide-, and K(+)-induced insulin secretion was not due to lower insulin stores, to any marked impairment of glucose metabolism or to altered function of K(+)-ATP channels (total K(+)-ATP currents were however decreased). It was partly caused by a decreased Ca(2+) influx (whole-cell Ca(2+) current) resulting in a smaller rise in cytosolic Ca(2+) ([Ca(2+)](i)). The situation was very different after short (2-5 h) CHX-treatment. Insulin secretion was 50-60% inhibited although islet glucose metabolism was unaffected and stimulus-induced [Ca(2+)](i) rise was not (2 h) or only marginally (5 h) decreased. The efficiency of Ca(2+) on secretion was thus impaired. The inhibition of insulin secretion by 15 h of CHX treatment was more slowly reversible (>4 h) than that of protein synthesis. This reversibility of secretion was largely attributable to recovery of a normal Ca(2+) efficiency. In conclusion, inhibition of protein synthesis in islets inhibits insulin secretion in two stages: a rapid decrease in the efficiency of Ca(2+) on exocytosis, followed by a decrease in the Ca(2+) signal mediated by a slower loss of functional Ca(2+) channels. Glucose metabolism and the regulation of K(+)-ATP channels are more resistant. Proteins with a short half-life appear to be important to ensure optimal Ca(2+) effects on exocytosis, and are the potential Achille's heel of stimulus-secretion coupling.

Role of alpha2-adrenoceptors on the hyperglycaemic and insulin secretory effects derived from alpha1- and beta-adrenoceptor stimulation in the rabbit.

1. In conscious fasted rabbits the insulin secretory response induced by the intravenous infusion of the alpha1-adrenoceptor agonist, amidephrine (10 microg kg(-1) min(-1)) was blocked by the simultaneous administration of clonidine (2 microg kg(-1) min(-1) i.v.). 2. The excitatory effect of amidephrine (10 microg kg(-1) min(-1)) on insulin secretion was similarly suppressed by the concomitant infusion of the selective alpha2-adrenoceptor agonist UK14304 (1 microg kg(-1) min(-1)). Both, the increase in blood glucose and the inhibition of insulin secretion found with UK14304 when infused alone were antagonized in rabbits previously treated with the very selective alpha2-adrenoceptor antagonist 2-methoxyidazoxan (1.5 microg kg(-1) min(-1)). 3. The combined administration of amidephrine (3 microg kg(-1) min(-1)) and isoprenaline (0.3 microg kg(-1) min(-1)) evoked a potentiated increase in insulin plasma levels in the face of a weak hyperglycaemia, an established reduction in blood pressure and tachycardia. 4. The potentiated insulin secretory response derived from alpha1- and beta-adrenoceptor stimulation was blunted by clonidine administration. In its presence a sustained hyperglycaemic response was found. 5. The increase in plasma lactate levels resulting from dual adrenoceptor stimulation (amidephrine: 10 microg kg(-1) min(-1) + salbutamol: 0.3 microg kg(-1) min(-1)) was smaller than the expected should addition or potentiation occurred. 6. Our results point to a possible physiological role played by alpha2-adrenoceptors on insulin secretion, since their stimulation by the endogenous catecholamines could lead to inhibition of insulin release, masking any potentiated response that otherwise should have appeared from alpha1- and beta-adrenoceptor stimulation.

Effect of age, birth cohort, and period of death on cerebrovascular mortality in Spain, 1952 through 1991.

BACKGROUND AND PURPOSE: The continued decrease in cerebrovascular disease in Spain remains unexplained. Age-period-cohort analysis enables description of birth cohort and period-of-death components. This study sought to describe these effects on the decline of stroke mortality in Spain. METHODS: Deaths due to cerebrovascular diseases in the period from 1952 through 1991 and the corresponding population figures were grouped into 11 age groups and 8 5-year periods, from which age-specific mortality rates for 18 birth cohorts were then computed. These were plotted for graphical presentation purposes and fitted to Poisson regression models to assess age, period, and cohort effects. RESULTS: An exponential age effect was present for both sexes regardless of cohort or period. A definite downward period effect was observable from 1962 to 1991, except for a sharp fall and peak in the periods 1967 to 1971 and 1972 to 1976, respectively, which was possibly ascribable to changes in diagnostic and coding practices. Age- and period-adjusted stroke mortality increased for earlier cohorts and decreased for generations born between 1892 and 1940. For post-1940 generations, there was an increasing risk of stroke mortality. CONCLUSIONS: The results suggest that a decrease in incidence coupled with an increase in survival may account for the observed decline in stroke mortality, but further studies on the Spanish population are needed to assess these findings. Although not yet definitive, there are signs of an increase in incidence among the more recent generations. If the decreasing period effect fails to offset this increase, future years may see a deceleration in the current decline in stroke mortality.

Comparative effects of calcium channel blockers and indomethacin on insulin secretion and blood pressure increase derived from alpha 1-adrenoceptor stimulation in the rabbit.

1. In conscious, fasted rabbits the intravenous infusion of the alpha 1-adrenoceptor agonist, amidephrine (3 and 10 micrograms kg-1 min-1) induced a dose related increase in insulin plasma levels. This effect was accompanied by a minor hypo- or hyperglycaemic response, depending on the dose of agonist infused. 2. A dose related increase in mean arterial pressure and reduction in heart rate were also found after amidephrine administration. 3. The insulin secretory response to amidephrine was not prevented in rabbits previously treated with atropine (5.26 micrograms kg-1 min-1). However, in the presence of muscarinic receptor blockade the bradycardic effect of amidephrine was either suppressed or attenuated. 4. Pretreatment with the calcium channel antagonist elgodipine (35 ng kg-1 min-1) or with indomethacin (0.66 mg kg-1 min-1) clearly blocked the effect of amidephrine on insulin secretion. 5. The haemodynamic changes induced by amidephrine were preserved in the presence of either verapamil (0.17 microgram kg-1 min-1) or indomethacin, whereas the hypertensive response was antagonized by elgodipine. 6. Our results suggest that the metabolic and haemodynamic changes mediated by amidephrine are two independent effects, insulin secretion requiring the presence of extracellular calcium and the synthesis of arachidonic acid metabolites.

No evidence for a role of reverse Na(+)-Ca2+ exchange in insulin release from mouse pancreatic islets.

We studied whether reverse Na(+)-Ca2+ exchange can increase cytoplasmic Ca2+ ([Ca2+]i) in mouse islets and contribute to insulin release. The exchange was stimulated by replacing Na+ with choline, sucrose, or lithium in a medium containing 15 mM glucose. Na+ omission increased electrical activity in B cells, [Ca2+]i, and insulin release. When voltage-dependent Ca2+ channels were blocked by nimodipine or closed by holding the membrane polarized with diazoxide, Na+ omission caused a slight hyperpolarization, a small rise in [Ca2+]i, and a marginal increase in insulin release (the latter only with choline). This small rise in [Ca2+]i was dependent on extracellular Ca2+ but was hardly augmented when intracellular Na+ was raised with alanine. When B cells were depolarized by 30 mM K+, Na+ omission did not affect the membrane potential but increased [Ca2+]i and insulin release. If Ca2+ channels were blocked by nimodipine, only marginal increases in Ca2+ and insulin release persisted, which were not different from those observed when the cells were not depolarized. This indicates that Ca2+ influx through voltage-dependent Ca2+ channels rather than via reverse Na(+)-Ca2+ exchange underlies the rise in [Ca2+]i and in insulin release produced by Na+ removal. No decisive support for Ca2+ influx by reverse Na(+)-Ca2+ exchange could be found.

Sulphonylureas do not increase insulin secretion by a mechanism other than a rise in cytoplasmic Ca2+ in pancreatic B-cells.

The following sequence of events is thought to underlie the stimulation of insulin release by hypoglycaemic sulphonylureas. Interaction of the drugs with a high-affinity binding site (sulphonylurea receptor) in the B-cell membrane leads to closure of ATP-sensitive K+ channels, depolarization, opening of voltage-dependent Ca2+ channels, Ca2+ influx and rise in cytoplasmic [Ca2+]i. Recent experiments using permeabilized islet cells or measuring changes in B-cell membrane capacitance have suggested that sulphonylureas can increase insulin release by a mechanism independent of a change in [Ca2+]i. This provocative hypothesis was tested here with intact mouse islets. When B-cells were strongly depolarized by 60 mM K+, [Ca2+]i was increased and insulin secretion stimulated. Under these conditions, tolbutamide did not further increase [Ca2+]i or insulin release, whether it was applied before or after high K+, and whether the concentration of glucose was 3 or 15 mM. This contrasts with the ability of forskolin and phorbol 12-myristate 13-acetate (PMA) to increase release in the presence of high K+. Tolbutamide also failed to increase insulin release from islets depolarized with barium (substituted for extracellular Ca2+) or with arginine in the presence of high glucose. Glibenclamide and its non-sulphonylurea moiety meglitinide were also without effect on insulin release from already depolarized B-cells. In the absence of extracellular Ca2+, acetylcholine induced monophasic peaks of [Ca2+]i and insulin secretion which were both unaffected by tolbutamide. Insulin release from permeabilized islet cells was stimulated by raising free Ca2+ (between 0.1 and 23 microM). This effect was not affected by tolbutamide and inconsistently increased by glibenclamide. In conclusion, the present study does not support the proposal that hypoglycaemic sulphonylureas can increase insulin release even when they do not also raise [Ca2+]i in B-cells.

The imidazoline SL 84.0418 shows stereoselectivity in blocking alpha 2-adrenoceptors but not ATP-sensitive K+ channels in pancreatic B-cells.

The novel alpha 2-adrenoceptor antagonist SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrochloride) is a racemic mixture of a (-) enantiomer (SL 86.0714) and a (+) enantiomer (SL 86.0715 or deriglidole). It was recently reported to inhibit alpha 2-adrenoceptors and ATP-sensitive K+ channels in mouse pancreatic B-cells, and to increase insulin release. We have now studied the stereospecificity of these responses with isolated mouse islets. Both enantiomers were equipotent in potentiating insulin release induced by 15 mM glucose alone. SL 86.0714 and deriglidole were also equally effective in inhibiting 86Rb efflux from islets perifused with a low-glucose medium, and in reversing the inhibition of glucose-induced insulin release caused by the opening of ATP-sensitive K+ channels with diazoxide. In contrast, deriglidole was approximately 100-fold more potent than SL 86.0714 in reversing the inhibition of insulin release caused by the activation of alpha 2-adrenoceptors with clonidine. The effects of SL 84.0418 are thus stereoselective on alpha 2-adrenoceptors, but not on ATP-sensitive K+ channels of pancreatic B-cells.