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Biomedical subjects

J E Donckier

Publications and source records attributed to J E Donckier.

At least 19 recordsLinked to original sources
PubMed2004

Expression of endothelin-1 by adrenocortical carcinoma: a new target for anti-cancer therapy?

Adrenocortical carcinoma is a rare neoplasm with poor prognosis. Endothelin-1 (ET-1) has been implicated in carcinogenesis, but has never been studied in this neoplasm. A 76-year-old woman with Cushing's syndrome due adrenocortical carcinoma was operated on and the tumour removed was studied by immunohistochemistry for ET-1. Patient history illustrates the poor prognosis of this cancer that became metastatic after one year. Immunohistochemical studies disclosed a strong expression of ET-1 by adrenocortical carcinoma cells. As shown in other cancers, ET-1 expression by adrenocortical carcinoma may suggest a pathogenic role of ET-1 in tumorigenesis that possibly could be countered by ET-1 receptor antagonists. These agents could open new therapeutic perspectives to treat a carcinoma known to have a poor prognosis.

Adrenal Cortex Neoplasms↗
PubMed2001

Antiproliferative effect of octreotide in somatotroph pituitary adenomas: discussion from a single case report.

The case of a 20-year-old man presenting with a rapidly expanding pituitary somatotrophic adenoma with a tumour volume doubling time of 426 days is reported. Preoperative octreotide therapy induced a 45% tumour shrinkage and proliferating cells were absent at the time of tumoural resection. The correlation between clinical and proliferation markers data in this single case report affords an opportunity to discuss the antitumoral effect of octreotide on somatotrophic adenomas which may result from a suppression of cell proliferation.

Adenoma↗
PubMed2001

Therapeutic role of bosentan in hypertension: lessons from the model of perinephritic hypertension.

Since its discovery in 1988, there has been increasing evidence that endothelin-1 (ET-1) plays an important role in the pathophysiology of hypertension and its related end-organ damages. First studies, using ET-1 administration in animals or in humans suspected this role by demonstrating the hypertensive properties of ET-1. The latter, due to stimulation of ET(A) receptors inducing sustained vasoconstriction have been reported to follow transient vasodilation linked with activation of an endothelial ET(B) receptor releasing nitric oxide (NO). In certain instances, ET(B) smooth-muscle receptors might also induce contraction. Cloning of these receptors helped to develop ET-1 receptor antagonists. As soon as one of them became available, bosentan, a dual (ET(A) and ET(B)) ET-1 receptor antagonist, we tested its effects in the canine model of perinephritic hypertension. Bosentan was found to exert striking hypotensive effects, due to peripheral vasodilation but without affecting cardiac function. In further experiments, we observed that effects of bosentan were additional to those of ACE inhibitors or angiotensin II antagonists. This opened new therapeutic perspectives and also suggested a proper role of ET-1 in hypertension, independent of the renin-angiotensin system. To explain this role, we demonstrated a real imbalance characterized by an impairment of the NO system in favor of the ET-1 pathway. Recent studies suggest that such an imbalance may also occur in human hypertension. Furthermore, the contribution of ET-1 to human hypertension appears more convincing since bosentan was shown to decrease blood pressure in hypertensive subjects. Finally, ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damages. Whether or not these compounds are able to prevent or to reverse target organ injuries in man remains to be investigated.

Animals↗
PubMed2001

Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension.

BACKGROUND: A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs. MATERIALS AND METHODS: In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB. RESULTS: In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs. CONCLUSIONS: Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

Occurrence of thyroid papillary carcinoma in young patients. A Chernobyl connection?

The risk of thyroid papillary carcinoma is increased by external radiation particularly in children under 15 years of age as shown by a marked increase in those exposed to radiation after Chernobyl. We were recently confronted in Belgium over a short period with four patients (3 F, 1 M) with papillary thyroid carcinoma who were aged 10 years, 2 months, 2 years and 6 years when the Chernobyl accident occurred. We thus raise the question of a possible relationship. The patients were aged 17, 11, 10, 19 years at presentation. They all presented fortuitously over 3 years which was a very unusual increase in our extensive experience in thyroid surgery (62 cases of thyroid cancer among 1014 thyroidectomies in adults vs 4 cases in 18 children since the Chernobyl accident in 1986). Two out of the four patients had psammoma bodies (identifiable on CT scanning and ultrasound) and thyroglobulin autoantibodies (TgAb). The first patient had positive lymph nodes at the time of surgery. The incidence of thyroid cancers in Belarus and Ukraine rose just 4 years after the Chernobyl disaster; because radioactive clouds passed over Belgium, we wonder whether the occurrence of thyroid cancer in our patients could be related to this irradiation. The mechanism of increased incidence of radiation-induced thyroid cancer is thought to be due to rearrangement of the tyrosine kinase domains of the RET and TTK genes. The other important similarities in our patients are the presence of psammoma bodies that can be visualized on radiological examination and the presence of TgAb that are more frequent in differentiated thyroid cancers. Whether or not these cases reflect an increased incidence in the population as a whole, clinicians must remain vigilant for this rare but curable cancer in young patients, especially if suggestive radiological features or TgAb are present.

Adolescent↗
PubMed1998

Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation.

BACKGROUND: Cardiac natriuretic peptides are activated in heart failure. However, their diagnostic and prognostic values have not been compared under the routine conditions of an outpatient practice. METHODS: We studied the diagnostic and prognostic value of plasma N- and C-terminal peptides of the atrial natriuretic factor prohormone (N-proANF and ANF respectively) and brain natriuretic peptide (BNP) to evaluate the severity of congestive heart failure (CHF) as reflected by the New York Heart Association (NYHA) classification and to predict its 2-year mortality. Peripheral plasma concentrations of the three natriuretic peptides were measured in 27 normal subjects (CTR), in 32 patients with coronary artery disease (CAD) and normal left ventricular ejection fraction and in 101 patients with chronic CHF in functional classes I and II (n = 61) or III and IV (n = 40). RESULTS: Plasma concentrations of the three peptides increased in the presence of CHF in relation to its severity (P < 0.01). BNP was unable to distinguish CTR from CAD, just as ANF could not differentiate CAD from CHF I-II; only N-proANF displayed a significant and continuous increase from CTR to CAD, CHF I-II and III-IV. Receiver-operating characteristic curves showed better evaluation of the degree of CHF by BNP than by ANF or ejection fraction (P < 0.05). Assessment of the 2-year prognosis revealed that N-proANF and BNP were the best independent predictors of outcome after the NYHA classification. These peptides identify a very high-mortality group. CONCLUSION: Plasma N-proANF and BNP concentrations are good indicators of the severity and prognosis of CHF in an outpatient practice. CAD does not stimulate BNP as long as ventricular dysfunction is not present, although increased N-proANF levels in this setting suggest an early humoral activation.

Aged↗
PubMed1998

Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension.

OBJECTIVE: To evaluate whether the cumulative hypotensive effect of the endothelin-1 receptor antagonist bosentan, previously demonstrated in the presence of an angiotensin converting enzyme inhibitor, persists under angiotensin II receptor blockade with losartan. DESIGN: The model of hypertension was canine renovascular hypertension (Page hypertension). METHODS: Ten conscious dogs, studied on two occasions, were administered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg per min) and then bosentan vehicle (experiment I) or losartan and then two cumulative doses of bosentan (a 0.3 mg/kg bolus plus 30 min infusion at 0.7 mg/kg per min; and a 3 mg/kg bolus plus 30 min infusion at 7 mg/kg per min; experiment II). RESULTS: At the end of the study, mean aortic pressure in dogs had decreased by 14% in experiment I (from 139 +/- 4.7 to 119 +/- 4.7 mmHg, P<0.05), whereas a 28% reduction occurred in experiment II (from 145 +/- 8.9 to 104 +/- 5.0 mmHg, P<0.005), corresponding to an additional 14% decrease after administration of bosentan (P<0.005 between groups). This cumulative effect of bosentan was related to a decrease in systemic vascular resistance (from 1220 +/- 119 to 847 +/- 189 mmHg/ml per min per kg x 10(3), P<0.05). Plasma angiotensin II level increased similarly in both experiments (in experiment I from 133 +/- 43 to 622 +/- 145 pg/ml, P=0.01; in experiment II from 198 +/- 63 to 771 +/- 134 pg/ml, P<0.005) whereas plasma endothelin-1 level increased only in experiment II (from 3.8 +/- 0.4 to 32.7 +/- 3.2 pg/ml, P<0.001). CONCLUSION: The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.

Angiotensin II↗
PubMed1997

Additional hypotensive effect of endothelin-1 receptor antagonism in hypertensive dogs under angiotensin-converting enzyme inhibition.

BACKGROUND: Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI). METHODS AND RESULTS: Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan. CONCLUSIONS: Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

Angiotensin-Converting Enzyme Inhibitors↗