Biomedical subjects

B Pirotte

Publications and source records attributed to B Pirotte.

At least 19 recordsLinked to original sources

PubMed2006

Endovascular treatment of intracranial aneurysms with a branch arising from the sac.

BACKGROUND AND PURPOSE: The endovascular treatment (EVT) of intracranial aneurysms is no more limited by the presence of a branch at the neck or by the neck width. Saccular aneurysms with a branch arising from the sac, however, are mostly candidates for surgery rather than embolization. We prospectively evaluated the feasibility and safety of the EVT in such cases. METHODS: Between May and November 2004, 9 consecutive patients with a saccular aneurysm that presents a branch arising from the sac were treated by embolization. There were 7 women and 2 men (mean age, 58 years). Six patients presented with a subarachnoid hemorrhage (SAH), and 3 were asymptomatic. All patients were treated by selective coiling with (n = 6) or without (n = 3) the remodeling technique. Clinical outcome was assessed with a modified Glasgow Outcome Scale at 3 months. RESULTS: EVT was successfully performed in all patients and resulted in 7 excellent outcomes and 2 deaths related to SAH complications. The arterial branch could be preserved in 7 cases and intentionally occluded in 2. Neither embolic nor ischemic complication occurred in the vascular territory of the involved branch. Angiographic results showed 5 neck remnants, 2 incomplete occlusions, and 2 complete occlusions. No rebleeding occurred. CONCLUSION: Our study, though limited by its small patient population, suggests that saccular intracranial aneurysms with a branch arising from the sac may be treated by endovascular approach with excellent clinical results; however, larger series with long-term follow-up are mandatory to confirm these preliminary results mostly in terms of anatomic stability.

Adult↗

PubMed2004

New trends in the design of drugs against Alzheimer's disease.

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.

Alzheimer Disease↗

PubMed2004

Recent developments in the chemistry of potassium channel activators: the cromakalim analogs.

Potassium channels play a crucial role in controlling the cell membrane potential. Among the different varieties of K(+) channels, the ATP-sensitive potassium channels (K(ATP) channels) have been characterized in numerous cell types, such as skeletal and smooth muscle cells, endocrine cells, cardiac cells and central neurons. Several molecules are known to activate K(ATP) channels and have been named "potassium channel openers" (PCOs). Such compounds may have a wide therapeutic potential and a few drugs are currently used as antihypertensive agents. Different chemical series of PCOs have been explored. This heterogeneous group of organic compounds comprises the benzopyran series including potent vasorelaxant drugs, such as cromakalim. The latter compound, a typical example of potassium channel opener, exerts its biological effect by activating K(ATP) channels. This review presents recent developments in the chemistry of cromakalim analoges and reports chemical aspects governing their potency and tissue selectivity.

Animals↗

PubMed2003

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo.

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

Animals↗

PubMed2003

Pharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Effects of BM-567 on osteogenic sarcoma-cell-induced platelet aggregation.

Evidence exists that a large number of tumor cells such as osteosarcoma cells stimulate platelet aggregation, which can be an early step in the metastatic processes of these tumors. Thromboxane A(2) (TXA(2)) is released during platelet aggregation, and it has been suggested that this release may be pathogenic for tumor metastasis for several reasons:Some tumors release large amounts of TXA(2) compared to normal tissue.TXA(2) potentiates tumor growth in culture and increases metastasis in animals.TXA(2) is a potent stimulant of platelet aggregation and causes vascular injuries that may promote implantation of tumor cell-platelet aggregates. If TXA(2) participates in tumor metastasis, it may be hypothesized that TXA(2) inhibitors should decrease tumor metastasis. So, we have evaluated the effects of the original TXA(2) synthase inhibitor and TXA(2) receptor antagonist BM-567 on platelet aggregation induced by osteosarcoma cells using MG-63 tumor cells. Results obtained showed that this drug inhibited both MG-63 tumor-cell-induced platelet aggregation and platelet TXA(2) release following the tumor cell stimulation with IC(50) values of 3.04x10(-7) and 2.51x10(-8)M, respectively.

Blood Platelets↗

PubMed2003

Pharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function.

The aim of this work was to evaluate the effects of BM-567 (N-pentyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on both thromboxane A(2) (TXA(2)) receptors (TP) and thromboxane synthase of human platelets. The drug affinity for TP receptors of human washed platelets has been determined. In this test, BM-567 showed a high affinity (IC(50): 1.1+/-0.1nM) for the TP receptors in comparison with BM-531 (IC(50): 7.8+/-0.7nM) and sulotroban (IC(50): 931+/-85nM), two TXA(2) antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 microM) (ED(100): 0.20+/-0.10 microM), U-46619, a stable TXA(2) agonist (1 microM) (ED(50): 0.30+/-0.04 microM) and collagen (1microgram ml(-1)) (% of inhibition: 44.3+/-4.3% at 10 microM) and inhibited the second wave of ADP (2microM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100((R))) was significantly prolonged (closure time: 215+/-21s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 microM, BM-567 completely reduced the TXB(2) production from human platelets stimulated with AA (600 microM). These results indicate that BM-567 is a novel combined TXA(2) receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency.

Blood Platelets↗

PubMed2002

Unusual CT features of dermoid cyst in the posterior fossa.

A dermoid cyst of the posterior fossa in a 73-year-old man is reported. The presentation of the cyst was unusual because of the age of the patient, the spontaneously hyperdense aspect of the mass on CT, the partial rim enhancement of the lesion, and the presence of perilesional edema. On pathologic examination, the cyst contained small amount of fat, hairs, necrosis, and small areas of hemorrhage. The amount of hemorrhage found could not explain the spontaneous hyperdensity of the lesion found on CT. The hyperdensity may be related to high protein content of the lesion.

Aged↗

PubMed2002

[The neurosurgery department].

Opened on November 1st, 2001, the Department of Neurosurgery has progressively grown to become worldwide renown in a few years. All the pathologies are covered, from lumbar disc hernia to intracranial tumors and vascular malformations. But the originality stays into the exceptional environment by the concentration of logistic resources and the ability of clinician and researchers who daily collaborate with the neurosurgical team. The Department of Neurosurgery has a strong reputation in several fields like intraspinal cord tumors or Pet-guided Neurosurgery in stereotactic biopsies, neuronavigation and Gamma Knife and, generally speaking, in the original approach of the treatment and follow-up of brain tumors. Neurodegenerative diseases also benefit of modern approaches trough the Gamma Knife, deep brain stimulation or fetal cell grafting into the brain in Parkinson and soon in Huntington diseases. Last but not least, the arrival for the 25th anniversary of Erasme Hospital of an interventional MRI will allow to follow in real-time the resection of brain tumors with an obvious benefit for the surgical performances and the quality of life of the patients. It will also open a new window for neurosurgical research through combination with functional MRI and Pet-Scan, reinforcing the reputation of Erasme Neurosurgical Department who has been distinguished in 1997 by the World Health Organisation as "WHO Collaborating Center for Research and Training in Neurosurgery" and nominated again in 2002 for a new 4-year period, which is unique in the Neurosurgical World.

Belgium↗

PubMed2001

The Zeiss-MKM system for frameless image-guided approach in epidural motor cortex stimulation for central neuropathic pain.

OBJECT: Twelve patients (seven female, and five male, mean age 55.6 years) suffering from refractory central (ischemic/traumatic [eight cases]) and neuropathic pain (trigeminal neuropathy [four cases]) underwent surgery for the implantation of an epidural motor cortex stimulation (MCS) device in which the authors used a frameless neuronavigation system, the Zeiss-MKM microscope. METHODS: The authors assessed the spatial accuracy of the neuronavigation system and its potential contribution to improve the quality of targeting pain. In these patients, the positions of the central sulcus, defined by stereotactic magnetic resonance MR imaging, intraoperative somatosensory evoked potentials (SSEPs) and subdural visual verification, were correlated into the stereotactic neuronavigation planning procedure. The mean spatial accuracy of distance between (MR) imaging-defined and actual central sulcus was 2.4 mm (range 5-10 mm). The intraoperative SSEPdefined central sulcus was close to that defined by MR imaging (mean distance 6.4 mm). Although very precise, intraoperative SSEP recordings were impaired by artifacts and wave attenuation in six of the 12 patients. Stereotactic correlations between anatomical and functional data in the navigation system corrected final targeting in 10 of 12 cases. Pain relief was obtained in eight patients. Indeed, inappropriate targeting probably explains the reported variable success rate of MCS and certainly underestimates the actual efficacy. CONCLUSIONS: Since intraoperative SSEP monitoring has, for many years, been considered the standard procedure to approach motor target, the development of an accurate stereotactic image guidance system could help to increase the efficacy of MCS on the alleviation of pain. The excellent spatial accuracy provided by the Zeiss-MKM navigation system allows precise data correlations that represent a remarkable means to validate functional MR imaging as an alternative to SSEP. The authors believe that developing stereotactic image guidance with such a navigation system could improve the success rate of MCS.

Deep Brain Stimulation↗

PubMed2001

Original 2-alkylamino-6-halogenoquinazolin-4(3H)-ones and K(ATP) channel activity.

A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)-ones were found to inhibit insulin release from pancreatic B-cells and to exhibit vasorelaxant properties. In contrast to their pyridothiadiazine dioxide isosteres previously described as more active on the endocrine than on the smooth muscle tissue, quinazolinones cannot be considered as tissue selective compounds. Biological investigations, including measurements of (86)Rb, (45)Ca efflux from pancreatic islet cells and measurements of vasodilator potency in rat aortic rings exposed to 30 or 80 mM KCl in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isopropylaminoquinazolin-4(3H)-ones. Such experiments showed that, depending on the tissue, these new compounds did not always express the pharmacological profile of pure K(ATP) channel openers. Analyzed by X-ray crystallography, one example of quinazolinones appeared to adopt a double conformation. This only suggests a partial analogy between the 2-alkylaminoquinazolin-4(3H)-ones and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. In conclusion, the newly synthesized quinazolinones interfere with insulin secretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully elucidate their mechanism(s) of action.

Adenosine Triphosphate↗

PubMed2001

Cavernous haemangioma in the cavernous sinus: case report and review of the literature.

We report a cavernous haemangioma in the left cavernous sinus. This lesions very rarely occurs in this site and is difficult to diagnose correctly preoperatively. CT, angiography and MRI permit differentiation of the cavernous haemangioma from other tumours in this region and thereby contribute to a better surgical approach. The radiological features of cavernous haemangioma reported in the literature are summarised.

Aged↗

PubMed2001

Synthesis and characterization of a quinolinonic compound activating ATP-sensitive K(+) channels in endocrine and smooth muscle tissues.

Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration-dependent decrease of insulin release was induced by 6-chloro-2-methylquinolin-4(1H)-one (HEI 713). The average IC(50) values were 16.9+/-0.8 microM for HEI 713 and 18.4+/-2.2 microM for diazoxide. HEI 713 increased the rate of (86)Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca(2+) but was inhibited by glibenclamide, a K(ATP) channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased K(ATP) channel openings. HEI 713 decreased (45)Ca outflow, insulin output and cytosolic free Ca(2+) concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca(2+). The drug did not affect the K(+)(50 mM)-induced increase in (45)Ca outflow. In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K(+) concentration. The drug elicited a glibenclamide-sensitive increase in (86)Rb outflow from perifused rat aortic rings. Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of K(ATP) channels ultimately leading to a decrease in Ca(2+) inflow.

Adenosine Triphosphate↗

PubMed2001

Effect on insulin release of compounds structurally related to the potassium-channel opener 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73): introduction of heteroatoms on the 3-alkylamino side chain of the benzothiadiazine 1,1-dioxide ring.

7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.

Animals↗

PubMed2000

3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: design, synthesis, and pharmacological evaluation.

A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.

Animals↗

PubMed2000

A potent diazoxide analogue activating ATP-sensitive K+ channels and inhibiting insulin release.

AIMS/HYPOTHESIS: To characterise the effects of BPDZ 73 (7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), a newly synthesised diazoxide analogue, on insulin secretory cells. METHODS: Measurements of 86Rb, 45Ca outflow, membrane potential, [Ca2+]i, insulin release in secretory cells as well as measurements of smooth muscle contractile activity and glycaemia were carried out. RESULTS: The analogue BPDZ 73 induced a dose-dependent decrease in insulin output. The IC50 value averaged 0.73 +/- 0.05 mumol/l. The drug increased the rate of 86Rb (42K substitute) outflow from perifused rat pancreatic islets. This effect was inhibited by glibenclamide, a KATP channel blocker. Measurements of DiBAC4(3) fluorescence further indicated that BPDZ 73 hyperpolarised the insulin secreting cells. It also decreased 45Ca outflow from pancreatic islets perifused throughout in the presence of 16.7 mmol/l glucose and extracellular Ca2+. By contrast, the drug did not affect the increase in 45Ca outflow mediated by K+ depolarisation. In single beta cells, BPDZ 73 inhibited the glucose-induced but not the K(+)-induced rise in [Ca2+]i. Moreover, in Wistar rats, i.p. injection of BPDZ 73 provoked a considerable increase in blood glucose concentration whereas diazoxide induced a modest rise in glycaemia. Lastly, the vasorelaxant properties of BPDZ 73 were slightly less pronounced than those of diazoxide. CONCLUSION/INTERPRETATION: The inhibitory effect of BPDZ 73 on the insulin-releasing process results from the activation of KATP channels with subsequent decrease in Ca2+ inflow and [Ca2+]i. The drug seems to be a KATP channel opener, more potent and more selective than diazoxide for insulin secreting cells.

Adenosine Triphosphate↗

PubMed2000

Coumarinic derivatives as mechanism-based inhibitors of alpha-chymotrypsin and human leukocyte elastase.

Novel coumarinic derivatives were synthesized and tested for their inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/K(I) = 4000 M(-1) s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of alpha-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modified chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol-water. From this calculation, it appears that differences in the inhibitory potency expressed by these molecules cannot only be explained by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack.

Chymotrypsin↗

PubMed2000

Therapeutic and chemical developments of cholecystokinin receptor ligands.

Cholecystokinin (CCK) is an important 'brain-gut' hormone located both in the gastrointestinal (GI) system and in the CNS. At least two different G-coupled high affinity receptors have been identified: the CCK-A and the CCK-B receptors. Although the complex biological role of CCK is, as yet, not fully understood, its connection with many different physiological processes both at the GI level and at the CNS level is now well established. There is much potential for therapeutic use of CCK receptor ligands, however, clear investigations have yet to be completed. Several chemical families have been investigated over the last 20 years to find potent, subtype selective and stable CCK receptor agonists and antagonists. The main goal was to discover new therapeutic drugs acting on GI and/or on CNS diseases and also, to obtain powerful pharmacological tools that could permit a better understanding of the biological role of CCK. Despite promising results from investigations into medicinal chemistry of CCK receptor ligands, the therapeutical applications of these ligands still remains to be defined. This article reviews the main biological role of CCK, the therapeutic potential of CCK-A and CCK-B receptor agonists and antagonists and the common compounds from the different families of ligands.

Animals↗

PubMed2000

Recent advances in inducible cyclooxygenase (COX-2) inhibition.

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances that are involved in several physiological processes but also in pathological conditions such as inflammation. Since ten years now, it is well known that this enzyme exists under two forms: a constitutive (COX-1) and an inducible form (COX-2). Both enzymes are sensitive to inhibition by conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Observations that COX-1, involved in several homeostatic processes, played a housekeeping role while COX-2 expression was associated with inflammation and other pathologies such as cancer proliferation have led to the development of COX-2 selective inhibitors in order to reduce the classical side-effects, of which gastric irritation is the most common, associated with the use of conventional NSAIDs.

Animals↗