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Biomedical subjects

J Hendrickx

Publications and source records attributed to J Hendrickx.

At least 19 recordsLinked to original sources
PubMed2006

The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.

Administration, Oral↗
PubMed2005

Large bolus dose vs. continuous infusion of cisatracurium during hypothermic cardiopulmonary bypass surgery.

BACKGROUND AND OBJECTIVE: We investigated whether a high bolus dose of cisatracurium (8x ED95) given at induction can provide muscle relaxation for the major part of a cardiac procedure with hypothermic cardiopulmonary bypass, avoid important postoperative residual curarization and cause no waste of product. METHODS: Twenty patients were randomly assigned either to Group 1 (n = 10) or Group 2 (n = 10). Those in Group 1 were given cisatracurium in a high bolus dose (0.4 mg kg(-1)). Those in Group 2 received cisatracurium 0.1 mg kg(-1) at induction followed after 30 min by a continuous infusion of cisatracurium. As an escape medication in case of patient movement, a bolus dose of cisatracurium 0.03 mg kg(-1) was given. RESULTS: In Group 1 (large cisatracurium bolus dose), the clinical duration of effect (until T1/T0 = 25%) was 110 min. Six of 10 patients in Group 1 required additional boluses of cisatracurium intraoperatively. Four of these six had received an additional bolus near the end of surgery and had a train-of-four (TOF) ratio = 0 at the end. The other four patients in Group 1 had a final TOF ratio >0.9. In Group 2 (continuous cisatracurium infusion), only two patients had a TOF ratio >0.9 at the end of surgery, no patient moved and none received additional boluses. The total amount of cisatracurium used in the bolus and infusion Groups was 34.5 +/- 7.8 and 21.3 +/- 5.7 mg, respectively (P = 0.0004). CONCLUSIONS: For continued neuromuscular block during hypothermic cardiac surgery, a high bolus dose of cisatracurium appears to be safe, although it is not an alternative to a continuous infusion, as its neuromuscular blockade does not cover the intraoperative period and a high incidence of movements occurs. In the patients who received a high bolus dose of cisatracurium, postoperative residual curarization appeared after additional boluses had been given. The consumption of cisatracurium by high bolus was significantly greater than with continuous infusion.

Aged↗
PubMed2003

Implications of the use of neuromuscular transmission monitoring on immediate postoperative extubation in off-pump coronary artery bypass surgery.

BACKGROUND AND OBJECTIVE: When continuous infusions of neuromuscular blocking drugs are administered during lengthy interventions and no routine antagonism of their effects is applied, there is a dramatic incidence of residual curarization. We have examined whether the use of neuromuscular transmission monitoring results in differences in the incidence of postoperative residual curarization, the use of antagonist agents, and the endotracheal extubation rate and outcome after continuous infusion of rocuronium in patients undergoing off-pump coronary artery bypass surgery. METHODS: Twenty patients were assigned to group 1 (n = 10, non-blinded neuromuscular transmission monitoring) or group 2 (n = 10, blinded neuromuscular transmission monitoring). In group 1, patients were given rocuronium at an infusion rate of 6 microg kg(-1) min(-1). The rate was manually adjusted in order to maintain T1/T0 at 10%. In group 2, a rocuronium infusion was started 30 min after induction of anaesthesia, at a rate of 6 microg kg(-1) min(-1); this rate was left unchanged during surgery. The rocuronium infusion was discontinued on completion of all vascular anastomoses; propofol was stopped at the beginning of closure of the subcutis and pirinitramide (piritramide) 15 mg was administered intravenously. Remifentanil was discontinued at the beginning of skin closure and neostigmine (50 microg kg(-1)) administered at the end of surgery when the train-of-four ratio was < 0.9 in group 1, and routinely in group 2. A 20 min test period for spontaneous ventilation was allowed once surgery had been accomplished. When the train-of-four ratio was > or = 0.9 (group 1), patients were extubated if also breathing spontaneously, fully awake and able to follow commands. When they met the clinical criteria for normal neuromuscular function after induced blockade, patients in group 2 were extubated when fully awake and able to follow commands. RESULTS: In group 1, the rate of rocuronium infusion required to keep T1/T0 at 10% was 5 +/- 1.9 microg kg(-1) min(-1); this was not significantly different from the fixed rate in group 2 (P = 0.15). One patient in group 2 was excluded. Eight out of 10 and eight out of nine patients in groups 1 and 2, respectively, reached the extubation criteria. Three out of eight, and five out of eight, patients from groups 1 and 2, respectively, were extubated in the operating room. At that time of endotracheal extubation, all three patients from group 1, but only four of the five patients from group 2 had a train-of-four ratio > or = 0.9. In group 2, one patient was reintubated in the intensive care unit. The incidence of pharmacological reversal was high in group 1. CONCLUSIONS: Although we found no additional benefit of using neuromuscular transmission monitoring, it seems an absolute necessity for safety reasons. Pharmacological antagonism was mandatory. However, in our opinion, it is not wise routinely to perform immediate postoperative extubation in off-pump coronary artery bypass surgery.

Aged↗
PubMed2002

The metabolism and excretion of galantamine in rats, dogs, and humans.

Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.

Animals↗
PubMed2001

Distribution and role of Na(+)/K(+) ATPase in endocardial endothelium.

OBJECTIVE: In mammalian cardiomyocytes, alpha isoforms of Na(+)/K(+) ATPase have specific localisation and function, but their role in endocardial endothelium is unknown. METHODS: Different alpha isoforms in endocardial endothelium and cardiomyocytes of rabbit were investigated by measuring contractile parameters of papillary muscles, by RT-PCR, by Western blots and by immunocytochemistry. RESULTS: Inhibition of Na(+)/K(+) ATPase by decreasing external K(+) from 5.0 to 0.5 mmol/l caused biphasic inotropic effects. The maximal negative inotropic effect at external K(+) of 2.5 mmol/l was significantly larger in +EE muscles (with intact endocardial endothelium) than in -EE muscles (with endocardial endothelium removed) (-22.5+/-2.4% versus -5.9+/-4.0%, n=7, P<0.05). Further decrease of K(+) to 0.5 mmol/l caused endothelium-independent positive inotropy (27.8+/-11.8% for +EE versus 18.6+/-11.3% for -EE, n=7, P>0.05). Inhibition of Na(+)/K(+) ATPase either by dihydro-ouabain (10(-9) to 10(-4) mol/l, n=4) or by K(+) decrease following inhibition of Na(+)-H(+) exchanger by dimethyl-amiloride (50 micromol/l, n=6) caused endothelium-independent positive inotropic effects only. RT-PCR and Western Blot demonstrated alpha(1) and alpha(2) Na-K-ATPase isoforms in cardiomyocytes, but only alpha(1) in cultured endocardial endothelial cells. Immunohistochemistry showed that alpha(1) in endocardial endothelium was predominantly present at the luminal side of the cell (n=7) and that alpha(1) and alpha(2) displayed different localisation in cardiomyocytes. CONCLUSIONS: These results suggested that negative and positive inotropic effects of Na(+)/K(+) ATPase inhibition in +EE muscles could be attributed to inhibition of endocardial endothelial alpha(1) and muscle alpha(2) isoform, respectively. Accordingly, the endocardial endothelial alpha(1) isoform of Na(+)/K(+) ATPase may contribute to blood-heart barrier properties of this endothelium and may control cardiac performance via endothelial Na(+)/H(+) exchange.

Animals↗
PubMed2000

Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions.

Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility. Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5-hydroxytryptamine-4 receptors and which is largely without central depressant or antidopaminergic side-effects. The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated. The major in vitro metabolite of cisapride was formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the production of norcisapride. By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent. The mean apparent K(m) against cisapride was 8.6+/-3.5 microM (n = 3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 microM; therefore it is unlikely that cisapride would inhibit the metabolism of co-administered drugs. In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism.

Anti-Ulcer Agents↗
PubMed2000

Dose requirements of infusions of cisatracurium or rocuronium during hypothermic cardiopulmonary bypass.

We investigated the influence of mild hypothermic cardiopulmonary bypass (CPB) on the dose requirements of cisatracurium or rocuronium used as a continuous infusion. We studied eight patients given cisatracurium and nine given rocuronium. They were ASA class III and IV and scheduled for elective coronary artery bypass grafting. Neuromuscular transmission was monitored electromyographically. After recovery of T1/T0 to 10%, a cisatracurium infusion or a rocuronium infusion was started at a rate of 1.5 or 10 micrograms kg-1 min-1, respectively, and adjusted to maintain T1/T0 at 15%. Infusion rate and duration were recorded before, during and after CPB in each patient and the mean infusion rates were calculated. One-way ANOVA showed a statistically significant difference between the cisatracurium infusion rates before, during and after CPB: A T1/T0 of 15% could be achieved with a mean infusion rate of 1.1, 0.75 and 0.98 micrograms kg-1 min-1 before, during and after CPB, respectively. There was no significant difference between the rocuronium infusion rates before, during and after CPB. The mean rocuronium infusion rate required to maintain T1/T0 at 15% throughout the procedure was 4.1 micrograms kg-1 min-1. Cisatracurium infusion rates should be halved during CPB. Even after CPB, requirements are reduced. The same tendency occurs with rocuronium, but the changes in infusion rate were not statistically significant.

Aged↗
PubMed2000

Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans.

Cytochrome P450 3A subfamily members (CYP3A) are the most abundant liver cytochrome P450 forms, responsible for the biotransformation of over 50% of all drugs. The expression and activity of isoforms CYP3A4 and CYP3A5 show wide inter-individual variation, influencing both drug response and disease susceptibility. The molecular basis for this variation has never been defined. In this study, we used midazolam to characterize CYP3A5 phenotype in a panel of liver samples. A clear bimodality in metabolism was observed. Analysis of the 5' flanking region of the CYP3A5 gene identified two linked polymorphisms, T-369G and A-45G, located in transcriptional regulatory elements which are associated with increased expression and activity of the gene. A polymerase chain reaction based detection assay is described facilitating future studies into both the metabolic consequences of this variation and disease association studies relating to CYP3A5.

5' Untranslated Regions↗
PubMed1999

Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II.

X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.

Base Sequence↗
PubMed1998

Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family.

Two homologous genes, EXT1 and EXT2, responsible for the development of benign multiple cartilagenous bone tumors (exostoses) on the long bones, have been identified in the past 2 years. Several arguments have been provided to support the hypothesis that these genes have tumor suppressor activity and that loss of function of these genes may contribute to the development of bone tumors. The recent identification of two EXT-like genes, EXTL1 and EXTL2, homologous to the EXT genes and to each other, revealed the existence of a larger family of genes. We now report the identification of a homologous EST (EST01365), not derived from the known EXT and EXTL genes, indicating the existence of one additional member of this gene family. We characterized this third EXT-like gene, EXTL3, and compared it with the other four members of the EXT-EXTL family. In view of its putative tumor suppressor function, the EXTL3 gene can be considered a candidate gene for the breast cancer locus on chromosome 8p12-p22.

Blotting, Northern↗
PubMed1998

Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years.

UNLABELLED: Phosphorylase kinase (PHK) is a regulatory enzyme in glycogen metabolism. Mutations in the gene encoding the alpha subunit of PHK (PHKA2) have been shown to be responsible for X-linked liver glycogenosis (XLG). XLG, a frequent type of glycogen storage disease, is characterised by hepatomegaly and growth retardation. Two subtypes of XLG have been described: XLG type I patients have a clear-cut PHK deficiency in liver and blood cells, whereas XLG type II patients have a normal or residual activity. Here, we present clinical, biochemical and molecular findings on a liver glycogenosis patient in whom the diagnosis XLG II only became clear after enzyme assays in the liver and identification of the disease-causing mutation. A missense mutation replacing arginine at amino acid position 186 by histidine (R186H) was identified in the PHKA2 gene. Mutations of the same arginine residue have been previously found in at least four other unrelated XLG II patients. CONCLUSION: Arginine at position 186 of the alpha subunit seems to play an important role in the structure or the regulation of PHK. In patients with XLG having normal or residual PHK activity where XLG II is suspected, the identification of mutations in PHKA2 leads to the final classification.

Adult↗
PubMed1998

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

Chromosome Mapping↗
PubMed1997

Prognosis of gastric carcinoma with emphasis on lymph node status.

UNLABELLED: A retrospective study of surgical treatment for 123 patients with primary gastric carcinoma was made. Tumour-stage, presence of distant organ metastases, lymph node involvement, depth of wall-penetration and curative resection were the important prognostic criteria. Five-year survival rate was 22.8% in the whole series and 37.5% after curative (R0 M0) resection (p = 0.0029). Seventy-two patients (58.5%), i.e. 47 without (N0) and 25 with lymph node metastases (N1 + N2), underwent, R0-resection. The overall recurrence rate was significantly lower (4% vs. 36%; p = 0.004) and the 5-year survival rate higher (46% vs. 28%; p = 0.007) for the R0-N0-group than for the R0-N1 + N2-group. Distant organ metastases-related mortality was similar in these two groups of patients (51% vs. 60%; p = 0.7). CONCLUSION: The poor prognosis of gastric carcinoma indicates the need for improved surgical technique and/or adjuvant therapy, but the necessity for adjuvant therapy without having performed D2 gastrectomy does not seem founded.

Aged↗
PubMed1996

Location of the hydroxyl functions in hydroxylated metabolites of nebivolol in different animal species and human subjects as determined by on-line high-performance liquid chromatography-diode-array detection.

Nebivolol hydrochloride (R067555), is a new antihypertensive drug. Aromatic and alicyclic hydroxylation at the benzopyran ring systems of nebivolol are important metabolic pathways. Generally, NMR is used to unambiguously assign the sites of hydroxylation. Because of the low dose rates and the extensive metabolism of nebivolol in the different species, NMR identification is not always possible, and therefore another spectroscopic technique was searched for to address this problem. UV-chromophore absorption is affected by the kind and arrangement of adjacent atoms and groups (auxochromes). The effect of these auxochromes (e.g. -NH2, -NR2, -SH, -OH, -OR and halogens) can be strongly influenced by the pH. This paper proves that HPLC at high pH combined with on-line diode-array detection is an excellent technique for the location of the hydroxyl functions in hydroxylated metabolites of nebivolol. With this technique it is possible to differentiate between glucuronidation at the automatic and aliphatic or alicyclic hydroxyl functions.

Adrenergic beta-Antagonists↗