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Biomedical subjects

R A Maes

Publications and source records attributed to R A Maes.

At least 37 records · Page 2Linked to original sources
PubMed1999

Intravesical drug delivery. Pharmacokinetic and clinical considerations.

Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are mitomycin (mitomycin C), thiotepa, ethoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new mitomycin derivative KW-2149. Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable. Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravesical treatment regimens.

Absorption↗
PubMed1998

Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder.

Children with attention-deficit hyperactivity disorder who are categorized as responders or non-responders to methylphenidate (MPH) on the basis of their electrophysiological P3 response in a selective attention task differ in metabolic patterns of the D- and L-threo MPH enantiomers. Non-responders showed significantly higher plasma concentrations of both D- and L-threo MPH enantiomers.

Analysis of Variance↗
PubMed1998

Discriminative stimulus properties of mCPP: evidence for a 5-HT2C receptor mode of action.

Previous drug discrimination studies with the serotonergic drug m-chlorophenylpiperazine (mCPP) showed conflicting results, with some authors concluding that the cue was mediated by 5-HT2C receptors, but others that it was definitively not. We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data. We trained rats to discriminate mCPP (2.0 mg/kg, PO) from water. We found that the mCPP cue generalized to m-trifluoromethyl-phenylpiperazine (TFMPP) and 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212), and partially to eltoprazine, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), fenfluramine and trazodone. A moderate level of generalization was obtained with quipazine, 1-(m-chlorophenyl)biguanide and clonidine. No generalization was found with flesinoxan, methiothepin, idazoxan and haloperidol. Mianserin and methysergide antagonized the mCPP stimulus, whereas ketanserin antagonized it partially. Metergoline, methiothepin and clozapine only marginally antagonized the mCPP stimulus. These results show that the discriminative stimulus effects of mCPP are predominantly mediated by 5-HT2C receptors, and to some extent by 5-HT1B receptors. When considering our results and other research together, the substitution tests clearly point to a 5-HT2C receptor mediated stimulus, with an additional role for 5-HT1B receptors. Antagonism studies are less clearcut, but are also suggestive of a 5-HT2C receptor mediated effect. A definitive answer as to whether other receptors, e.g. 5-HT2B and 5-HT7, are of any importance in mCPP's discriminative stimulus properties has to wait for more selective ligands.

Animals↗
PubMed1998

Stimulus properties of fluvoxamine in a conditioned taste aversion procedure.

A conditioned taste aversion (CTA) procedure in mice was used to investigate the stimulus effects of the serotonin reuptake inhibitors (SSRIs) fluvoxamine and fluoxetine. Fluvoxamine elicited a reliable CTA (ED50 = 24 mg/kg, SC) and a number of drugs were tested as pre-exposure drugs. Pre-exposure to the serotonin (5-HT)1A receptor agonists flesinoxan and +/- -8-hydroxy-dipropylaminotetralin (8-OH-DPAT) prevented the CTA induced by fluvoxamine (50 mg/kg, SC). Pre-exposure with the 5-HT2C receptor agonist MK 212 [6-chloro-2(1-piperazinyl)pyrazine] partially prevented the fluvoxamine-induced CTA, pre-exposure with the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] did not prevent the CTA induced by fluvoxamine. Flesinoxan pre-exposure also prevented the taste aversion induced by fluoxetine (10 mg/kg, SC) completely. This contrasts previous results obtained with fluoxetine, where was found that its stimulus is primarily mediated by 5-HT2C, and to a lesser degree by 5-HT1A receptors. Therefore, we compared the two SSRIs directly. Pre-exposure to fluvoxamine prevented the fluoxetine-induced CTA, whereas pre-exposure to fluoxetine only partially prevented the fluvoxamine-induced CTA. We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and, based primarily on the cross-comparison tests, that the two SSRIs have somewhat different stimulus properties.

Animals↗
PubMed1998

Angiogenesis: possibilities for therapeutic interventions.

Vascular proliferation normally occurs only during embryonic development, the female reproductive cycle and wound healing. Various pathological conditions such as diabetic retinopathy are characterized by persistent, uncontrolled angiogenesis. At the other hand, impaired development of new blood vessels has been found to be related with myocardial infarction. A series of anti-angiogenic drugs are currently included in experimental cancer treatment, whereas the failure of ulcers to heal may be limited by increased angiogenesis upon administration of growth factors. In the present review control mechanisms of the vasculature are summarized and therapeutic approaches discussed.

Angiogenesis Inducing Agents↗
PubMed1998

Survival after massive ecstasy overdose.

INTRODUCTION: The toxicity profile of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is well known. This designer drug is usually taken at "house parties" and may cause severe complications, sometimes leading to death, even when taken in relatively small units (1 or 2 tablets). Up to now, only a few cases of survival after ingestion of an overdose of Ecstasy have been described. In most cases the users developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, and renal failure. CASE REPORT: We describe a man who, after ingesting 50 tablets of Ecstasy (in combination with oxazepam and alcohol) at home, recovered within 2 days. Presenting features were unconsciousness, apnea, and convulsions. It is suggested that in most cases severe 3,4-methylenedioxymethamphetamine toxicity results from an interaction between direct pharmacological effects of the drug and the prevailing environmental conditions (high ambient temperature, dancing in trance, little fluid intake).

Adult↗
PubMed1997

Effects of 5-HT1A receptor ligands in a modified Geller-Seifter conflict model in the rat.

In a modified Geller-Seifter conflict procedure, rats were trained to lever-press for food under a multiple variable interval-fixed ratio (VI30: food; FR10: food + shock) schedule of reinforcement. The ability to antagonize response suppression in the punished period is considered a good predictor for anxiolytic activity. Chlordiazepoxide and alprazolam increased punished responding. The 5-HT1A receptor agonists flesinoxan (R(+)-N-[2[4-(2,3-dihydro-2-2-hydroxymethyl-1,4-benzodioxin-5-yl)- 1-piperazinyl]ethyl]-4-fluorobenzoamide; 0.1-10.0 mg/kg) and 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino)tetralin; 0.03-0.5 mg/kg) significantly increased punished responding, supporting a role of the 5-HT1A receptor in anxiety. 8-OH-DPAT and flesinoxan also reduced unpunished responding. The anxiolytic effects of 8-OH-DPAT and flesinoxan could only be antagonized with a high dose (1.0 and 3.0 mg/kg respectively) of the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). All doses of WAY-100635 antagonized the 5-HT1A-induced effects on unpunished responding. The dissimilarity in dose-response curve of WAY-100635 on punished and unpunished behaviour poses questions about the mediation of these effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Pretreatment with 5-HT1A receptor agonist flesinoxan attenuates Fos protein in rat hypothalamus.

The 5-HT1A receptor agonist flesinoxan has anxiolytic activity and concurrently enhances plasma corticosterone levels in rats. After a second injection of flesinoxan 24 h later, the corticosterone response disappears, but not the anxiolytic effects. Male rats received two injections with either flesinoxan or vehicle within 24 h. Flesinoxan challenge enhanced Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, the central amygdala, and the dorsolateral part of the bed nucleus of the stria terminalis and plasma corticosterone levels in the vehicle-pretreated rats. Flesinoxan pretreatment resulted in an attenuated response of plasma corticosterone levels and Fos-positive neurons in the paraventricular nucleus of the hypothalamus, but not in the central amygdala and the bed nucleus after a flesinoxan challenge. The differential desensitization levels for both behaviour and neuroendocrine responses after flesinoxan treatment seem to correspond to different organization levels in the brain, like limbic system and hypothalamus.

Animals↗
PubMed1997

Detection of alprazolam in hair by negative ion chemical ionization mass spectrometry.

A sensitive and specific method for the quantitative determination of alprazolam (AL) in hair has been developed. After the addition of deuterium labeled triazolam as an internal standard, hair samples (20 mg) were digested with 1 N NaOH at 40 degrees C overnight. Calibrators containing known concentrations of AL dried onto drug-free hair were also prepared and digested. After digestion, the solution was cooled, adjusted to pH 9 with 6 N HCl and 1 ml of saturated sodium borate buffer was added. The digested solutions were extracted with toluene:methylene chloride (7:3) and the organic phase was evaporated to dryness. Extract residues were treated with BSTFA and 1% TMCS and analyzed on a Finnigan-MAT mass spectrometer in the negative-ion chemical ionization mode with methane as the reagent gas. Chromatographic separation was achieved on a Restek-200 capillary column using hydrogen as the carrier gas. The assay was capable of detecting 25 pg/mg of AL and was linear to 250 pg/mg. Intra-assay precision was 11.1% at 25 pg/mg and 5.4% at 150 pg/mg. Inter-assay precision was 11.2% at 25 pg/mg and 5.3% at 150 pg/mg. This method has been used to study the hair incorporation of AL into Long-Evans rats who received 5.0 mg/kg or 7.5 mg/kg i.p. twice a day for 5 days. Preliminary results indicate that the AL concentration in the pigmented and non-pigmented hair on day 14 ranged from 60 to 100 pg/mg.

Alprazolam↗
PubMed1997

Gas chromatographic/mass spectrometric assay for profiling the enantiomers of 3,4-methylenedioxymethamphetamine and its chiral metabolites using positive chemical ionization ion trap mass spectrometry.

A qualitative GC/MS profile was obtained and its mass spectrometric features characterized for the analysis of the enantiomers of (RS)-3,4-methylenedioxymethamphetamine (MDMA) and its metabolites (RS)-3,4-methylenedioxyamphetamine (MDA), (RS)-4-hydroxy-3-methoxymethamphetamine (HMMA) and (RS)-4-hydroxy-3-methoxyamphetamine (HMA). A chiral derivatization method was selected to obtain the diastereomers required for the separation of the respective enantiomers with a non-chiral GC stationary phase. The selected derivatization consisted of a reaction with N-heptafluorobutyryl-(S)-prolyl chloride combined with a consecutive reaction with N-methyl-N-trimethylsilyltrifluoroacetamide, resulting in N-[heptafluorobutyryl-(S)-prolyl]-O-trimethylsilyl derivatives. Detection was carried out with electron ionization and positive chemical ionization (PCI) ion trap mass spectrometry. Mass spectra of the derivatives of reference standards of the compounds of interest obtained with PCI demonstrated that this method simultaneously induces proton and charge-transfer reactions in the ion trap. The advantage is that high mass information is provided while some fragmentation remains to elucidate structural details. Subsequently, in three urine samples obtained from different and unrelated MDMA intoxications, the enantiomers of MDMA and MDA were identified. In some urine samples also HMMA and/or HMA were found. In addition to these compounds, an unexpected compound and/or additional chiral metabolite, N-hydroxy-(RS)-3,4-methylenedioxyamphetamine, was identified in two out of three urine samples. Preliminary results also indicated an enantioselective metabolism in the N-demethylation pathway for MDMA in humans.

Biotransformation↗
PubMed1997

Renal excretion of iodine-131 labelled meta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours.

Iodine-131 labelled meta-iodobenzylguanidine ([131I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [131I]MIBG (3.1-7.5 GBq) to 17 patients (n=32 courses), aged 2-73 years, 56%+/-10%, 73%+/-11%, 80%+/-10% and 83%+/-10% of the dose was cumulatively excreted as total radioactivity in urine at t=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%-18% of [131I]meta-iodohippuric acid ([131I]MIHA), the cumulatively excreted radioactivity consisted of >85% [131I]MIBG, with 6% of the dose excreted as free [131I]iodide, 4% as [131I]MIHA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [131I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [131I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [131I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.

3-Iodobenzylguanidine↗
PubMed1997

Flesinoxan pretreatment differentially affects corticosterone, prolactin and behavioural responses to a flesinoxan challenge.

To determine whether alterations in 5-HT1A receptor mediated responses induced by a single injection with a selective 5-HT1A receptor agonist is a transient effect, or whether the (de)sensitisation is more persistent, rats were pretreated with the selective and full 5-HT1A receptor agonist, flesinoxan (3 mg/kg SC once daily) for either 1 day or 1 week. Twenty-four hour after the last pretreatment injection, rats were challenged with flesinoxan (3 mg/kg SC), and the effects on plasma corticosterone and prolactin levels, lower lip retraction and behaviour in the shock-probe burying test were determined. Several 5-HT1A receptor mediated responses were modified differentially following the flesinoxan pretreatment. However, all changes induced by a single flesinoxan injection remained present upon repeated flesinoxan administration. The differential changes in the responses to flesinoxan cannot easily be explained by differences in pre- or postsynaptically 5-HT1A mediated responses. The prolactin response to flesinoxan, which is thought to be mediated postsynaptically, was enhanced, whereas the corticosterone response to flesinoxan, which is also mediated postsynaptically, was attenuated. The presynaptically mediated lower lip retraction response was attenuated as well, whereas the behavioural effects of flesinoxan remained relatively unaffected following repeated flesinoxan administration. Upon prolonged flesinoxan pretreatment, the changes induced by a single flesinoxan injection remained present or increased further. Although repeated flesinoxan administration (1 day and 1 week) resulted in 20% lower plasma flesinoxan concentrations, this effect could not explain the neuroendocrine and behavioural findings.

Animals↗
PubMed1997

Discriminative stimulus properties of eltoprazine.

Rats were trained to discriminate eltoprazine (1-(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazine) (1.0 mg/kg p.o.) from demineralized water in a two lever operant procedure. Eltoprazine generalized to the 5-HT1B receptor agonist anpirtoline (6-chloro-2-[piperidyl-4-thiol]-pyridine hydrochloride), the 5-HT(1A,1B) receptor agonists batoprazine (8-(1-piperazinyl)-2H-1-benzopyran-2-one) and 1-NP (1-(1-naphthyl)piperazine hydrochloride), and to the 5-HT(1B/2C) receptor agonist mCPP (1-(3-chlorophenyl)piperazine dihydrochloride). The 5-HT1A receptor agonist flesinoxan (R(+)-N-[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4-benzodioxin-5-yl) -1-piperazinyl]ethyl]-4-fluorobenzoamide) generalized partially and the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) failed to antagonize the eltoprazine cue, suggesting that 5-HT1A receptors are of limited importance in the discriminative stimulus properties of eltoprazine. Methiothepin, mCPP, mianserin and alprazolam did not antagonize the eltoprazine cue. The 5-HT(1A,1B,1D) receptor agonist GR46611X (3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxy-benzyl)acrylam ide) and the 5-HT(1B,1D) receptor antagonist GR127935T (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide) did neither generalize to nor antagonize the eltoprazine cue, whereas (-)-alprenolol showed partial antagonism and substitution. These results show that the eltoprazine discriminative stimulus is mediated by the 5-HT1B receptor, although the lack of good 5-HT1B receptor antagonists weakens this conclusion.

Animals↗
PubMed1997

Activated oxazaphosphorines are transported predominantly by erythrocytes.

PURPOSE: Oxazaphosphorines are metabolised by a variety of pathways, one of which leads to activation and the formation of alkylating compounds. However, the transport forms conveying activated oxazaphosphorines to the tumour cell have not been fully characterised. There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma. We have now determined the concentrations of ifosfamide and seven of its metabolites in the plasma and erythrocytes of patients receiving a six-hour intravenous infusion of ifosfamide. PATIENTS AND METHODS: Red cells from five patients, receiving a total of eight cycles of ifosfamide, were separated from plasma using the MESED instrument, and analysis of red cells and plasma performed using Gas Chromatography-Mass Spectrometry (GC/MS). RESULTS: The concentration of all compounds in the erythrocyte compartment was higher than or equal to those in plasma, and isophosphoramide mustard and carboxyifosfamide showed a particular affinity for the erythrocyte. The red cell fraction can contain as much as 77% of the total blood concentration of isophosphoramide mustard. CONCLUSIONS: Erythrocyte associated isophosphoramide mustard is an important transport form of activated ifosfamide. Red cells may have a role in the delivery of activated oxazaphosphorines to tissues.

Antineoplastic Agents, Alkylating↗
PubMed1996

Correlation of the response to cisplatin of human ovarian cancer cell lines, originating from one tumor but with different sensitivity, with the recovery of DNA adducts.

Cis-Diamminedichloroplatinum(II) (CDDP) is used in the treatment of various cancers, with or without ionizing radiation. During treatment, resistance may develop, and cross-resistance can also occur. DNA is the main target for CDDP and ionizing radiation, and we therefore evaluated the correlation between the amount of CDDP-DNA adducts and the cytotoxic activity of CDDP in human ovarian cancer cell lines with different platinum sensitivities. DNA-adduct levels were investigated 18 hr after CDDP exposure in three cell lines originating from the same human ovarian cancer. The least sensitive cells appeared to have the largest amounts of CDDP-DNA adducts, while the most sensitive had higher adduct levels than the parental cells. The proportion of the four adducts measured (i.e., Pt-G, Pt-AG, Pt-GG, and G-Pt-G) was comparable in all cell lines, with a preference for Pt-GG adduct formation (> 50% of the adducts). Intracellular CDDP concentrations were higher in sensitive than in resistant cells, in contrast to the degree of CDDP adduct formation. Data obtained following continuous exposure of CDDP-resistant cells to CDDP suggest that DNA repair is partly responsible for resistance to CDDP. We conclude that the amount of CDDP-DNA adduct formation in cancer cells is not a predictor of CDDP cytotoxicity.

Antineoplastic Agents↗
PubMed1996

Determination of alprazolam and alpha-hydroxyalprazolam in human plasma by gas chromatography/negative-ion chemical ionization mass spectrometry.

A sensitive and specific method was developed for the determination of alprazolam and its major metabolite alpha-hydroxyalprazolam in plasma. After the addition of deuterium-labeled internal standards, plasma samples were buffered to pH 9 with 1 ml of saturated sodium borate buffer, extracted with toluene-methylene chloride (7:3) and evaporated to dryness. The residues were treated with N,O-bis(trimethylsilyl)trifluoroacetamide containing 1% of trimethylchlorosilane and analyzed on a Finnigan-MAT mass spectrometer operated in the negative-ion chemical ionization mode with methane as the reagent gas. Chromatographic separation was achieved on a Restek-200 capillary column using hydrogen as the carrier gas. The assay was linear from 0.25 to 50 ng ml-1 for both compounds. The intra-assay precision for alprazolam was 16.1% at 0.5 ng ml-1 and 4.6% at 50 ng ml-1 and that for alpha-hydroxyalprazolam was 15.8% at 0.5 ng ml-1 and 4.2% at 50 ng ml-1. The method was used to determine alprazolam and alpha-hydroxyalprazolam in human plasma samples collected after a single 2 mg oral does of alprazolam. A peak concentration of 32.9 ng ml-1 of alprazolam was detected at 1 h following the dose.

Adult↗
PubMed1996

Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. An individual dosing strategy has been recommended to yield the most optimal exposure, expressed as the area under the concentration-time curve (AUC). The formula developed by Calvert et al. (dose = target-AUC x [GFR + 25]) can be used to achieve this. However, due to the inconvenient [51Cr]-ethylenediamine-tetraacetic acid ([51Cr]-EDTA)-based measurement of the glomerular filtration rate (GFR), its application in the clinic has thus far been limited. Chatelut and co-workers have recently proposed a formula to estimate carboplatin clearance using the serum creatinine concentration. We retrospectively tested the Chatelut equation and the Calvert formula using either the creatinine clearance based on 24-h urine collection or the creatinine clearance based on the formula of Cockcroft and Gault. The latter equations were shown to predict the carboplatin clearance reasonably well, although systematic overprediction and underprediction occurred. However, the formula proposed by Chatelut and co-workers had no significant bias and was precise. It is proposed that this formula be used to calculate the optimal carboplatin dosage after prospective validation has been performed.

Adult↗