M. Strolin Benedetti
Battelle Memorial Institute
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European Journal of Clinical Pharmacology | 2005
M. Strolin Benedetti; Rhys Whomsley; Eugene Baltes; F. Tonner
RationaleThe aim of this review article is to analyse which antiepileptic drugs (AEDs) alter thyroid hormone homeostasis in humans and when this can be explained, at least partially, by the induction of the glucuronoconjugation pathways.MethodsElectronic databases were searched which have provided more than 300 articles. These have been integrated with fundamental books and personal information by experts in the different areas examined.ResultsAlteration of thyroid hormone homeostasis by phenobarbital/primidone, phenytoin, and carbamazepine clearly occurs in humans. However, it is not associated with thyroid-stimulating hormone (TSH) increase and the clinical significance of altered serum concentrations of thyroid hormones by these antiepileptic drugs has remained unclear. The published information on the effect of the other antiepileptic drugs examined in this review article on thyroid hormones is lacking (felbamate, pregabalin, zonisamide) or limited. Oxcarbazepine appears to have some effects. Topiramate would need further investigations as well as gabapentin. Levetiracetam, tiagabine, vigabatrine, and lamotrigine do not alter at all, or only minimally, thyroid hormone homeostasis.ConclusionConcerning the antiepileptic drugs which alter thyroid hormone homeostasis, it is highly probable that the mechanism of induction of uridine diphosphate glucuronosyltransferases (UGT) is involved, at least partially, in such an alteration. However, it is not possible to estimate the relative contribution of the UGT induction by these drugs on the total alteration observed in thyroid hormone levels, as other mechanisms not investigated, or not examined in the present article, could contribute.
Journal of Pharmacy and Pharmacology | 1994
M. Strolin Benedetti; P. Marrari; M. Colombo; M. G. Castelli; Michael Arand; Franz Oesch; P. Dostert
Abstract— The effects of the potent anticonvulsant FCE 26743 ((S)‐2‐(4‐(3‐fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in‐vitro and ex‐vivo using rat tissue homogenates. In‐vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO‐B, with IC50 values about 10−7 m for MAO‐B and higher than 10−5 m for MAO‐A. When determined ex‐vivo in brain, the ED50 value for the inhibition of MAO‐B was 1·1 mg kg−1 (p.o.) 1 h post‐dosing, whereas MAO‐A remained virtually unaffected after administration of 60 mg kg−1. Similar effects were seen in liver. Following oral administration of 5 mg kg−1 FCE 26743 to rats, brain MAO‐B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short‐acting MAO‐B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0–8 h urines after administration of a 119 mg kg−1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.
Journal of Pharmacy and Pharmacology | 1975
M. Strolin Benedetti; A. Louis; A. Malnoë; Michel Schneider; R. Lam; L. Kreber; Robert L. Smith
FOWLER, L. J. (1973). FOWLER, L. J. & JOHN, R. A. (1972). Biochem. J., 130, 569-573. KANAZAWA, I. MIYATA, Y. , TOYOKURA, Y . & OTSUKA, M. (1973). KONIG, J. F. R. & KLIPPEL, R. A. (1963). Williams & Wilkins: Baltimore. LOWE, I. P., ROBINS, E. & EYERMAN, G. S. (1958). TARSY, D., PYCOCK, C., MELDRUM, B. & MARSDEN, C. D. (1975). UNDERSTEDT, U. (1971). UNGERSTEDT, U. & ARBUTHNOTT, G. W. (1970). Brain Res., 11, 77-92. J. Neurochem., 21, 437-440.
Gerontology | 1985
H. Cao Danh; M. Strolin Benedetti; P. Dostert
Glutamine synthetase (GS) activity was measured in whole brain, different brain areas, liver and heart of 23- to 26-month-old rats, and then compared to matched animals of 3 months. A significant increase of GS activity was found in whole brain (25%) of old rats, as well as in all brain areas studied, but particularly in midbrain (36%), hypothalamus (32%), brainstem (32%), striatum (27%) and cerebellum (22%). A significant decrease of GS activity (21%) was found in liver and no significant difference in heart of old rats when compared to matched animals of 3 months. The present results suggest that an increase of GS activity in brain of old rats may be an adaptive phenomenon, and the regulatory mechanisms for GS with increasing age are different, depending on the tissues.
Journal of Pharmacy and Pharmacology | 1983
P. Dostert; M. Strolin Benedetti; C. Guffroy
MD 780236, a selective inhibitor of the B form of MAO behaves as an irreversible inhibitor in in‐vitro conditions and mainly as a short‐acting inhibitor in ex‐vivo experiments. The enantiomer with the R absolute configuration (MD 240928) is fully reversible in ex‐vivo conditions, whereas the S‐enantiomer (MD 240931) has kept the irreversible component of the inhibition seen with MD 780236. The corresponding racemic alcohol derivative (MD 760548) is also a short‐acting inhibitor of the B form of MAO; its S‐enantiomer, which has an absolute configuration corresponding to that of MD 240928, has a selectivity towards the B form superior to that of the other enantiomer. The mechanism of the MAO inhibition by MD 780236 is discussed.
Journal of Pharmacy and Pharmacology | 1979
P. E. Keane; J. P. Kan; N. Sontag; M. Strolin Benedetti
Rats were administered toloxatone 100 mg kg−1 p.o., and killed 0·5 to 8 hours later. Toloxatone reversibly inhibited type A MAO, but did not affect the activity of type B MAO in whole brain. Cerebral concentrations of noradrenaline, dopamine and 5‐hydroxytryptamine were increased after toloxatone, while their metabolite concentrations were reduced. Synaptosomal uptake processes of these amines were not altered by toloxatone.
Journal of Pharmacy and Pharmacology | 1978
J. P. Kan; A. Malone; M. Strolin Benedetti
This paper reports on the monoamine oxidase (MAO, EC 1.4.3.4.) inhibiting properties in virro and in vivo, of a new oxazolidin-2-one derivative with antidepressant activity in animals (Gouret, Mocquet & others, 1977) and potential clinical efficacy in man (Martin, 1973). A comparison has been made with clorgyline, a specific inhibitor of M A 0 A (Johnston, 1968) and (k)-deprenyl, a specific inhibitor of M A 0 B (Knoll & Magyar, 1972) (for a review see Houslay, Tipton & Youdim, 1976).
Journal of Pharmacy and Pharmacology | 1984
P. Dostert; C. Guffroy; M. Strolin Benedetti; Thierry Boucher
The purpose of the present work was to study the semicarbazide‐sensitive amine oxidase (SSAO) inhibitory properties of MD 240931 and MD 240928 (the two enantiomers of MD 780236) as well as those of the corresponding primary amines, MD220662 and MD220661, in rat heart and aorta. MD 240928 and MD 240931 are rather weak SSAO inhibitors, MD 240931 being more potent than MD 240928. Of the four compounds studied, the most potent inhibitor of SSAO is MD 220662, its IC50 value ranging from 2·10−6 to 6·10−6m. The SSAO inhibitory potency of this compound does not change significantly with the time of preincubation in both the absence and presence of clorgyline (10−4m). MD 220661 is also an inhibitor of SSAO; however, its SSAO inhibitory potency, which without preincubation is comparable to that of MD 220662, does decrease with the time of preincubation to the same extent in both the absence and presence of clorgyline (10−4 m). These results suggest that MD 220661 is not only an inhibitor of SSAO, but is also a substrate of the enzyme.
Cellular and Molecular Life Sciences | 1977
K. T. Morgan; M. Strolin Benedetti
The14C-labelled, substituted benzamide neuroleptic Tiapride has been found to accumulate transiently in the pituitary gland of the rat following a single dose, and a prolonged retention of the drug was observed in the pars intermedia.
European Journal of Clinical Pharmacology | 1992
Antonio E. Pontiroli; B. Fattor; G. Pozza; E. Pianezzola; M. Strolin Benedetti; L. Musatti
SummaryFacial skin flush is the most frequent adverse effect induced by acipimox (ACX), a nicotinic acid analogue used in the management of hyperlipidaemia. The aims of the study were to evaluate the frequency, magnitude and reproducibility of the ACX flush in previously unexposed healthy subjects and to assess any possible relationship with the dose and plasma level of ACX.Seventy four healthy subjects received, on two different mornings, ACX 250 mg and placebo (P), according to a single blind, randomized, cross-over design; 33 had a clear flush after ACX and not after P.25 of those subjects were retested on five different mornings, with P, and with ACX 31.2, 62.5, 125.0, 250.0 mg, according to a double blind, randomized, cross-over design. Any increase in the local skin temperature was recorded by a thermocouple fixed to the left check.Subjective and objective assessment of the flush were strongly correlated with thermographic recordings. They indicated that a 120 min flush occurred after doses of ACX > 62.5 mg. In 12 of the 25 subjects, 6 with the highest and 6 with the lowest thermographic recordings, plasma ACX levels were determined. Subjects with different thermographic records had superimposable plasma ACX levels after all doses of ACX. Only the 6 subjects with the highest skin temperatures showed a significant relationship between the thermographic record and the plasma ACX.The data indicate that flush is a frequent, reproducible and dose-related adverse effect of ACX.