Summary
Heterozygous familial hypercholesterolaemia (HtFH) is associated with an increased risk of coronary artery disease. Prevention is possible by increasing the number of functioning receptors of low density lipoproteins (LDLs) in the liver. This is partly achieved by treatment with bile acid sequestrants, such as cholestyramine, but the effect is limited because of a concomitant increase in cholesterol synthesis.
It was the purpose of this study to determine whether the increase in cholesterol synthesis could be influenced by treatment with cyclandelate, since it is known that cyclandelate inhibits cholesterol synthesis in rats.
Ten patients received cyclandelate (3.2g daily in 2 doses) or placebo in a double- blind crossover study, with each treatment period of 3 months’ duration. During these periods, treatment with cholestyramine (16g daily) was continued. No evidence was found of inhibition of cholesterol synthesis by cyclandelate, as indicated by the serum concentration of the cholesterol precursor, lanosterol, which remained unchanged. Neither the serum concentration of LDL, nor those of high density lipoprotein (HDL) cholesterol, apolipoprotein B, A- I or A- II, were affected. Thus, it can be concluded that treatment with cyclandelate was not effective in lowering serum cholesterol concentrations in patients with familial hypercholesterolaemia who received concomitant cholestyramine therapy.
Résumé
L’hypercholestérolémie familiale hétérozygote est responsable d’un risque accru de coronaropathie, pouvant être évité par l’augmentation du nombre des récepteurs hépatiques des lipoprotéines de faible densité (LDL). Cette prévention peut être en partie obtenue à l’aide d’un traitement par des fixateurs des acides biliaires, comme la cholestyramine, mais cet effet est néanmoins limité en raison de l’augmentation concomitante de la synthèse du cholestérol.
Le cyclandélate inhibant la synthèse du cholestérol chez le rat, le but de la présente étude était de déterminer si ce produit possède une quelconque influence sur l’augmentation de cette synthèse chez l’homme.
Au cours d’une étude croisée en double-insu, chaque patient a reçu quotidiennement 3,2 g de cyclandélate en 2 prises ou un placebo, chaque période de traitement durant 3 mois. L’administration de 16 g quotidiens de cholestyramine s’est poursuivie pendant toute la durée de l’étude. Les concentrations sériques du lanostérol, précurseur du cholestérol, étant restées inchangées, cette étude n’a pas pu mettre en évidence une quelconque inhibition de la synthèse du cholestérol par la cyclandélate. Les taux sériques de LDL n’ont pas été modifiés par le traitement; il en est allé de même pour les taux sériques du cholestérol des lipoprotéines de haute densité (HDL) et des apolipoprotéines B, AI et AH. Il faut donc conclure que le cyclandélate n’a pas abaissé de façon efficace la cholestérolémie chez des patients atteints d’hypercholestérolémie familiale et recevant un traitement concomitant par la cholestyr- amine.
Riassunto
La ipercolesterolemia (HtFH) familiäre eterozigotica è associata ad un aumentato rischio di malattia coronarica. Incrementando il numéro dei recettori funzionali délie lipoprotéine di bassa densità (LDL) nel fegato è possibile la prevenzione. Questa si ottiene in parte mediante trattamento con sequestranti dell’acido biliare quali colestiramina, ma l’effetto è limitato perché si ha un concomitante aumento délia sintesi del colesterolo.
Lo scopo di questo studio era di determinare se Vawnento nella sintesi del colesterolo potesse essere influenzato dal trattamento con ciclandelato dato che è noto che il ciclandelato inibisce la sintesi del colesterolo nel ratto.
Dieci pazienti ricevettero ciclandelato o placebo alla dose di 3,2 g al giorno, suddivisa in due volte, in uno studio di crossover in doppio cieco; ogni trattamento durò tre mesi. Durante questi periodi il trattamento con colestiramina venne continuato alla dose quotidiana di 16 g. Non si evidenziò inibizione alla sintesi del colesterolo da parte del ciclandelato come indicato dalla concentrazione del precursore del colesterolo (il lanosterolo), che rimase inalterata. Nonfurono influenzate nemmeno la concentrazione nel siero di LDL, né quella delle lipoproteine di alta densità (HDL), colesterolo, apolipoproteina B, A-I o A-II Pertanto si può concludere che il trattamento con ciclandelato non è stato efficace nel ridurre la concen- trazione del colesterolo nel siero di pazienti con ipercolesterolemia familiäre che ricevevano una terapia concomitante di colestiramina.
Samenvatting
Heterozygote familiale hypercholesterolemie (HtFH) geeft een verhoogd risico op coronair vaatlijden. Preventie is mogelijk door het aantal functionerende LDL-receptoren in de lever te verhogen. Dat wordt gedeeltelijk bereikt door behandeling met galzuur bindende Stoffen zoals cholestyramine, maar het effect is beperkt ten gevolge van een gelijktijdige stijging van de cholesterolsynthese.
Het doel van deze studie was na te gaan of de stijging van de cholesterolsynthese kon worden beïnvloed door behandeling met cyclandelaat, aangezien men weet dat cyclandelaat de cholesterolsynthese bij ratten remt.
Tien patiënten kregen tijdens een dubbelblinde, gekruiste studie 3,2 g cyclandelaat in 2 dosissen of placebo per dag. Elke behandelingsperiode duurde 3 maanden. Tijdens die pe- rioden werd de behandeling met 16 g cholestyramine per dag voortgezet. Er kon geen rem- ming van de cholesterolsynthese door cyclandelaat worden vastgesteld, zoals bleek uit de serumconcentratie van de cholesterolprecursor lanosterol, die onveranderd bleef Noch de serumconcentratie van LDL, noch die van HDL of de apolipoproteïnen B, A-I of A-Il werd beïnvloed. De conclusie was daarom dat behandeling met cyclandelaat de serumcholesterol concentraties niet verlaagt bij patiënten die tegelijkertijd met cholestyramine behandeld worden.
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Gevers Leuven, J.A., v. d. Voort, H., Kempen, H.J. et al. The Effect of Cyclandelate on Cholesterol Metabolism in Patients with Familial Hypercholesterolaemia. Drugs 33 (Suppl 2), 131–135 (1987). https://doi.org/10.2165/00003495-198700332-00024
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DOI: https://doi.org/10.2165/00003495-198700332-00024