Nicergoline

Structural formula
General
Non-proprietary name	Nicergoline
other names	[(8 β ) -10-methoxy-1,6-dimethylergolin-8-yl] methyl-5-bromopyridine-3-carboxylate
Molecular formula	C 24 H 26 BrN 3 O 3
External identifiers / databases
EC number	248-694-6
ECHA InfoCard	100.044.252
PubChem	34040
DrugBank	DB00699
Wikidata	Q2623398
Drug information
ATC code	C04 AE02
properties
Molar mass	484.4 g · mol
Melting point	138-139 ° C
pK s value	7.78
solubility	very heavy in water (0.013 mg / ml); soluble in acetone , chloroform , ethanol and dilute acetic acid
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 302
	P: no P-phrases
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Nicergoline is a medicinal substance that is used in the treatment of chronic organic brain-related performance disorders. Nicergoline is a partially synthetically produced derivative of lysergic acid .

history

Nicergoline was developed in the 1960s in search of adrenoceptor- blocking substances derived from the ergot alkaloids . It was patented by FarmItalia in 1966 . The aim - following the understanding of the etiology of dementia at the time - was to use it as a blood circulation-enhancing substance for the treatment of brain disorders in old age. Nicergoline has been on the market as a therapeutic agent since the 1970s. Today it is used for various forms of memory, performance and behavior disorders in old age.

chemistry

presentation

The synthesis of nicergoline starts from the methyl ester of lysergic acid and takes place over several steps. In the first reaction step, this tetracyclic methanol is photochemically added to the double bond in ring D. This creates the so-called lumi-ergoline 10-methoxydihydrolysergic acid methyl ester. The Esterfunktion this addition product is reacted with lithium aluminum hydride to the alcohol is reduced , so that 10-Methoxydihydrolysergol is obtained. This alcohol is esterified with 5-bromo-nicotinoyl chloride . Finally, which is indole - nitrogen with potassium deprotonated with methyl iodide methylated . An analogous synthesis can also start from lysergol .

Stereochemistry

Nicergoline has three centers of chirality . There are theoretically 8 stereoisomers of Nicergoline. Since the synthesis takes place starting from (5 R , 8 R ) -lysergic acid methyl ether and the methoxylation in position 10 is diastereoselective anyway, only the (5 R , 8 R , 10 S ) -diastereomer of nicergoline is used.

Clinical information

Application areas (indications)

Nicergoline is approved for the supportive treatment of chronic brain disorders in old age, especially in patients with dementia syndromes in primarily degenerative, vascular dementia and mixed forms. Before starting treatment, an underlying disease that needs to be specifically treated should be excluded. A meta-analysis of existing clinical studies provided "some evidence" of an improvement in clinical symptoms and the overall clinical picture in predominantly older patients with mild to moderate cognitive and behavioral disorders of various causes, including cerebrovascular disorders and Alzheimer's disease .

Contraindications (contraindications)

Nicergoline is contraindicated in the case of known hypersensitivity to this active ingredient or to another ergot alkaloid derivative . Further restrictions of use include a recent myocardial infarction , severe bradycardia , tendency to collapse, orthostatic hypotension and acute bleeding. Due to pharmacodynamic interactions, nicergoline must not be used at the same time as α or β sympathomimetics .

Drug interactions

Thanks to its effect on the adrenergic system, nicergoline shows pharmacodynamic interactions with many other drugs. Nicergoline, for example, has an increased blood pressure lowering effect when used at the same time as antihypertensive drugs . The effects of beta blockers on the heart can also be increased by nicergoline. The effect of α- or β-sympathomimetics, however, is weakened by nicergoline.

Nicergoline inhibits platelet aggregation . Pharmacological interactions with other platelet aggregation inhibitors are therefore possible.

Adverse effects (side effects)

For nicergoline, there are only few data on the occurrence and frequency of adverse drug reactions. Insomnia, tiredness, head pressure, reddening of the skin and a feeling of heat are reported as common (1 to 10%). The frequency of drops in blood pressure, dizziness and stomach upset cannot be estimated.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Like many ergolines, nicergoline mediates its effects through various pharmacological mechanisms. Nicergoline is primarily an α ₁ -adrenoceptor antagonist and as such mediates an expansion through the sympathetic tone of constricted blood vessels and thus an increase in arterial blood flow. It also has anticoagulant properties. In addition, nicergoline also influences the function of other neurotransmitters. The metabolic function of Nicergoline, combined with an improved use of oxygen and glucose , also has a positive effect . In addition, nicergoline is said to have neurotrophic and antioxidant properties.

Absorption and distribution in the body (pharmacokinetics)

After oral administration, nicergoline is quickly and almost completely absorbed from the intestine. Like other substances derived from ergot alkaloids, nicergoline is subject to a pronounced first-pass effect . Nicergoline is predominantly bound to the acid alpha-1 glycoprotein in the blood plasma . Nicergoline is almost completely metabolized in the body with ester hydrolysis or N -demethylation to form the phase I metabolites, some of which are still biologically active. The dominant phase II metabolites are the conjugates with glucuronic acid . Most of it is excreted in the urine . The biological half-life is 2.5 hours. The half-life of the active metabolites can vary from person to person.

Trade names

Nicergoline is marketed under various trade names in over 50 countries.

Monopreparations : Sermion (D, A, CH); Ergobel (D), Ergotop (A), Nicergin (A), Nicerium (D) and other generics (D)

Individual evidence

↑ ^a ^b ^c ^d ^e ^f Entry on nicergoline. In: Römpp Online . Georg Thieme Verlag, accessed on July 17, 2019.
↑ ^a ^b Datasheet Nicergoline, analytical standard, for drug analysis at Sigma-Aldrich , accessed on November 7, 2016 ( PDF ).
↑ ^a ^b H. Herrschaft: Neuro-Psychopharmaka. A therapy manual . Ed .: P. Riederer, G. Laux, W. Pöldinger. 2nd Edition. Vol. 5. Springer, Vienna 1999, Nicergolin, p. 671-683 .
↑ ^a ^b ^c ^d ^e ^f Specialist information ergobel 30. Kwizda Pharma GmbH. As of December 2010.
↑ ^a ^b M. Fioravanti, L. Flicker: Efficacy of nicergoline in dementia and other age associated forms of cognitive impairment . In: The Cochrane database of systematic reviews . No. 4 , 2001, p. CD003159 , doi : 10.1002 / 14651858.CD003159 , PMID 11687175 .
↑ Bengt Winblad et al. a .: Therapeutic use of nicergoline . In: Clinical Drug Investigation . tape 28 , no. 9 , 2008, p. 533-552 , PMID 18666801 .

[römpp-1] ↑ ^a ^b ^c ^d ^e ^f Entry on nicergoline. In: Römpp Online . Georg Thieme Verlag, accessed on July 17, 2019.

[Sigma-2] Datasheet Nicergoline, analytical standard, for drug analysis at Sigma-Aldrich , accessed on November 7, 2016 ( PDF ).

[Herrschaft_(1999)-3] H. Herrschaft: Neuro-Psychopharmaka. A therapy manual . Ed .: P. Riederer, G. Laux, W. Pöldinger. 2nd Edition. Vol. 5. Springer, Vienna 1999, Nicergolin, p. 671-683 .

[Fachinformation_ergobel_30-4] ↑ ^a ^b ^c ^d ^e ^f Specialist information ergobel 30. Kwizda Pharma GmbH. As of December 2010.

[Fioravanti_&_Flicker_(2001)-5] M. Fioravanti, L. Flicker: Efficacy of nicergoline in dementia and other age associated forms of cognitive impairment . In: The Cochrane database of systematic reviews . No. 4 , 2001, p. CD003159 , doi : 10.1002 / 14651858.CD003159 , PMID 11687175 .

[Winblad_et_al._(2008)-6] Bengt Winblad et al. a .: Therapeutic use of nicergoline . In: Clinical Drug Investigation . tape 28 , no. 9 , 2008, p. 533-552 , PMID 18666801 .