Cilostazol

Structural formula
General
Non-proprietary name	Cilostazol
other names	6- [4- (1-cyclohexyl-1 H -tetrazol-5-yl) butoxy] -3,4-dihydroquinoline-2-one ( IUPAC )
Molecular formula	C 20 H 27 N 5 O 2
Brief description	colorless crystals
External identifiers / databases
EC number	689-122-9
ECHA InfoCard	100.215.897
PubChem	2754
ChemSpider	2652
DrugBank	DB01166
Wikidata	Q258591
Drug information
ATC code	B01 AC
Drug class	Phosphodiesterase inhibitors
properties
Molar mass	369.46 g · mol -1
density	1.26 g cm −3
Melting point	158–159 ° C ( polymorph A) ; 136 ° C (polymorph B) ; 146 ° C (polymorph C) ;
solubility	9 mg l −1 in water
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
Toxicological data	> 5000 mg kg −1 ( LD 50 , rat , oral ) ; > 5000 mg kg −1 ( LD 50 , mouse , oral ) ; > 2000 mg kg −1 ( LD 50 , dog , oral ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cilostazol (trade name Pletal ^® ; manufacturer Otsuka ) is a drug from the group of selective phosphodiesterase 3 inhibitors . It is used for the symptomatic treatment of arterial circulatory disorders ( PAD ).

Forms of trade

Cilostazol tablets are available under the name Pletal (pharmaceutical company: Otsuka Pharmaceutical Europe ) in doses of 50 mg and 100 mg. Pletal is distributed in Germany by UCB Pharma and its subsidiary Sanol .

Mechanism of action

Cilostazol is a type III phosphodiesterase inhibitor . Inhibition of phosphodiesterase increases the concentration of cyclic adenosine monophosphate (cAMP). This improves the endothelial function and the aggregation of blood platelets ( thrombocyte aggregation ) is inhibited. The growth inhibition of vascular muscle cells also leads to a vasodilating effect.

application areas

Cilostazol is used to extend pain-free walking distance in peripheral arterial circulatory disorders ( PAD ) in stage 2 ( intermittent claudication ). The recommended dose of cilostazol is 100 mg twice a day.

Based on reports of cardiovascular and haemorrhagic reactions and interactions, the European Medicines Agency has reviewed the benefits and risks of cilostazol. The indication was then restricted and the recommendations regarding dosage, contraindications and special warnings changed:

Cilostazol should only be prescribed in patients in whom changes in lifestyle (e.g. cessation of smoking, exercise, diet) have not sufficiently improved the symptoms of intermittent claudication ("second line use"). It should not be used in patients taking two or more antiplatelet drugs or anticoagulants, in patients with unstable angina or who have had a myocardial infarction or coronary intervention in the past six months or a history of severe tachyarrhythmia.

Routinely, patients treated with Cilostazol should be checked to ensure that treatment is still appropriate and complies with the revised contraindications, special warnings and precautions.

Side effects

The most common side effects described are headache and diarrhea. Serious adverse cardiovascular and hemorrhagic effects were also reported, which is why the European Medicines Agency started a risk assessment process in May 2011.

For regional anesthesia procedures close to the spinal cord ( spinal anesthesia or epidural anesthesia ), Cilostazol should be discontinued 42 hours in advance and given again at least five hours after the procedure.

Individual evidence

↑ Chandgude, AL; Dömling, A .: Convergent Three-Component Tetrazole Synthesis in Eur. J. Org. Chem. 2016, 2383-2387, doi : 10.1002 / ejoc.201600317 .
↑ Whittall, LB; Whittle, RR; Stowell, GW: Polymorphic forms of cilostazol in Acta Cryst. C 58 (2002) 0525-0527, doi : 10.1107 / S0108270102012544 .
↑ Nishi, T .; Tabusa, F .; Tanaka, T .; Shimizu, T .; Kanbe, T .; Kimura, Y .; Nakagawa, K .: Studies on 2-Oxoquinoline Derivatives as Blood Platelet Aggregation Inhibitors. II. 6- [3- (1-Cyclohexyl-5-tetrazolyl) propoxy] -1, 2-dihydro-2-oxoquinoline and Related Compounds in Chem. Pharm. Bull. 31 (1983) 1151-1157, doi : 10.1248 / cpb.31.1151 , pdf .
↑ Komasaka, T .; Fujimura, H .; Tagawa, T .; Sugiyama, A .; Kitano, Y .: Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro / in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds in Chem. Pharm. Bull. 62 (2014) 1073-1082, doi : 10.1248 / cpb.c14-00232 , pdf .
↑ ^a ^b ^c Stowell, GW; Behme, RJ; Denton, SM; Pfeiffer, I .; Sancilio, FD, Whittall, LB; Whittle, RR: Thermally-Prepared Polymorphic Forms of Cilostazol in J. Pharm. Sci. 91 (2002) 2481-2488, doi : 10.1002 / jps.10240 .
↑ Takács-Novák, K .; Urac, M .; Horváth, P .; Völgyi, G .; Anderson, BD; Avdeef, A .: Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study in Eur. J. Pharm. Sci. 106 (2017) 133-144, doi : 10.1016 / j.ejps.2017.05.064 .
↑ ^a ^b ^c data sheet Cilostazol, ≥98% (HPLC), powder from Sigma-Aldrich , accessed on December 1, 2019 ( PDF ).
^ ^A ^b ^c A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2001) Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .
↑ ^a ^b ^c ^d ^e Specialist information Pletal 50 mg and 100 mg tablets , as of March 2009, Otsuka Pharmaceutical Europe Ltd. Available on the portal of the federal and state governments, PharmNet.Bund .
↑ European Medicines Agency recommends restricting use of cilostazol-containing medicines
↑ Rote-Hand-Brief from May 1st, 2013 (PDF; 3.1 MB) Rote-Hand-Brief from the manufacturer Otsuka from May 1st, 2013.
↑ European Medicines Agency: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP), 16-19 May 2011.
↑ Wiebke Gogarten, Hugo Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia In: AINS - anesthesiology · intensive care medicine · emergency medicine · pain therapy. 47, 2012, pp. 242-252, doi : 10.1055 / s-0032-1310414 .

Web links

S3 guideline for diagnosis and therapy of peripheral arterial occlusive disease (PAD) of the German Society for Angiology - Society for Vascular Medicine. In: AWMF online (as of 11/2015)
Entries in the NIH Study Register.Retrieved March 1, 2010

[1] Chandgude, AL; Dömling, A .: Convergent Three-Component Tetrazole Synthesis in Eur. J. Org. Chem. 2016, 2383-2387, doi : 10.1002 / ejoc.201600317 .

[Whittall-2] Whittall, LB; Whittle, RR; Stowell, GW: Polymorphic forms of cilostazol in Acta Cryst. C 58 (2002) 0525-0527, doi : 10.1107 / S0108270102012544 .

[Nishi-3] Nishi, T .; Tabusa, F .; Tanaka, T .; Shimizu, T .; Kanbe, T .; Kimura, Y .; Nakagawa, K .: Studies on 2-Oxoquinoline Derivatives as Blood Platelet Aggregation Inhibitors. II. 6- [3- (1-Cyclohexyl-5-tetrazolyl) propoxy] -1, 2-dihydro-2-oxoquinoline and Related Compounds in Chem. Pharm. Bull. 31 (1983) 1151-1157, doi : 10.1248 / cpb.31.1151 , pdf .

[Komasaka-4] Komasaka, T .; Fujimura, H .; Tagawa, T .; Sugiyama, A .; Kitano, Y .: Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro / in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds in Chem. Pharm. Bull. 62 (2014) 1073-1082, doi : 10.1248 / cpb.c14-00232 , pdf .

[Whittle-5] Stowell, GW; Behme, RJ; Denton, SM; Pfeiffer, I .; Sancilio, FD, Whittall, LB; Whittle, RR: Thermally-Prepared Polymorphic Forms of Cilostazol in J. Pharm. Sci. 91 (2002) 2481-2488, doi : 10.1002 / jps.10240 .

[Takacs-6] Takács-Novák, K .; Urac, M .; Horváth, P .; Völgyi, G .; Anderson, BD; Avdeef, A .: Equilibrium solubility measurement of compounds with low dissolution rate by Higuchi's Facilitated Dissolution Method. A validation study in Eur. J. Pharm. Sci. 106 (2017) 133-144, doi : 10.1016 / j.ejps.2017.05.064 .

[Sigma-7] ta sheet Cilostazol, ≥98% (HPLC), powder from Sigma-Aldrich , accessed on December 1, 2019 ( PDF ).

[Kleemann-8] A ^b ^c A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2001) Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .

[FI-9] Specialist information Pletal 50 mg and 100 mg tablets , as of March 2009, Otsuka Pharmaceutical Europe Ltd. Available on the portal of the federal and state governments, PharmNet.Bund .

[10] European Medicines Agency recommends restricting use of cilostazol-containing medicines

[11] Rote-Hand-Brief from May 1st, 2013 (PDF; 3.1 MB) Rote-Hand-Brief from the manufacturer Otsuka from May 1st, 2013.

[12] European Medicines Agency: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP), 16-19 May 2011.

[13] Wiebke Gogarten, Hugo Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia In: AINS - anesthesiology · intensive care medicine · emergency medicine · pain therapy. 47, 2012, pp. 242-252, doi : 10.1055 / s-0032-1310414 .