Praziquantel

Structural formula
1: 1 mixture of ( R ) -enantiomer (top) and ( S ) -enantiomer (bottom)
General
Non-proprietary name	Praziquantel
other names	( RS ) -2- (Cyclohexylcarbonyl) -2,3,4,6,7,11b-hexahydro-1 H -pyrazino [2,1- a ] isoquinolin-4-one ( IUPAC )
Molecular formula	C 19 H 24 N 2 O 2
Brief description	white to almost white, polymorphic , crystalline and hygroscopic powder
External identifiers / databases
CAS number 55268-74-1 ( racemate ) EC number 259-559-6 ECHA InfoCard 100.054.126 PubChem 4891 DrugBank DB01058 Wikidata Q424145
Drug information
ATC code	P02 BA01
Drug class	Anthelmintics
properties
Molar mass	312.41 g mol −1
Melting point	136 ° C ( racemic compound ) 110 ° C ( enantiomers )
solubility	very sparingly soluble in water (400 mg l −1 ) Easily soluble in dichloromethane and ethanol
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 H and P phrases H: no H-phrases P: no P-phrases
Toxicological data	2840 mg kg −1 ( LD 50 ,  rat ,  oral ) 24540 mg kg −1 ( LD 50 ,  mouse ,  oral ) > 200 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 .

Praziquantel is an anthelmintic , a drug used for worm infections . It is effective against flatworms (Platyhelminthes) as tapeworms (Cestoda) and flukes (Trematoda) (including the blood fluke (Schistosoma)). The opening of the calcium channels of the contractile cells of the worm's outer skin caused by the active substance leads to spastic paralysis of the worm and consequently to its death and expulsion with the stool in the case of internal parasites ( endoparasites ).

Development history

Praziquantel was developed in the 1970s as part of a research collaboration between Bayer AG and Merck . In 1980 the drug was first marketed under the name Biltricide .

Together with the Swiss Tropical and Public Health Institute, Astellas Pharma Inc. and TI Pharma, Merck started an international public-private partnership in 2012 with the aim of developing a therapy suitable for young children for the treatment of schistosomiasis. Since these cannot be treated with the drugs available to date, small children represent a reservoir for the parasite, which makes it difficult to eradicate. This initiative is sponsored by the Bill & Melinda Gates Foundation .

synthesis

A four-step synthesis starts from isoquinoline , with an N - acylation corresponding to the Reissert reaction being carried out in the first step in the presence of potassium cyanide using cyclohexanecarboxylic acid chloride . The resulting addition compound is then hydrogenated in the presence of Raney nickel , the cyclohexanecarboxamide function being rearranged. In the third step, a second N acylation is carried out using chloroacetic acid chloride . A ring closure reaction in the presence of triethylamine gives the target compound in the last step. The synthesis sequence leads to the racemate.

The enantiomers can be separated from the racemate by continuous countercurrent chromatography over cellulose triacetate as the chiral stationary phase with methanol as the mobile phase with subsequent multistage crystallization.

properties

Binary phase diagram of chiral praziquantel.

Praziquantel is chiral and contains a stereocenter, so there are two enantiomers . The ( R ) - and the ( S ) -form show a melting point of 110.6 ° C. The melting enthalpy is 18.5 kJ mol ⁻¹ , the melting entropy 48.18 kJ mol ⁻¹ K ⁻¹ . The racemate has a melting point of 136.2 ° C. A melting enthalpy of 25.7 kJ mol ⁻¹ and a melting entropy of 62.89 kJ mol ⁻¹ K ^{−1 were} determined for the racemate . The phase diagram shows eutectic melts between the enantiomer and the racemate at 101 ° C. with an enantiomer content of 14%. A second polymorphic form with a melting point between 133-135 ° C can be obtained from a glassy solidified melt of the racemate at 90-100 ° C.

The commercial preparations contain the drug as a racemate . The solubilities of the racemate at 25 ° C be in water 0.4 g · l ^-1 , in Methanol 158 g · l ^-1 , in ethanol 97 g · l ^-1 and in 2-propanol 54 g · l ^-1 . The temperature dependence of the solubility in methanol is given in the following table:

T in ° C	5.4	9.2	15.6	19.1	24.3	29.2	34.7	38.3
S in g l −1	64.2	75.1	101.7	120.5	157.5	207.9	290.5	363.6

The crystal structure has so far only been investigated of the ( R ) or ( - ) enantiomer. This crystallizes in a monoclinic crystal lattice and is present as a hemihydrate as a result of the crystallization from methanol / water.

application

Praziquantel is administered orally (i.e. by swallowing). Its plasma half-life is - depending on liver and kidney function - one to two and a half hours. It must be given in different durations and doses depending on the type and location of the parasite. For some tapeworms, a single treatment at a low dose (10-25 milligrams per kilogram of body weight) is sufficient; if internal organs or even the central nervous system are affected , treatment for up to two weeks with maximum doses of up to 50 milligrams per kilogram of body weight is indicated.

Praziquantel is also used in veterinary medicine, including for deworming aquarium fish.

Since 2007, praziquantel has been used specifically to eradicate schistosomiasis (schistosomiasis). The Merck KGaA is to the World Health Organization (WHO) for ten years annually over 25 million praziquantel tablets free of charge. The tablets can treat 27 million children; in 2007 Merck announced that it would be supplying 200 million tablets. In 2012, the company promised 250 million a year.

So far (as of 2011) there are no indications of resistance to praziquantel in the Schistosoma species S. haematobium , S. mansoni and S. japonicum, which are dangerous for humans .

Side effects

Abdominal pain, myalgias (muscle pain), nausea , vomiting , loss of appetite or headache as an expression of the effects on the human calcium channels occur occasionally to frequently . Weakness, dizziness , drowsiness, tiredness, as well as increased temperature and urticaria (hives) are common. Rarely meningism and confusion.

For the nomenclature of the frequencies, see side effect .

Trade names

Monopreparations

Biltricide (D), Cesol (D), Cysticide (D)

Veterinary medicine

Anipracit, Aniprazol KH, Band-ex, Bihelminth, Broadline, Caniquantel, Cestocur, Docatel, Dolpac, Droncit, Drontal, Equest Pramox, Equimax, Eqvalan duo, Fenprasel, Fenquantel, Furexel Combi, Milbactor, Milbemax, Plerion, Prazinex, Praziquasel, Profender, Professional Tremazol, Strantel, Tremazol, Vermis-Ex, VetBancid

Individual evidence

1. ↑ ^{a b} Data sheet PRAZIQUANTEL CRS (PDF) at EDQM , accessed on July 26, 2008.
2. ↑ ^{a b c d} Y. Liu, X. Wang, J.-K. Wang, CB Ching: Structural Characterization and Enantioseparation of the Chiral Compound Praziquantel. In: J Pharm Sci . 93, 2004, pp. 3039-3046. doi: 10.1002 / jps.20211 .
3. ↑ ^{a b c d e f g} Y. Liu, X. Wang, J.-K. Wang, CB Ching: Investigation of the Phase Diagrams of Chiral Praziquantel. In: Chirality . 18, 2006, pp. 259-264. doi: 10.1002 / chir.20251 .
4. ↑ ^{a b} Entry on praziquantel in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ↑ Praziquantel data sheet from Sigma-Aldrich , accessed on May 9, 2017 ( PDF ).
6. ↑ ^{a b c} A. Klemmann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances. 4th edition. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 .
7. ↑ Technical information Biltricide® 600mg film tab. In: Yellow List. August 2013, accessed on October 28, 2016 : "Date of issue of approval: May 23, 1980" 
8. ↑ Patent DE2457971 : Process for the production of 2-acyl4-oxo-pyrazino-isoquinoline derivatives. Published June 10, 1976 , inventor: J. Seubert. ‌
9. ^ Peter Andrews, Herbert Thomas, Rolf Pohlke, Jürgen Seubert: Praziquantel . In: Medicinal Research Reviews . tape 3 , no. 2 , 1983, p. 147-200 , doi : 10.1002 / med . 2610030204 .
10. ↑ Bee-Gim Lim, Chi-Bun Ching, Reginald BH Tan, Siu-Choon Ng: Recovery of ( -) - praziquantel from racemic mixtures by continuous chromatography and crystallization . In: Chemical Engineering Science . tape 50 , no. 14 , 1995, pp. 2289-2298 , doi : 10.1016 / 0009-2509 (95) 00082-G .
11. ↑ M. Kuhnert – Brandstätter, M. Geiler, I. Wurian: Contribution to the microscopic characterization and identification of medicinal products with the inclusion of UV spectroscopy. In: Sci. Pharm. 51, 1983, pp. 34-41.
12. ^ ^{A b} J. Seubert, R. Pohlke, F. Loebich: Synthesis and properties of praziquantel, a novel broad spectrum anthelmintic with excellent activity against Schistosomes and Cestodes . In: Experientia . tape 33 , no. 8 , p. 1036-1037 , doi : 10.1007 / BF01945954 .
13. ↑ Thorsten Meyer, Harald Sekljic, Stefan Fuchs, Heiko Bothe, Dieter Schollmeyer, Christian Miculka: Taste, A New Incentive to Switch to (R) -Praziquantel in Schistosomiasis Treatment . In: PLoS Neglected Tropical Diseases . tape 3 , no. 1 , 2009, p. e357 , doi : 10.1371 / journal.pntd.0000357 .
14. ↑ Andrew J. Mitchell, Melissa S. Hobbs: The Acute Toxicity of Praziquantel to Grass Carp and Golden Shiners . In: North American Journal of Aquaculture . tape 69 , no. 3 , 2007, p. 203-206 , doi : 10.1577 / A06-056.1 .
15. ^ A. George, P. Sparrow: Toxic Treatments in Aquaculture - (II) Praziquantel and its Impact on Goldfish in Baitproduction. In: J Fish Toxic Biochem. (4), 2005, pp. 322-335.
16. ↑ ava: Merck Serono wants to eradicate schistosomiasis. In: Doctors newspaper. January 30, 2012.
17. ↑ eb: Merck KGaA supports the fight against schistosomiasis. In: Doctors newspaper. December 15, 2011.
18. ↑ Merck and WHO decide on partnership. In: Doctors newspaper . April 26, 2007.
19. ↑ merck.de: Merck KGaA and WHO agree on partnership to combat schistosomiasis in Africa ( memento of February 6, 2015 in the Internet Archive ), accessed on June 21, 2014.
20. ↑ merckgroup.com: Merck tenfold donation of tablets to eradicate schistosomiasis. ( Memento of May 18, 2012 in the Internet Archive ) Retrieved February 12, 2012.
21. ^ Zanzibar: gearing up to eliminate schistosomiasis. At: who.int on March 7, 2012.
22. ^ R. Liu, HF Dong et al.: Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis. In: Parasites & vectors. Volume 4, 2011, p. 201, doi: 10.1186 / 1756-3305-4-201 . PMID 22004571 . PMC 3207908 (free full text).

Web links

• Entry on Praziquantel at Vetpharm, accessed August 11, 2012.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !