Ganciclovir

Structural formula
General
Non-proprietary name	Ganciclovir
other names	2 - [(2-Amino-6-hydroxy-purin-9-yl) methoxy] propane-1,3-diol
Molecular formula	C 9 H 13 N 5 O 4
Brief description	white, odorless powder
External identifiers / databases
EC number	627-054-3
ECHA InfoCard	100.155.403
PubChem	3454
ChemSpider	3336
DrugBank	DB01004
Wikidata	Q417640
Drug information
ATC code	J05 AB06 ; S01 AD09 ;
Drug class	Antiviral
Mechanism of action	DNA polymerase inhibitor
properties
Molar mass	255.23 g mol −1
Melting point	242–255 ° C (decomposition)
Vapor pressure	≤ 0.001 hPa (22 ° C)
pK s value	2.2; 9.4
solubility	heavy in ethanol ; soluble in dilute mineral acids and alkali hydroxide solutions
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances danger
H and P phrases	H: 360
	P: 201-308 + 313
Toxicological data	> 2000 mg kg −1 ( LD 50 , mouse , oral ) ; > 1000 mg kg −1 ( LD 50 , dog , oral ) ; ~ 900 mg kg −1 ( LD 50 , mouse , iv ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ganciclovir is an analogue of the nucleobase guanine . It is used as an antiviral agent against herpes viruses .

chemistry

Ganciclovir is - like the analogues acyclovir and penciclovir - a derivative of the nucleobase guanine, which occurs as a component of DNA and RNA . Since ganciclovir is weakly acidic (pKa 9.4) due to the NH acidity of the lactam group , it forms a sodium salt that is used therapeutically.

application

Ganciclovir is mainly used for diseases caused by the cytomegalovirus (CMV, synonymous human herpesvirus 5 / HHV 5). CMV infections are of particular importance

in case of immunodeficiency in the context of transplants or an AIDS disease, as well as
during pregnancy.

(For details, see the main article on cytomegaly ).

Ganciclovir is also effective against keratitis herpetic ("eye herpes") and can be administered topically in the form of an eye gel.

It is also used experimentally for the treatment of malignant degeneration, e.g. B. in oncolytic viruses . In biochemistry, ganciclovir is used in conjunction with selection markers for negative selection.

Mode of action

Ganciclovir works against all human herpes viruses , but primarily against the cytomegalovirus (CMV) (is about 10 times more phosphorylated in CMV-infected cells, thus more activated than in healthy cells). In infected cells it is first phosphorylated to monophosphate by viral kinases and then phosphorylated by cellular kinases to 5'-triphosphate . Particularly in virus-infected cells, it is first converted by the cell's own guanine kinase into ganciclovir triphosphate, in order to be incorporated into the viral DNA as a synthetic nucleoside analogue , whereby this leads to chain termination as the viral polymerase breaks off a base after incorporation of the ganciclovir .

Administration and pharmacokinetics

Since its oral bioavailability is less than 5%, it is usually given as an infusion in two single doses of 5 mg per kg of body weight each twelve hours apart. With a pH of 11, the solution of its sodium salt is strongly alkaline , so the infusion must be made slowly through a large vein. Misinfusions (into an artery, subcutaneous tissue, or muscle) should also be avoided for the same reason .

In patients, mean plasma concentrations of approximately 6 mg / l were achieved after an infusion time of 60 minutes. The substance is mainly excreted unchanged via the kidneys, the elimination half-life being around 1.5 to 3 hours with normal kidney function. Dose adjustments must be made in the event of impaired creatinine clearance .

For oral administration, 1 g is taken three times a day with meals; Topical applications in gel form in the eye area have been on the German market since 2006.

unwanted effects

Since ganciclovir has significantly higher toxic properties than, for example, acyclovir (it is phosphorylated, i.e. activated, much more strongly than acyclovir in non-infected cells), high side-effect rates are to be expected.

The most commonly observed side effects are neutropenia , thrombocytopenia and anemia , less common: eosinophilia, increase in transaminases or urea and creatinine concentrations in plasma; central nervous side symptoms such as dizziness, headache, hallucinations, cramps; Symptoms related to the gastrointestinal tract (nausea, vomiting and diarrhea); Skin manifestations.

Trade names

Monopreparations

Cymeven (D), Cymevene (A, CH), Virgan (D)

Individual evidence

↑ ^a ^b ^c ^d ^e ^f data sheet ganciclovir ( memento of the original from February 17, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. at Roche , accessed on February 17, 2017 (PDF). @1@ 2

↑ ^a ^b ^c Entry on ganciclovir. In: Römpp Online . Georg Thieme Verlag, accessed on July 6, 2019.

↑ ^a ^b Ganciclovir data sheet from Sigma-Aldrich , accessed on February 17, 2017 ( PDF ).

↑ pharmazie.com : Cymevene “Roche” 500 mg dry substance for infusion preparation (PDF; 53 kB), accessed on August 29, 2013.

[roche-1] ↑ ^a ^b ^c ^d ^e ^f data sheet ganciclovir ( memento of the original from February 17, 2017 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. at Roche , accessed on February 17, 2017 (PDF). @1@ 2

[römpp-2] Entry on ganciclovir. In: Römpp Online . Georg Thieme Verlag, accessed on July 6, 2019.

[sigma-3] Ganciclovir data sheet from Sigma-Aldrich , accessed on February 17, 2017 ( PDF ).

[4] rmazie.com : Cymevene “Roche” 500 mg dry substance for infusion preparation (PDF; 53 kB), accessed on August 29, 2013.