VALGANCICLOVIR HYDROCHLORIDE
Flammability | 1 | |
Toxicity | 2 | |
Body Contact | 0 | |
Reactivity | 1 | |
Chronic | 2 | |
SCALE: Min/Nil=0 Low=1 Moderate=2 High=3 Extreme=4 |
To treat cytomegalovirus ( CMV) retinitis. After oral administration, both diastereomers
are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a
synthetic analogue of 2' - deoxyguanosine, which inhibits replication of human
cytomegalovirus in vitro and in vivo. In CMV- infected cells ganciclovir is initially
phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further
phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is
then slowly metabolized intracellularly (half- life 18 hours). As the phosphorylation is
largely dependent on the viral kinase, phosphorylation of ganciclovir occurs
preferentially in virus- infected cells. The virustatic activity of ganciclovir is due to
inhibition of viral DNA synthesis by ganciclovir triphosphate. Viruses resistant to
ganciclovir can arise after prolonged treatment with valganciclovir by selection of
mutations in either the viral protein kinase gene (UL97) responsible for ganciclovir
monophosphorylation and/or in the viral DNA polymerase gene (UL54). Virus with mutations
in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the
UL54 gene may show cross- resistance to other antivirals that target the same sites on
viral DNA polymerase. The current working definition of CMV resistance to ganciclovir in
in vitro assays is IC50= 1.5 绀
Limited evidence of a carcinogenic effect.
Accidental ingestion of the material may be damaging to the health of the individual. Adverse effects include bone-marrow suppression have been seen following use of ganciclovir.. The main clinical toxicity of ganciclovir includes leucopenia and thrombocytopenia. Animal studies show aspermatogenesis, mutagenicity, teratogenicity and carcinogenicity. Approximately 40% of patients receiving the material have manifested neutropenia (neutrophil count less than 1000/mm3). Neutropenia typically occurs in the first or second week of induction therapy. Other side-effects may include chills, oedema, infections, malaise, sore throat, epistaxis, arrhythmia, hypertension or hypotension, abnormal thoughts or dreams, ataxia, coma, confusion, dizziness, headache, nervousness, paraesthesia, psychosis, somnolence, tremor, nausea, vomiting, anorexia, diarrhoea, haemorrhage, abdominal pain, athralgia, myalgia, muscle twitching, alopecia, pruritis, urticaria, haematuria. Animal data suggests that ganciclovir produces inhibition of spermatogenesis and subsequent infertility in males. These effects were reversible.Female infertility as also been demonstrated.
Although the material is not thought to be an irritant, direct contact with the eye may cause transient discomfort characterized by tearing or conjunctival redness (as with windburn). Slight abrasive damage may also result. The material may produce foreign body irritation in certain individuals.
The material is not thought to produce adverse health effects or skin irritation following contact (as classified using animal models). Nevertheless, good hygiene practice requires that exposure be kept to a minimum and that suitable gloves be used in an occupational setting. Open cuts, abraded or irritated skin should not be exposed to this material. Entry into the blood-stream, through, for example, cuts, abrasions or lesions, may produce systemic injury with harmful effects. Examine the skin prior to the use of the material and ensure that any external damage is suitably protected.
The material is not thought to produce either adverse health effects or irritation of the respiratory tract following inhalation (as classified using animal models). Nevertheless, adverse effects have been produced following exposure of animals by at least one other route and good hygiene practice requires that exposure be kept to a minimum and that suitable control measures be used in an occupational setting. Persons with impaired respiratory function, airway diseases and conditions such as emphysema or chronic bronchitis, may incur further disability if excessive concentrations of particulate are inhaled. Limited evidence exists that the substance may cause irreversible but non-lethal mutagenic effects following a single exposure.
There has been concern that this material can cause cancer or mutations, but there is not enough data to make an assessment. Ample evidence from experiments exists that there is a suspicionthis material directly reduces fertility. Exposure to the material may result in a possible risk of irreversible effects. The material may produce mutagenic effects in man. This concern is raised, generally, on the basis ofappropriate studies with similar materials using mammalian somatic cells in vivo. Such findings are often supported by positive results from in vitro mutagenicity studies. Long term exposure to high dust concentrations may cause changes in lung function i.e. pneumoconiosis; caused by particles less than 0.5 micron penetrating and remaining in the lung. Prime symptom is breathlessness; lung shadows show on X-ray. Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1?and 1.4? respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons.All tumours were of epithelial or vascular origin except for histiocytic sarcoma of the liver.. No carcinogenic effects were seen at 1 mg/kg/day. At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. In an 18 month study, ganciclovir was carcinogenic in mice after oral doses of 20 mg and 100 mg daily. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7?the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1?the AUC of the recommended human intravenous dose. Daily intravenous doses of 20 mg/kg did not impair female fertility but doses as low as 3 mg/kg caused reduction in the weight of pups; higher doses were associated with hypoplasia of testes and seminal vesicles in male pups. In male mice fertility was decreased after daily intravenous doses of 2 mg/kg. Effects were reversible at this dose level but became irreversible at 10 mg/kg. Valganciclovir (which metabolises to ganciclvir) caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir (and valganciclovir) could cause inhibition of human spermatogenesis Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered doses that produced 2?the human exposure based on AUC comparisons. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality. Daily intravenous doses administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month- old male offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.7?the human AUC. Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion.