Source: Registered Drug Product Database (NG) Publisher: Ajanta Pharma Limited, Ajanta House, Charkop, Kandivli (West), Mumbai - 400 067, India Manufacturing site address: Ajanta Pharma Limited, B-4/5/6, M.I.D.C. Area, Paithan, Dist. Aurangabad, Maharashtra, India, Telephone: (0091) 2431232123, Fax: (0091) 2431232088, e-mail: info@ajantapharma.com
Aceclofenac is a nonsteroidal agent with marked anti-inflammatory and analgesic properties. The mode of action of aceclofenac is largely based on the inhibition to prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.
Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependent on the inhibition of prostaglandin synthesis. This inhibition appears, however to be on a selective basis.
After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion.
Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L.
The mean plasma elimination half-life is around 4 hours. Aceclofenac is highly protein bound (>99%). Aceclofenac circulates mainly as unchanged drug. 4'-Hydroxyaceclofenac is the main metabolite detected in plasma. Approximately two-thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.
No changes in the pharmacokinetics of aceclofenac have been detected in the elderly.
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. The concentration in plasma reaches a peak in 30 to 60 minutes and the plasma half-life is 1–4 hours after therapeutic doses. Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 30% may be bound at the concentrations encountered during acute intoxication. Following therapeutic doses 90-100% of the drug may be recovered in the urine within the first day. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation.
The results from preclinical studies conducted with aceclofenac are consistent with those expected for NSAIDs. The principal target organ was the gastro-intestinal tract. No unexpected findings were recorded.
Aceclofenac was not considered to have any mutagenic activity in three in vitro studies and an in vivo study in the mouse.
Aceclofenac was not found to be carcinogenic in either the mouse or rat.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
There was no evidence of teratogenesis in rats although the systemic exposure was low and in rabbits, treatment with aceclofenac (10 mg/kg/day) resulted in a series of morphological changes in some fetuses.
Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6,000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (0.7 times) or mice (1.2 to 1.4 times the MHDD, based on a body surface area comparison).
Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay using human lymphocytes. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1,500 mg/kg/day to the rat model (3.6 times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8 times the MHDD, based on a body surface area comparison), suggesting a threshold effect.
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