Dexketoprofen is the tromethamine salt of S-(+)-2 - (3-benzoylphenyl)propionic acid, an analgesic, anti-inflammatory and antipyretic drug, which belongs to the non-steroidal anti-inflammatory group of drugs (M01AE).
The mechanism of action of non-steroidal antiinflammatory drugs is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, PGF2α and PGD2 and also prostacyclin PGI2 and thromboxanes (TxA2 and TxB2). Furthermore, the inhibition of the synthesis of prostaglandins could affect other inflammation mediators such as kinins, causing an indirect action which would be additional to the direct action.
Dexketoprofen has been demonstrated to be an inhibitor for COX-1 and COX-2 activities in experimental animals and humans.
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. It is a non-selective, partial agonist of μ-, δ- and κ-opioid receptors with a higher affinity for μ-receptors. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound.
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.
Tramadol has an antitussive action. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.
Preclinical studies have shown a synergistic interaction between the active ingredients observed during both acute and chronic inflammation models and suggest that lower doses of each active ingredient allow to obtain effective analgesia.
Concomitant administration of dexketoprofen and tramadol had no effects on the pharmacokinetic parameters of either component in healthy subjects.
In normal healthy adults, peak plasma concentrations of dexketoprofen and tramadol are reached in about 30 min (range 15 to 60 min) and 1.6 to 2 hours, respectively.
After oral administration of dexketoprofen to humans, the Cmax is reached at 30 min (range 15 to 60 min).
When administered concomitantly with food, the AUC does not change, however the Cmax of dexketoprofen decreases and its absorption rate is delayed (increased tmax).
The distribution half-life and elimination half-life values of dexketoprofen are 0.35 and 1.65 hours, respectively. As with other drugs with a high plasma protein binding (99%), its volume of distribution has a mean value below 0.25 l/kg.
In multiple-dose pharmacokinetic studies, it was observed that the AUC after the last administration is not different from that obtained following a single dose, indicating that no drug accumulation occurs.
After administration of dexketoprofen only the S-(+) enantiomer is obtained in urine, demonstrating that no conversion to the R-(-) enantiomer occurs in humans.
The main elimination route for dexketoprofen is glucuronide conjugation followed by renal excretion.
More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of concomitant intake of food.
The difference between absorbed and non-metabolised available tramadol is probably due to low first-pass effect. The first-pass effect after oral administration is a maximum of 30%.
Tramadol has a high tissue affinity (Vd,β=203±40l). Protein binding is about 20%.
Following a single oral dose administration of tramadol 100 mg as capsules or tablets to young healthy volunteers, plasma concentrations were detectable within approximately 15 to 45 minutes within a mean Cmax of 280 to 208 mcg/L and Tmax of 1.6 to 2h.
Tramadol passes the blood-brain and placenta barrier. Very small amounts of the substance and its O-desmethyl derivative are found in the breast milk (0.1% and 0.02% respectively of the applied dose).
In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2–4. Its half life t½β (6 healthy volunteers) is 7.9 h (range 5.4–9.6 h) and is approximately that of tramadol.
The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite.
Elimination half-life t½β is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4.
Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively have been determined. In patients with renal insufficiency (creatinine clearance <5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100–300 ng/ml is usually effective.
Preclinical data with the combination revealed no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
The combination of dexketoprofen and tramadol had not significant effect on cardiovascular system as assessed by both in vitro and in vivo tests. Less effect on gastrointestinal transit were observed with the combination as compared to tramadol alone.
A 13-week chronic toxicity study in rats, gave No Observed Adverse Effect Levels (NOAELs) of 6 mg/kg/day for dexketoprofen and 36 mg/kg/day for tramadol (highest tested doses), when administered both singularly or in combination (corresponding to AUC-based exposures at the NOAEL after single doses of 25.10 times and 1.38 times the human exposure to dexketoprofen and tramadol, respectively, at a single clinical dose of 25 mg dexketoprofen and 75 mg tramadol).
No new toxicities, different from those previously described for dexketoprofen or tramadol were observed.
Preclinical data on dexketoprofen revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and immunopharmacology. The chronic toxicity studies carried out in mice and monkeys gave a No Observed Adverse Effect Level (NOAEL) of 3 mg/kg/day. The main adverse effect observed at high doses was gastrointestinal erosions and ulcers that developed dose-dependently.
In repeated oral and parenteral administration of tramadol during 6 to 26 weeks to rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.
In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects.
According to knowledge gained so far, tramadol can be classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).
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