Pharmacokinetics and pharmacodynamics of metamizol in co-administration with morphine under acute and chronic treatments in arthritic rats.

OBJECTIVE: To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments. METHODS: Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol. KEY FINDINGS: The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration. CONCLUSIONS: The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process.

Antinociceptive effects of tramadol in co-administration with metamizol after single and repeated administrations in rats.

Combinations of two analgesic drugs of the same or different class are widely used in clinical therapy to enhance its antinociceptive effects and reduce the side effects. In order to evaluate a possible antinociceptive synergistic interaction of metamizol s.c., a nonsteroidal antiinflammatory drug (NSAID), and tramadol s.c., an atypical opioid (opioid receptor agonist), were administered alone or in combination. In the present study, the antinociceptive efficacy and the possible development of pharmacological tolerance produced by the combination tramadol plus metamizol during a 4-day treatment in rats using the plantar test was evaluated. Male Wistar rats were s.c. injected with tramadol (17.8 mg/kg), metamizol (177.8 mg/kg) or the combination tramadol plus metamizol three times a day for 4 days. Both metamizol and tramadol produced antinociceptive effects with a low rate trend towards tolerance development at the end of the treatment. The antinociceptive efficacy of tramadol and metamizol co-administration gradually decreased after the second injection. These data suggest that when the combination is given in a unique administration it results in an important potentiation of their individual antinociceptive effects. But, the repeated coadministration of tramadol plus metamizol results in a development of tolerance.

High-performance liquid chromatographic assay for metamizol metabolites in rat plasma: application to pharmacokinetic studies.

In order to evaluate the pharmacokinetics of metamizol in the presence of morphine in arthritic rats, after subcutaneous administration of the drugs, an easy, rapid, sensitive and selective analytical method was proposed and validated. The four main metamizol metabolites (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) were extracted from plasma samples (50-100µl) by a single solid-phase extraction method prior to reverse-phase high performance liquid chromatography with diode-array detection. Standard calibration graphs for all metabolites were linear within a range of 1-100µg/ml (r(2)≥0.99). The intra-day coefficients of variation (CV) were in the range of 1.3-8.4% and the inter-day CV ranged from 1.5 to 8.4%. The intra-day assay accuracy was in the range of 0.6-9.6% and the inter-day assay accuracy ranged from 0.9 to 7.5% of relative error. The lower limit of quantification was 1µg/ml for all metabolites using a plasma sample of 100µl. Plasma samples were stable at least for 4 weeks at -20°C. This method was found to be suitable for studying metamizol metabolites pharmacokinetics in arthritic rats, after simultaneous administration of metamizol and morphine, in single dose.

Effect of metamizol on morphine pharmacokinetics and pharmacodynamics after acute and subchronic administration in arthritic rats.

The aim of the present study was to investigate whether metamizol alters the pharmacokinetics of morphine and to determine the relationship between morphine plasma levels and antinociceptive effect produced after co-administration of drugs under acute and subchronic treatments using the pain-induced functional impairment model in rat (PIFIR model). Administration of morphine+metamizol under acute treatment produced a significantly higher antinociceptive effect than that obtained with morphine alone (P<0.05). This effect remained unaltered after subchronic treatments for 6 and 12 days. In addition, after the simultaneous administration of the drugs in a single dose, a pharmacokinetic interaction was found, which significantly (P<0.001) increased maximum plasma concentration (C(max)), concentration at 4h (C(4h)), partial areas under the plasma concentration-time curve from zero to 4h (AUC(0-4)) and from zero to 24h (AUC(0-24)). Moreover, whereas plasma concentration of morphine markedly decreased up to 4h (C(4h)) after subchronic administration of the opioid, multiple dosing of the morphine+metamizol combination produced an accumulation of the drug in plasma (P<0.001). The increase observed in morphine plasma levels after co-administration of metamizol may be explained by a possible enzymatic inhibition of the glucuronosyl-transferase system involved in the metabolism of morphine. This study reveals both a pharmacodynamic and a pharmacokinetic interaction between morphine and metamizol, leading to an increased antinociceptive effect and a delay in tolerance development.

Anti-nociceptive synergism of morphine and gabapentin in neuropathic pain induced by chronic constriction injury.

In order to detect an anti-nociceptive interaction between morphine and gabapentin, the anti-allodynic and anti-hyperalgesic effects of these drugs, administered either separately or in combination, were determined using the von Frey and acetone tests in a rat model of neuropathic pain (Bennett model). Morphine and gabapentin individually induced moderate attenuation of mechanical hyperalgesia, whereas the morphine and gabapentin combination completely decreased hyperalgesia. Morphine showed its maximal effect at 30 min post-injection in the acetone test; however, this effect gradually returned to the baseline value. Gabapentin did not produce an anti-allodynic effect, whereas the morphine and gabapentin combination completely decreased allodynia behavior at 30 min post-injection, an effect that persisted until 120 min. The area under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the combinations were significantly greater than the theoretical sum of effects produced by each drug alone or similar to the theoretical sum. The analysis of the effect, expressed as the AUC of the time course, supports the hypothesis that the combination of these drugs is useful in neuropathic pain therapy.

The antinociceptive efficacy of morphine, metamizol, or their combination in an experimental rat model with different levels of inflammatory pain.

The purpose of this work was to evaluate the antinociceptive efficacy of an optimal morphine and metamizol combination on different levels of nociception (levels I, II, and III) using the "Pain-induced functional impairment model in the rat". The effect of acetylsalicylic acid was examined as a reference drug at the same levels of nociception. The antinociceptive effects produced by morphine (3.2 mg/kg s.c.) and metamizol (177.8 mg/kg s.c.) were studied either individually or in combination. The antinociceptive efficacies were expressed as either areas under the curve (AUCs), maximum effects as functionality index in percent of the time course, or the antinociceptive effects produced at 2 h after administration. Unlike morphine, the antinociceptive effects of acetylsalicylic acid decreased with increasing intensity of nociception. In summary, the analysis of antinociceptive efficacies produced by the co-administration of these drugs for different levels of nociception revealed that co-administration provided potentiated and better antinociceptive coverage throughout our observation time than did the individual drugs or the expected theoretical sum (using AUC or effects after 2 h). This is the first study to demonstrate that an optimal morphine and metamizol combination is able to produce potentiation of antinociceptive effects during intense pain.

[Antinociceptive effects of the combination metamizol + morphine in rats with intense pain (arthritic gout-type pain produced with AU)]. / Efectos antinociceptivos de la combinación metamizol+morfina en ratas con dolor intenso (artritis de tipo "gota" producida por ácido úrico).

BACKGROUND: The antinociceptive effects of metamizol and morphine administered either separately or in combination were determined in the "Pain-Induced Functional Impairment Model in the Rat" (PIFIR antinociceptive model). METHODS: Intense nociception (or intense pain) was induced by the intra-articular injection of uric acid (50%) in the right hind limb inducing its dysfunction. Animals then received analgesic agents, and the recovery of functionality over time was assessed as an expression of antinociception. RESULTS: Metamizol (177.8 mg/kg s.c.) or morphine (3.2 mg/kg s.c.) separately resulted in a lower antinociceptive effect (22.1+/-5.4 area units [au] and 31.8+/-9.4 au, respectively). Moreover, the combination of metamizol (177.8 mg/kg) with morphine (3.2 mg/kg) resulted in a potentiation (293.7+/-16.6 au). The antinociceptive effect observed using the combination was significantly greater than expected on the basis of addition of the individual effects. The percent change in antinociceptive effects, using the combination, was 444.9%. CONCLUSIONS: This represents the first study to show that metamizol + morphine can produce potentiation of their antinociceptive effects in intense pain.

High-performance liquid chromatographic assay for morphine in small plasma samples: application to pharmacokinetic studies in rats.

In order to perform a reliable pharmacokinetic study of morphine during subchronic treatment in rats, an easy, rapid, sensitive and selective analytical method was proposed and validated. The analyte and internal standard (naloxone) were extracted from plasma samples (100 microL) by a single solid-phase extraction method prior to reverse-phase high performance liquid chromatography (HPLC) along with electrochemical detection (ED). Standard calibration graphs were linear within a range of 3.5-1,000 ng/mL (r=0.999). The intra-day coefficients of variation (CV) were in the range of 5.8-8.5% at eight concentration levels (7-1,000 ng/mL) and the inter-day coefficient of variation ranged from 7.4 to 8.8%. The intra-day assay accuracy was in the range of -5-10% and the inter-day assay accuracy ranged from 3.0 to 9.3% of relative error (RE). The limit of quantification was 3.5 ng/mL using a plasma sample of 100 microL (15.8% of CV and 12.8% of RE). Plasma samples were stable for 2 months at -20 degrees C. This method was found to be suitable for pharmacokinetic studies in rats, after subcutaneous administration of morphine (5.6 mg/kg per day) in subchronic treatment for 6 and 12 days.

Comparison of dissolution profiles for albendazole tablets using USP apparatus 2 and 4.

The in vitro dissolution of albendazole from three different commercially available products (200 mg tablets) was studied using U.S. Pharmacopeia (USP) Apparatus 2 and USP Apparatus 4 in order to compare the release performance of the drug in two essentially different dissolution systems. For both cases, 0.1 N HCl was used as dissolution medium. Only the reference product and one of the generic products studied met the 80% USP 24 specification for albendazole dissolved at 30 min, using USP Apparatus 2. Although the reference product reached 80% of albendazole dissolved at 30 min when Apparatus 4 was used, the generic products' dissolution performance was markedly reduced in this system. Though dissolution rate was slower using Apparatus 4, the total quantity of albendazole dissolved from the reference product, represented by area under the dissolution profile, was practically the same regardless of the system used. Dissolution kinetics of albendazole was adequately described by Weibull's function for all the products. The dissolution time (t(d)) derived from data fitting to this function showed significant differences among the products studied. Data analysis based on analysis of variance (ANOVA) showed nonequivalence among the dissolution profiles of generic products compared with the reference product either with the dissolution vessel system or the flow-through cell, as well as nonequivalence among the dissolution profiles using both apparatuses with the same product. Though differences in the dissolution profiles for generic products against the reference product in both systems were found, USP Apparatus 4 showed higher discriminative capacity in differentiating the release characteristics of the products tested.

Behavior of long-term dantrolene sodium-treated rat skeletal muscles: histochemical and electromechanical aspects

Histochemical and electrochemical studies were carried out on skeletal rat muscles treated with dantrolene sodium (DS) for 60 days. Histochemical experiments revealed a conversion from fast twitch (type II) to slow twitch (type I) fibers for soleus (S), gastrocnemius (GM), and extensor digitorum longus (EDL) muscles. However, a significant decreased of muscle contractility was not observed in these chronically treated rat muscles in opposition to both those directly exposed in vitro as the muscles obtained from only 1-h DS-treated animals