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Background: The combination of indomethacin, prochlorperazine and caffeine (IPC) is one of the most utilized formulations for the treatment of migraine attacks in Italy. Several patients suffering from chronic headache overuse this symptomatic medication in the attempt to control their headache., Objective: To verify whether overuse of IPC combination by chronic headache patients is associated with modified disposition of its components., Methods: We studied indomethacin, prochlorperazine, and caffeine disposition in 34 female subjects suffering from primary headaches, subdivided into four groups: eight migraine patients occasionally using IPC combination suppositories-group 1; nine patients with chronic headache and probable medication-overuse headache, daily taking one or more suppositories of the IPC combination-group 2; 11 migraine patients occasionally using "mild" suppositories of the IPC combination-group 3; six migraine patients occasionally taking tablets of the IPC combination-group 4. The IPC combination habitually used was administered to each patient. Blood samples were taken at baseline and at fixed intervals up to 6h after administration. Plasma levels of indomethacin and prochlorperazine were assayed by high-pressure liquid chromatographic (HPLC) method; caffeine levels were assayed by enzyme multiplied immunoassay test (EMIT). Pharmacokinetic parameters were calculated by means of a computer software (P K Solutions 2.0. Summit Research Services, Montrose, CO, USA)., Results: Half-life of indomethacin was longer, and clearance lower, in group 2 than in the other groups; AUC of indomethacin in group 2 was twice that in group 1 (P<0.05, Newman-Keuls' test). Peak concentrations and AUC(0-->infinity) of caffeine were significantly higher in group 2 than in the other groups (P<0.05, Newman-Keuls' test). We could not define prochlorperazine disposition because it was not detectable in the majority of blood samples., Conclusion: Overuse of IPC combination in chronic headache patients is associated with increased plasma levels of indomethacin and caffeine, and with delayed elimination of indomethacin; the high and sustained concentrations of these drugs may cause rebound headache, organ damages, and perpetuate medication-overuse headache.

The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong and prolonged in others. Methadone is mostly metabolised in the liver; the main step consists in the N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among individuals, and such variability is the responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2 are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants and antiretroviral drugs, which can cause pharmacokinetic interactions. In particular, antiretrovirals, which are CYP3A4 inducers, can decrease the levels of methadone, so causing withdrawal symptoms. Buprenorphine, too, is metabolised by CYP3A4, and may undergo the same interactions as methadone. Since it is impossible to foresee the time-lapse from the administration of another drug to the appearing of withdrawal symptoms, nor how much the daily dose of methadone should be increased in order to prevent them, patients taking combined drug treatments must be carefully monitored. The so far known pharmacokinetic drug-drug interactions of methadone do not have life-threatening consequences for the patients, but they usually cause a decrease of the concentrations and of the effects of the drug, which in turn can cause symptoms of withdrawal and increase the risk of relapse into heroin abuse.

Patients suffering from migraine take drugs for many years in order either to relieve or to prevent recurrent migraine attacks. When two or more drugs are co-administered, there is always the possibility of drug-drug interaction. Interactions can be either kinetic or dynamic. The former are the most frequent ones. Mechanisms of kinetic interaction can be different, but the most common are represented by the induction or inhibition of enzymes of the cytochromes p450 (CYP) system. This system plays an important role in the disposition of a large number of drugs, including those used for migraine. This review examines the interactions between triptans-the most effective drugs for the therapy of migraine attacks-and drugs for migraine prophylactic treatment.

The pharmacokinetics of naltrexone have been scarcely explored in patients during chronic treatment despite the observation that the pharmacological effect of the drug is related to its plasma concentrations. In this study we investigated the time course of serum levels of naltrexone and its active metabolite, 6 beta-naltrexol, in 13 heroin addicts (3 F, 10 M; age 22-32 years) in the 24 h after 100 mg of naltrexone orally. Six patients were studied once, at different times during chronic treatment, whereas in seven patients the study was done at the beginning and after 1 month of naltrexone treatment. Four of these patients also repeated the study after 3 months of naltrexone treatment. Serum naltrexone and 6 beta-naltrexol were assayed by GLC with a nitrogen-phosphorus detector. Our results showed large differences among patients in serum naltrexone and 6 beta-naltrexol levels. On the other hand, there were no differences in serum time course of both substances in the same patient over 3 months. Peak levels and AUCs of naltrexone were lower than those of 6 beta-naltrexol in ten addicts and higher than those of the metabolite in three patients. No significant differences in the apparent half-lives of the two drugs were detected among groups. These data are consistent with the occurrence of a decreased first-pass metabolism of naltrexone in three patients leading to a larger availability of an oral dose. The increased bioavailability of the drug is not very important for opioid receptor antagonist activity but may play a role in naltrexone treatment safety.

Background/aims: Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone., Methods: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysis., Results: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200 +/- 97 ng/ml x 24 h; 6 beta-naltrexol, 2467 +/- 730 ng/ml x 24 h, p < 0.01). In severe cirrhosis serum levels of 6 beta-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-naltrexol/naltrexone ratio at 2 h: controls, 10.91 +/- 4.80; cirrhosis, 0.39 +/- 0.18, p < 0.01). The area under the curve for naltrexone (1610 +/- 629 ng/ml x 24 h) was significantly greater than in controls, whereas that for 6 beta-naltrexol (2021 +/- 955 ng/ml x 24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups., Conclusions: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.

It has been found that acute ethanol (EtOH) intoxication to rats caused approximately 40% depletion of mitochondrial reduced glutathione (GSH). A GSH reduction of similar extent was also observed after the administration to rats of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis. The combined treatment of EtOH plus BSO induced a further mitochondrial GSH decrease up to 70% with respect to control. The presence of lipid hydroperoxides in the mitochondrial membrane was observed whenever an additional oxidative stress was associated to a condition of GSH depletion as in the case of EtOH or EtOH plus BSO. Under these conditions a severe derangement in mitochondrial oxidative functions occurred.

Since plasma reduced glutathione (GSH) seems to reflect liver GSH content, we have assessed plasma GSH in patients using paracetamol daily. In these patients a significant lower plasma GSH concentration was found with respect to controls. After the i.v. administration of GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests that the possible protective effect of GSH administration is due to the availability of plasma thiol compounds that enter the cell rather than GSH itself.

A simple and reliable reversed-phase high-performance liquid chromatographic method with coulometric detection is described for the quantitation of naltrexone and its metabolite, 6 beta-naltrexol, in plasma samples of healthy volunteers who received orally 50 mg of naltrexone. The analytes and the internal standard, naloxone, are extracted with an octadecyl solid-phase extraction column before chromatography. The mobile phase is 0.01 M potassium phosphate (pH 3)-acetonitrile (85:15, v/v) and it is pumped at 0.8 ml/min. The coulometric detector is formed by two electrodes set at +0.20 V and +0.70 V, with a palladium reference electrode. The limit of quantitation observed was 5 ng/ml for both naltrexone and 6 beta-naltrexol. This method can be used to investigate pharmacokinetic parameters of different pharmaceutical preparations of this opioid antagonist.