Manon Vézina

Massive Diltiazem Overdosage: Clinical and Pharmacokinetic Observations:

was continued for a further three months with good clinical response. Blistering decreased, the rate of cicatrization increased, and there was a striking reduction in the extent of granulomatous tissue on the back (Figure 2). The side effects of treatment were drowsiness and an increase in alkaline phosphatase when plasma levels of phenytoin exceeded 25 ILg/ml; below 20 ILg/ml these side effects disappeared. After eight months, therapy was withdrawn with the informed consent of the patient. The clinical pharmacologist then began a doubleblind placebo treatment that was stopped 44 days later because of a deterioration in the patients condition. With the renewal of phenytoin treatment it took two months to regain a stable steady state. Phenytoin appears to exert a favorable influence on the course of RDEB, as previously reported in the literature; moreover, this drug can dramatically improve even the granulomatous lesions of the rare vegetans variant of this disease.

Effects of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen in humans.

Compliance to nonsteroidal anti-inflammatory drug therapy can be compromised by gastrointestinal side effects. To overcome this problem, food, antacid, or sucralfate are often co-administered with nonsteroidal anti-inflammatory drugs. Three studies were conducted on three groups of 12 volunteers in order to determine the influence of food or sucralfate on the pharmacokinetics of naproxen and ketoprofen. In a crossover experimental design, the first group received a single dose (50 mg) of ketoprofen with and without sucralfate (2 g). The second group received single (100 mg) and multiple (100 mg twice daily for 5 days) doses of enteric-coated ketoprofen with and without food. The third group received single (500 mg) and multiple (500 mg twice daily) doses of naproxen with and without sucralfate. Multiple blood samples were drawn and analyzed by high-pressure liquid chromatography. Short- and long-term pharmacokinetic parameters were determined. Results in group 1 showed that neither ketoprofen bioavailability nor maximal plasma concentration and time to reach maximal concentration were affected by the administration of sucralfate. However, in group 2 absorption of ketoprofen was markedly affected by food. In the presence of food, maximal plasma concentration decreased from 10.7 to 6.3 micrograms/ml after single-dose administration and 12.1 to 8.0 micrograms/ml after multiple-dose administration. The time to reach maximal plasma concentration was also modified by food, increasing from 2.8 to 7.1 hours after single-dose and 2.8 to 7.6 hours after multiple-dose administration. Food caused a significant decrease in the bioavailability of ketoprofen (over 40 percent) following both single-dose (23.8 versus 13.1 micrograms.hour/ml) and multiple-dose (29.3 versus 16.8 micrograms.hour/ml) administration. Results obtained in group 3 showed that sucralfate reduced the absorption rate constant of naproxen, from 1.7 to 1.2 hours-1 and from 1.5 to 0.7 hour-1 following single- and multiple-dose administration, respectively. However, bioavailability of naproxen was not affected by sucralfate administration. Overall, these studies have shown that sucralfate does not alter the pharmacokinetics of naproxen and ketoprofen; the amount of drug absorbed remains constant. However, plasma concentrations of ketoprofen after single- and multiple-dose administration were greatly affected by food, with a decrease of greater than 40 percent in bioavailability.

Methyl isobutyl ketone metabolites and potentiation of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone.

Methyl isobutyl ketone (MIBK) has recently been shown to potentiate the cholestasis induced by manganese-bilirubin (Mn-BR) or manganese (Mn) in rats. In this study, we investigated the effect of 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK), two major metabolites of MIBK, on these models of cholestasis. Dosages varying from 1.88 to 15 mmol/kg 4MPOL or 4-OHMIBK were administered once, 18 hr prior to the administration of a cholestatic Mn-BR combination. The cholestatic effect of the manganese-bilirubin combination was enhanced with dosages of 4MPOL of 3.75 mmol/kg and larger. On the other hand, dosages smaller than 15 mmol/kg of 4-OHMIBK did not potentiate the Mn-BR cholestasis. Daily pretreatment for 3 days resulted in an increased response to the cholestatic challenges of either Mn-BR or Mn alone. 4MPOL administered repetitively was a better potentiator than 4-OHMIBK with the Mn-BR model of cholestasis. However, with Mn alone, 4-OHMIBK proved to be more effective. 4MPOL and 4-OHMIBK per se were devoid of cholestatic properties, since the bile flow measured prior to the cholestatic challenge was not decreased and in some cases was significantly greater than that of vehicle-pretreated animals. These results show that MIBK metabolites can potentiate the cholestatic form of hepatotoxicity.

Potentiation by methyl isobutyl ketone of the cholestasis induced in rats by a manganese-bilirubin combination or manganese alone

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK). In a previous study, MIBK was shown to potentiate the cholestasis induced by taurolithocholate in rats. We investigated the possibility that this ketone could potentiate the cholestasis induced by a combination of manganese and bilirubin (Mn-BR) or by manganese alone in rats. Dosages varying from 1.88 to 15 mmol/kg MIBK were administered once, 18 hr prior to the administration of the cholestatic Mn-BR combination. The cholestatic effect of the manganese-bilirubin combination is enhanced with dosages of MIBK of 3.75 mmol/kg and more. Daily ketone pretreatment for 3 days resulted in an increased response to the cholestatic challenges of either Mn-BR or Mn alone. MIBK per se is devoid of cholestatic properties, since the bile flow measured prior to the cholestatic challenge is not decreased and in some cases is significantly greater than that from vehicle-pretreated animals. These results show that MIBK can potentiate cholestatic as well as necrogenic forms of hepatotoxicity.

Chloroform interaction with chlordecone and mirex: correlation between biochemical and histological indices of toxicity and quantitative tissue levels

The purpose of this study was to investigate whether the tissue distribution of chlordecone (CD) and mirex (M) might explain the difference in the potentiation of CHCl3 liver injury. Male Sprague-Dawley rats received either a single oral dose of CD or M (1, 2.5, 5, 10, 25, or 50 mg/kg) or three single daily doses of CD or M (0.5, 2, or 10 mg/kg). Eighteen hours following the last treatment, the animals were divided into two groups. The first group was killed and residues of CD or M in plasma, kidney, liver, and adipose tissue were measured by gas-liquid chromatography. The other group received CHCl3 (0.5 ml/kg, po) and was killed 24 hr later. Biochemical and histological indices of liver injury were evaluated. CD administered either singly or repetitively is more effective than M in potentiating the CHCl3-induced liver injury. This was exhibited by a higher increase in the plasma activities of the enzymes alanine aminotransferase and ornithine carbamoyl transferase and a greater alteration of the morphological pattern. There was a very good correlation between biochemical and histological indices. However, the severity of the liver injury did not parallel tissue concentrations. With M, a relatively poor potentiation of the liver damage was observed although adequate hepatic concentrations were present.

Sucralfate drug interaction studies.

This section reviews the literature on drug interactions with sucralfate. Since sucralfate is poorly absorbed, most of the dose remains in the gastrointestinal tract and the potential exists for sucralfate to affect the absorption of other drugs. Potential mechanisms of these interactions include adsorption, complexation, decreased dissolution resulting from altered pH, and the formation of a physical barrier to absorption.