Ketoconazole impairs biliary excretory function in the isolated perfused rat liver.

The effects of ketoconazole (KT) on the hepatic excretory function was investigated in the isolated perfused rat liver. KT, at the concentrations of 5 X 10(-5) M or 10(-4) M caused dose-dependent decreases of the biliary bile acid concentration and excretion rate, with no significant effect on bile flow rates. Neither dose altered perfusate flow through the liver. Furthermore, at the same two concentrations, KT impaired the sulfobromophthalein transport in a dose-dependent manner. In contrast, the drug did not alter 14C-sucrose bile to perfusate ratio and did not cause enzyme release from the liver into the perfusate. The study demonstrates that KT possesses an intrinsic toxicity in the isolated perfused rat liver and suggests caution in the use of this drug in hepatopathic patients

Therapeutic index of taurocholate or tauroursodeoxycholate in experimental drug-induced cholestasis.

The therapeutic index of either taurocholate (TC) or tauroursodeoxycholate (TUDC) administration in the treatment of drug-induced cholestasis was evaluated in perfused rat liver using a dose-response study. During estradiol-17-beta-glucuronide cholestasis, TC was more effective than TUDC in ameliorating bile flow but showed a low margin of safety since high doses caused additional toxicity. In contrast, TUDC ameliorated cholestasis even at very high doses with no adverse effects. In the model of chlorpromazine cholestasis, TC infusion did not correct but rather aggravated cholestasis, whereas TUDC at nonsaturating doses reversed the cholestasis and only at very high doses caused some toxicity. TUDC shows a good therapeutic index and may be employed with a reasonable margin of safety in the treatment of drug cholestasis

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Infection of intravascular prostheses: how to treat other than surgery.

Long-term antimicrobial therapy may be effective in some patients with intravascular prosthesis infection. However, this approach does not represent an alternative to surgery when this is feasible, but is merely the best opportunity for patients too ill to tolerate a re-intervention. Prosthetic valve endocarditis may be treated with antibiotic therapy alone in selected patients who are haemodynamically stable with non-staphylococcal infections and no para-valvular complications. In contrast, infections of pacemaker leads or other implantable cardiac devices require complete hardware removal, as infection recurrence always occurs, even after a seemingly effective initial treatment. Attempts to treat conservatively infections of abdominal aortic grafts can be successful in a few cases, provided the patient is stable, the pathogen has been identified, and antibiotic susceptibility has been demonstrated. Treatment requires at least 4-6 weeks and may be followed by a sequential oral regimen once the acute phase of the infection has subsided. The correct duration of this treatment is often unknown and relapses are common after treatment withdrawal. The availability of novel antibacterial and antifungal agents - showing fast microbicidal activity that includes biofilm micro-organisms - such as daptomycin and caspofungin, or having a wide antimicrobial spectrum, such as tigecycline, may increase the probability of long-standing suppression or even eradication of the infection in these particular subsets of inoperable patients. However, so far, very little experience is available on the efficacy and tolerability of these drugs in intravascular prosthesis infections. Controlled studies are lacking and difficult to plan. Well-designed prospective studies may help to establish guidelines and reach a multidisciplinary consensus on the optimal therapeutic approach, and are therefore awaited

Visceral leishmaniasis during pregnancy treated with meglumine antimoniate.

Data on the efficacy and safety of pentavalent antimony in the treatment of visceral leishmaniasis during pregnancy are scanty. A case of visceral leishmaniasis in a 39-year-old woman in the second trimester of pregnancy is reported here. The patient was hospitalized in poor condition with high fever and pancytopenia which had lasted for 6 weeks. A bone marrow aspirate revealed numerous amastigotes and serodiagnosis for Leishmania was positive at a high titer. The patient was successfully treated with meglumine antimoniate at a daily dose of 850 mg of antimony for 20 days. She delivered at term a healthy female baby who remains in good condition at 18 months of age. Thus a dose of 850 mg of antimony, which is lower than that presently recommended, seems to be effective and non toxic to the fetus when administered at the second trimester of pregnancy