These observations underscore the importance of including drug tissue levels to obtain a better understanding of L-AmB efficacy. The sustained concentrations of bioactive AmB in many tissues provide a further rationale for investigating L-AmB prophylactic regimens.

Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 ؋ 10 4 to 5.7 ؋ 10 4 conidia) or intranasally (5.8 ؋ 10 7 conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P < 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P < 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

Key Clinical MessageHemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyper activation of the immune system. Rare cases associated with HELLP syndrome and other similar conditions in pregnancy have been reported. Despite the improved survival rates with etoposide and dexamethasone‐based regimens, HLH remains a challenging disease. Experience in pregnant patients is exceedingly rare.

1. Beagle dogs dosed orally with 14C-tazadolene succinate excreted much of the dose in the urine (mean 63.1% in 5 days with most excreted in the first 24 h). A lesser proportion of the dose was excreted in the faeces (mean 20.7%) and again most of this was voided in the first 24 h. 2. Four metabolites were identified and quantified in the urine, namely 3-hydroxy-(M1), 4-hydroxy- (M2a), and 3-methoxy-4-hydroxy-tazadolene (M2b) and N-[2-(phenylmethylene)cyclohexyl]-beta-alanine (M3). 3. In the 24 h urine, M2a and b glucuronides accounted for 17.7% dose, unconjugated M2a and b for 11.3%, and M3 for 18.3%. Insufficient M1 was present to be quantified. The same metabolites were seen in the 24 h faeces, but at lower concn. Thus M2a and b glucuronides, M2a and b, and M3 were 3.2%, 4.9% and 3.5% dose respectively. 4. All three phenols were present in plasma as their glucuronides as well as the beta-alanine derivative. They all had the same tmax of 2 h and t1/2 lambda 1 of the order of 1 h.

SUMMARYThree radiolabelled forms of trospectomycin (6'-n-propylspectinomycin sulphate hydrate) have been synthesised, namely [8'-''C]-, [6',7'-3H]-, and [5',6',7'-3H]-trospectomycin. Although all three forms of the drug are metabolically stable and therefore suitable for use in animal studies the I4C compound is produced in poor yield as is the [6',7'-3H]trospectomycin. On the other hand, the [5',6',7'-3H]-form is produced in good yield and appears to be the labelled form of choice.Following subcutaneous administration of any of the labelled forms to rats, more than 50% of the dose was excreted in the urine as unchanged drug during the first 6h after dosing. Approximately 80% and 10% of the dose appeared in the urine and faeces respectively after 6 days.