Enhanced pulmonary accumulation of liposomal amphotericin B (AmBisome) in acute liver transplant failure.

Plasma and tissue concentrations of amphotericin B were determined in a patient treated with liposomal amphotericin B during liver transplant failure. A cumulative rise in amphotericin B plasma concentrations was observed accompanied by an enhanced pulmonary deposition of the drug. Failure of the liver as a major component of the reticuloendothelial system may cause elevated plasma concentrations of liposomal amphotericin B and may consequently enhance deposition of liposomes in the lungs as a substitutive clearing organ.

Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients.

The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (Cmax) and areas under concentration-time curves (AUC) were 8- to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median Cmaxs were 8.4-fold higher (14.4 versus 1.7 microg/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P = 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P = 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.

Serum pharmacology of amphotericin B applied in lipid emulsions.

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

Pharmacokinetics of liposomal amphotericin B (AmBisome) versus other lipid-based formulations.

To lower amphotericin B-associated toxicity, amphotericin B may be integrated into liposomes (AmBisome) or can be administered in Intralipid 20% emulsions (Ampho-B/Lipid). The present study compares the pharmacokinetic characteristics of standard amphotericin B dissolved in glucose 5% (Ampho-B/G) (n = 6) to the alternative formulations Ampho-B/Lipid (n = 8) and Ambisome (n = 10). Ampho-B/G and Ampho-B/Lipid were infused at a dose of 1 mg/kg, while the dose of AmBisome was increased to 3 mg/kg. Infusion duration was 1 h. Pharmacokinetics of Ampho-B/G, AmB/Lipid and AmBisome showed striking differences, specifically with regard to the respective Cmax and AUC values. In fact, after application of AmB/Lipid mean Cmax values were reduced to 39% and mean AUC values were lowered to 57% compared with application of Ampho-B/G in the same patients. This compares with a 1.8-fold greater Vss for Ampho-B/Lipid and a clearance rate which was 2.1-fold faster. By contrast, application of AmBisome (at a three-fold greater dose) resulted in Cmax and AUC values eight-fold and 12-fold greater than those reached by Ampho-B/G. The higher Cmax values achieved by AmBisome relate to a four-fold smaller Vss compared with Ampho-B/G. Assuming a linear relationship between AmBisome dose and Cmax, it was concluded that even at equal doses the liposomal formulation of amphotericin B would result in significantly greater Cmax and AUC values than Ampho-B/G or Ampho-B/Lipid.

Exogenous interleukin 2 (IL 2) reconstitutes deficient in vitro T-cell growth of patients with chronic lymphocytic leukemia of B-cell lineage (B-CLL).

Mechanisms of tumor growth are concerned with the possibility that neoplasms are disturbed in their response to growth factors. Interleukin 2 (IL 2) is secreted by activated T-cells and is required for autocrine T-cell growth. Controversy exists as to the functional capacity of T-lymphocytes in patients with B-cell chronic lymphocytic leukemia (CLL). We studied 14 patients with previously untreated, early CLL. Data were compared to 16 healthy individuals. Immunophenotyping showed that T-cells in B-CLL are highly activated as evidenced by HLA-DR and IL 2 receptor expression. Membrane receptors for IL 2 on the patients' T-cells were overexpressed. The T4:T8 ratio was 1.5. T-cells for in vitro studies were isolated by their ability to form E-rosettes with AET and repeated Ficoll density gradient centrifugation. Purified T-cells were grown on semisolid agar and their capability to form colonies investigated using a variety of exogenous stimulants. It was found that patients with CLL showed a pronounced impairment in forming T-cell colonies. However, colony formation was restored to normal by adding exogenous recombinant IL 2, indicating that endogenous IL 2 production of T-cells is deficient. This finding might have implications for the therapeutical use of IL 2 in CLL patients.

CFU-gm colony formation of peripheral blood and bone marrow in adult acute leukemia at presentation, during remission, and at relapse.

Granulocyte/macrophage colony-forming unit (CFU-gm) formation was studied simultaneously in bone marrow and peripheral blood of 52 previously untreated adult patients with acute non-lymphocytic (ANLL) and 36 with acute lymphoblastic leukemia (ALL). They were followed during induction therapy at monthly intervals while in remission and in 19 ANLL and 22 ALL cases, until relapse. Patients showing a decreased colony number in the marrow but normal or increased colony numbers in the peripheral blood had a high probability of entering remission. Non-responding patients displayed an opposite pattern. The higher the degree of marrow repopulation with granulocytic progenitor cells after induction treatment, the longer remission duration and survival for ANLL patients and the longer survival for ALL patients. CFU-gm formation returned to normal in the early stages of complete remission, but then declined progressively. At ANLL and ALL relapse, colony growth was reduced markedly while cluster formation remained normal. The number of marrow colonies and clusters in ANLL were significantly higher at first and second relapse compared to the growth pattern at first presentation. A similar trend had been observed in ALL, suggesting a selection advantage.

Kinetics of colony-forming cells (CFU-c) in adult acute leukemia and their prognostic relevance.

The in vitro growth pattern of bone marrow and peripheral blood in soft-agar cultures was studied in 50 previously untreated patients with adult acute leukemia. Patients were followed from time of first diagnosis, during induction treatment, in remission at various time intervals, at relapse and during subsequent re-induction therapy. The distribution of granulopoietic progenitor cells was analysed to determine their prognostic significance for remission incidence, remission duration and survival. All patients revealed an abnormal growth. ANLL patients showing a decreased clone number in the marrow but an increased number of clones in the peripheral blood, had a significant higher probability to enter remission and a significant longer remission than those having clones within normal range at first presentation. On the contrary, ALL patients responding to induction treatment, had a better colony and cluster growth in the bone marrow than those failing to respond. No significant correlation was found between in vitro growth and survival. It is concluded that colony-forming cells of both bone marrow and peripheral blood seems to be of some value in predicting the response rate and length of remission in ANLL and ALL, and in possibly selecting patients with a high chance to respond to current cytostatic regimens.

Lack of prognostic value of T-, B- and null-lymphocytes in adult acute leukemia.

The distribution of T-, B- and null-lymphocytes was studied in the peripheral blood of 38 adult patients with acute nonlymphocytic leukemia (ANLL) and 15 with acute lymphocytic leukemia (ALL) at first diagnosis, during induction treatment, and in remission. Thirteen ANLL and 9 ALL patients were followed until relapse and during reinduction therapy. T- and B-cells were detected by specific membrane marker. The pre- and posttreatment pattern of lymphocyte subpopulations was analyzed to determine their prognostic significance for remission incidence, remission duration, and survival. It was observed that in both types of leukemia, T-cells are more affected by the leukemic process and cytostatic drugs than B-cells. Nonresponding patients possibly have a reduced potential for recruiting precursor T- and B-cells. At first diagnosis, no significant correlation was found between pre- or posttreatment variables and prognosis. At relapse, ANLL patients had a longer second remission when a high proportion of B-cells was found; ALL patients with a high lymphocyte count before and after treatment, experienced longer survival.