Optimal dosing of intravenous tacrolimus following pediatric heart transplantation.

BACKGROUND: Early experience with intravenous tacrolimus at high doses (0.1-0.15 mg/kg/day) was associated with frequent clinical toxicity. The optimal dosing regimen after pediatric heart transplantation is unknown. METHODS: We retrospectively reviewed data on the last 45 pediatric heart transplant recipients to document the time required to achieve therapeutic blood levels and the safety of 2 differing intravenous dosing regimens (tacrolimus 0.03 & 0.05 mg/kg/day as continuous i.v. infusion). Target plasma levels were (1.2-1.7 ng/ml) with levels >2.0 ng/ ml considered toxic, and target whole blood levels were 15-20 ng/ml with levels >25 ng/ml considered toxic. RESULTS: Mean age at transplantation was 7.5 +/- 5.6 years (0.1-18), and 14 were infants. Intravenous tacrolimus was commenced at a mean of 7 +/- 3 hours (range 2-16) after arrival in the ICU. Eight patients were excluded from analysis because of protocol modifications. Of the remaining 37 pts, 9 received initial infusion at 0.03 mg/kg/day; 3 (33%) achieved 'therapeutic' levels within 48 hours and 1 patient had a toxic level (27 ng/ml) at 36 hours. Twenty-eight patients received 0.05 mg/kg/day; 18 (64%) achieved therapeutic levels within 48 hours and 9 (32%) developed toxic levels. Patients with toxic whole blood levels had higher tacrolimus levels on first blood assay compared to those who did not develop toxicity (16.4 +/- 3.4 vs 9.3 +/- 3.9, p < .0001; level >10 ng/ml on first assay in 7/7 toxic patients vs 7/19 without toxicity, p = .004). Patients receiving the higher dose regimen had fewer episodes of moderate or severe rejection (> or =Grade 3A) at first biopsy than those receiving the lower dose infusion (32% vs 75%; p = .046). No patient required renal dialysis. CONCLUSIONS: Dosing below 0.05 mg/kg/day may result in clinically important delay in achieving therapeutic levels. Toxicity may be reduced by frequent monitoring of levels for the first 48 hours after transplantation especially when the initial level is >10 ng/ml.

Radioimmunoassay for the measurement of S9788 in serum and microdialysis samples.

S9788, 6-[4-(2,2-di-(fluorophenyl)-ethylaminol-1-piperdinyl]-N,N'-d i-2-propenyl-1, 3,5-triazine- 2, 4-diamine, is a novel compound designed to reverse tumour multidrug resistance associated with cancer chemotherapy. A specific and sensitive radioimmunoassay has been developed for the analysis of S9788 in serum samples and adapted for samples obtained by microdialysis. The limit of quantitation is 0.2 ng ml-1 in perfusion medium and there is no cross reactivity of the antibody with known metabolites of the parent compound or with certain cytotoxic compounds likely to be coadministered with S9788. Maximum probe recovery during microdialysis was 66% at a flow of 1 microliter min-1, using Ringer/BSA (70 mg ml-1) as the perfusion medium. The assay has sufficient sensitivity, precision, accuracy and specificity for the analysis of rat and human serum and microdialysis perfusate samples. The assay has been successfully applied to the determination of S9788 in rat plasma (total concentration) and the microdialysate of the same samples.

The comparative disposition of [14C]-fotemustine in non-tumourous and tumourous mice.

The distribution and excretion of radioactivity from [14C]-fotemustine was examined in mice with melanomas at different stages of development to determine whether the disease state substantially alters the disposition of the drug and its metabolites. Normal BDF1 mice and mice that had been subcutaneously grafted with B16 melanoma either 1, 3, 7, 14 or 21 days previously were used. The animals were killed at either 5 min, or at 3, 24 or 96 h after receiving an intravenous dose of [14C]-fotemustine (20 mg/kg) and were examined either by whole-body autoradiography or by liquid scintillation counting of excreta and tissues of interest. The majority of the [14C]-fotemustine dose was excreted in the urine, with similar amounts being measured in both non-tumourous animals (61.6% +/- 13.1%) and tumourous mice grafted 14 days previously (67.2% +/- 5.7%). Small amounts of radioactivity, again similar in both non-tumourous and tumourous mice, were recovered in the faeces (5.4% +/- 5.6% and 3.6% +/- 1.8%, respectively) and as carbon dioxide (7% +/- 3.5% and 6.4% +/- 1%, respectively), with minimal amounts being expired as chloroethanol (less than 1%). When mice were examined 5 min after dosing, there was extensive tissue distribution accounting for 75% +/- 10% of the dose. The highest concentrations determined by both whole-body autoradiography and liquid scintillation counting were measured in the excretory organs, with 33 and 28 micrograms Eq/g being found in the liver and kidney, respectively. High levels were also seen in the lung and plasma (19.8 and 19.5 micrograms Eq/g, respectively). Analysis of variance indicated that groups of tissues, such as the excretory organs, blood and plasma or the pigmented tissues, showed distinct but inconsistent patterns. Only tumours at 14 and 21 days of development were suitable for examination, and these showed levels of 12.1 micrograms Eq/g; however, the tumour-to-plasma ratio increased from between approx. 0.5 and 0.6 at 5 min to approx. 2 at 96 h after dosing, suggesting retention within the melanoma, whereas the ratio for the femur remained at approx. 1. Whole-body autoradiography showed that the distribution in the tumour was not uniform, but rather was concentrated in the peripheral area (presumably viable cells) as opposed to the central necrotic region. Thus, the high and sustained concentration of radioactivity found in the active cells of the melanoma may provide an explanation for the high efficacy of the drug.

The pharmacology of phagocytosis.

The biochemical mechanisms underlying the processes of chemotaxis, adhesion, phagocytosis and lysosomal enzyme secretion are described. Particular attention is drawn to the roles of aerobic glycolysis, the hexose monophosphate shunt, cyclic adenosine monophosphate, cyclic guanosine monophosphate and the microtubular and microfilament systems. The way in which drugs modify these pathways is discussed with reference to agonists and antagonists of beta-receptors, agonist and antagonists of muscarinic receptors, prostaglandins, colchicine, Cytochalasin B, and to steroidal and non-steroidal anti-inflammatory agents. The possibility that anti-inflammatory agents produce a significant effect in this manner is considered.

Anti-inflammatory properties of human inflammatory exudate.

An inflammatory exudate collected from a site of major surgery (partial gastrectomy) was found to possess definite anti-inflammatory properties when tested by the carrageenin oedema technique (a method widely adopted for the assessment of potential anti-rheumatic agents). Such anti-inflammatory properties could not be detected in the serum of normal healthy adults or in an abdominal asdtes fluid. The active component in the exudate showed several properties in common with a similar anti-inflammatory substance present in inflammatory exudates of animal origin.