Pharmakokinetics of Mistletoe Lectins after Intravenous Application of a Mistletoe Product in Healthy Subjects.

Mistletoe lectins (ML) have cytotoxic and immunomodulating properties, and subcutaneously applied mistletoe products (MP) containing ML have approval for supportive cancer treatment. MP are also given off-label intravenously, but data about pharmacokinetics are widely lacking. Therefore, the aim of our phase I trial was to evaluate the pharmacokinetics and safety of intravenously applied natural ML. Initially, 12 healthy male volunteers were planned to receive a single infusion of 2000 mg Helixor® P. We had to terminate the study prematurely after the inclusion of eight subjects due to elevation of all subjects' liver enzymes. ML was detected in all subjects after infusion. The mean half-life of serum ML was 7.02 ± 2.01 h. Mean alanine transaminase increased from 23 ± 6 to a maximum of 445 ± 260 U/L, and mean aspartate aminotransferase increased from 24 ± 3 to a maximum of 318 ± 33 U/L 72 h after infusion. Severity grading for drug-induced liver injury was mild. Participants did not suffer from any liver-specific symptoms and recovered completely. As a conclusion, the dose of 2000 mg Helixor® P caused transient liver injury in healthy subjects and should, therefore, not be used for initial patient treatment. Liver enzymes should be monitored in patients receiving intravenous treatment with Helixor® P.

Safety of intravenously applied mistletoe extract - results from a phase I dose escalation study in patients with advanced cancer.

BACKGROUND: Mistletoe extracts have anti-tumor properties and are approved for subcutaneous use in cancer patients. Data on Intravenous application are limited. METHODS: An aqueous extract from pine-mistletoe was used to investigate maximum tolerable dose (MTD) and safety of intravenous application. It was infused once weekly for 3 weeks in patients with advanced cancer. Any type of cancer was included; relevant exclusion criteria were concurrent chemo- or radiation therapy. The classical phase I 3 + 3 dose escalation scheme was followed. Predefined dose groups were 200, 400, 700, 1200 and 2000 mg. Maximum planned dose was 2000 mg. With the MTD three more patients should be treated for 9 weeks in order to evaluate intermediate term tolerability. Weekly during the treatment and 1 week later tolerability, clinical status, safety laboratory parameters and adverse events were documented. RESULTS: Twenty-one patients (3 in the dose groups 200, 400, 700 and 1200 mg, respectively, 9 in the dose group 2000 mg) were included. MTD was not reached. Because one dose-limiting toxicity (DLT), an allergic reaction, occurred during infusion of 2000 mg, three more patients had to be included in this dose group and tolerated it, as well as the three patients who received 2000 mg for 9 weeks. Occasionally in the dose group 2000 mg mild to moderate fever occurred. CONCLUSION: Weekly infusions of 2000 mg of the pine-mistletoe extract were tolerated and can be used in further studies but had a risk for allergic reactions and fever. German Clinical Trials Register (Trial registration number DRKS00005028).

In vitro response of stimulated B-CLL lymphocytes of patients treated with Viscum album L. extracts.

BACKGROUND: Extracts from Viscum album (VA-E) have been shown to induce apoptosis and immunoactivation. To exclude possible B-CLL propagating effects, the in vitro reactions of cultured peripheral blood B-CLL cells were analysed. PATIENTS AND METHODS: Intracellular expression of apoptosis-associated mitochondrial Apo2.7 and proliferation-associated Ki-67 molecules in B-CLL cells from patients treated with VA-E for 12 months were measured after incubation with various stimuli. RESULTS: Within the observation period, the susceptibility of the B-CLL cells towards the apoptosis-inducing potential of the VA-E significantly decreased. This effect could be due to the presence of physiologically-induced anti-mistletoe lectin antibodies which may block the effects of cytotoxic mistletoe lectins. No significant induction of Ki-67 was observed, but an increase of non-specific binding, even in untreated medium controls, did occur within the last months. CONCLUSION: In this in vitro setting of the observational study, no stimulation of leukemic cells from the patients treated with VA-E was profound.