In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin.

We evaluated the TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunotoxin in both murine and nonhuman primate models. TXU-PAP caused dose-limiting cardiac toxicity in BALB/c mice. In a SCID mouse model of invariably fatal human T-lineage acute lymphoblastic leukemia (ALL), TXU-PAP therapy resulted in a marked improvement of leukemia-free survival without any side effects. Whereas 100% of control mice treated with PBS, unconjugated TXU antibody, or B43-PAP (an immunotoxin that does not react with T-lineage ALL cells) died of disseminated human leukemia within 80 days (median survival, 37 days), 80 +/- 13% of SCID mice treated with 15 microgram of TXU-PAP (median survival, >120 days) and 100% of mice treated with 30 microgram of TXU-PAP (median survival, > 120 days) remained alive and free of leukemia for >120 days. In cynomolgus monkeys, TXU-PAP showed favorable pharmacokinetics with an elimination half-life of 8.1-8.7 h. The monkeys treated with TXU-PAP at dose levels of 0.05 mg/kg/day x 5 days and 0.10 mg/kg/day x 5 days tolerated the therapy very well, without any significant clinical compromise or side effects, and at necropsy, no gross or microscopic lesions were found. This study provides a basis for further evaluation of TXU-PAP as an investigational biotherapeutic agent in the treatment of T-lineage ALL.

Toxicity profile of the investigational new biotherapeutic agent, B43 (anti-CD19)-pokeweed antiviral protein immunotoxin.

The investigational biotherapeutic agent, B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin, has shown substantial anti-leukemic activity in SCID mouse models of human B-lineage leukemia and lymphoma. In this report, we describe the results of a comprehensive preclinical toxicity study which determined the toxicity profile of B43-PAP in BALB/c mice. Administration of unconjugated B43 monoclonal antibody was not associated with any toxicity, whereas B43-PAP caused dose-limiting and cardiac and renal toxicities which were fatal. In addition, B43-PAP also caused multifocal skeletal myofiber necrosis, which was associated with abnormal gait and lethargy. Notably, parenteral administrations of methylprednisolone, pentoxyphylline, or dopamine were able to markedly reduce B43-PAP related toxicity. This study provides a basis for further evaluation of the toxicity of B43-PAP in monkeys and humans.

Gas chromatography-mass spectrometry evidence for several endogenous auxins in pea seedling organs.

Qualitative analysis by gas chromatography-mass spectrometry (GC-MS) of the auxins present in the root, cotyledons and epicotyl of 3-dold etiolated pea (Pisum sativum L., cv. Alaska) seedlings has shown that all three organs contain phenylacetic acid (PAA), 3-indoleacetic acid (IAA) and 4-chloro-3-indoleacetic acid (4Cl-IAA). In addition, 3-indolepropionic acid (IPA) was present in the root and 3-indolebutyric acid (IBA) was detected in both root and epicotyl. Phenylacetic acid, IAA and IPA were measured quantitatively in the three organs by GC-MS-single ion monitoring, using deuterated internal standards. Levels of IAA were found to range from 13 to 115 pmol g(-1) FW, while amounts of PAA were considerably higher (347-451 pmol g(-1) FW) and the level of IPA was quite low (5 pmol g(-1) FW). On a molar basis the PAA:IAA ratio in the whole seedling was approx. 15:1.

[Comparison between the intravenous TRH-test and the T4-thyroid suppression test for the diagnosis of borderline hyperthyroidism]. / Vergleich von intravenösem TRH-Test und T4-Schilddrüsensuppressionstest zur Diagnostik der Grenzhyperthyreose.

In a prospective study of 60 patients with T3 and/or T4 values within +/- 10% of the upper limit of normal, the suppressibility of thyroid storage values before and after oral administration of 3 mg L-thyroxine was tested and compared with the results of an intravenous TRH test. In 46 patients the results of the two methods agreed (77%): in 31 patients (52%) radioiodine uptake could not be suppressed nor TSH stimulated in the TRH test. Physiological suppression of the storage values in normal TSH stimulation after TRH as a sign of completely euthyroid function was present in 15 (25%). In the remaining 14 patients, 13 had a suppressed TRH test. In all patients radioiodine uptake could be suppressed either normally (above 50%) or partially (20-30%). A normal T4 suppression test in the absence of TSH rise after TRH indicates that biologically active TSH is circulating, even though not demonstrated by radioimmuno-assay. A normal T4 suppression test is an important argument against treating a given case of hyperthyroidism. The T4 suppression test reveals smooth gradation between euthyroid and hyperthyroid states. If the TRH test is normal one can assume a physiological T4 suppression test and no further tests are needed. If the TRH test is negative and there is only slight elevation of the thyroid hormones, the T4 suppression test is indicated before definitive treatment of hyperthyroidism is initiated.